INMUNO: BOARDS AND BEYOND Flashcards by Karla Chavez

What is systemic lupus erythematosus (SLE)?

An autoimmune disorder commonly occurring in middle-aged women, characterized by non-specific symptoms like fatigue and fever, and often symmetrical, polyarticular arthritis.

How well did you know this?

Not at all

Perfectly

What are common symptoms of SLE?

Fatigue, fever, symmetrical polyarticular arthritis, signs of joint inflammation (warmth, erythema, swelling), and skin manifestations such as a “butterfly rash.”

How well did you know this?

Not at all

Perfectly

Describe the classic skin manifestation of SLE.

The “butterfly rash,” which involves a rash on the malar skin (cheeks) and nose.

How well did you know this?

Not at all

Perfectly

What is the significance of C3 levels in lupus?

C3 is the most abundant complement protein, and lupus leads to decreased C3 levels due to complement consumption. Low serum complement levels are characteristic of lupus.

How well did you know this?

Not at all

Perfectly

Name two other conditions that can cause low serum complement levels (besides from lupus)

Post-streptococcal glomerulonephritis and membranoproliferative glomerulonephritis.

How well did you know this?

Not at all

Perfectly

What are interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-α)?

Inflammatory cytokines that act as pyrogens, triggering fever and causing other inflammatory responses, including joint swelling.

How well did you know this?

Not at all

Perfectly

What effects does TNF-α have on the body?

It causes vascular leakage, reduces the utilization of fatty acids, and can lead to cachexia.

How well did you know this?

Not at all

Perfectly

In a woman with SLE, what would you expect regarding cytokine levels?

Increased serum levels of IL-1 and TNF-α, especially during episodes of inflammation such as fever and joint swelling.

How well did you know this?

Not at all

Perfectly

What does recurrent Neisseria meningitidis infections indicate?

A classic presentation of “late complement deficiency,” which involves a deficiency of complement factors C5 to C9.

How well did you know this?

Not at all

Perfectly

What is the role of complement factors C5 to C9?

They are required for the formation of the membrane attack complex (MAC), a key defense mechanism against encapsulated bacteria like Neisseria.

How well did you know this?

Not at all

Perfectly

How do patients with C5-C9 deficiency typically present outside of Neisseria infections?

They are usually healthy and do not experience severe or life-threatening infections from other causes.

How well did you know this?

Not at all

Perfectly

Are recurrent infections with Neisseria meningitidis life-threatening in patients with C5-C9 deficiency?

No, they are common but rarely severe or life-threatening.

How well did you know this?

Not at all

Perfectly

What autoimmune disorder is most commonly associated with deficiencies in early complement proteins (C1 through C4)?

Systemic lupus erythematosus (SLE), often developing at an early age.

How well did you know this?

Not at all

Perfectly

Why is it paradoxical that complement deficiencies are linked to an inflammatory disorder like SLE?

Complement deposition is a component of inflammatory reactions, yet deficiencies in early complement proteins (C1-C4) are associated with SLE.

How well did you know this?

Not at all

Perfectly

How do children with early complement deficiencies present in terms of infections?

They may have recurrent infections, but these infections are not typically limited to Neisseria, as seen in late complement deficiencies.

How well did you know this?

Not at all

Perfectly

What specific complement deficiency is associated with infections due to encapsulated bacteria in early childhood?

Complete deficiency of C3, a major opsonin of the complement system, is linked to infections, especially with pneumococcus.

How well did you know this?

Not at all

Perfectly

What is factor H?

A glycoprotein found in human plasma, synthesized by the liver and some blood cells, that binds to C3b and inhibits complement activation.

How well did you know this?

Not at all

Perfectly

How does factor H affect complement activation?

It binds to C3b and destroys C3b convertase, halting the complement activation process.

How well did you know this?

Not at all

Perfectly

In which types of cells has factor H expression been demonstrated?

In cells from several malignancies, including lung carcinomas.

How well did you know this?

Not at all

Perfectly

How do tumors utilize factor H to evade the immune system?

By synthesizing factor H, tumors can inhibit complement activation and evade immune detection.

How well did you know this?

Not at all

Perfectly

Is produced by the liver and binds mannose found in bacteria. As an activator of the immune system, blocking MBL activity would not increase complement activity as shown in the graph.

Mannose-binding lectin (MBL)

How well did you know this?

Not at all

Perfectly

Is a complement protein, and the first protein of the classical pathway. Blocking C1 activity would limit complement activation, not increase complement activity

Complement component 1 (C1)

How well did you know this?

Not at all

Perfectly

Is an acute phase reactant produced by the liver in response to inflammation. It can bind bacterial polysaccharides to activate the complement system. Blocking CRP activity would limit complement activation

C-reactive protein (CRP)

How well did you know this?

Not at all

Perfectly

What symptoms are consistent with paroxysmal nocturnal hemoglobinuria (PNH)?

Hemolytic anemia (reduced hemoglobin, jaundice, increased reticulocyte count), recurrent abdominal pain, and a history of thrombosis.

How well did you know this?

Not at all

Perfectly

What causes PNH?

A lack of glycosylphosphatidylinositol (GPI) anchor proteins that hold CD55 and CD59 on the surface of erythrocytes.

What are CD55 and CD59, and what role do they play in PNH?

CD55 (decay accelerating factor) and CD59 prevent complement activation on red blood cells. Their absence allows the complement system to attack erythrocytes, leading to hemolysis.

When is hemolysis most evident in PNH patients?

In the morning, when urine is especially concentrated, causing it to turn red due to the presence of heme.

Does hemolysis occur only at night in PNH?

No, hemolysis occurs throughout the day, despite the name "nocturnal."

Besides erythrocytes, which other blood components can be affected by PNH?

Leukocytes and platelets, potentially leading to pancytopenia.

What are some common features of PNH?

Thrombosis (most common cause of death), abdominal pain, fatigue, jaundice, and erectile dysfunction in men.

Why might PNH be diagnosed late?

It is a rare disorder that can be easily missed for many years before a diagnosis is made.

What causes hereditary angioedema?

Deficiency of the C1 inhibitor protein.

What is the main symptom of hereditary angioedema?

Recurrent episodes of swelling and edema due to excess bradykinin.

What causes hereditary spherocytosis?

Deficiency of spectrin, a red blood cell membrane protein.

What abnormality is observed in the peripheral blood of patients with hereditary spherocytosis?

The presence of spherocytes (abnormally shaped red blood cells).

What complication may arise from hereditary spherocytosis?

Splenomegaly due to splenic destruction of red blood cells.

What is the role of glucose-6-phosphate dehydrogenase (G6PD) in red blood cells?

G6PD helps generate nicotinamide adenine dinucleotide phosphate (NADPH), which protects cells from oxidative damage

How does G6PD deficiency affect red blood cells?

It leaves red blood cells vulnerable to oxidative damage due to insufficient NADPH levels

What triggers hemolysis in patients with G6PD deficiency?

Exposure to oxidative triggers such as fava beans and certain medications.

What is the consequence of hemolysis in G6PD-deficient patients?

It can lead to anemia and related symptoms.

What causes hereditary angioedema (HAE)?

Deficiency of the C1 inhibitor protein.

What are the functions of the C1 inhibitor protein?

It inhibits the activity of complement factor C1 and breaks down the inflammatory protein bradykinin.

Why do patients with HAE experience recurrent episodes of swelling?

Elevated bradykinin levels lead to vascular leakage and edema, especially during physiological events that increase bradykinin.

What are common triggers for swelling in HAE patients?

Dental work, cold exposure, and certain foods.

What are the potential serious consequences of laryngeal swelling in HAE?

It can lead to hypoxemia and death.

Why do standard treatments like epinephrine, antihistamines, and glucocorticoids not work in HAE?

They do not counteract the effects of bradykinin, which is responsible for the swelling.

What is the first-line treatment for HAE?

Infusion of C1 inhibitor concentrate from human plasma.

What is the role of complement factor C1 in the classical pathway?

C1 cleaves C4, leading to the production of a C3 convertase.

What clinical finding is associated with HAE due to the deficiency of C1 inhibitor?

Low C4 levels due to the consumption of C4 in the absence of C1 inhibitor.

In absence of C1 inhibitor, C4 is consumed, leading to low C4 levels, one of the hallmark clinical findings of

HAE

What clinical scenario is indicated by recurrent Neisseria infections in a patient?

Terminal complement deficiencies (deficiencies in complement proteins C5-C9).

Why are Neisseria bacteria particularly problematic in patients with terminal complement deficiencies?

Neisseria are encapsulated bacteria that resist phagocytosis, making them highly reliant on the complement system for defense.

What is the CH50 test?

A screening test for complement deficiencies that assesses the function of the complement system.

How is the CH50 test conducted?

Sheep RBCs with antibodies are mixed with the patient’s serum; normal results indicate all complement components are present and functioning.

What does an abnormal CH50 test result indicate?

One or more factors are deficient in the complement system.

Would the CH50 test be normal or abnormal in the scenario of terminal complement deficiencies?

Abnormal.

Is a component of complement activation via the lectin pathway.

Mannose binding lectin

Is a surface marker that protects cells from complement mediated destruction.

CD59

What autoimmune disorder is commonly associated with deficiencies in early complement proteins (C1-C4)?

Systemic lupus erythematosus (SLE), often developing at an early age.

Why is it paradoxical for complement deficiencies to be linked to an inflammatory disorder like SLE?

Because complement deposition is a component of inflammatory reactions, and deficiencies would generally be expected to reduce inflammation.

What is still unclear regarding early complement deficiencies and the development of SLE?

The exact mechanism by which deficiencies in early complement proteins lead to the development of SLE is not well understood.

How do early complement deficiencies affect infection susceptibility in children?

Children may have recurrent infections, but these infections are not typically limited to Neisseria, unlike late complement deficiencies.

What is the significance of complete deficiency of C3 in early complement deficiencies?

It is a major opsonin of the complement system and is associated with increased susceptibility to infections, particularly from encapsulated bacteria like pneumococcus.

What is the most common cause of community-acquired bacterial pneumonia?

Streptococcus pneumoniae.

What are pathogen-associated molecular patterns (PAMPs)?

Molecular sequences recognized as foreign by innate immune cells, capable of triggering an immune response.

How do bacterial PAMPs interact with immune cells?

They bind to toll-like receptors (TLRs) on macrophages and other cells, initiating an immune response.

What happens after PAMPs bind to toll-like receptors?

Cytokine release occurs, leading to an acute inflammatory response.

What role does Prostaglandin E2 play in inflammation?

It is an important mediator of inflammation, but it is not produced by bacteria and does not initiate the immune response.

What are alpha and beta receptors?

Adrenergic receptors activated by epinephrine and norepinephrine, important for the sympathetic nervous system response.

Do adrenergic receptors (alpha and beta) initiate the inflammatory response?

No, they do not initiate the inflammatory response, even though they can be activated during infection.

What is cellulitis and what commonly causes it?

Cellulitis is a skin infection of the dermis caused by Group A Streptococcus (S. pyogenes).

How does cellulitis typically develop?

It often develops after damage to the skin, allowing bacterial entry.

What do inflammatory cells like macrophages release during inflammation?

Cytokines into the circulation, leading to systemic features like fever, chills, and sweats.

What are two key cytokines that cause systemic effects of infection?

Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α).

What is the role of IL-1 in the body?

IL-1 is an "endogenous pyrogen" that acts on the hypothalamus to raise body temperature, causing fever.

What was TNF-α originally described as, and what are its systemic effects?

Originally described as a factor causing necrosis of tumor cells; it causes fever, cachexia, and vascular leak during inflammation.

What cytokines are associated with chronic inflammation?

IFN-gamma and IL-12.

What type of inflammation is cellulitis of 24 hours duration an example of?

Acute inflammation.

What is the role of Prostaglandin E2 in the context of fever?

It is produced in the hypothalamus in response to pyrogens and works locally to alter the temperature set point to cause fever; it does not circulate systemically.

The mechanism of fever involves a pyrogen like TNF-alpha that circulates systemically leading to increased production of

PGE2 which works locally in the hypothalamus.

What is acute endocarditis?

A bacterial infection of the cardiac valves, typically presenting with nonspecific symptoms like fever, chills, and sweats.

What is a classic physical examination finding in acute endocarditis?

A new cardiac murmur.

What are the most common bacteria that cause endocarditis?

Staphylococcus aureus and Viridans group streptococci.

What are acute phase reactants?

Proteins whose serum levels rise in response to inflammation, including C-reactive protein and clotting factors like fibrinogen.

How is the erythrocyte sedimentation rate (ESR) related to inflammation?

The ESR increases in parallel with acute phase reactants, reflecting the speed at which red blood cells settle due to inflammation.

What causes the increase in ESR during inflammation?

Increased levels of fibrinogen, which causes red blood cells to aggregate and settle more quickly.

