Primary Immunodeficiencies (PIDs)

Question 1

Describe the Adenosine Deaminase (ADA) deficiency form of SCID.

Answer 1

T-, B-, and NK-. Leads to accumulation of toxic by-product deoxyadenosine.

Question 2

Describe the Purine Nucleoside Phosphorylase (PNP) deficiency form of SCID.

Answer 2

T-, B-, and NK+/-. Leads to accumulation of intracellular deoxyguanosine triphosphate (dGTP). Antibody levels are unchanged. Characterized early onset neurological abnormalities and autoimmune disorders. Can be treated with HSCT.

Question 3

Describe the Artemis deficiency form of SCID.

Answer 3

T-, B-, and NK+. Characterized by radiosensitivity. Infant presents with diarrhea, candidiasis, and pneumocystis jiroveci, and increased risk of lymphomas. Can be treated with HSCT.

Question 4

Describe the RAG1/RAG2 deficiency form of SCID.

Answer 4

T-, B-, and NK+. Leads to impaired V(D)J recombination. Infant presents with diarrhea, candidiasis, and pneumocystis jiroveci. Can be treated with HSCT.

Question 5

Describe the Omeen Syndrome form of SCID.

Answer 5

A form of RAG1/RAG2 deficiency SCID that retains partial function of RAG1/RAG2. Characterized by severe erythroderma, splenomegaly, eosinophilia, and high IgE. Can be treated with HSCT.

Question 6

Describe the Jak3 deficiency form of SCID.

Answer 6

T-, B+, and NK+. Leads to defect in IL-2 receptor signaling. Low levels of serum Ig. Can be treated with HSCT.

Question 7

In primary agammaglobulinemia, at what point is the developing B cell typically arrested in? What kind of mutation usually causes it?

Answer 7

Typically arrested in the pre-B cell stage. Usually caused by X-linked trait, but autosomal recessive forms also exist.

Question 8

Describe the BTK deficiency form of agammaglobulinemia.

Answer 8

B-, T+, and NK+. Caused by X-linked mutation, leading to a defect in rearrangement of Ig heavy chain. Serum antibodies are typically totally absent or very low. Can be treated with HSCT.

Question 9

Describe Isolated IgG Subclass deficiency.

Answer 9

B+, T+, and NK+. Patients are usually asymptomatic but may be associated with recurrent infections. IgG subclasses, such as IgG2, are low but IgM/IgA/IgE are normal.

Question 10

What point of B cell maturation is affected by an IgA deficiency?

Answer 10

Terminal differentiation, mature B cell converting to a plasma cell.

Question 11

Describe IgA deficiency.

Answer 11

B+, T+, and NK+. Characterized by recurrent infections, may be asymptomatic. Very common, most affected patients are healthy.

Question 12

How can an IgA deficiency cause anaphylaxis during an IVIG treatment?

Answer 12

Patients with undetectable IgA levels may have serum anti-IgA IgG which can lead to anaphylaxis in response to IVIG treatment.

Question 13

Describe DiGeorge Syndrome (DGS).

Answer 13

T-, B+, and NK+. Caused by microdeletion of 22q11.2 region, leading to a T cell deficiency. Characterized by classic triad: cardiac anomalies, hypocalcemia, and hypoplastic thymus. Humeral immunity is usually intact.

Question 14

Describe Hyper IgM (HIGM) Syndromes. What are its two main causes?

Answer 14

B+, T+, and NK+. Can be caused either by an X-linked CD40L deficiency (2/3), or an autosomal CD40 deficiency (1/3). B cell is unable to perform class switching or somatic hypermutation. Cannot produce plasma B cells. Can be treated with HSCT.

Question 15

Describe transient hypogammaglobulinemia of infancy.

Answer 15

B+, T+, and NK+. Occurs when intrinsic Ig production is delayed for up to 36 months. Leads to low IgG and IgA concentrations but IgM may be normal or low. Ig concentrations normalize between 2-4 years.

Question 16

Describe Common Variable Immune Deficiency (CVID).

Answer 16

B-/+, T+, and NK+. Characterized by defect in antibody production. Can be defect in maturation or differentiation of B cells. Diagnosed based on history of recurrent pyogenic sinopulmonary infections, usually at 20-30 years of age. Can be treated with HSCT.

Question 17

Describe the Common γ-chain Deficiency form of SCID.

Answer 17

T-, B+, NK-. The most common form of SCID. Caused by an X-linked mutation on the gene that encodes for the γ-chain of IL-2R. Also leads to nonfunctional B cells because there are no helper T cells. Characterized by failure to thrive, severe thrush, opportunistic infections, and chronic diarrhea.

Question 18

Describe the IL-7R α-chain deficiency form of SCID.

Answer 18

T-, B+, and NK+. T cells unable to form IL-7R, leading to defect in T cell development. Ig levels are low due to no helper T cells. Can be treated with HSCT.

