Immune, Biochem & physio Flashcards
(30 cards)
VLDL Metabolism
VLDL is synthesized in the liver from triglycerides, cholesterol, and apolipoproteins.
2. Lipolysis:
VLDL travels in the bloodstream and encounters lipoprotein lipase (LPL) in muscle and adipose tissue. LPL hydrolyzes triglycerides from VLDL, releasing fatty acids for energy and converting VLDL into smaller IDL particles.
3. IDL Fate:
IDL can be taken up by the liver, particularly through the LDL receptor, or further metabolized by hepatic lipase into LDL.
4. IDL Remnants:
VLDL remnants are cholesterol-rich and triglyceride-poor particles that can be further catabolized to LDL under the action of hepatic lipase and LPL.
LDL Metabolism
Formation: LDL is formed from VLDL remnants via the action of hepatic lipase.
Receptor-Mediated Uptake: LDL is taken up by various tissues, including the liver, through the LDL receptor.
Intracellular Metabolism: In peripheral tissues, LDL is used for various functions, including hormone production, cell membrane synthesis, and storage.
Liver Clearance: Excess LDL is also absorbed by the liver via the LDL receptor.
Scavenger Pathway: Damaged LDL can be recognized by scavenger receptors on macrophages, leading to their uptake and potential accumulation as foam cells, contributing to plaque formation.
One Brain, Two Kidneys, Liver, and Pancreas (B-cells), Three Brain and Placenta, Four Muscle and Adipose.” This relates each GLUT transporter to its primary locations in the body: GLUT1 (brain, erythrocytes, placenta), GLUT2 (liver, kidneys, pancreas), GLUT3 (brain, placenta), and GLUT4 (muscle, adipose tissue).
P53 action
p53 acts as a “guardian of the genome,” ensuring that cells with damaged DNA do not progress into S phase for replication. In the G1/S checkpoint, p53 triggers cell cycle arrest, allowing time for DNA repair, or if damage is too severe, apoptosis
Porphyria cutanea tarda (PCT)
a common, manageable porphyria characterized by skin fragility, blistering, and photosensitivity, primarily on sun-exposed areas like the hands. It’s caused by a deficiency of the enzyme uroporphyrinogen decarboxylase (UROD), leading to a buildup of porphyrins in the body.
Dark Urine, Hyperpigmentation, Hypertrichosis
Acute intermittent porphyria (AIP)
rare, inherited metabolic disorder characterized by a partial deficiency of the enzyme porphobilinogen deaminase (PBGD). This deficiency leads to a buildup of porphyrin precursors in the liver, which can trigger symptoms like severe abdominal pain, neurological issues, and psychiatric disturbances.
Lead poisoning
an mimic some symptoms of porphyria, a group of disorders related to heme production, due to its interference with heme synthesis. However, lead poisoning primarily affects a specific enzyme in heme synthesis, ALA dehydratase, leading to an increase in ALA levels without a corresponding increase in porphobilinogen (PBG), unlike acute porphyria.
Achalasia
presents with difficulty swallowing (dysphagia) for both solids and liquids, regurgitation, chest pain, and weight loss. Symptoms often progress gradually over months or years, with some individuals experiencing mild, manageable symptoms initially.
The insulin receptor
transmembrane protein primarily located on the surface of cells, specifically in the plasma membrane. It’s found in tissues like the liver, skeletal muscle, and fat. The receptor’s structure is a dimer, made up of two subunits: the α-subunit, which binds to insulin, and the β-subunit, which contains the tyrosine kinase domain.
Types of Hernias
Inguinal Hernia: The most common type, found in the groin area. It can be indirect (enters the inguinal canal) or direct (pushes through a weakened spot in the abdominal wall).
Femoral Hernia: Occurs in the groin, but below and lateral to the pubic tubercle, as opposed to inguinal hernias which are located above and medial to the pubic tubercle.
Umbilical Hernia: A bulge at the belly button, often seen in infants and can also occur in adults.
Incisional Hernia: A bulge at the site of a previous surgical incision.
Epigastric Hernia: A bulge above the belly button and below the breastbone
Ghrelin’s Role
Ghrelin is a peptide hormone that acts as a signal to the brain, telling it that the body needs food. It increases appetite, promotes fat storage, and can also influence other functions like sleep-wake cycles and glucose metabolism
hunger hormone
Cryoglobulinemia
a condition where abnormal proteins in the blood, called cryoglobulins, clump together at lower temperatures, potentially causing vasculitis and other symptoms.