Where do most acute phase reactants originate?

Most come from the liver.

What major trigger stimulates the release of acute phase reactants?

Interleukin-6 (IL-6).

Besides stimulating liver release of acute phase reactants, what else does IL-6 do?

It can cause fever by acting on the hypothalamus, making it a pyrogen.

What is bronchiolitis and what is its most common viral cause in children under 2 years old?

Bronchiolitis is a respiratory infection commonly caused by respiratory syncytial virus (RSV).

What are typical symptoms of bronchiolitis?

Wheezing, intercostal retractions, and nasal flaring.

How is bronchiolitis typically diagnosed?

Diagnosis is usually made clinically based on symptoms.

What is the primary treatment for bronchiolitis?

Treatment is primarily supportive, although antiviral medications can be used in some cases.

What type of virus is RSV?

Single-stranded RNA virus.

How does RSV infect the body?

It invades nasopharyngeal and lower respiratory epithelial cells.

How is RSV cleared from the body?

Virally-infected cells present viral antigens in the context of MHC Class I, which are recognized by CD8+ T-cells.

What is the role of CD8+ T-cells in clearing RSV infection?

CD8+ T-cells trigger apoptosis of the infected cells to help clear the virus.

Are found in smooth muscle of the lungs. Their activation with beta agonists like albuterol can be used to dilate the bronchioles and relieve wheezing in RSV infection. These receptors are not, however, important for clearing the virus.

Beta-2 receptors

RSV replication occurs within respiratory epithelial cells where the virus is protected from

Macrophages

Produce mucous which protects the airways from pathogens. These cells do not play a direct role in clearance of virally-infected cells.

Goblet cells

What is the most common childhood malignancy?

Acute lymphoblastic leukemia (ALL).

What type of cells does ALL result from the abnormal proliferation of?

Lymphoblasts, most commonly B-cell precursors.

What are common presenting symptoms of ALL?

Fatigue, splenomegaly, and symptoms related to anemia or thrombocytopenia (e.g., pallor, easy bruising, petechiae).

What is the primary treatment for ALL?

Chemotherapy targeting rapidly-dividing cancer cells.

What are common side effects of chemotherapy in ALL?

Mucositis due to GI epithelial cell damage and bone marrow suppression.

How does bone marrow suppression from chemotherapy affect the risk of infection?

It impairs the production of white blood cells, increasing the risk of infections.

What is the absolute neutrophil count (ANC) used to measure?

The risk of infection in patients undergoing chemotherapy.

Why are neutrophils significant in the context of chemotherapy?

They have a short lifespan (1-5 days) and are the first cells to decline with bone marrow suppression; they make up about 50% of white blood cells and are key to innate immunity.

What does neutropenia indicate?

Impairment of innate immunity and a significant risk of infection.

How are patients with neutropenia monitored during chemotherapy?

They are carefully monitored for signs of infection, and chemotherapy may be temporarily discontinued until neutropenia resolves.

What growth factor may be administered to boost neutrophil counts?

Granulocyte colony-stimulating factor (GCSF).

Granulocytes include neutrophils, eosinophils, and basophils. Since the majority of circulating granulocytes are neutrophils, the terms neutropenia and granulocytopenia are often used

Interchangeably.

Antibodies like IgG derive from B-cells and plasma cells. These cells can live for years, and do not decline as rapidly as neutrophils in patients on chemotherapy.

Complement proteins are synthesized in the liver and are not significantly affected by chemotherapy. CD4+ T-cells and natural killer cells are lymphocytes that can live for years. They do not decline as rapidly as neutrophils in patients on chemotherapy.

What is the primary goal of vaccination?

To generate antigen-specific circulating antibodies and memory lymphocytes.

What type of immune response is generated after the first dose of vaccination?

A relatively weak immune response with production of IgM antibodies, some IgG antibodies, and memory B-cells.

Why is the initial peak production of IgG antibodies after the first vaccination relatively slow?

There are no memory cells present prior to the first exposure.

What happens after the second vaccination in terms of immune response?

Antigens are recognized by memory B-cells, which rapidly differentiate into IgG-secreting plasma cells.

How does the second vaccination affect the quantity of circulating IgG antibodies?

It leads to an increased quantity of circulating IgG antibodies.

What is the impact of memory B-cells on the time required to reach peak antibody production during subsequent vaccinations?

The time required to reach peak antibody production is decreased.

What are common clinical features at presentation for a child with ALL?

Nonspecific symptoms such as fatigue, malaise, fever, and often hepatosplenomegaly.

How does infiltration of the bone marrow by malignant cells affect blood counts in ALL?

It can lead to anemia and thrombocytopenia, predisposing to bleeding, bruising, or petechiae.

What type of cells are primarily involved in most cases of ALL?

Immature B-cells (pre-B lymphocytes or B-cell lymphoblasts).

How are leukemic B-cells typically described morphologically?

They have a "large nucleus with scant cytoplasm."

What cell surface markers are typically expressed by leukemic B-cells in ALL?

CD19 and CD22, both classic B-cell markers.

What is the significance of CD10 in ALL?

It is also called the "common acute lymphoblastic leukemia antigen" (CALLA) and is often expressed by leukemic B-cells.

What immunoglobulin characteristics are present in leukemic B-cells compared to mature B-cells?

Immunoglobulins or light chains may be present but are usually not found on the cell surface as they would be in mature B-cells.

What T-cell marker will not be expressed in leukemic B-cells?

CD3.

What is the most common congenital infection in humans?

Congenital cytomegalovirus (CMV) infection.

What percentage of children born with CMV infection have symptoms at birth?

About 10%.

What are some common symptoms of symptomatic congenital CMV infection?

Petechiae, jaundice, hepatosplenomegaly, small size, and microcephaly.

What is the most serious long-term consequence of congenital CMV infection?

Sensorineural hearing loss.

What type of virus is CMV, and what is a characteristic feature of herpes viruses?

CMV is a herpes virus, and it can lead to a permanent, dormant state of infection (latent infection) after primary infection.

During latent infection with CMV, where does low-level replication occur?

Within peripheral and bone marrow white cells.

What type of antibodies indicate active CMV infection?

IgM antibodies.

What type of antibodies can be found during both active and latent CMV infection?

IgG antibodies.

How does the presence of anti-CMV IgG antibodies in the mother relate to her infection status?

It indicates that she had a CMV infection at some point during her pregnancy, either as a primary infection or reactivation, but does not indicate an active infection currently.

How can we determine that the baby has an active CMV infection?

By the presence of both IgM and IgG antibodies in the baby, with IgM indicating that the antibodies were produced by the baby.

At what gestational age can the fetus start producing its own antibodies?

Around 20 weeks gestation.

Why do newborns rely on maternal antibodies for protection?

The newborn antibody response is relatively weak, and most antibodies in the newborn come from the mother.

Why can't IgM antibodies cross the placenta?

IgM antibodies are too large to cross the placental barrier.

What does the presence of IgM antibodies in a newborn indicate?

It indicates that the antibodies were produced by the baby, suggesting a congenital infection.

Which type of infection can lead to the presence of IgM antibodies in a baby?

Congenital infection.

If a baby has IgM antibodies, what can we infer about the mother's infection status?

The mother does not have IgM antibodies, indicating she does not have an active infection; the baby's IgM is from the baby itself.

All herpes viruses can enter a latent state and reactivate.

CMV, Epstein Barr, Herpes Simplex

Why don't maternal IgM antibodies provide protection to the fetus?

IgM antibodies are large pentamers that cannot cross the placenta.

What type of immune response is typically associated with polysaccharide vaccines?

A relatively weak and short-lived B-cell response primarily consisting of IgM antibodies

How do polysaccharide vaccines activate B-cells?

They activate B-cells in a T-cell-independent manner, without the support of T-cell-helper activity.

Why are polysaccharide antigens often combined with carrier proteins in vaccines?

The carrier protein activates T-cells, leading to a more robust B-cell antibody response than if the polysaccharide were used alone.

What is a common carrier protein used in polysaccharide vaccine formulations?

Tetanus toxoid.

How can Group B strep (GBS) infections be transmitted from mother to baby?

GBS frequently colonizes the genital tract and can be passed to newborns during vaginal delivery.

What interventions are commonly taken for mothers colonized with GBS during delivery?

They receive antibiotics at the time of delivery to reduce the risk of transmitting the infection to the baby.

What serious conditions can babies develop if infected with GBS during childbirth?

Sepsis, pneumonia, or meningitis.

Have any GBS vaccine candidates become widely used?

No, despite research efforts, none of the vaccine candidates have become widely used.

Are found on mucosal surfaces like those of the GI tract and nasopharynx. They are rarely produced in response to vaccination except when oral vaccines are used (e.g.: some polio vaccines).

IgA antibodies

Are monomeric antibodies like IgG whose function is poorly understood. Like IgA, they are more commonly associated with mucosal sites. These would not be produced in response to a polysaccharide vaccine.

IgD antibodies

Bind to mast cells and eosinophils for defense against parasites and are often associated with allergy. These would not be produced in response to a polysaccharide vaccine.

IgE antibodies

Can cross the placenta and would provide protection for the baby. If this woman had produced IgG antibodies, the baby would have had protection against GBS.

IgG antibodies

What do killed vaccines contain?

Virus particles but not live viruses.

How do killed vaccines activate B-cells?

The virus particles are recognized by B-cells and engulfed by antigen-presenting cells, which present vaccine proteins to CD4+ T-cells in the context of MHC class II.

What type of antibodies are generated in response to killed vaccines?

Systemic IgM and IgG antibodies.

What is a key limitation of killed vaccines regarding T-cell response?

They do not generate a robust CD8+ T-cell response.

What do live attenuated vaccines contain?

A virus that has been weakened (attenuated) but can replicate in human cells.

How do live attenuated vaccines activate CD8+ T-cells?

Virally-infected cells present viral antigens in the context of MHC class I.

What are the effects of live attenuated vaccines compared to killed vaccines?

Live attenuated vaccines generate both systemic IgG antibodies and a robust CD8+ T-cell response, while killed vaccines primarily activate B-cells.

What are the two types of polio vaccines mentioned, and how do they differ?

The injected killed polio vaccine (Salk vaccine) and the live attenuated oral vaccine (Sabin vaccine); both generate systemic IgG antibodies, but the Sabin vaccine also activates CD8+ T-cells.

No CD8 T-cell response occurs with the injected, killed vaccine because CD8+ T-cell activation requires virally-infected cells

To present antigens in the context of MHC class I.

What is the typical age range for patients with precursor T-cell acute lymphoblastic leukemia/lymphoma?

Teens or early twenties.

What are common symptoms at presentation for this malignancy, precursor T-cell acute lymphoblastic leukemia/lymphoma?

Pallor and weakness from anemia, bleeding and petechiae from thrombocytopenia, and a large mediastinal mass.

What complications can arise from a large mediastinal mass in T-cell acute lymphoblastic leukemia/lymphoma?

Tracheal obstruction and superior vena cava syndrome.

What indicates that malignant cells are of T-cell lineage?

The presence of T-cell receptor gene rearrangement on diagnostic testing.

What does it mean if cancer cells are described as "double negative"?

They do not express CD4 or CD8, indicating they are immature T-cells.

Where are double negative T-cells normally found?

In the subcapsular zone of the thymus.

What surface markers are associated with B-cells?

CD19, CD20, and surface immunoglobulin.

What is the general CD marker classification for T-cells and B-cells?

CD markers with numbers less than 10 are mostly T-cell markers; CD numbers 19 to 23 are mostly B-cell markers.

What is the most common form of renal cancer?

Renal cell carcinoma (RCC).

What is the classic triad of clinical findings for RCC?

Flank pain, hematuria, and a palpable abdominal mass.

What percentage of RCC patients present with the classic triad?

Less than 10%.

How does renal cell carcinoma typically spread?

Via the bloodstream, often through the renal vein.

What is the most common site of metastases for RCC?

The lungs.

What is the prognosis for stage 4 RCC with distant metastases?

Very poor, with a 5-year survival rate of less than 10%.

What types of immune cells does IL-2 activate?

CD4+ T-cells, CD8+ T-cells, and natural killer (NK) cells.

Why is IL-2 significant in cancer therapy?

It was discovered as a T-cell growth factor, leading to advancements in immunotherapy. IL-2 is a T-cell activator.

How is hepatitis B transmitted?

Through sexual contact, sharing dirty needles, accidental needle sticks, or from pregnant women to their child.

What are common symptoms of acute hepatitis B?

Malaise, nausea, right upper quadrant pain, jaundice, and dark urine.

What laboratory findings are typical in acute hepatitis B?

Marked elevations of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), usually over 1000 U/L.

Which serological markers are present in the acute phase of hepatitis B?

Hepatitis B surface antigen (HBsAg) and IgM to hepatitis core antibody (anti-HBc).

