Primary immunodeficiency

Question 1

recurrent sinopulmonary bacterial infections

Answer 1

screen for humoral immunity deficiency

Question 2

recurrent viral/fungal infections

Answer 2

screen for cellular immunity

Question 3

skin abscess/fungal infections

Answer 3

screen for phagocyte defect

Question 4

bacteremia or meningitis w encapsulated bacteria

Answer 4

screen for complement defect

Question 5

Lab: differential count of blood cells

Answer 5

Screens for: T cells, B cell, or combined

look for: decreased numbers of T cells, B cells, or platelets

Question 6

Lab: DTH skin test

Answer 6

Screens for: T cell defects

Look for: Negative = possible impaired T cell response

Question 7

Lab: IgG, IgM, and IgA

Answer 7

screens for: humoral immunodeficiency

look for: decrease in any or all immunoglobulins

Question 8

Lab: Ab testing to specific Ag after immunization

Answer 8

screens for: humoral immunodef.

look for: decrease or absent Ab response to vaccination

Question 9

Lab: Total hemolytic complement assay

Answer 9

Screens for: complement deficiency

look for: decrease or absent components in classical pathway

Question 10

Lab: nitroblue tetrazolium test

Answer 10

screens for: phagocytic disorder

look for: abnormal result

Question 11

Adenosine Deaminase (ADA) deficiency

Answer 11

- combined B/Tcell deficiency
absent or low IgG, IgA, IgM; T-, B-, NK-
autosomal recessive
second most common cause of SCID
ADA essential for metabolic function of various cells, especially T cells. ADA def leads to accumulation of deoxyadenosine (toxic for lymphocytes)
- HSCT is the treatment, 
avoid all live vaccines

Question 12

Purine Nucleoside phosphorylase (PNP) Deficiency

Answer 12

T-, B+, NK+/- (decreased); normal IgG, IgA, IgM
- PNP deficiency leads to accumulation of intracellular deoxyguanosine triphosphate, toxic to lymphocytes leading to decreased peripheral T cells. B cells are normal
- autoimmune disorders commonly associated, including hemolytic anemia, thyroid disease, arthritis, lupus
- treatment: HSCT
avoid all live vaccines

Question 13

Artemis Deficiency

Answer 13

T-, B-, NK+; absent or low IgG, IgA, and IgM
rare form of autosomal recessive radiosensitive SCID
- present with diarrhea, candidiasis, infections with opportunistic bacteria pneumocystis jivroveci
- absent T/B cells, normal NK
increased risk of developing lymphoma
- treatment: HSCT
Avoid all live vaccines

Question 14

Rag1/Rag2 deficiency

Answer 14

T-, B-, NK+; absent or low IgG, IgA, IgM
autosomal recessive
-RAG defects cause impaired V(D)J recombination, leads to defective expression of pre-TCR and pre-BCR
- presents with diarrhea, candidiasis, and infections with opportunistic bact. Pneumocystis jiroveci
-leaky RAG1/RAG2 deficiency allows for partial function and leads to milder form called OMENN, severe erythroderma, splenomegaly, eosinophilia, high IgE

Question 15

Deficiency of Jak3

Answer 15

T-, B+, NK-; Very low IgG, IgA, IgM
autosomal recessive
Defect in IL-2 receptor signaling
- T cells heavily depend on signaling from Jak3, and IL2 uses as well --> T and NK cells unable to be replicated
Treatment: Definitive treatment
Avoid all live vaccines

Question 16

DiGeorge Syndrome (DGS)

Answer 16

T-, B+, NK+; Normal IgG, IgA, IgM
T cell deficiency.
Results from microdeletion of 22q11.2 region
Classic triad: cardiac anomalies, hypocalcemia, and hypoplastic thymus (not completely developed thymus) leading to T cell disfunction. Humoral immunity in tact in most patients.
Frequent upper respiratory infections.
Live vaccines can be given if patients have CD8 T cell count above a certain threshold

Question 17

Agammaglobulinemia

Answer 17

B-, T+, NK+; no IgG, IgM, IgA
X linked disease due to mutation in Bruton tyrosine kinase on X chrome (AR forms also exist, we are only talking about X linked)
B-cell development arrested at pre-B cell stage, defect in rearrangement of Ig heavy chain genes
diagnosis in 5-6 month old infants
treatment: HSCT

Question 18

IgG subclass deficiencies

Answer 18

B+, T+, NK+; Some IgG subclasses low, normal IgM, IgA, IgE
caused by defects in several genes
may be asymptomatic, may be associated with recurrent viral/bacterial infections, frequently respiratory tract
low levels IgG2 assoc with poor response to polysaccharide Ags in children
IgG4 levels vary widely, many healthy people have no IgG4

Question 19

IgA deficiency

Answer 19

B+, T+, NK+; No IgA, normal IgG, IgM

• higher in male patients, 50% are asymptomatic due to translocation of IgM across mucosal epithelium
• 85% with recurrent infections of encapsulated bacteria
• often develop autoimmune diseases and allergies
• can get serum sickness after IVIG transfusion due to anti-IgA IgG –> non-IgE mediated Anaphylaxis

