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Flashcards in Innate Autoimmune Diseases Deck (41)
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What is neutropenia, and what are the three most common types? Describe them.

Disorders characterized by low numbers of granulocytes, usually defined as neutrophil count of less than 500 cells/ul (normal is more than 2,000)

1. Severe congenital neutropenia (Kostmann syndrome): autosomal recessive disorder associated w/gene abnormality of granulocyte colony stimulating factor (G-CSF) or its receptor (G-CSFR) -> susceptible to bacterial and fungal infections, incl normal flora

2. Cyclic neutropenia: autosomal dominant disorder in which neutropenia occurs every 2 to 4 weeks and lasts about 1 week (associated with gene defect termed ELA-2; gene that encodes elastase, a serine protease)

3. Benign chronic neutropenia: low, but not life-threatening neutropenia, and often asymptomatic


What is the primary effect of C1, C2, C4 deficiency? Why?

- Immune complex disease - Small immune complexes created by Ab binding to its antigen is usually further opsonized by activation of the classical cascade, promoting their uptake and destruction


Describe paroxysmal nocturnal hemoglobinuria, and its treatment.

- Rare, acquired, potentially life-threatening disease characterized by complement-induced intravascular hemolytic anemia, red urine (due to hemoglobin in urine), and thrombosis

- Results from genetic deficiency of glycophosphatidylinositol, required for surface expression of CD59 and DAF

- TX: allogeneic bone marrow transplantation the only curative therapy, although complement component C5-specific monoclonal Ab (eculizumab or Solaris) is effective at reducing need for blood transfusions, improving QOL and reducing risk of thrombosis


You order a dihydrorhodamine flow cytometry test on a 4 y/o patient that has a history of repeated fungal and bacterial infections. The test is negative for break down of dihydrorhodamine. Based on this finding, what would be your presumptive diagnosis?



How do you dx NK cell deficiency?

Difficult, but flow cytometry for NK cells and NK T cells helps


How would you diagnose and treat Chediak-Higashi syndrome?

- Diagnosis: genetic testing and appearance of neutrophils (poorly organized and larger than normal, azurophilic granules)

- Treatment: pts that don't receive bone marrow transplant typically develop fatal lymphoma-like proliferative disease and die young


A 3 y/o patient with a history of bacterial infections is being evaluated for inherited genetic defects. His history is significant for delayed umbilical cord sloughing. What defect do you suspect?



Your young patient suffers from repeated staphylococcal and streptococcal infections and neurological difficulties. He also suffers from partial albinism. Genetic testing will reveal a genetic defect of what?



What is asplenia? How does it affect susceptibility? What clinical interventions are available?

- Inherited disorder (genes affected not identified): pts have elevated susceptibility to encapsulated bacterial pathogens (Strep pneumo, Neisseria, H influenzae) - Esp. susceptible to septic infections with these pathogens b/c spleen is one of blood filters (w/liver) and splenic macros take up complement or Ab opsonized bacteria in blood - Acquired asplenia (splenectomy after trauma) leads to similar susceptibility, esp. w/young patients - Clinical intervention: 1) vaccination for encapsulated bac recommended, 2) prophylactic AB tx recommended prior to dental procedures, and on showing symptoms of respiratory infection or fever


What immunodeficiency is associated with NEMO? What is the tx?

- Immunodeficiency: recurrent bacterial and viral infection (mycobacterium avium is common opportunistic pathogen) due to lack of expression of cytokines/chemokines - Treatment: biweekly injections of gamma globulin from healthy donor or bone marrow transplant; stem cell transplant (from umbilical cord) has also shown promise


What are the 3 categories of NK cell deficiency?

1. Absolute (ANKD): complete absence of NK cells (and NKT cells) or total lack of NK cell function 2. Classical (CNKD): lack NK cells and NK cell function - distinguished from ANKD by presence of NKT cells 3. Functional (FNKD): (near) normal NK cell #'s but absent or severely decreased NK cell function; usually have NKT cells, but not a requirement for dx


Your 2 y/o patient has a history of relatively severe bacterial and fungal infections. Clinical studies that he has normal concentrations of IgA, IgG, and IgM in his serum and normal T cell numbers in peripheral blood. Additional history is unremarkable except that he experienced delayed separation of his umbilical cord. What deficiency do you expect?



Describe leukocyte adhesion deficiency, and its impact on susceptibility.