What percentage of patients fully recover from acute hepatitis B?

Most patients fully recover, but some may develop chronic hepatitis B.

What is the primary role of cytotoxic CD8+ T-cells in viral infections?

To recognize virally-infected cells and induce apoptosis, thereby eliminating the cellular machinery needed for viral replication.

How do hepatocytes present viral antigens to CD8+ T-cells?

Hepatocytes present viral antigens on their surface in the context of MHC class I molecules.

What type of infections are children with interferon-gamma (IFN-γ) receptor deficiency prone to?

Atypical (non-tuberculosis) mycobacterial infections.

What is the role of CD4+ Th1 cells in the immune response to mycobacteria?

Th1 cells secrete IFN-γ to stimulate macrophages, enhancing their ability to fight infections.

What cytokine do macrophages release to stimulate Th1 cells?

Interleukin-12 (IL-12).

What genetic deficiencies can impair the immune response to mycobacteria?

Deficiencies in either the IL-12 receptor or the IFN-γ receptor.

What rare disorder is associated with deficiencies in the IFN-γ receptor or IL-12 receptor?

Mendelian susceptibility to mycobacterial disease (MSMD).

What is Bacillus Calmette-Guerin (BCG)?

A live, attenuated form of Mycobacterium bovis used as a vaccine against tuberculosis.

Why can the BCG vaccine cause infection in children with MSMD?

Because BCG is a live vaccine, it can lead to infection in individuals with impaired immune responses to mycobacteria.

What should be considered in a child with recurrent atypical mycobacterial infections?

What is the common name for infectious mononucleosis?

"Mono" or "the kissing disease."

How is Epstein-Barr virus (EBV) primarily transmitted?

Through direct contact, often via saliva.

What age group is most commonly affected by EBV-related infectious mononucleosis?

Young patients, especially college students.

List some common symptoms of infectious mononucleosis.

Fatigue, headache, malaise, hepatosplenomegaly, pharyngitis, and cervical lymphadenopathy.

What type of virus is EBV?

A herpes DNA virus.

Which type of cells does EBV infect and transform?

B-cells.

Name some B-cell malignancies associated with EBV.

Burkitt’s lymphoma and Hodgkin’s lymphoma.

What are atypical lymphocytes, and how do they appear in EBV infection?

Atypical lymphocytes are larger than normal lymphocytes with nucleoli in the nucleus and indented cytoplasm.

What laboratory criteria can help diagnose EBV infection?

At least 50% lymphocytes and at least 10% atypical lymphocytes in the white blood cell count.

What type of T-cells increase in number during an EBV infection, and what is their role?

CD8+ (cytotoxic) T-cells, which help eliminate EBV-infected B-cells.

What happens to EBV after the acute infection resolves?

It enters a dormant (latent) state and can remain lifelong in the host.

When does reactivation of EBV typically occur?

It can reactivate later in life, especially in immunocompromised individuals.

What can reactivation of EBV in immunocompromised patients lead to?

It can lead to B-cell malignancies, similar to those associated with HIV infection

What is a common condition that can trigger EBV reactivation?

Immunocompromised states, such as HIV infection.

What organism causes pneumocystis pneumonia (PCP)?

Pneumocystis jirovecii, a fungus.

In which patients does PCP typically cause disease?

It primarily affects immunocompromised patients, such as those with HIV/AIDS or those undergoing cytotoxic chemotherapy.

How is PCP diagnosed?

Through silver staining of respiratory specimens, which reveals small, round fungi.

What is the role of alveolar macrophages in defending against Pneumocystis?

They recognize the fungus and activate, releasing cytokines that lead to the activation of CD4+ T-cells.

Why are CD4+ T-cells important in preventing PCP?

A lack of CD4+ T-cells limits the activity of the adaptive immune system, reducing host defense against Pneumocystis.

What conditions can lead to increased risk of developing PCP besides HIV?

Malignancy, cytotoxic chemotherapy, and glucocorticoid use.

What subtype of malignant melanoma is characterized by irregularly bordered pigment macules in sun-exposed areas?

Superficial spreading melanoma.

What are "areas of regression" in melanoma?

Regions of the tumor with decreased melanoma cells replaced by inflammatory cells, fibrosis, and other findings, indicating a host response to tumor growth.

What is believed to play a significant role in the regression of melanoma?

CD8+ cytotoxic T-c

What is Felty’s syndrome?

A rare complication of severe rheumatoid arthritis characterized by the triad of rheumatoid arthritis, neutropenia, and splenomegaly.

Felty’s Syndrome

Triad: Rheumatoid arthritis, neutropenia, splenomegaly. Complications: Increased susceptibility to infections. Management: Neutropenia may improve after splenectomy.

Definition: Red blood cells with a central “halo of pallor.” Causes: Decreased ratio of cell volume to cell membrane. Associated Conditions: Microcytic anemias (iron deficiency, thalassemia), liver disease.

Target Cells (Codocytes)

Mechanism: Splenectomy increases red cell membrane size, reducing the volume-to-membrane ratio. Role of Spleen: Red pulp contains Cords of Billroth. Functions: Conditioning of red cells and removal of aging cells.

Target Cells and Splenectomy

Risk Factor: Increased risk in patients without a spleen (e.g., following splenectomy).

Meningitis and Streptococcus pneumoniae

Function: Critical for defense against encapsulated bacteria. Mechanism: Removes bacteria from the blood. Recognizes opsonized (IgG and complement-coated) bacteria via splenic macrophages.

Role of the Spleen

Deficiency: Splenectomized patients have impaired ability to clear IgG-coated bacteria. Consequences: Increased bacterial growth. More frequent and severe infections.

Implications of Splenectomy

Most Important Pathogen: Streptococcus pneumoniae (up to 60% of infections). Other Encapsulated Bacteria: Haemophilus influenzae type B Neisseria meningitidis

Common Pathogens in Splenectomized Patients

Functions: Removal of aging red cells. Immune response to blood-borne pathogens.

Major Roles of the Spleen

Patients without a spleen are at higher risk for infections, particularly from: - Encapsulated bacteria (e.g., Streptococcus pneumoniae). - Blood-borne parasites that infect red cells (e.g., Babesia, Ehrlichia, Malaria).

Risks of Splenectomy

Type: Protozoan, tick-borne illness. Transmission: Transmitted to blood following a tick bite. Mechanism: Invades red cells, similar to Plasmodium species in malaria.

Babesia Overview

Asymptomatic Majority: Most infected patients remain asymptomatic. Severe Infections in Asplenic Patients: Symptoms due to hemolysis may include: - Fever - Anemia - Jaundice - Hemoglobinuria - Renal failure Diagnosis: Blood smear shows parasites within red cells.

Symptoms and Complications of Babesiosis

Candida species are fungi that cause a number of infections including oral candidiasis (“thrush”), esophagitis, and vulvovaginitis (“yeast infections”). ? are risk factors for candida infections

Neutropenia and glucocorticoid medications

Condition: Viral infection of the pharynx causing reactive lymphadenopathy. Key Feature: Germinal centers in lymph nodes are sites of B-cell proliferation.

Viral Infection and Reactive Lymphadenopathy

B-cell Receptors: Unique receptors for specific antigens. Activation Process: Binding of antigen triggers proliferation and differentiation into plasma cells, which synthesize antibodies.

B-cell Activation and Antibody Production

Class Switching: B-cells change antibody production from one class to another (e.g., IgM to IgG). Somatic Hypermutation: B-cells develop point mutations in variable region genes. Alters B-cell receptor, potentially improving antigen binding.

B-cell Processes Under T-cell Cytokines

Proliferation: B-cells with altered receptors that bind antigen more avidly will proliferate more. Outcome: Strengthens and targets the immune response to the antigen over time.

Impact of Somatic Hypermutation

Also Known As: Thymic aplasia, 22q11.2 deletion syndrome. Cause: Deletion of a portion of the long arm of chromosome 22. Congenital Abnormalities: Affects heart, thymus, and parathyroid glands.

DiGeorge Syndrome Overview

Pharyngeal Pouches: Affected structures derive from the 3rd and 4th pharyngeal pouches, which fail to develop in DiGeorge syndrome

Developmental Origin .

Common Defects: - Cardiac defects (e.g., Tetralogy of Fallot). - Hypocalcemia. - Reduced T-cell numbers. Immunodeficiency: Leads to recurrent infections due to T-cell abnormalities.

Clinical Features DiGeorge

Location: T-cells reside in the paracortex of lymph nodes (between outer cortex and inner medulla). Impact of DiGeorge Syndrome: Paracortex is underdeveloped due to lack of T-cells from the thymus.

T-cell Localization in Lymph Nodes

Definition: A myeloproliferative disorder where bone marrow is replaced by fibrous tissue. Common Complaint: Fatigue at diagnosis.

Primary Myelofibrosis Overview

Anemia: Normocytic anemia in about 50% of cases due to ineffective erythropoiesis. Platelet and White Cell Counts: Variable; may be increased or decreased. Blood Smear Finding: Presence of tear drop cells (dacrocytes).

Primary Myelofibrosis: Lasb Findings

Bone Marrow Biopsy: Often results in a dry tap (inability to remove fluid and cells) due to fibrous tissue accumulation.

Primary Myelofibrosis: Bone Marrow and Biopsy Characteristics

Causes: Marked splenomegaly and hepatomegaly due to extramedullary hematopoiesis (EH). Role of Spleen: Important for blood cell development. In fetal life, hematopoiesis occurs in the liver and spleen before bone marrow maturation. In cases of bone marrow failure, hematopoietic stem cells can proliferate in the liver and spleen.

Primary Myelofibrosis: Splenomegaly and Hepatomegaly

Definition: A type of penicillin hypersensitivity occurring 7 to 10 days after administration. Clinical Presentation: - Less dramatic than acute reactions; typically no hypotension, bronchospasm, or anaphylactic shock. - Symptoms may include rash, fever, and joint pain.

Subacute Penicillin Allergy Overview

- Type of Reaction: Type III hypersensitivity reaction. - Mediators: Mediated by IgG and the complement system. Immune complexes deposit in skin, joints, and kidneys.

Mechanism of Subacute Penicillin Hypersensitivity

Deposition Locations: Skin, joints, and kidneys are classic sites for immune complex deposition. Antibody Type: IgG antibodies are primarily involved in forming immune complexes. Timeframe for Symptoms: Symptoms occur a week or more after exposure to the antigen due to the time required for B-cells to produce sufficient IgG.

Subacute Penicillin Allergy: Immune Complex Formation

A drug reaction occurring days to weeks after exposure and involving the skin, joints, and kidneys is almost always ?. These are classic locations for deposition of antigen-antibody complexes.

A type III hypersensitivity reaction

Definition: A variant of type III hypersensitivity reaction to injected insulin. Mechanism: Involves antigen-antibody complexes that form and deposit in tissues.

Arthus Reaction Overview

Classic Form: Antigen-antibody complexes circulate and deposit in skin, joints, and kidneys. Example: Systemic lupus erythematosus (SLE) is a classic autoimmune disorder illustrating this reaction.

Type III Hypersensitivity

Local Reaction: Occurs due to preformed antibodies against antigens (e.g., insulin or an additive). Timing: Initial exposure: No reaction (antibodies not yet developed). After several days: Antibodies react with injected antigens, causing a localized reaction (e.g., nodule formation).

Characteristics of the Arthus Reaction

Key Timing: Nodule developed six hours after injection. Too slow for type I (immediate) reactions and too fast for type IV (delayed) reactions. Not Type II Reaction: The reaction is against a component of injected insulin, not against cells or tissues.

Timing and Differentiation

Definition: An immediate hypersensitivity reaction, such as a reaction to a bee sting. Timing: Early symptoms occur within minutes of exposure to the antigen.

Type I Hypersensitivity Overview

Cause: Antigen binds to preformed IgE antibodies on mast cells. Result: Histamine release leading to symptoms such as: - Wheezing - Urticaria (itchy, red, raised plaques on the skin)

Mechanism of Type I Hypersensitivity

Timing: Develop about six hours after the initial symptoms. Mechanism: Caused by the influx of inflammatory cells (macrophages, neutrophils, eosinophils) that release cytokines. Outcome: Lesions become firm and indurated due to cell migration and cytokine release.

Late Symptoms of Type I Hypersensitivity

Key Point: Induration may indicate: Late Type I Reaction: Preceded by an early reaction within minutes. Arthus Reaction: Occurs six hours after exposure, not preceded by an early reaction. Type IV Reaction: Delayed hypersensitivity occurring 24 to 48 hours after exposure. Importance of Timing: Timing of events is crucial for distinguishing between types of hypersensitivity reactions.

Induration in Hypersensitivity Reactions

Definition: A hypersensitivity reaction characterized by circulating antibodies. Association: Commonly occurs in the setting of hepatitis C; up to 90% of patients with cryoglobulinemia have hepatitis C.