Type I: Typically associated with cancers of the blood or immune system.
Type II and III (Mixed Cryoglobulinemia): Often seen in people with chronic inflammatory conditions like hepatitis C or autoimmune diseases. which involve immune complexes containing polyclonal immunoglobulins (IgG) and monoclonal or polyclonal IgM with rheumatoid factor (RF) activity
Type II:
Contains monoclonal IgM (or IgG/IgA) with RF activity + polyclonal IgG.
Strongly linked to HCV infection (60-90% of cases)
Also associated with lymphoproliferative disorders (e.g., MALT lymphoma) and autoimmune diseases (e.g., Sjögren’s syndrome, lupus)
Type III:
Contains polyclonal IgM + polyclonal IgG.
Often seen in autoimmune diseases (e.g., rheumatoid arthritis, SLE) and chronic infections (HCV, HBV, HIV) 1
- Causes & Risk Factors
HCV infection (most common cause, ~80% of mixed cases)
Other infections: HBV, HIV, EBV, bacterial endocarditis
Autoimmune diseases: Sjögren’s syndrome, lupus, rheumatoid arthritis
Lymphoproliferative disorders (e.g., B-cell lymphomas)
Female predominance (3:1 ratio), typically affects ages 45-60 - Symptoms & Clinical Manifestations
Classic triad (Meltzer’s triad): Purpura, arthralgia, weakness (seen in ~30% of cases)
Skin:
Palpable purpura (most common, lower extremities).
Raynaud’s phenomenon, ulcers, livedo reticularis
Kidneys:
Membranoproliferative glomerulonephritis (MPGN) (proteinuria, hematuria, renal failure)
Neurologic:
Peripheral neuropathy (sensory > motor)
Joints:
Arthralgia (non-erosive, symmetric)
Liver:
Hepatomegaly, cirrhosis (if HCV-related)
- Diagnosis
Cryoglobulin test (must be collected/preprocessed at 37°C to avoid false negatives)
Lab findings:
Low C4 complement (more than C3)
Elevated rheumatoid factor (RF) (90% of cases)
HCV antibody/PCR (if infection suspected)
Biopsy:
Leukocytoclastic vasculitis (skin/kidney biopsy)
Renal biopsy: Shows subendothelial deposits, MPGN pattern - Treatment
HCV-associated:
Direct-acting antivirals (DAAs, e.g., sofosbuvir/ledipasvir) → resolves cryoglobulinemia in ~50% of cases
Immunosuppressive therapy (severe cases):
Rituximab (anti-CD20, first-line for vasculitis)
Corticosteroids (pulse methylprednisolone for acute flares)
Plasmapheresis (for life-threatening hyperviscosity or renal failure)
Autoimmune/Lymphoma-associated:
Treat underlying condition (e.g., rituximab + chemotherapy for lymphoma) - Prognosis
Good if HCV is treated early (~70% remission with DAAs)
Poor if renal failure, severe vasculitis, or lymphoma develops
Arthus reaction and serum sickness
both type III hypersensitivity reactions caused by immune complexes, but they differ in their location and timing.
Arthus reaction is a localized reaction that typically occurs within 24 hours of exposure, often at the injection site of a vaccine.
Serum sickness, on the other hand, is a systemic reaction that usually appears 6-15 days after exposure to a foreign protein, and can affect multiple organs and systems.
A biphasic anaphylactic reaction
Biphasic anaphylaxis is characterized by a recurrence of anaphylactic symptoms after an initial resolution period, without re-exposure to the trigger. It’s essentially a “two-part” reaction, with a second wave of symptoms appearing after the initial symptoms have subsided.
IgA Deficiency
IgA deficiency (also called selective IgA deficiency or SIgAD) is characterized by low or absent IgA levels in the blood and secretions, but normal levels of IgG and IgM.
Neutrophils- Most abundant white blood cell (WBC); phagocytoses bacteria, releases NETs (neutrophil extracellular traps).
Macrophages -Phagocytosis, cytokine release (TNF-α, IL-1, IL-6), antigen presentation.
