Innate Autoimmune Diseases

Question 1

What is neutropenia, and what are the three most common types? Describe them.

Answer 1

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

Question 2

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

Answer 2

• 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

Question 2

Describe paroxysmal nocturnal hemoglobinuria, and its treatment.

Answer 2

• 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

Question 2

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?

Answer 2

CGD

Question 4

How do you dx NK cell deficiency?

Answer 4

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

Question 4

How would you diagnose and treat Chediak-Higashi syndrome?

Answer 4

• 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

Question 4

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?

Answer 4

CD18

Question 4

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?

Answer 4

LYST

Question 6

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

Answer 6

• 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

Question 6

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

Answer 6

• 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

Question 7

What are the 3 categories of NK cell deficiency?

Answer 7

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

Question 8

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?

Answer 8

CD18

Question 9

Describe leukocyte adhesion deficiency, and its impact on susceptibility.

Answer 9

• 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

Question 9

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?

Answer 9

Neutrophils (NETs)

Question 10

Describe C1 INH deficiency and its treatment.

Answer 10

• 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

Question 11

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

Answer 11

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

Question 12

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

Answer 12

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

Question 14

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

Answer 14

Increased susceptibility to bacterial infections

Question 15

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?

Answer 15

NEMO

Question 16

What is the clinical presentation of NK cell deficiency?

Answer 16

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

Question 16

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?

Answer 16

Any of the complement component C5-C9 deficiencies

Question 17

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?

Answer 17

Glu-6-P deficiency

Question 18

How does C3 deficiency affect complement and host susceptibility?

Answer 18

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

Question 19

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?

Answer 19

NK cell devo defect or perforin deficiency

Question 20

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?

Answer 20

Neutropenia

Question 21

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

Answer 21

• 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)

Question 22

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

Answer 22

• 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

Question 23

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?

Answer 23

Chediak-Higashi

Question 25

How does Factor I deficiency affect susceptibility? Why?

Answer 25

• 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

Question 27

What is the standard treatment for CGD?

Answer 27

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

Question 29

Name two general negative effects of deficiencies of complement control proteins.

Answer 29

• Sometimes more susceptible to bacterial infections because of C3 depletion resulting from constant activation of pathways - Other deficiencies of these proteins can lead to autoimmune-like destruction of RBCs due to excessive MAC formation

Question 30

What is the clinical presentation of MBL deficiency?

Answer 30

Increased susceptibility to severe bacterial infection (probably b/c acute phase response impaired; also the activator of the lectin pathway)

Question 32

What is chronic granulomatous disease (CGD), and how does it affect pt. susceptibility to infection?

Answer 32

• Usually inherited as X-linked trait in auto recessive fashion; caused by mutation resulting in nonfunctional gp91 protein (p91 PHOX), the heme-binding subunit of NADPH oxidase - Phagocytes can’t produce ROS (most notably, superoxide radical) - Chronic bacterial and fungal infections, and make granulomas more readily than healthy patients - Susceptibility to organisms that make catalase: S aureus, E coli, Klebsiella, Aspergillus, SERRATIA MARCESCENS, Nocardia, and Candida - Children with CGD typically healthy at birth, but most common infection in infancy Serratia bacteria in skin or bone -> any infant with this (or any of the other listed infections) should be tested for CGD

Question 33

Describe two diagnostic tests used to test for CGD.

Answer 33

1. Nitroblue tetrazolium (NBT) dye test: normal phagocytes produce NADPH oxidase that gives rise to ROS that oxidize the NTB, producing a blue color. CGD neutrophils cannot cause this color change (- test). This test is dated. 2. Preferred test is dihydrorhodamine test: flow cytometric assay that determines whether neutrophils produce an oxidative burst that can reduce dihydrorhodamine to rhodamine (which fluoresces green). CGD patient cells will have a negative test.

Question 34

A 7 month-old patient presented to his pediatrician with a respiratory infection. A blood culture grew out Serratia marcescens. The pediatrician should order a test to determine if this child has what inherited immunodeficiency?

Answer 34

CGD

Question 35

A 6 y/o patient has a history of infections with encapsulated bacterial pathogens. What deficiency do you expect?

Answer 35

Asplenia

Question 36

Your patient suffers from anemia and recurrent extracellular bacterial infections. What genetic defect would you expect?

Answer 36

Glucose-6-phosphate dehydrogenase

Question 37

How does Factor D deficiency affect susceptibility?

Answer 37

• Susceptibility to encapsulated bacteria and Neisseria (b/c essential part of the alternative pathway) - Similar effect with lack of properdin (Factor P), which is a stabilizer for alternative pathways convertases

Question 39

A newly identified bacterial pathogen is now known to secrete a protease that has specificity for dimeric IgA molecules. The bug’s ability to produce this virulence factor indicates that its most important transmission route is…?

Answer 39

Mucosal surfaces (i.e., sexual transmission, respiratory tract, etc.)

Question 40

What is NEMO deficiency?

Answer 40

• X-linked hypohidrotic ectodermal dysplasia and immunodeficiency - Genetic defect in protein (IKK-gamma or NEMO) needed for NFKB activity (important transcription factor for physical development and innate immunity) - Most TLR signaling activates NFKB, which controls cytokine expression - Patients have devo defects: deep set eyes, sparse and/or fine hair, conical or missing teeth, and often a skin condition that leads to unusual blistering and skin color changes (incontinentia pigmenti)

Question 41

Your 23 y/o patient presents in the emergency department with severe edema in her lips. With no other case history, what genetic deficiency do you suspect in this patient?

Answer 41

HANE