Cryoglobulinemia Overview

Formation: Cryoglobulins are antibodies that bind to antigens and circulate in the blood. Deposition: These antibodies deposit in tissues of the skin, nerves, joints, and kidneys, leading to symptoms consistent with type III hypersensitivity reactions.

Mechanism of Cryoglobulinemia

- Vasculitis: Inflammation of arterioles and capillaries due to deposition of antigen-antibody complexes. Skin: - Purpura: Red or purple spots that do not blanch under pressure, indicating blood leakage from damaged vessels. - Neuropathy: Common, leading to symptoms like arm pain due to nerve inflammation. - Joint Involvement: Can cause arthralgias.

Clinical Features Cryoglobulinemia

Components - Purpura - Weakness - Arthralgias Prevalence: Present in about 80% of patients with cryoglobulinemia.

Meltzer’s Triad

Renal Involvement: Complication: ?may develop as a result of cryoglobulinemia.

Glomerulonephritis

Cause: Follows an infection with Streptococcus pyogenes (group A strep). Initial Misdiagnosis: Often mistaken for a viral illness due to overlapping symptoms.

Overview of Rheumatic Fever

Major Criteria (2): - Carditis - Sydenham’s chorea Minor Criteria (2): - Fever - Arthralgia Murmur: Systolic murmur indicates mitral regurgitation due to mitral valve inflammation.

Diagnostic Criteria: Rheumatic Fever

Complications: 50% of patients may develop mitral stenosis 10 to 20 years after the initial episode due to scarring. Mortality Risk: Major cause of death is heart failure or arrhythmias due to severe carditis.

Long-term Effects: Rheumatic Fever

- Type of Reaction: Type II autoimmune reaction with antibodies against cell surface antigens. Molecular Mimicry: Structural similarity between streptococcal antigens and human proteins leads to cross-reactivity. Result: Antibodies formed against bacterial antigens affect heart tissues, causing carditis and fibrinoid necrosis of heart valves.

Mechanism of Carditis

Affected Areas: - Nerves: Chorea - Skin: Erythema marginatum - Joints: Arthritis Mechanisms: Less understood compared to carditis.

Other Symptoms of Acute Rheumatic Fever

Major Mechanisms: - Phagocytosis - Complement activation - Antibody-dependent cellular cytotoxicity (ADCC) ADCC in Rheumatic Fever: Antibodies attract natural killer cells and other leukocytes, leading to cytotoxic effects, believed to contribute to carditis.

Mechanisms of Cell Death in Type II Hypersensitivity

Definition: A genetic condition leading to absence of humoral immunity. Inheritance: X-linked disorder, primarily affecting males.

Overview of X-linked Agammaglobulinemia (XLA)

Age of Onset: Recurrent lower respiratory tract infections typically start after six months of age when maternal IgG is no longer present. Physical Examination Findings: - Small or absent tonsils - Decreased or absent lymph nodes - Few or no germinal centers.

Presentation and Symptoms of X-linked Agammaglobulinemia (XLA)

Cause: Mutation in the BTK gene (Bruton's tyrosine kinase). Effect: - Functional absence of BTK leads to defective B-cell maturation. - B-cell precursors fail to develop into functional B-cells, resulting in impaired humoral immunity.

Pathophysiology of X-linked Agammaglobulinemia (XLA)

- B-cell Levels: Decreased levels of mature B-cells in affected individuals. - Germinal Centers: Few or absent in lymphoid tissues.

Laboratory Findings in X-linked Agammaglobulinemia (XLA)

Definition: A condition characterized by absent serum IgA levels with normal IgG and IgM levels. Presentation: Often presents in young children with recurrent bacterial upper respiratory infections and diarrhea due to giardiasis, indicating impaired mucosal immunity.

Overview of Selective IgA Deficiency

Symptoms: - Majority of patients are asymptomatic. - Less than a third seek medical attention due to recurrent infections. Common Infections: Increased susceptibility to upper respiratory infections and gastrointestinal infections (e.g., giardiasis).

Clinical Features of Selective IgA Deficiency

Anti-IgA Antibodies: Patients with total IgA deficiency may develop these antibodies if exposed to blood products. Transfusion Reactions: - Exposure to even trace amounts of IgA (e.g., in red cell transfusions) can cause anaphylactic transfusion reactions. Transfusion Precautions: - Screen for anti-IgA antibodies before transfusion. - Use blood products from another IgA-deficient individual if possible. - If documented anti-IgA antibodies are present, consider saline-washed RBC transfusions.

Complications of Selective IgA Deficiency

Immunoglobulin Assay Results: Absent serum IgA with normal levels of IgG and IgM.

Laboratory Findings in Selective IgA Deficiency

Definition: A condition characterized by low serum levels of IgG, along with low IgA or IgM. Distinction: Low IgG levels differentiate CVID from selective IgA deficiency.

Overview of Common Variable Immunodeficiency (CVID)

Antibody Response: Patients exhibit weak or absent antibody responses to infections. B-cell Function: Poor differentiation and antibody secretion by B-cells.

Pathophysiology of Common Variable Immunodeficiency (CVID)

Age of Onset: Can be diagnosed in early childhood, but over half of cases are identified after age 30. Acquisition: Most cases are sporadic, with 90% of patients having no family history. Cause: Poorly understood; thought to involve a combination of genetic defects with variable penetrance.

Diagnosis of Common Variable Immunodeficiency (CVID)

Infections: Increased susceptibility to: - Upper and lower respiratory infections (e.g., otitis media, pneumonia, sinusitis, bronchitis) - Gastrointestinal infections (e.g., giardiasis). - Autoimmune Diseases: Higher risk for conditions like pernicious anemia, ulcerative colitis, and vitiligo. Malignancies: Increased risk for some cancers, particularly Hodgkin lymphoma.

Clinical Features of Common Variable Immunodeficiency (CVID)

Definition: A genetic condition caused by failure of the 3rd and 4th pharyngeal pouches to form. Alternate Names: Also known as DiGeorge syndrome or thymic aplasia.

Overview of 22q11.2 Deletion Syndrome (DiGeorge Syndrome)

Facial Abnormalities: - Micrognathia (small jaw) - Cleft palate - Broad nasal bridge - Short philtrum - Low-set ears Cardiac Defects: - Truncus arteriosus (single overriding great vessel) - Tetralogy of Fallot

Clinical Features of 22q11.2 Deletion Syndrome (DiGeorge Syndrome)

Impaired Parathyroid Development: - Affects parathyroid glands due to their origin from the 3rd and 4th pharyngeal pouches. Consequences: - Low serum parathyroid hormone (PTH) levels - Hypocalcemia, leading to tetany and seizures during infancy.

Endocrine Manifestations of 22q11.2 Deletion Syndrome (DiGeorge Syndrome)

Testing Method: Best diagnosed by chromosomal microarray to detect small deletions that older FISH testing may miss.

Diagnosis of 22q11.2 Deletion Syndrome (DiGeorge Syndrome)

Definition: An inherited immunodeficiency condition often caused by a genetic abnormality in the STAT3 gene. Key Feature: Characterized by elevated serum IgE levels.

Overview of Job Syndrome (Hyper-IgE Syndrome)

Gene Involved: Mutation in the STAT3 gene affects the regulation of T-helper cells type 17 (Th17). Cytokine Role: Th17 cells produce interleukin 17 (IL-17), crucial for neutrophil recruitment and activation. Impact: Poor Th17 function leads to increased susceptibility to bacterial infections requiring neutrophils.

Pathophysiology of Job Syndrome (Hyper-IgE Syndrome)

Skin Rash: Rash resembling atopic dermatitis (eczema) appears within the first few weeks of life. - Distinction: Unlike classic atopic dermatitis, which typically appears after three months of age. - Infections: Frequent bacterial infections, particularly with S. aureus (e.g., folliculitis, abscesses), and may also include: - Mucocutaneous candidiasis - Bronchitis - Pneumonia

Clinical Features of Job Syndrome (Hyper-IgE Syndrome)

Facial Appearance: Characteristic features include a broad nose, deep-set eyes, and a prominent forehead.

Physical Characteristics of Job Syndrome (Hyper-IgE Syndrome)

Eczema and Immunodeficiency: When considering a patient with eczema and immunodeficiency, think of: - Hyper-IgE syndrome - Wiskott-Aldrich syndrome

Key Points to Remember for Job Syndrome (Hyper-IgE Syndrome)

Definition: A condition characterized by recurrent, noninvasive infections caused by Candida albicans due to T-cell dysfunction. Presentation: Affects the skin, mucous membranes, and nails.

Overview of Chronic Mucocutaneous Candidiasis (CMCC)

Role of T-cells: T-cells are crucial for cell-mediated immunity against fungal infections. T-cell Dysfunction: Leads to increased susceptibility to Candida infections and may be associated with: - Deficiencies in cytokine synthesis and receptors. - Abnormal activity of autoimmune regulator (AIRE) genes.

Pathophysiology of Chronic Mucocutaneous Candidiasis (CMCC)

Common Autoimmune Conditions: Patients often have other autoimmune disorders, including: - Type I diabetes - Autoimmune thyroiditis - Additional autoimmune conditions

Associated Autoimmune Disorders in Chronic Mucocutaneous Candidiasis (CMCC)

AIRE Gene Role: AIRE genes are responsible for T-cell maturation in the thymus. Impact of Mutations: Mutations in AIRE lead to dysfunctional T-cells, increasing the risk of: - Fungal infections - Autoimmune diseases

Genetic Factors in Chronic Mucocutaneous Candidiasis (CMCC)

Definition: An immunodeficiency disorder characterized by abnormal function of T-cells and B-cells. Common Cause: Most commonly due to an X-linked defect in the interleukin 2 (IL-2) receptor, specifically the IL2RG gene.

Overview of Severe Combined Immunodeficiency (SCID)

Gene Involved: The IL2RG gene codes for the gamma chain of the IL-2 receptor. Impact of Abnormalities: Mutations in this gene lead to dysfunctional T-cells and B-cells.

Pathophysiology of Severe Combined Immunodeficiency (SCID)

Recurrent Infections: Patients experience severe, recurrent infections such as: - Bacterial gastrointestinal disease - Oral candidiasis - Respiratory tract infections Physical Findings: - Absent thymic shadow on chest X-ray (indicative of absent T-cells). - Absence of peripheral lymphoid tissue (lymph nodes, tonsils). - Commonly associated with recurrent eczematous rashes.

Clinical Features of Severe Combined Immunodeficiency (SCID)

Newborn Screening: In many US states, SCID is screened at birth using PCR amplification of T-cell receptor excision circles (TRECs). Confirmatory Tests: Diagnosis is confirmed by: - Low T-cell count - Mutation in the IL2RG gene.

Diagnosis of Severe Combined Immunodeficiency (SCID)

Is caused by an X-linked mutation of the WAS gene, which leads to the inability of T-cells to organize the actin cytoskeleton. Actin cytoskeleton polymerization is necessary for T-cell reaction to antigens. WAS leads to an eczematous rash, recurrent infections, and thrombocytopenia. The thymus is normal in WAS.

Wiskott-Aldrich syndrome (WAS)

Definition: A genetic disorder characterized by cerebellar ataxia, recurrent sinopulmonary infections, and decreased immunoglobulin levels. Genetic Cause: Caused by an autosomal recessive mutation in the ATM gene.

Overview of Ataxia-Telangiectasia (AT)

ATM Gene Role: The ATM gene is essential for DNA repair, particularly through nonhomologous end-joining. Impact of Mutation: Deficiency in DNA repair leads to neurological symptoms and immunodeficiency.

Pathophysiology of Ataxia-Telangiectasia (AT)

- Neurological Symptoms: Cerebellar ataxia, leading to balance and coordination issues. - Telangiectasias: Conjunctival telangiectasias develop before age five; may also appear on exposed skin, especially the face. - Infections: Decreased immunoglobulin levels predispose patients to recurrent respiratory tract infections.

Clinical Features of Ataxia-Telangiectasia (AT)

Increased Cancer Risk: Patients have a higher incidence of cancer after age 10, primarily: - Lymphomas - Acute leukemias

Complications of Ataxia-Telangiectasia (AT)

Definition: A disorder characterized by abnormal B-cell class switching, resulting in primarily IgM antibody production. Common Mechanism: Most commonly caused by a defective CD40 ligand on T-cells.

Overview of Hyper-IgM Syndrome

CD40 Ligand Role: The CD40 ligand allows T-cells to bind to B-cells, providing necessary signals for class switching. Impact of Deficiency: Without proper signaling, B-cells cannot switch from producing IgM to other antibody types (IgA, IgG).