Dendritic Cells- Bridge innate & adaptive immunity; present antigens to T-cells.
Natural Killer (NK)- Cells Kill virus-infected & cancerous cells (release perforin & granzymes).
Mast Cells = Release histamine (allergies, anaphylaxis).
Eosinophils = Attack parasites; contribute to allergies.
Basophils = Release heparin & histamine (inflammatory response).
- Combined Immunodeficiencies (CIDs): These disorders affect both the T-cell and B-cell immune systems, resulting in impaired adaptive immunity. Examples include Severe Combined Immunodeficiency (SCID) and Wiskott-Aldrich Syndrome.
- Predominantly Antibody Deficiencies: These PIDs primarily affect the humoral immune response, leading to reduced levels or impaired function of antibodies. Examples include Common Variable Immunodeficiency (CVID) and X-linked agammaglobulinemia.
- Phagocyte Defects: These PIDs involve defects in phagocytes, which are white blood cells responsible for engulfing and destroying pathogens. Examples include Chronic Granulomatous Disease (CGD) and Leukocyte Adhesion Deficiency (LAD).
- Complement Deficiencies: The complement system is a crucial part of innate immunity, and these PIDs involve defects in complement proteins. Examples include deficiencies in early or late complement pathway components.
- Diseases of Immune Dysregulation: These PIDs involve abnormalities in the regulation of immune responses, leading to conditions like autoimmune diseases. Examples include Autoimmune Lymphoproliferative Syndrome (ALPS) and Hyper-IgE Syndromes (HIES).
vessel vasculitis
Large-vessel vasculitis
Takayasu arteritis
Giant cell arteritis
Medium-vessel vasculitis
Polyarteritis nodosa
Kawasaki disease
Small-vessel vasculitis
ANCA-associated vasculitis (granulomatosis with polyangiitis [formerly known as Wegener’s granulomatosis], microscopic polyangiitis, EGPA [Churg-Strauss syndrome])
Immune complex vasculitis
Anti-glomerular basement membrane disease
Cryoglobulinaemic vasculitis
IgA vasculitis (Henoch-Schonlein)
Hypocomplementaemic urticarial vasculitis (anti-C1q vasculitis)
Variable vessel vasculitis
Behcet’s disease
Cogan’s syndrome
Systemic Lupus Erythematosus (SLE)
A. Immune Dysregulation
Loss of self-tolerance: Autoantibodies target nuclear and cytoplasmic antigens (e.g., dsDNA, histones) due to defective apoptosis clearance and aberrant immune activation
Type I interferon (IFN) pathway: Overactivation of plasmacytoid dendritic cells (pDCs) drives IFN-α production, promoting autoimmunity
B-cell hyperactivity: Autoreactive B-cells produce pathogenic autoantibodies (e.g., anti-dsDNA), forming immune complexes that deposit in tissues (kidneys, skin, joints)
B. Genetic & Environmental Triggers
Genetics: HLA-DRB1, IRF5, STAT4 polymorphisms increase risk. Complement deficiencies (C1q, C4) are strongly linked
Hormonal: Estrogen enhances B-cell activation (female predominance, 9:1 ratio)
Environmental: UV light, infections (EBV), smoking, and drugs (e.g., hydralazine) trigger flares
C. Tissue Damage Mechanisms
Immune complex deposition: Activates complement (↓C3/C4), causing inflammation (e.g., glomerulonephritis, vasculitis)
Direct antibody effects: Anti-dsDNA cross-reacts with renal antigens, while anti-Ro/SSA disrupts cardiac conduction in neonatal lupus
- Diagnosis of SLE
A. Clinical Criteria (ACR/EULAR 2019)
Entry criterion: Positive ANA (≥1:80 titer).
Weighted criteria (≥10 points required):
Clinical domains:
Mucocutaneous (malar rash, discoid lupus, oral ulcers).
Arthritis (synovitis in ≥2 joints).
Renal (proteinuria >0.5 g/day or biopsy-proven nephritis).
Neurologic (seizures, psychosis).
Hematologic (leukopenia, thrombocytopenia, hemolytic anemia).
Immunologic domains:
Anti-dsDNA, anti-Smith (Sm), antiphospholipid antibodies.
Low complement (C3/C4).