Question 19

Describe the Bare Lymphocyte Syndrome Type 2 (BLS II) form of SCID.

Answer 19

T+, B+, and NK+. Caused by mutation in transcription factor that regulates expression of HLA II, leading to low levels of CD4+ cells. Frequently leads to death in early childhood. Can be treated with HSCT.

Question 20

Describe MHC Class I deficiency.

Answer 20

T+, B+, and NK-. Caused by a mutation in TAP1. CD8 cells are unable to recognize infected cells, leads to recurring viral infections. CD4 cells are unaffected. Ig production is normal. HSCT is not used because MHC I is on all cells.

Question 21

Describe CD3 complex deficiencies.

Answer 21

T-, B+, and NK+. Caused by a defect in a CD3 subunit. Antibody responses is also typically decreased. Can be treated with HSCT.

Question 22

Describe defects in the IL-12/IFN-γ pathway.

Answer 22

Patients with defects in either IL-12 or IL-12R do not produce Th1 cells. Th1 releases IFN-γ which is needed to control intracellular bacterial infections. Can also caused by defect in IFN-γ receptor.

Question 23

Describe Th17 deficiency.

Answer 23

Caused by mutations in either IL-17, IL-17R or transcription factors STAT1, STAT3, or AIRE. Leads to unusual susceptibility to chronic mucocutaneous candidiasis.

Question 24

Describe IPEX syndrome.

Answer 24

Self-reactive T effector cells are not inhibited due to X-linked mutation in FOXP3. Leads to loss of inhibition by CD4+CD25+ Treg cells. Can be treated with HSCT.

Question 25

Describe ALPS syndrome.

Answer 25

Caused by defects in either Fas, FasL, caspase-8, or caspase-10. Leads to effector T cells resistant against apoptosis. Cannot be treated with HSCT because it doesn’t just affect immune cells.

Question 26

Describe Wiskott-Aldrich Syndrome (WAS).

Answer 26

T-, B+, and NK-. X-linked disorder that leads to decreased IgM, but normal IgG and elevated IgA and IgE. Leads to recurrent bacterial and viral infections.

Question 27

Describe the two major types of NK cell deficiency (NKD).

Answer 27

Classical (CNKD): absence of NK cells (GATA2 deficiency).
Functional (FNKD): defective NK cell activity (perforin deficiency).

Both lead to severe viral infections.

Question 28

Describe Chronic Granulomatous Disease (CGC)

Answer 28

A type of phagocytic disorder caused by defective NADPH oxidase. Phagocyte cannot make O2 radicals, leading to impaired phagocytosis. Especially susceptible to catalase-positive organisms.

Question 29

Describe G6PD deficiency.

Answer 29

X-linked deficiency of PPP leading to lack of NADPH. Similar presentation as CGD (has granulomas).

Question 30

Describe leukocyte adhesion deficiencies (LAD).

Answer 30

Without infection, neutrophil count is twice the normal. Neutrophils cannot adhere and migrate into tissues due to deficiencies in CD11 and CD18. Also leads to delayed attachment of the umbilical cord.

Question 31

Describe Chediak-Higashi Syndrome.

Answer 31

Caused by defect in neutrophil granules (missing cathepsin G and elastase). Leads to abnormal giant granules and granulomas. Also leads to lymphoproliferative syndrome, partial albinism, and no NK activity.

Question 32

Describe abnormalities of the early classical complement pathway.

Answer 32

Deficiencies in C1 and C4 linked to development of systemic lupus erythematous (SLE) or rheumatoid arthritis (RA). Deficiency in C2 is the most common and leads to recurrent respiratory infections.

Question 33

Describe abnormalities associated with defects in C3 of the classical complement pathway.

Answer 33

Phenotype is indistinguishable from antibody deficiencies, although it is less frequent than Ig deficiencies.

Question 34

Describe abnormalities of the late complement pathway. What does it increase susceptibility to?

Answer 34

Defects in C5-C9 lead to defect in membrane attack complex. Leads to increased susceptibility to infections with Neisseria species.

Question 35

Describe C1-INH deficiency.

Answer 35

Deficiency in regulatory protein of the classical pathway. Can cause to Hereditary Angioedema (HAE) via the production of bradykinin.

Question 36

Describe Paroxysmal Nocturnal Hemoglobinuria (PNH).

Answer 36

Caused by failure to regulate formation of MAC via deficiency of DAF (CD55) and CD59. Leads to RBCs susceptible to complement.

Question 37

Describe MyD88 deficiency.

Answer 37

Causes impaired signaling of all TLRs except TLR3. Leads to severe infections caused by pyogenic bacteria, but normal resistance to other pathogens. Patients characteristically lack both fevers and elevated levels of pro-inflammatory proteins.

Question 38

Describe TLR3 deficiency.

Answer 38

Autosomal dominant disorder which results in increased susceptibility to HSV encephalitis.