Pathophysiology of Hyper-IgM Syndrome

Serum Immunoglobulin Levels: - Low IgA and IgG - Normal or increased IgM (often normal in younger patients) - Infection Risks: Recurrent sinopulmonary infections primarily due to encapsulated organisms (e.g., Streptococcus pneumoniae). - Opportunistic Infections: Pneumocystis jirovecii pneumonia is common, often presenting with: Hypoxemia without significant fever Bilateral patchy “ground glass” opacities on chest X-ray

Clinical Features of Hyper-IgM Syndrome

Pneumocystis Diagnosis: Requires deep lung specimen; sputum tests are not sensitive, especially in infants.

Key Point: Differentiate hyper-IgM syndrome (recurrent respiratory infections) from hyper-IgE syndrome (eczema, skin abscesses, craniofacial abnormalities).

Definition: An X-linked disorder characterized by abnormal cytoskeleton function due to mutations in the WAS gene. Key Features: Impaired immune function, thrombocytopenia, and eczema.

Overview of Wiskott-Aldrich Syndrome

Cytoskeleton Role: WAS gene mutations disrupt actin cytoskeleton polymerization, essential for T-cell and platelet signaling. Consequences: Impaired T-cell function leads to increased risk of recurrent infections, while thrombocytopenia results from increased platelet destruction in the spleen.

Pathophysiology of Wiskott-Aldrich Syndrome

Infections: Recurrent infections, such as otitis media, due to impaired immune response. Thrombocytopenia: Small platelets lead to: Purpura Recurrent rectal bleeding with anemia. Eczema: Associated with a hyperallergic state; likely linked to increased IgA and IgE levels.

Clinical Manifestations of Wiskott-Aldrich Syndrome

Common Symptoms: Failure to thrive is common in primary immunodeficiencies affecting T-lymphocytes. Differential Diagnosis: Remember to differentiate between Wiskott-Aldrich syndrome (eczema, immunodeficiency, thrombocytopenia) and Hyper-IgE syndrome (eczema, recurrent infections, skin abscesses).

Key Points for Diagnosis

Definition: An autosomal recessive disorder caused by a defect in CD18, a subunit of beta-2 integrin, affecting leukocyte adhesion. Key Features: Recurrent infections, absence of pus, and high neutrophil counts.

Overview of Leukocyte Adhesion Deficiency Type 1 (LAD1)

CD18 Defect: Inability of neutrophils to migrate to infection sites due to dysfunctional adhesion molecules. Consequences: Neutrophils remain in circulation, leading to elevated counts. Inability to form pus at infection sites (pus consists of dead neutrophils).

Pathophysiology of LAD1

Infections: Recurrent bacterial infections with minimal pus formation. Delayed Cord Separation: Umbilical stump remains attached for 30 days or more due to lack of neutrophil migration. Risk of omphalitis (infection of the umbilical stump) with redness and induration.

Clinical Manifestations of LAD1

Common Misconception: Delayed cord separation is often attributed to excessive cleaning by caregivers, which

Can prevent bacterial colonization and neutrophil migration, not solely LAD1.

Definition: An immunodeficiency disorder characterized by recurrent infections, oculocutaneous albinism, and thrombocytopenia. Key Features: Recurrent pyogenic infections, skin hypopigmentation, and easy bruising.

Overview of Chediak-Higashi Syndrome (CHS)

Infections: Recurrent skin, respiratory tract, and mucous membrane infections due to immunocompromise. Oculocutaneous Albinism: Varying degrees of skin hypopigmentation, silvery-white hair, and blue eyes. Thrombocytopenia: Pancytopenia with easy bruising and mucosal bleeding.

Clinical Manifestations of CHS

Genetic Cause: Mutation in the lysosomal trafficking regulator gene (LYST). Mechanism: Abnormal LYST protein leads to impaired vesicle fusion with lysosomes. Enlarged granules in neutrophils, T-cells, and melanocytes.

Pathophysiology of CHS

- Impaired Immune Function: Giant granules in neutrophils and T-cells reduce their functionality, increasing infection risk. - Melanosome Dysfunction: Enlarged pigment-containing granules in melanocytes are not transferred to keratinocytes, resulting in albinism. - Platelet Defects: Deficient serotonin-containing granules lead to reduced platelet counts and coagulation issues.

Implications of LYST Mutation

Definition: An immunodeficiency disorder characterized by recurrent infections with catalase-positive organisms. Key Features: Increased susceptibility to infections, especially by organisms like Staphylococcus, Pseudomonas, Aspergillus, and Nocardia.

Overview of Chronic Granulomatous Disease (CGD)

Enzyme Deficiency: Caused by a deficiency in NADPH oxidase. Impact: Failure to produce reactive oxygen species (superoxide, hydrogen peroxide, hypochlorous acid) needed for killing bacteria and fungi. Results in ineffective clearance of catalase-positive organisms.

Pathophysiology of CGD

Common Infections: Pneumonia (lungs) Skin abscesses Organisms: Frequent infections with catalase-positive bacteria and fungi.

Clinical Manifestations of CGD

Neutrophil Function Testing: Dihydrorhodamine (DHR) Test: Measures the oxidative burst in neutrophils. Flow Cytometry: Detects poor fluorescence of activated phagocytes when exposed to DHR, indicating impaired respiratory burst.

Diagnosis of CGD

Definition: A form of rejection that occurs months to years after organ transplantation. Significance: Major cause of morbidity and mortality in transplanted organ recipients, particularly hearts, lungs, and kidneys.

Overview of Chronic Allograft Rejection

Mechanism: Driven by recipient T-cells (lymphocytes) that attack donor tissues. Results from mismatches in donor and recipient MHC (Major Histocompatibility Complex) molecules. Process: Gradual and progressive damage to the transplanted organ.

Pathophysiology of Chronic Rejection

Symptoms: Gradual decline in organ function. Specific symptoms depend on the transplanted organ (e.g., heart failure in cardiac transplant).

Clinical Features of Chronic Rejection

Immunosuppressive Therapy: - Used to reduce the immune response against the transplanted organ. - Common drugs include corticosteroids, calcineurin inhibitors, and antiproliferative agents. Limitations: While immunosuppressants can slow the process, they often cannot completely prevent chronic rejection.

Management of Chronic Rejection

Definition: Protein-based vaccines stimulate the immune system to produce antibodies against specific antigens. Mechanism: Protein antigens are processed by antigen-presenting cells (APCs) and presented to CD4 T-lymphocytes via MHC class II.

Overview of the Immune Response to Protein Vaccines

Function: CD4 Helper T-cells activate B-cells, leading to the production of protective antibodies. Importance: Effective communication between CD4 T-cells and B-cells is essential for mounting an immune response.

Role of CD4 T-Cells in Antibody Production

Definition: HLA (Human Leukocyte Antigen) genes encode for MHC molecules that present antigens to T-cells. Impact of HLA Genes: A defect in HLA genes can impair MHC processing, leading to a failure in T-cell activation and subsequent B-cell antibody production.

HLA Genes and Immune Response

Outcome: Lack of CD4 T-cell activation results in no antibody response to the vaccine. Clinical Implication: This can lead to increased susceptibility to infections that the vaccine was intended to prevent.

Consequences of Impaired MHC Processing

Live, attenuated virus vaccines enter human cells and replicate. Their antigens are presented to lymphocytes in the context of

MHC Class I

Definition: HLAs are proteins that constitute MHC class I and II molecules, crucial for immune system function. Genetic Basis: HLAs are encoded by HLA genes located on chromosome 6.

Overview of Human Leukocyte Antigens (HLAs)

Mechanism: HLA genes are inherited in an "en bloc" manner, meaning offspring receive complete sets of HLA genes from each parent. Parental Contribution: Each parent contributes two sets of HLA genes, resulting in four potential combinations for the offspring.

Inheritance of HLA Genes

Combinations: The possible combinations of HLA genes from parents are: F1M1 F1M2 F2M1 F2M2 Chance of Pairing: The probability that a sibling shares the same two sets of HLA genes is 25%.

Probability of HLA Gene Pairing

Father's HLA Genes: Two sets, F1 and F2. Mother's HLA Genes: Two sets, M1 and M2. Offspring Combinations: The combinations illustrate the equal likelihood of any pairing occurring.

Genetic Diagram Explanation

Definition: Each individual has two sets of HLA genes that encode for major histocompatibility complex (MHC) class I and II molecules. Inheritance: One set of HLA genes is inherited from the mother and one from the father.

HLA Genes and MHC Molecules

Probability: Siblings have a 25% chance of being HLA matched, meaning they have the same HLA antigen genes. Significance: Matched siblings have a lower rate of significant organ rejection during solid organ transplantation, but rejection is still possible.

Sibling HLA Matching

Response Mechanism: Even with a two-haplotype match (same major HLA antigens), there can still be an immune response due to differences in minor histocompatibility antigens. Implication: This necessitates the use of immunosuppression, even among matched siblings.

Minor Histocompatibility Antigens

Unique Case: When an organ is donated from an identical twin, all major and minor histocompatibility antigens are typically identical. Outcome: In this scenario, immunosuppression is generally not required.

Exception for Identical Twins

Definition: GCA, also known as temporal arteritis, is the most common form of systemic vasculitis. Risk Factors: Primarily affects patients aged 70 to 79, with a higher prevalence in females.

Giant Cell Arteritis (GCA) Overview

Symptoms: Patients typically present with: Temporal and frontal headaches Scalp tenderness Pain with chewing (jaw claudication) Constitutional symptoms (fever, fatigue, weight loss)

Clinical Presentation of GCA

Elevated Markers: Significant increases in: Erythrocyte sedimentation rate (ESR) C-reactive protein (CRP)

Laboratory Findings in GCA

Serious Risk: The most severe complication is permanent vision loss due to ophthalmic artery occlusion.

Complications of GCA

Biopsy: Diagnosis is confirmed through temporal artery biopsy. Histopathological Findings: Typical findings include: - Lymphocytes - Macrophages - Multinucleated giant cells (granulomatous inflammation) - Inflammation most pronounced in the media of the vessel wall

Diagnosis of GCA

Medication: High-dose corticosteroids are administered for a minimum of 2 to 4 weeks. Goal: Treatment aims to prevent vision loss and manage symptoms. Relapse Risk: Relapses can occur, particularly if initial treatment is insufficient.

Treatment for GCA

Definition: KD is a systemic inflammatory disease primarily affecting medium-sized arteries. Key Symptoms: Characterized by fever, conjunctivitis, rash, cervical lymphadenopathy, and mucous membrane changes.

Kawasaki Disease (KD) Overview

Symptoms Include: - Prolonged fever - Bilateral conjunctivitis - Rash (polymorphous: macular, maculopapular, or targetoid) - Cervical lymphadenopathy - Erythema of palms and soles - Mucous membrane changes (e.g., strawberry tongue)

Clinical Presentation of KD

Polymorphous Rash: The rash can present with various types of lesions, including: - Macular - Maculopapular - Targetoid Skin Desquamation: May develop as the disease progresses.

Rash Characteristics in KD

Hospital Admission: Children are typically admitted for treatment. Medications: - Intravenous immune globulin (IVIG) - Aspirin therapy Purpose of Treatment: Aimed at preventing coronary artery aneurysms, the most significant long-term complication.

Treatment for Kawasaki Disease

How IVIG and Aspirin Work: This combination is believed to: Decrease cytokine and platelet production Augment T-cell activity Reduce the risk of aneurysm formation.

Mechanism of Treatment KD

Definition: A segmental, thrombosing vasculitis primarily associated with smoking. Key Characteristics: Segmental involvement of vasculature (not all vessels) Thrombus formation leading to vessel inflammation

Thromboangiitis Obliterans (Buerger’s Disease) Overview

Non-Atherosclerotic Disorder: Ischemia results from thrombus formation in the arteries and veins of the distal extremities. Inflammatory Thrombi: Comprised of inflammatory elements (neutrophils and giant cells) that occlude blood vessels.

Pathophysiology of Buerger’s Disease

Symptoms Include: - Superficial thrombophlebitis: Painful nodules along venous distribution - Raynaud’s phenomenon: Discoloration of extremities in response to cold or stress - Digit ischemia: Reduced blood flow leading to pain or tissue damage

Clinical Presentation of Buerger’s Disease

Clinical Diagnosis: Based on: - History of smoking - Age less than 45 - Presence of digital ischemia

Diagnosis of Buerger’s Disease

Effective Therapy: Complete abstinence from tobacco is crucial. Prevention of Amputations: Smoking cessation is the only proven method to reduce the risk of severe complications.

Treatment and Management Buerger’s Disease

Patient Population: Buerger’s disease primarily affects younger patients (under 45). Comparison with Peripheral Arterial Disease (PAD): Both conditions are seen in smokers, but PAD typically occurs in older patients.