Question 20

Hyper IgM Syndromes (HIGM)

Answer 20

B+, T+, NK+; High IGM, low IgG and IgA
impaired class switching and somatic hyper mutation
- increased susceptibility to bacterial infection
X linked (CD40L) or Autosomal recessive (CD40)
*CD40L binds CD40 on B cells, triggers terminal differentiation associated with class switching and somatic hypermutation.
treatment: HSCT

Question 21

Transient hypogammaglobulinemia of infancy

Answer 21

B+, T+, NK+; low IgG/IgA, IgM normal or low
- maternal IgG disappears in infants after 6 months, intrinsic IgG production begins immediately after birth
BUT in transient hypogammaglobulinemia - intrinsic Ig production delayed for up to 36 months
- increased susceptibility to sinopulmonary infections
-usually normalizes within 2-4 years
- symptomatic treatment

Question 22

Common variable immune deficiency (CVID)

Answer 22

B-/+, T+, NK+; LOW IgG and IgA, sometimes low IgM
- heterogenous group of diseases assoc with hypogammaglobulinemia, defect in Ab production
- number of B cells reduced or normal
- mutations in receptors for B cell growth factors and costimulators
- recurrent pyogenic sinopulmonary infections
-often with recurrent infections, autoimmune disease, and lymphomas
autosomal recessive

Question 23

Common y chain Deficiency (yC or IL-2Ry)

Answer 23

T-, B+, NK-; Very low IgG, IgA, and IgE
most common form of SCID (45% of all cases)
X-linked recessive trait
- encodes Gamma chain shared by the T cell growth factor receptor (IL2Ry) and others. IL-2Ry shared with other cytokine receptors: IL-4, IL-7, IL-9, IL-15, IL-21
no functional B cells, T cells are unable to help. Results in Low Ig
- classically present with failure to thrive, sever thrush, opportunistic infections, and chronic diarrhea
HSCT definitive treatment
avoid all live viral vaccines

Question 24

IL-7Ra Chain deficiency

Answer 24

T-, B+, NK+; Very low IgG, IgA, IgE
autosomal recessive
- IL7 plays a role in early T cell development
- IgG, IgA, IgE low to absent despite presence of B cells because no T cell co-stim signaling
-present with classic SCID symptoms
HSCT definitive treatment
avoid all live vaccines

Question 25

Bare lymphocyte Syndrome Type 2 (BLS II)