Antibody Prevalence in SLE Clinical Significance
ANA ~98% Screening test; low specificity
Anti-dsDNA 30–60% Correlates with nephritis, disease activity
Anti-Sm 20–30% Pathognomonic for SLE
Anti-Ro/SSA 30–40% Neonatal lupus, Sjögren’s overlap
Anti-La/SSB 10–15% Often co-occurs with anti-Ro
Antiphospholipid (aPL) 30–40% Thrombosis, recurrent pregnancy loss
Anti-histone 50–80% Drug-induced lupus (e.g., procainamide)
ANA-negative SLE: Rare (<2%); test for anti-Ro/SSA or anti-phospholipid antibodies
Disease monitoring: Rising anti-dsDNA + low C3/C4 often predict flares
Treatment implications:
Hydroxychloroquine (HCQ) reduces flares and mortality
Biologics (belimumab, anifrolumab) target IFN/B-cell pathways
Post-Streptococcal Glomerulonephritis (PSGN)
Post-streptococcal glomerulonephritis (PSGN) is an immune-mediated kidney disease that occurs 1–3 weeks after a group A streptococcal (GAS) infection (e.g., pharyngitis or impetigo). It is the most common cause of acute nephritic syndrome in children.
Pathophysiology
Trigger: Nephritogenic strains of Streptococcus pyogenes (e.g., M-types 1, 12, 49).
Immune complex deposition:
Anti-streptococcal antibodies bind to bacterial antigens (e.g., NSAP or SPE-B) → form immune complexes that deposit in glomeruli.
Complement activation (↓C3, normal C4) → inflammation → proliferative glomerulonephritis.
Histopathology:
Light microscopy: Diffuse endocapillary proliferation (hypercellular glomeruli).
Immunofluorescence: “Lumpy-bumpy” granular deposits (IgG, C3).
Electron microscopy: Subepithelial humps (characteristic of PSGN).
- Clinical Features
Classic triad:
Hematuria (cola-colored urine).
Edema (periorbital, dependent).
Hypertension (due to fluid overload).
Other symptoms:
Oliguria (reduced urine output).
Fatigue, malaise.
Mild proteinuria (usually <3 g/day).
- Diagnosis
A. Laboratory Findings
Test Findings
Urinalysis Hematuria, RBC casts, mild proteinuria
Serum C3 Low (returns to normal in 6–8 weeks)
ASO titer Elevated (if prior pharyngitis)
Anti-DNase B Elevated (if prior skin infection)
Renal function ↑Creatinine (if severe)
B. Kidney Biopsy (if atypical presentation)
Indications:
No evidence of prior streptococcal infection.
Severe renal dysfunction (creatinine rapidly rising).
Persistent low C3 beyond 8 weeks (consider MPGN or lupus nephritis). - Management
Supportive care:
Primary Immunodeficiency (PID) Categories
- Combined Immunodeficiencies (T-cell & B-cell defects)
Severe Combined Immunodeficiency (SCID)
Cause: Defects in IL2RG, ADA, RAG1/2 genes.
Features: Recurrent infections (viral, fungal, bacterial), failure to thrive, absent thymus on CXR.
Omenn Syndrome (Partial RAG deficiency)
Erythroderma, eosinophilia, lymphadenopathy. - Antibody Deficiencies (B-cell defects)
X-linked Agammaglobulinemia (Bruton’s disease)
Cause: BTK gene mutation → absent B cells.
Features: Recurrent sinopulmonary infections (after 6 months when maternal IgG declines).
Common Variable Immunodeficiency (CVID)
Cause: Unknown (heterogeneous).
Features: Low IgG/IgA, recurrent infections, autoimmune diseases (ITP, SLE), lymphoma risk. - Phagocytic Cell Defects
Chronic Granulomatous Disease (CGD)
Cause: Defective NADPH oxidase (CYBB, NCF1 genes).
Features: Recurrent Staphylococcus, Aspergillus infections, granulomas.
Leukocyte Adhesion Deficiency (LAD)
Cause: Defective integrins (CD18).
Features: Delayed umbilical cord separation, severe periodontitis. - Immune Dysregulation Disorders
IPEX Syndrome (FOXP3 mutation)
Triad: Autoimmune enteropathy, endocrinopathy (DM), dermatitis.