Key Points on Demographics

Definition: A large vessel vasculitis characterized by thickening of the aortic arch and its branching vessels. Key Features: - Constitutional symptoms (fever, weight loss, fatigue) - Affects primarily young women

Takayasu’s Arteritis Overview

Symptoms Include: - Carotid bruits - Decreased pulses in upper extremities - Discrepancies in blood pressure between upper and lower extremities

Clinical Presentation of Takayasu’s Arteritis

Elevated erythrocyte sedimentation rate (ESR) Elevated C-reactive protein (CRP)

Laboratory Findings of Takayasu’s Arteritis

Methods: - Combination of clinical symptoms and imaging - Angiogram shows narrowing of the aorta and large vessels

Diagnosis of Takayasu’s Arteritis

Primary Treatment: Long-term glucocorticoid therapy. Side Effects of Steroids: - Osteoporosis - Cataracts - Weight gain - Cushingoid features (moon face, buffalo hump) - Hyperlipidemia - Hyperglycemia

Treatment for Takayasu’s Arteritis

Osteoporosis Prevention: - Vitamin D and calcium supplementation - Regular monitoring of bone mineral density - Consider bisphosphonates prophylactically or if bone density declines

Management of Steroid Side Effects

Inhibition of T-cell Activity: - Binds to cyclophilin, forming a complex that inhibits calcineurin. - Calcineurin activates NFAT, promoting IL-2 production. - Decreased IL-2 synthesis inhibits T-cell activation, reducing rejection risk.

Mechanism of Action of Cyclosporin

Vasoconstriction: - Causes vasoconstriction of afferent and efferent arterioles. - Results in reduced renal blood flow and decreased glomerular filtration rate (GFR). - May lead to increased serum creatinine (nephrotoxicity).

Effects on the Renal System of Cyclosporin

Common Adverse Effects: - Hypertension - Nephrotoxicity - Gingival hyperplasia - Hirsutism - Hyperlipidemia

Side Effects of Cyclosporine

Inhibition of T-cell Activity: - Binds to FK506 binding protein, forming a complex that inhibits calcineurin. - Calcineurin activates NFAT, promoting IL-2 production. - Decreased IL-2 synthesis inhibits T-cell activation, reducing rejection risk.

Mechanism of Action of Tacrolimus

Vasoconstriction: - Causes vasoconstriction of afferent and efferent arterioles. - Leads to reduced renal blood flow and decreased glomerular filtration rate (GFR). - May result in increased serum creatinine (nephrotoxicity).

Effects on the Renal System: Tacrolimus

Nephrotoxicity: - Typically reversible with dosage reduction. - Monitor serum creatinine levels to adjust dosage as needed.

Nephrotoxicity and Dosage Adjustments: Tacrolimus

Adverse Effects: - Hypertension - Nephrotoxicity - Potentially increased risk of infections due to immunosuppression

Common Side Effects of Tacrolimus

Inhibition of IL-2 Response: - Binds to FK-binding protein, forming a complex that inhibits mTOR. - mTOR promotes cell growth in response to cytokines. - Decreases T-cell and B-cell activation by blocking IL-2 response.

Mechanism of Action of Sirolimus

Differences from Cyclosporine and Tacrolimus: - Sirolimus blocks the response to IL-2; cyclosporine and tacrolimus inhibit IL-2 synthesis. - Sirolimus is not associated with nephrotoxicity, unlike cyclosporine and tacrolimus.

Comparison with Other Immunosuppressants

Mechanism and Advantages: - Coated with sirolimus or similar drugs to inhibit inflammatory response. - Lower rates of restenosis compared to bare metal stents, which often caused re-narrowing of coronary vessels.

Drug-Eluting Stents

Use in Myocardial Infarction: - Sirolimus-eluting stents are used to treat coronary atherosclerotic narrowing during STEMI. - Enhance blood flow and reduce the risk of recurrent ischemia.

Application in STEMI Treatment

Inhibition of Dihydrofolate Reductase: - Competitively inhibits dihydrofolate reductase. - Decreases levels of tetrahydrofolate, impairing thymidine nucleotide synthesis. - Leads to impaired DNA synthesis, affecting rapidly-dividing cells.

Mechanism of Action of Methotrexate

Impact on Cell Types: - Primarily affects white blood cells, bone marrow cells, and gastrointestinal epithelial cells. - Reduces activity of lymphocytes, helping to manage inflammatory conditions (e.g., rheumatoid arthritis).

Effects on Rapidly-Dividing Cells: Methotrexate

Clinical Features of Mucositis: - Symptoms include redness, burning in the mouth, and ulcer formation. - Caused by decreased proliferation of GI epithelial cells due to methotrexate.

Mucositis as a Side Effect: Methotrexate

Bone Marrow Suppression: - Inhibition of DNA synthesis in red cell precursors leads to megaloblastic anemia. - Characterized by reduced hemoglobin and hematocrit, and increased mean corpuscular volume (MCV).

Other Toxicities of Methotrexate

Inhibition of IMP Dehydrogenase: - Inhibits inosine monophosphate (IMP) dehydrogenase. - Decreases purine synthesis, impairing DNA synthesis.

Mechanism of Action of Mycophenolate Mofetil

Effects on Lymphocytes: - Primarily inhibits DNA synthesis in B-cells and T-cells. - IMP dehydrogenase is the rate-limiting enzyme for purine synthesis only in lymphocytes.

Target Cells of Mycophenolate Mofetil

- Used as prophylaxis for transplant rejection. - Helps reduce the risk of organ rejection in transplant recipients.

Use of Mycophenolate Mofetil

Alkylating Agent: - Adds alkyl groups to DNA bases. - Causes DNA cross-linking and inhibits DNA synthesis.

Mechanism of Action of Cyclophosphamide

Use in Vasculitis: - Used for treatment of vasculitis syndromes, such as granulomatosis with polyangiitis (Wegener’s disease).

Indications for Cyclophosphamide

Hemorrhagic Cystitis (HC): - Presents as hematuria (ranging from microscopic to large blood clots). - Associated with lower urinary tract symptoms: burning with urination, urinary frequency, sensation of incomplete emptying.

Side Effects of Cyclophosphamide

Toxic Metabolite: - Caused by acrolein, a toxic metabolite of cyclophosphamide affecting the bladder.

Cause of Hemorrhagic Cystitis: Cyclophosphamide

Mesna binds to acrolein, reducing the risk of hemorrhagic cystitis.

Prevention of Hemorrhagic Cystitis: Cyclophosphamide

Cumulative Dose and Duration: - Most common in patients on continuous, daily oral therapy for extended periods with high cumulative doses.

Risk Factors for Hemorrhagic Cystitis: Cyclophosphamide

Purine Analog: - Similar chemical structure to purine bases (adenosine and guanosine). - Decreases synthesis of purines, leading to decreased DNA synthesis.

Mechanism of Action of Azathioprine

Enzyme Function: - Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) converts free purine bases into purine nucleotides. - Key in purine metabolism.

Role of HGPRT

Conversion to 6-MP: Azathioprine is converted to 6-mercaptopurine (6-MP) in the body.

Azathioprine as a Prodrug

Mechanism of Inhibition: 6-MP competes for binding with HGPRT, limiting purine nucleotide production.

Competition with HGPRT: Azathioprine

Aberrant Nucleotide: - HGPRT converts 6-MP into thioinosinic acid monophosphate. - This aberrant nucleotide can be incorporated into DNA, halting DNA synthesis.

Formation of Thioinosinic Acid Monophosphate: Azathioprine

Used as an immunosuppressant in conditions like autoimmune diseases and transplant rejection prophylaxis.

Clinical Uses of Azathioprine

Inflammatory arthritis primarily affecting the spine and sacroiliac joints

Ankylosing Spondylitis (AS) Overview

Pain in the spine and sacroiliac joints.

Clinical Features of AS

Genetic Link: - Many patients with AS carry the HLA B27 gene. - Incidence of AS is as high as 6% among HLA B27 carriers.

HLA B27 Association: Ankylosing Spondylitis

Chimeric antibody (part mouse, part human).

Infliximab Overview

Target: - Binds to tumor necrosis factor alpha (TNF-alpha). - Limits the effects of TNF-alpha, which is involved in inflammatory processes.

Mechanism of Infliximab

Route: - Administered as an intravenous infusion. Frequency: - Given at regular intervals for treatment.

Administration of Infliximab

Effective in treating various inflammatory conditions, including ankylosing spondylitis.

Indications for Infliximab

Also known as aseptic necrosis or osteonecrosis; refers to the death of bone tissue due to a lack of blood supply.

Avascular Necrosis (AVN) Overview

Common in patients with systemic lupus erythematosus (SLE), especially those on glucocorticoid therapy.

Common Causes of AVN

- Vascular damage to the blood supply of bone leads to necrosis of bone marrow elements. - Progressive joint failure typically occurs within a few years, often requiring hip replacement surgery.

Mechanism of AVN in Lupus

- Glucocorticoid therapy is linked to avascular necrosis, though the exact mechanism is unclear. - Potential mechanism: Increase in size of bone marrow adipocytes, which may obstruct venous outflow.

Glucocorticoids and AVN

AVN can lead to significant mechanical failure of the hip joint and necessitate surgical intervention.

Clinical Implications

A hypersensitivity (allergic) disorder affecting the kidneys, leading to inflammation of the renal interstitium.

Interstitial Nephritis Overview

Common Triggers: Often caused by medications (e.g., antibiotics, NSAIDs), infections, or autoimmune conditions.

Causes of Interstitial Nephritis

Symptoms: - Acute renal failure, fluid overload (dyspnea, edema, rales). - Rash consistent with hives may accompany the condition.

Clinical Presentation: Interstitial Nephritis

- White blood cell (WBC) casts: indicate nephron inflammation. - Sterile pyuria: presence of urinary WBCs without bacteria, common in interstitial nephritis.

Urinalysis Findings: Interstitial Nephritis

Urine Eosinophils: - Eosinophils may be present but are not always seen in interstitial nephritis; their presence supports the diagnosis.

Eosinophils in Urine: Interstitial Nephritis

Inflammation due to hypersensitivity reactions leads to renal dysfunction and potential damage to the nephron.

Pathophysiology: Interstitial Nephritis

A condition of decreased bone density due to long-term use of glucocorticoids, increasing the risk of fractures.

Glucocorticoid-Associated Osteoporosis Overview

Symptoms: - Generally asymptomatic until a fracture occurs. - Commonly presents with vertebral fractures, often identified incidentally via X-ray.

Clinical Presentation of Glucocorticoid-Associated Osteoporosis

DXA Testing: - Dual-energy X-ray absorptiometry (DXA) is used to assess bone density. - T-score: Compares patient’s bone density to that of a healthy 30-year-old. - A T-score of -2.5 indicates osteoporosis.

Diagnosis of Glucocorticoid-Associated Osteoporosis

Effects on Bone: - Increase bone resorption by osteoclasts. - Decrease bone formation by osteoblasts. - Alter gene expression in osteoblasts due to the presence of glucocorticoid nuclear receptors.

Mechanism of Action of Glucocorticoids in Osteoporosis

Inhibit osteoblast proliferation, leading to decreased bone formation over time.

Long-Term Effects of Glucocorticoids in Osteoporosis

Lipid Solubility: - Steroid hormones are lipid-soluble and cross cell membranes to exert effects intracellularly. - Look for alterations in DNA transcription affecting cell growth, differentiation, and protein synthesis in questions regarding steroid hormones.

Key Point on Steroid Hormones in Glucocorticoid-Associated Osteoporosis

Acute kidney injury (AKI) caused by the non-steroidal anti-inflammatory drug (NSAID) ibuprofen.

Acute Kidney Injury Due to Ibuprofen (NSAID) Use

NSAIDs inhibit cyclooxygenase (COX), decreasing prostaglandin synthesis.

Acute Kidney Injury Due to Ibuprofen (NSAID) Use: Prostaglandin Synthesis Inhibition:

Vasodilation: - Prostaglandins function as vasodilators in the kidneys. They help dilate the afferent arteriole to maintain renal perfusion, especially during conditions of low blood flow.

Role of Prostaglandins in Kidneys:

- Inhibition of prostaglandin synthesis leads to afferent arteriolar vasoconstriction. - Resulting in acute kidney injury, evidenced by rising serum creatinine levels.

Consequences of NSAID Use: Acute Kidney Injury:

Definition: Anti-inflammatory medications for asthma. Mechanism: Lipophilic; cross cell membranes and bind to cytoplasmic receptors, translocating to the nucleus.

Glucocorticoids in Asthma Treatment

Action: Modify gene transcription; inactivate pro-inflammatory transcription factor NF-kB. Effect: Decrease inflammatory cytokines (e.g., IL-1, TNF-α), suppress inflammation.

Gene Regulation and NF-kB: Glucocorticoids in Asthma

Impact: Increase synthesis of IL-10, an anti-inflammatory cytokine. Functions of IL-10: Inhibits other cytokines, antigen presentation, and activity of eosinophils/mast cells.