Answer 25

``` T+, B+, NK-; variable hypogammaglobulinemia - rare autosomal recessive, HLA class II negative SCID no MHC class II on professional APCs --> deficiency in CD4+ cells - genes for MHC class 2 on chrome 6 are intact, the mutations occur in transcription factors that regulate MHC2 expression recurrent respiratory, GI, and urinary infections, frequent death in early childhood - HSCT definitive treatment ```

Question 26

MHC Class I deficiency

Answer 26

T+, B+, NK+ - mutation in TAP1 molecules to transfer peptides to ER - CD8+ cells and NK cells are functionally deficient, causes recurring viral infections - normal CD4+ cells, normal Ab production, normal DTH (delayed type hypersensitivity) HSCT not recommended

Question 27

CD3 Complex deficiencies

Answer 27

T-, B+, NK+; low IgG, IgA, IgM - deficiencies of CD3 subunits can cause autosomal recessive form SCID - presents in infancy with lymphopenia and decreased T cells, normal B and NK - decreased specific antibody responses - HSCT indicated

Question 28

IPEX (immunodysregulation, polyendocrinopathy and enteropathy, X-linked syndrome)

Answer 28

self-reactive T effector cells are not inhibited, mutation in FOXP3 results in loss of inhibition by CD4+CD25 Treg Cell HSCT is curative

Question 29

ALS (autoimmune lymphoproliferative syndrome)

Answer 29

- defects in either Fas, FasL, Caspase 8, or Caspase 10, results in abrogated formation of death-inducing signaling complex (DISC) and resistance of effector T cells to apoptosis

Question 30

Wiskott-Aldrich Syndrome (WAS)

Answer 30

T-, B+, NK-; Low IgM, normal Ig (total), elevated IgA and IgE - X linked disorder: thrombocytopenia, eczema, cellular and humoral immunodeficiency, autoimmune disease and malignancy - mutations in WASP - recurrent bacterial infections

Question 31

IFN-y-IL-12 Axis deficiency

Answer 31

- positive regulatory loop Macrophages and DCs produce IL-12, binds to IL-12R and stimulates T and NK cells to release IFN-y - IFN-y binds with macrophage and cross link IFN-y receptor, activates production of H2O2 and TNF-a and IL-12 -lead to increased susceptibility to nontuberculosis mycobacteria - mutations in genes encoding: IFN-y receptor, IL-12 receptor, p40 subunit of IL-12

Question 32

Defects in IL-12/IFN-y Pathway

Answer 32

IL-12 essential for differentiation of naive T cells into Th1 cells - mutations in IL-12 or IL-12R, do not produce Th-1 ctokine IFN-y, necessary for control of intracellular bacterial infections - present with selective susceptibility to intracellular pathogens - May also have defects in Th17 that account for recurrent fungal infections

Question 33

Th17 deficiency

Answer 33

Activation of innate immune responses by Candida through Prrs direct subsequent development of naive T cells into Th17 cells - unusual susceptibility to chronic mucocutaneous candidiasis - associated with mutations in genes for IL-17, IL-17R OR STAT1, STAT3, or AIRE - severe atopic disease (allergic), or recurrent staph aureus skin abscesses

Question 34

NK cell deficiency (NKD)

Answer 34

more than 40 known immunodef. to impair NK cells - to consider this, NK cells represent major immunologic abnormality - CLASSICAL NKD - absence of NK cells (ex. GATA2 deficiency with NK cell lymphopenia) - FUNCTIONAL NKD - presence of NK cells with defective NK cell activity (ex. perforin deficiency) - severe or disseminated viral infections, such as cytomegalovirus (CMV) and herpes (HSV)

Question 35

Chronic Granulomatous Disease (CGD)

Answer 35

granuloma = mass of immune cells forming at sites of infection or inflammation - most frequent phagocytic primary immunodeficiency , more common in males - enzymatic deficiency of NADPH oxidase in phagocytes, fail to generate superoxide anion and other O2 radicals - defective leimation of extracellular pathogens: bacteria and fungi - susceptible to recurrent infection with catalase-positive organisms (staphylococci)

Question 36

G6PD Deficiency

Answer 36

X-linked recessive genetic disease - associated with anemia, G6P is especially important in RBC metabolism (glycolysis) - lack of substrate for NADPH - similar manifestation to CGD and also can form granulomas

Question 37

Leukocyte Adhesion Deficiencies (LAD)

Answer 37

- caused by mutations in CD18 gene - defective or deficient beta2 integrin - neutrophil count is twice the normal even without ongoing infection. - neutrophils unable to aggregate, do not bind to intercellular adhesion molecules on endothelial cells (necessary for egress from vasculature to transport to sites of inflammation) - infected foci contain few neutrophils and heal slowly, enlarging borders and dysplastic scars - delayed detachment of umbilical cord, slow wound healing, severe bacterial infections, failure to form pus - early death, poor prognosis flow cytometric assessment of neutrophil adhesion molecules CD11 and CD18

Question 38

Chediak-Higashi Syndrome

Answer 38

Autosomal recessive wheelchair-bound and die of infection in their early 30s - the structure of neutrophil granule appears as abnormal giant granules - do not contain cathepsin G and elastase - manifested as abnormalities in chemotaxis and degranulation - prone to recurrent pyogenic granulomas caused by staphylococci and streptococci - blunted neutrophilia due to delayed diapedisis biphasis immunodeficiency (1st-susceptibility to infections, 2nd-accelerated lymphoproliferative syndrome with hepatosplenomegaly and lymphadenopathy after 25-30 years) - azurophilic GIANT cytoplasmic inclusions in blood cells, partial albinism, no NK activity

Question 39

CP immunodeficiencies

Answer 39

CP responsible for rapid clearance of immune complexes, apoptotic cells and cell debris from damaged tissues - primary C1 and C4 deficiency linked to development of systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) - without complement, debris complexes grow too large to be easily cleared, no longer soluble and form deposits in the tissues - site of inflammation * *Primary C2 deficiency is most common complement in caucasian populations - found in young children with recurrent S. pneumoniae infections

Question 40

MAC deficiencies (C8 mostly)

Answer 40

autosomal recessive - increased susceptibility to Neisserial infections -could be inherited, acquired, or due to complement consumption d/t chronic complement activation by ongoing infection *diagnosis: absent C8 levels in presence of normal C3 and C4 - consistent with C8 def absence of C8 in presence of low C3 and C4 - suggest complement consumption

Question 41

Hereditary Angioedema (HAE)

Answer 41

deficiency of CP control protein (C1-INH) - recurrent swelling in extremities, face, lips, larynx, or GI - byproduct of kinin-generating pathway. Production of bradykinin through the pathway --> tissue permeability - acute treatments include C1 inhibitor, a replacement therapy

Question 42

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Answer 42

Failure to regulate formation of MAC - somatic mutation causes deficiency of glycosylphosphatidylinositol (GPI) - PNH cells lack all proteins linked through GPI anchor to their cellular membranes - most important DAF (CD55) and CD59. Complement regulatory proteins involved in protecting RBC from complement - causes intravascular hemolysis

Question 43

Deficiency of TLRs

Answer 43

MyD88 deficiency - impaired signaling for all TLRs except TLR3 (MyD88 independent) - abnormally frequent and severe infections caused by pyogenic bacteria - normal resistance to other common pathogens - characteristically lack fevers and elevated ESR/CRP despite active infection low levels of TNF-a, IL-1, and IL-6 during infection **TLR3 deficiency is autosomal dominant disorder, leads to increased susceptibility to HSV encephalitis