Familial Hemophagocytic Lymphohistiocytosis (HLH)
Cause: Defective cytotoxic T/NK cells (PRF1, UNC13D).
Features: Fever, hepatosplenomegaly, cytopenias, hyperferritinemia. - Complement Deficiencies
C1-C4 Deficiencies → Lupus-like syndrome, Neisseria infections.
C5-C9 Deficiencies → Recurrent Neisseria meningitidis infections. - Autoinflammatory Disorders
Familial Mediterranean Fever (FMF) (MEFV gene)
Features: Periodic fever, serositis (peritonitis, pleuritis).
Cryopyrin-Associated Periodic Syndromes (CAPS)
Features: Urticaria-like rash, sensorineural hearing loss. - Defects in Intrinsic & Innate Immunity
Mendelian Susceptibility to Mycobacterial Disease (MSMD)
Cause: IFNGR1/2, IL12RB1 mutations.
Features: Severe TB/non-TB mycobacterial infections. - Bone Marrow Failure Syndromes
Dyskeratosis Congenita (Telomere defect)
Triad: Nail dystrophy, leukoplakia, bone marrow failure. - Phenocopies of PID (Somatic Mutations)
Autoimmune Lymphoproliferative Syndrome (ALPS)
Features: Lymphadenopathy, splenomegaly, double-negative T cells (TCRαβ+ CD4– CD8–). - Other Well-Defined PIDs
Wiskott-Aldrich Syndrome (WAS gene)
Triad: Thrombocytopenia, eczema, recurrent infections.
Ataxia-Telangiectasia (ATM gene)
Features: Cerebellar ataxia, telangiectasias, lymphoma risk.
Diagnostic Approach
Clinical Clues:
Recurrent sinopulmonary infections → Antibody deficiency.
Persistent fungal/viral infections → T-cell defect.
Granulomas + Aspergillus infections → CGD.
Lab Workup:
CBC (lymphopenia, neutropenia).
Immunoglobulins (IgG, IgA, IgM).
Flow cytometry (T/B/NK cell counts).
Genetic testing (definitive diagnosis).
Treatment
Antibody deficiency → IVIG/SCIG.
SCID → HSCT (curative).
CGD → Prophylactic antifungals (itraconazole), IFN-γ.
Combined Immunodeficiencies (CIDs)
Hallmark: Absent or dysfunctional T cells ± B/NK cell defects.
Clinical Presentation:
Early-onset infections (oral thrush, Pneumocystis jirovecii pneumonia, CMV).
Failure to thrive, chronic diarrhea.
Graft-versus-host disease (GVHD) from maternal T cells or transfusions.
B. Leaky SCID & Atypical SCID
Partial T-cell function (milder than classic SCID but still life-threatening).
Disorder Genetic Defect Key Features
Cartilage-Hair Hypoplasia RMRP Short-limbed dwarfism, sparse hair, Hirschsprung disease
MHC Class II Deficiency CIITA, RFX5 CD4+ lymphopenia, recurrent viral/bacterial infections
Clinical Presentation
Infections:
Viral (CMV, EBV, adenovirus).
Fungal (Candida, Pneumocystis).
Bacterial (pyogenic organisms).
Autoimmunity: Cytopenias, enteropathy.
Malignancy: Lymphoma (especially in DNA repair defects like ATM).
Advanced Testing
Genetic sequencing (targeted panels or whole exome).
Thymic imaging (absent thymus in SCID).
Enzyme assays (e.g., ADA activity).
- Management
A. Urgent Interventions
Isolation (protective environment).
Avoid live vaccines and non-irradiated blood products.
PCP prophylaxis (trimethoprim-sulfamethoxazole).
IVIG replacement (if hypogammaglobulinemia).
B. Definitive Therapy
HSCT (Hematopoietic Stem Cell Transplant): Curative for SCID (best outcomes if done <3.5 months).
Gene therapy: Approved for ADA-SCID and IL2RG-SCID.
Enzyme replacement: PEG-ADA for ADA-SCID.
- Prognosis
Untreated SCID: Fatal within first year.
Post-HSCT survival: >90% if transplanted early (without active infection).
Syndromic CIDs (e.g., Ataxia-Telangiectasia): Manage complications (cancer surveillance).
Summary Table: Key CIDs