IL-10 and T-cells: Glucocorticoids in Asthma

Definition: Systemic inflammatory disease affecting medium-sized arteries. Symptoms: Fever, bilateral conjunctivitis, rash (polymorphous), cervical lymphadenopathy, erythema of palms/soles, mucous membrane changes (e.g., strawberry tongue).

Kawasaki Disease Overview

Types: Can be macular, maculopapular, or targetoid. Other Features: Skin desquamation may develop.

Rash Characteristics: Kawasaki Disease

Hospitalization: Required for management. Medications: Intravenous immune globulin (IVIG) and aspirin therapy. Purpose: Prevent coronary artery aneurysms; IVIG and aspirin decrease cytokine/platelet production, reducing T-cell activity and aneurysm formation.

Treatment: Kawasaki Disease

Definition: Large vessel vasculitis causing thickening of the aortic arch and its branches. Symptoms: Constitutional symptoms (fever, weight loss, fatigue), carotid bruits, decreased upper extremity pulses, blood pressure discrepancies between upper and lower extremities

Takayasu’s Arteritis Overview

Laboratory Findings: Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Imaging: Angiogram shows narrowing of the aorta and large vessels.

Takayasu’s Arteritis Diagnostic Criteria

Primary Treatment: Long-term glucocorticoid therapy. Side Effects: Osteoporosis, cataracts, weight gain, Cushingoid features, hyperlipidemia, hyperglycemia.

Takayasu’s Arteritis Treatment and Side Effects

Recommendations: Vitamin D and calcium supplementation, regular monitoring of bone mineral density. Additional Treatment: Consider bisphosphonates for prevention or if bone density decreases.

Takayasu’s Arteritis Osteoporosis Management

Definition: A form of vasculitis affecting medium-sized arteries. Symptoms: Tender skin nodules, purpura, multisystem involvement (renal failure, asymmetric peripheral neuropathy).

Polyarteritis Nodosa (PAN) Overview

Nodules: Subcutaneous and tender to the touch. Neuropathy: Asymmetric, can include motor or sensory deficits (e.g., difficulty buttoning a shirt, decreased sensation).

Polyarteritis Nodosa (PAN) Presentation

Biopsy Findings: Transmural inflammation and fibrinoid necrosis in affected tissues (often skin or nerve). Fibrinoid Necrosis: Pink fibrin deposits surrounding blood vessels observed microscopically

Polyarteritis Nodosa (PAN) Diagnosis

Common Associations: Chronic hepatitis B (up to 1/3 of cases), hepatitis C, hairy cell leukemia. Etiology: Immune complex-mediated type III hypersensitivity reaction, especially in hepatitis B.

Polyarteritis Nodosa (PAN) Associations

Treatment Options: Combination of antivirals (for hepatitis B) and either glucocorticoids or cyclophosphamide.

Polyarteritis Nodosa (PAN) Treatment

Definition: A small vessel vasculitis syndrome. Symptoms: Constitutional symptoms (fever, malaise, weight loss), upper airway involvement (sinusitis, rhinorrhea, ear ache), and lower airway symptoms (hemoptysis, cough, dyspnea).

Granulomatosis with Polyangiitis (GPA) Overview

Kidney Effects: Glomerulonephritis characterized by elevated serum creatinine, proteinuria, dysmorphic red cells, and red cell casts.

Granulomatosis with Polyangiitis (GPA) Kidney Involvement

Autoantibodies: GPA is an ANCA-mediated disorder. Common ANCAs: c-ANCA (anti-proteinase-3) is the most common in GPA; p-ANCA (anti-myeloperoxidase) is associated with Churg-Strauss syndrome and microscopic polyangiitis.

Granulomatosis with Polyangiitis (GPA) and ANCAs

Recognition: Boards may not use c-ANCA and p-ANCA terminology; be prepared to identify them by target: proteinase-3 (c-ANCA) or myeloperoxidase (p-ANCA).

Key Point on ANCAs

Context: GPA is part of pulmonary-renal syndromes, which also include eosinophilic granulomatosis with polyangiitis (EGPA) and anti-glomerular basement membrane disease (Goodpasture's syndrome). Distinguishing Features: Recognize the clinical and laboratory characteristics of these disorders.

Granulomatosis with Polyangiitis (GPA) and Pulmonary-Renal Syndromes

Definition: A small vessel vasculitis syndrome, also known as Churg-Strauss syndrome. Key Features: Eosinophilic infiltration of multiple organs, especially the lungs.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) Overview

Presentation: Asthma that is refractory to standard therapy; may be mistaken for typical asthma. Chest X-ray Findings: Pulmonary opacities and pleural effusions.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) Respiratory Symptoms

Involvement: Ear, nose, and throat; symptoms may include nasal discharge and otitis media. Skin Findings: Tender subcutaneous nodules (commonly on elbows, hands, or legs) and palpable purpura.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) ENT Symptoms

Eosinophils: Peripheral eosinophilia is a hallmark; eosinophils stain red with eosin dye. Serum IgE: Elevated serum IgE antibodies are commonly observed in EGPA.

Eosinophils and Laboratory Findings in EGPA

Related Disorders: Part of pulmonary-renal syndromes, which include granulomatosis with polyangiitis (GPA) and anti-glomerular basement membrane disease (Goodpasture's syndrome). Key Distinctions: Recognize distinguishing features among these conditions.

Context of EGPA in Pulmonary-Renal Syndromes

Definition: Autoimmune condition with autoantibodies against components of the glomerular basement membrane. Association: When kidney involvement is accompanied by pulmonary hemorrhage, it is termed Goodpasture's syndrome.

Anti-Glomerular-Basement-Membrane Disease Overview

Autoantibodies: Primarily IgG against the alpha-3 chain of type IV collagen found in glomeruli and alveoli. Type of Reaction: Example of type II hypersensitivity (autoantibodies against tissue antigens).

Goodpasture's Syndrome Mechanism

Renal Symptoms: Glomerulonephritis with increased serum creatinine, proteinuria, dysmorphic red cells, and red cell casts. Pulmonary Symptoms: Cough, dyspnea, hemoptysis due to alveolar hemorrhage.

Clinical Features of Goodpasture's Syndrome

Related Disorders: Includes granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Distinguishing Features: Key to differentiate among these conditions based on symptoms and affected areas.

Context of Goodpasture's Syndrome in Pulmonary-Renal Syndromes

Key Difference: Goodpasture's syndrome does not involve upper airway symptoms (e.g., nasal passages and sinuses) unlike GPA. Clinical Relevance: This distinguishing feature may be emphasized in exam questions.

Distinction Between Goodpasture's Syndrome and GPA (polyangiitis with granulomatosis (Wegener’s))

Definition: Autoimmune disorder causing T-cell-mediated destruction of intralobular bile ducts. Symptoms: Fatigue, pruritus, pale stools, jaundice, bilirubinuria.

Primary Biliary Cirrhosis (PBC) Overview

Key Lab Results: - Elevated transaminases - Increased total and direct bilirubin - Markedly elevated alkaline phosphatase Diagnostic Hallmark: Presence of anti-mitochondrial antibodies (AMA).

Laboratory Findings in PBC

Gold Standard: Liver biopsy reveals granulomas from T-cell attack on bile ducts.

Liver Biopsy in PBC

Common Associations: - Rheumatoid arthritis - Systemic lupus erythematosus - Sjögren’s syndrome Prevalence: Up to 65% of PBC patients exhibit symptoms of Sjögren’s syndrome.

Associated Autoimmune Disorders

Definition: Autoimmune disorder causing destruction of salivary and lacrimal glands. Primary Symptoms: Keratoconjunctivitis sicca (dry eyes) Xerostomia (dry mouth)

Sjögren’s Syndrome Overview

Ocular Symptoms: - Itching - Photophobia - “Sandy” or gritty feeling in eyes Oral Symptoms: - Halitosis - Dental caries - Difficulty chewing dry foods

Symptoms of Sjögren’s Syndrome

Common Issues: - Dry skin - Arthralgias - Raynaud’s phenomenon (discoloration of extremities)

Extraglandular Complications

Lymphocytic sialadenitis (inflammation of salivary glands) Aggregated lymphocytes, usually around ducts.

Biopsy Findings in Sjögren’s Syndrome

Initial Management: - Avoid alcohol and tobacco - Drink water - Chew sugar-free gum - Use topical fluoride - Artificial saliva for nighttime relief

Treatment for Xerostomia

Muscarinic Agonist: Pilocarpine: Increases saliva and improves dry eye symptoms Common Side Effects: - Sweating - Urinary frequency - Nausea - Diarrhea

Pharmacological Treatment

- Salivation - Lacrimation - Urination - Defecation - GI distress - Emesis

Effects of Muscarinic Agonists (SLUDGE)

- Urinary retention - Dilated pupils - Constipation - Bronchodilation

Opposite Effects (Muscarinic Antagonists like Atropine):

Key Symptoms: Keratoconjunctivitis sicca: Dry eyes, itching, photophobia, gritty sensation (worse at night). Extraglandular Complications: Xerosis (dry, scaly skin) Arthralgias Raynaud’s phenomenon

Sjogren’s Syndrome

Diagnosis: - Requires histopathologic findings (lymphocytic infiltration) or presence of autoantibodies. Specific Autoantibodies: Anti-SS-A and Anti-SS-B.

Sjogren’s Syndrome

Development of neonatal lupus in 1 to 2% of cases.

What is a potential risk for infants when anti-SS-A and anti-SS-B antibodies are present during pregnancy?

How does neonatal lupus present in affected infants?

With red, circular lesions on the face and scalp and complete heart block.

What is the risk associated with complete heart block in infants with neonatal lupus?

Fetal demise in 5 to 20% of cases.

What is limited cutaneous scleroderma, and who does it most commonly affect?

An autoimmune disorder primarily affecting women aged 30 to 50, characterized by skin thickening and systemic symptoms.

What are the symptoms associated with limited scleroderma, summarized by the CREST acronym?

C: Calcinosis (calcium deposits) R: Raynaud’s phenomena (discoloration of extremities) E: Esophageal dysmotility S: Sclerodactyly T: Telangiectasias (dilated capillaries)

What are some significant complications and associated findings in limited scleroderma?

Severe complications include pulmonary disease (pulmonary hypertension or interstitial lung disease) and positive anti-centromere antibodies. The pathophysiology involves antibody-mediated fibroblast activation leading to excess collagen deposition.

What is limited scleroderma, and what are its classic symptoms?

An autoimmune disorder affecting women aged 30 to 50, characterized by sclerodactyly, Raynaud’s phenomena, and esophageal dysmotility (part of CREST syndrome).

What are sclerodactyly and Raynaud’s phenomena?

Sclerodactyly is shiny, thickened skin with loss of wrinkles, while Raynaud’s phenomena involves discoloration of extremities in cold weather, often leading to finger ulcers.

What autoantibodies are commonly found in limited scleroderma?

Positive anti-centromere antibodies.

What are the severe complications associated with limited scleroderma?

Pulmonary disease (including pulmonary hypertension and interstitial lung disease), exertional dyspnea, right heart failure, and 5 to 15% risk of primary biliary cirrhosis.

How do complications in limited scleroderma differ from diffuse scleroderma?

Patients with limited scleroderma typically do not develop cardiac complications or renal failure.

What is malignant hypertension in the context of scleroderma?

A severe hypertension linked to worsening kidney function due to a scleroderma renal crisis.

What is scleroderma, and who does it most commonly affect?

An autoimmune disease characterized by excess collagen deposition, primarily affecting women aged 30 to 50.

What are the main symptoms of diffuse scleroderma?

Diffuse skin thickening (sclerosis), Raynaud’s phenomena, and early involvement of visceral organs (e.g., esophageal dysmotility, heartburn, interstitial lung disease, cardiac disease, arthralgias).

What is a scleroderma renal crisis?

A life-threatening complication presenting with significant hypertension, an acute rise in serum creatinine, and decreased urine output without hematuria or proteinuria.

How is scleroderma renal crisis typically treated?

A life-threatening complication presenting with significant hypertension, an acute rise in serum creatinine, and decreased urine output without hematuria or proteinuria.

What antibody is associated with diffuse scleroderma and an increased risk of renal crisis?

Anti-RNA polymerase III antibody.

How prevalent are anti-RNA polymerase III antibodies in patients with scleroderma renal crisis?

They are detected in the serum of up to 50% of patients with scleroderma renal crisis.