- Genetic deficiency of functional CD18 (an integrin adhesion molecule normally expressed by phagocytes; component of LFA-1) - Without this integrin, phagocyte migration to inflamed tissues defective, and pt is susceptible to EC pathogens (both bacterial and fungal), esp. encapsulated bacteria - Characteristic delayed sloughing of umbilical cord


Your 14 y/o patient has contracted a cutaneous infection with a gram positive extracellular bacterium that is considered an emerging pathogen. Although this bug is understudied, it has been determined that this bug produces and secretes Dnases. This virulence factor interferes with an effector function of which immune system cell type?

Neutrophils (NETs)


Describe C1 INH deficiency and its treatment.

- C1 INH binds to C1r:C1s, forcing them to dissociate from C1q, controlling spontaneous activation of C1 that always occurs - Deficiency causes serious illness characterized by systemic edema (b/c of overproduction of anaphylatoxins) - Aka, hereditary angioneurotic edema (HANE) and is treated by monthly injections of C1 INH replacement therapy


How do deficiencies of complement components C5-C9 affect susceptibility? Which of these is not like the others?

- Increased susceptibility to Neisseria species (because no formation of MAC) - C5 (powerful anaphylatoxin)


What are the three genetic deficiencies associated with NK cell deficiency?

1. Defective formation of cytoplasmic granules 2. Defective perforin 3. Defects in devo in bone marrow


How does reduced deposition of C3b affect patient susceptibility to pathogens?

Increased susceptibility to bacterial infections


Your young patient suffers from recurrent bacterial and viral infections. You observe several unusual facial features as well as teeth that have a conical shape. You expect clinical and/or genetic testing to reveal what deficiency?



What is the clinical presentation of NK cell deficiency?

Highly variable, but typically increased incidence and severity of viral and other infections, esp: 1. Varicella zoster virus (chickenpox/shingles), herpes viruses, cytomegaloviruses, EBV 2. Mycobacterium avium/intracellulare (MAI: opportunistic pathogens; surface ligands for activation of NK cells?) 3. Trichophyton fungus, one of leading causes of hair, skin, and nail infections in humans


Your 6 y/o patient that has been mostly healthy is being evaluated because he recently suffered a near fatal septic infection with a gram negative encapsulated diplococcal bacterium. Clinical and genetic studies are most likely to identify what genetic immunodeficiencies in this patient?

Any of the complement component C5-C9 deficiencies


A 4 y/o patient has had several infections with extracellular bacteria over the past few months. Clinical studies reveal that he has normal numbers of all cell types and a normal array of antibody isotypes in his serum. The only remarkable findings were low serum levels of C3 and factor B and anemia. What genetic immunodeficiency do you suspect?

Glu-6-P deficiency


How does C3 deficiency affect complement and host susceptibility?

- Results in no ability to activate any of the complement cascades - Leaves the patient susceptible to bacterial infections, particularly encapsulated bacteria


A 2 y/o boy has a history of repeated viral infections. He displays no unusual susceptibility to bacterial or fungal infections. What genetic deficiencies could be responsible for susceptibility to viral infections?

NK cell devo defect or perforin deficiency


Your 3 y/o patient has a history of bacterial and fungal infections that resolve slowly. He has normal numbers of B cells and T cells in peripheral blood and his serum contains a normal array of antibody isotypes. What genetic immunodeficiency is most likely in this case?



Describe Chediak-Higashi syndrome, and its standard clinical presentation.

- Genetic defect of gene encoding protein involved in IC vesicle formation, LYST -> phagocytes unable to fuse lysosomes with phagosomes, impairing their ability to kill phagocytosed bugs - Presentation: triad of 1) partial albinism (melanosome formation also dependent on LYST), 2) recurrent pyogenic infection (strep and staph), and 3) neurological disorders - Infection of skin, lungs, and respiratory tract most common (S aureus, S pyogenes, and Pneumococcus)


List four primary immunodeficiencies that have a high incidence of associated neutropenia. What is one of the mechanisms of this neutropenia?

- X-linked hyper-IgM syndrome - - X-linked agammaglobulinemia (XLA) - WHIM Syndrome - Griselli Syndrome Some patients with these disorders produce neutrophil-specific autoantibodies that cause neutropenia


Your patient is being evaluated due to heightened susceptibility to bacterial and fungal infections. The patient has relatively normal numbers of all cell types and a normal array of antibody isotypes in the blood. A blood smear is shown here. What deficiency would you expect?



How does Factor I deficiency affect susceptibility? Why?

- Similar in phenotype to a C3 deficiency because final result is depletion of C3b -> reduced cleavage of C3b or C4b, allowing more C3 convertases to form, resulting in accelerating reaction that uses up all the C3


What is the standard treatment for CGD?

- Prophylactic TMP-SMX (sulfonamide AB used in tx of a variety of bacterial infections) - Itraconazole (antifungal) - IFN-gamma (unknown protective mechanism)