Definition: An autoimmune disorder affecting synovial joints. Demographics: Most commonly occurs in females aged 40 to 60. Key Symptoms: - Gradual onset of symmetric joint inflammation - Morning stiffness that improves throughout the day Commonly affected joints: Metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints

Rheumatoid Arthritis (RA)

Key Symptoms: - Ulnar deviation - Subcutaneous nodules (often on the elbow) - Popliteal (Baker’s) cysts Episcleritis (erythema and pain of the episclera) Other Systemic Findings: - Pericarditis - Pleuritis

Clinical Features of RA

Mechanism: - Inflammation of the synovium - Synovial hypertrophy - Joint erosion

Pathophysiology of RA

- Rheumatoid factor (80% of patients are positive) - Anti-citrulline peptide antibody (ACPA) - most specific for RA

Diagnostic Markers in RA

Definition: A swelling in the popliteal fossa (back of the knee) containing synovial fluid. Association: Commonly occurs in patients with rheumatoid arthritis (RA). Key Symptoms: Posterior knee pain Stiffness, worse with prolonged standing or activity

Baker's Cyst in RA

Key Issues: Rupture: Leads to swelling, erythema, and warmth of the calf Mimicking Conditions: Symptoms of rupture can mimic deep venous thrombosis (DVT)

Complications of Baker's Cyst

Key Symptoms: - Gradual onset of symmetric joint inflammation Commonly affected joints: - Metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints - Morning stiffness that improves throughout the day - Up to 35% present with subcutaneous nodules (most commonly on elbow and forearm)

Symptoms of Rheumatoid Arthritis

Mechanism: - Inflammation of the synovium (hyaluronic acid-secreting tissue) - Leads to synovial thickening, infiltration of granulation tissue - Results in erosion of cartilage and bone

Pathophysiology of RA

Definition: An autoimmune disorder characterized by synovial inflammation and hypertrophy, leading to joint erosion. Key Symptoms: - Gradual onset of symmetric joint inflammation Commonly affected joints: Metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints Morning stiffness that improves throughout the day

Chronic Rheumatoid Arthritis (RA)

Key Features: - Ulnar deviation - Swan neck deformity: Hyperextended PIP joints and flexed distal interphalangeal (DIP) joints - Scleritis: Inflammation of the sclera with severe pain during eye movement

Classic Symptoms of Long-standing RA

Elevated erythrocyte sedimentation rate (ESR): A nonspecific marker of inflammation

Inflammatory Markers in RA

Definition: A rare complication of RA characterized by a triad of RA, neutropenia, and splenomegaly. Mechanism: Unknown; usually occurs in patients with longstanding, severe RA. Complications: Chronic neutropenia increases risk of recurrent bacterial infections (most commonly respiratory and skin infections). Treatment: Disease-modifying anti-rheumatic drugs (DMARDs) like methotrexate.

Felty Syndrome

- Osteoporosis: Secondary to disease progression and chronic steroid use; increases risk of hip fractures. - Secondary Amyloidosis: May occur in RA patients. - Increased Risk of Coronary Artery Disease

Long-term Complications of RA

Definition: An autoimmune disorder characterized by synovial inflammation and hypertrophy, leading to joint erosion. Demographics: Primarily occurs in females aged 40 to 60. Risk Factors: - Cigarette smoking - Obesity - Genetic markers (HLA-DR4)

Overview of Rheumatoid Arthritis (RA)

Elevated ESR and C-reactive protein (CRP)

Symptoms of RA

Key Medications: - Nonsteroidal anti-inflammatory drugs (NSAIDs) - Glucocorticoids - Disease-modifying antirheumatic drugs (DMARDs) First choice: Methotrexate and leflunomide Note: Contraindicated during pregnancy

Treatment Options for RA

Definition: A monoclonal antibody that binds to TNF-α, reducing its activity (cytokine) Indications: Effective in decreasing inflammation in RA and Crohn’s disease. Side Effects: - Serious bacterial infections - Reactivation of latent tuberculosis

Infliximab in RA Treatment

Complications: - Pericarditis - Pleuritis - Ocular involvement (scleritis and uveitis)

Overview of New Onset Rheumatoid Arthritis (RA)

Key Findings: Elevated inflammatory markers: - Erythrocyte sedimentation rate (ESR) - C-reactive protein (CRP) Rheumatoid factor (RF) positivity: 80% of patients Most specific marker: Anti-citrulline peptide antibody (ACPA)

Laboratory Findings in RA

Definition: A disease-modifying antirheumatic drug (DMARD). Mechanism of Action: Inhibits uridine monophosphate synthesis by blocking the conversion of dihydroorotic acid to orotic acid. Common Side Effects: - Diarrhea: Reported in up to 33% of patients Note: Most commonly transient, acute diarrhea in the first weeks of treatment Usually resolves spontaneously, but may require dose adjustment

Leflunomide in RA Treatment

Definition: A multisystem autoimmune disorder. Key Clinical Features: - Arthritis - Skin rash (classically a malar rash) Autoantibodies: - Antinuclear antibodies (ANA) - Anti-double stranded DNA (anti-dsDNA) antibodies

Overview of Systemic Lupus Erythematosus (SLE)

Mechanism: - Self-reactive lymphocytes produce antibodies to host nuclear antigens. - Loss of tolerance: Immune cells fail to tolerate self-antigens, leading to an immune response. - Formation of immune complexes: Autoantibodies bind to circulating host antigens, creating antibody-antigen complexes.

Pathophysiology of SLE

SLE is a classic example of type III hypersensitivity mediated by antigen-antibody complexes. - Immune complexes deposit in tissues throughout the body, contributing to the disease's multisystem effects.

Hypersensitivity in SLE

Constitutional symptoms: Headache, fever - Arthritis and arthralgias Skin lesions: Classically a malar rash (acute cutaneous lupus) Renal disease: May include glomerulonephritis with red blood cell casts

Systemic Lupus Erythematosus (SLE)

Mechanism: - Clinical manifestations are mediated by antinuclear antibody formation and circulating immune complexes. Immune complexes can deposit in various tissues, leading to inflammation and damage.

Pathophysiology of SLE

Diagnosis Requirement: At least 4 of the 11 criteria from the American College of Rheumatology (ACR) and the Systemic Lupus International Collaborating Clinics (SLICC). Criteria Described in this Case: - Arthritis/synovitis - Malar rash (acute cutaneous lupus) - Glomerulonephritis Next Step: Testing for a fourth criterion is indicated for diagnosis.

Diagnosis Criteria for SLE

Specific Antibodies Associated with SLE: - Anti-double-stranded DNA (anti-dsDNA) Highly specific for SLE Sensitive: Present in 50-70% of SLE patients - Anti-Smith antibodies (anti-Sm) Highly specific for SLE but not sensitive

Antinuclear Antibodies in SLE

Most Appropriate Test: - Testing for anti-dsDNA is preferred because it is both sensitive and specific for SLE, fulfilling a fourth criterion for diagnosis.

Recommended Testing for SLE Diagnosis

Definition: A form of non-bacterial thrombotic endocarditis (NBTE) characterized by deposition of sterile platelet thrombi. Common Populations Affected: - Patients with advanced malignancy - Patients with systemic lupus erythematosus (SLE)

Overview of Libman-Sacks Endocarditis

- Untreated patients may develop valve deformity and mitral valve regurgitation. Presentation of Mitral Valve Regurgitation: - Classically presents with a holosystolic murmur at the apex. - Symptoms of severe mitral regurgitation can include fatigue and shortness of breath, indicative of left heart failure.

Complications of Libman-Sacks Endocarditis

Lesion Composition: - Platelet thrombi - Strands of fibrin - Immune complexes - Mononuclear cells

Biopsy Findings in NBTE

Trigger for Lesion Formation: Unknown, but endothelial injury in a hypercoagulable state appears to be required for the development of lesions.

Pathogenesis of Libman-Sacks Endocarditis

Definition: A syndrome triggered by medication, resembling systemic lupus erythematosus (SLE). Commonly Associated Drugs: - Procainamide - Hydralazine - Isoniazid

Overview of Drug-Induced Lupus

Key Symptoms: - Fever - Arthritis Symptoms similar to SLE Differences from SLE: Low blood cell counts, skin rashes, and kidney disease are uncommon in drug-induced lupus.

Clinical Features of Drug-Induced Lupus

Key Antibodies: Anti-histone antibodies present in >95% of patients with drug-induced lupus. Diagnostic Criteria: Currently, there are no standard diagnostic criteria for drug-induced lupus.

Laboratory Findings in Drug-Induced Lupus

Initial Approach: - Stop the offending medication. - Provide supportive treatment until symptoms resolve.

Treatment for Drug-Induced Lupus

Definition: An immune-mediated disease caused by the passage of maternal antibodies to the fetus. Common Manifestations: - Skin rash - Cardiac abnormalities

Overview of Neonatal Lupus

Key Issues: - May include 1st, 2nd, or 3rd degree heart block. EKG findings in 3rd degree heart block: - Bradycardia - No relationship between P waves and QRS complexes - Treatment for heart block often requires a permanent pacemaker.

Cardiac Manifestations of Neonatal Lupus

Key Antibodies Implicated: - Anti-Ro antibodies (anti-SSA) - Anti-La antibodies (anti-SSB) Association: Mothers are more likely to have these antibodies if they have an autoimmune condition such as: - Systemic lupus erythematosus - Sjögren syndrome - Rheumatoid arthritis

Maternal Antibodies in Neonatal Lupus

Also called aseptic necrosis or osteonecrosis, it refers to the death of bone tissue due to a lack of blood supply. Common Cause: Vascular damage leading to necrosis of bone marrow elements, especially in patients with lupus who take steroids.

Avascular Necrosis

Damage to the blood supply of the femoral head leads to necrosis and mechanical failure of the hip joint. - The process is progressive; joint failure typically occurs within a few years, often necessitating hip replacement surgery.

Pathophysiology of Avascular Necrosis

Potential Mechanism: - The link between glucocorticoids and avascular necrosis is unclear but may involve: Increases in bone marrow adipocyte size, blocking venous outflow.

Association with Glucocorticoids: avascular necrosis

Definition: Osteonecrosis is a general term for necrosis of bone. Known Causes: - Some cases have an obvious cause of ischemic damage (e.g., femoral neck fracture). - In many cases, the exact cause is unknown, but they are often associated with lupus or glucocorticoid therapy.

General Terms and Causes of Osteonecrosis

A hypersensitivity (allergic) disorder of the kidneys leading to inflammation. Key Result: Inflammation can cause acute renal failure and fluid overload symptoms (e.g., dyspnea, edema, rales).

Overview of Interstitial Nephritis

Key Indicators: - White Blood Cell (WBC) Casts: Indicate nephron inflammation. - Sterile Pyuria: Presence of urinary WBCs without bacteria, a classic finding in interstitial nephritis. - Urine Eosinophils: Another classic finding but may not always be present.

Laboratory Findings in Interstitial Nephritis

Associated Symptoms: - Rash consistent with hives, which can occur with antibiotic-induced interstitial nephritis. - Other symptoms related to fluid overload due to renal failure.

Clinical Features of Interstitial Nephritis

Cause: Acute kidney injury in this patient is caused by the non-steroidal anti-inflammatory drug (NSAID) ibuprofen.

Overview of Acute Kidney Injury (AKI)

NSAIDs inhibit the synthesis of prostaglandins by blocking the enzyme cyclooxygenase (COX). Prostaglandins are lipid molecules that function as vasodilators in the kidneys.

Mechanism of Action of NSAIDs

Prostaglandins dilate the afferent arteriole to maintain renal perfusion, especially under conditions of poor renal perfusion.

Role of Prostaglandins in Renal Function

This patient has poor renal perfusion due to heart failure and treatment with diuretics (spironolactone and furosemide). The kidneys rely on prostaglandins to maintain perfusion in such conditions.

Impact of Heart Failure and Diuretics on Renal Perfusion

Result of NSAID Use: Inhibition of prostaglandin synthesis by ibuprofen leads to afferent arteriolar vasoconstriction, resulting in acute kidney injury (evidenced by rising serum creatinine levels).

Consequence of Prostaglandin Inhibition

Definition: Glucocorticoids are steroid hormones with anti-inflammatory effects beneficial for patients with asthma.

Overview of Glucocorticoids

Key Mechanism: - Glucocorticoids are lipophilic and can cross cell membranes. - They bind to a cytoplasmic receptor that translocates to the nucleus, modifying gene transcription.

Mechanism of Action of Glucocorticoids

Key Action: - Glucocorticoids inactivate pro-inflammatory transcription factors, notably nuclear factor-kappa B (NF-kB). NF-kB increases the expression of inflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor α (TNF-α).

Inactivation of Pro-inflammatory Factors

Result of NF-kB Inactivation: By inactivating NF-kB, glucocorticoids suppress inflammation in asthma.

Anti-inflammatory Effects of Glucocorticoids

Glucocorticoids increase the synthesis of interleukin 10 (IL-10), an anti-inflammatory cytokine. Role of IL-10: - Inhibits production of other cytokines - Reduces antigen presentation Impairs function of eosinophils and mast cells

Glucocorticoids and IL-10 Synthesis

INMUNO: BOARDS AND BEYOND Flashcards

(538 cards)