Primary Immunodeficiencies

Question 1

Adenosine Deaminase (ADA) Deficiency

Answer 1

• autosomal recessive
• second most common SCID
• accumulation of toxic deoxyadenosine
• no B/T/NK cells

Question 2

Purine Nucleoside Phosphorylase (PNP) Deficiency

Answer 2

• autosomal recessive
• accumulation of deoxyguanosine triphosphate (dGTP)
• HSCT treatment
• normal Ig lvls, NK +/-

Question 3

Artemis Deficiency

Answer 3

• autosomal recessive
• T and B cells decreased, NK cells normal
• RADIOSENSITIVITY
• pneumocytis jiroveci pneumonia

Question 4

RAG1/RAG2 Deficiency

Answer 4

• autosomal recessive
• impaired VDJ recombination = defective pre-TCR/BCR expression
• leaky RAG1/2 = OMENN SYNDROME (high IgE and eosinophilia)

Question 5

JAK3 Deficiency

Answer 5

• autosomal recessive
• defect in IL-2 receptor signaling
• very low Ig even though B cells are present
• no T cells = no class switch for B cells

Question 6

BTK Kinase Deficiency (Agammaglobulinemia)

Answer 6

• X-linked (also autosomal recessive form)
• mutation in tyrosine kinase (Bruton)
• defect in Ig HEAVY CHAIN REARRANGEMENT
• Igs are VERY low or TOTALLY ABSENT

Question 7

Isolated IgG Subclass Deficiencies

Answer 7

• defects in several genes (usually asymptomatic)
• decreased concentrations of one or more IgG subclasses
• other Ig classes normal

Question 8

IgA Deficiency

Answer 8

• higher in MALE patients
• recurrent infections/asymptomatic
• may have serum anti-IgA IgG = non-IgE mediated anaphylaxis

Question 9

DiGeorge Syndrome

Answer 9

• autosomal dominant
• LOW T-Cells, but mostly intact Humoral Immunity
• 22q11.2 microdeletion
• commonly suffer from upper respiratory infections

Question 10

Hyper IgM Syndromes (HIGM)

Answer 10

• X-linked (CD40L deficiency) –> male only
• autosomal recessive (CD40 deficiency) –> both
• high IgM, low IgG/IgA
• increased bacterial susceptibility

Question 11

Transient Hypogammaglobulinemia of Infancy

Answer 11

• low IgA/IgG; IgM normal or low
• intrinsic Ig production is delayed up to 36 months
• increased susceptibility to sinopulmonary infections

Question 12

Common y Chain Deficiency

Answer 12

• X-linked recessive (no T or NK cells)
• X-linked
• MOST COMMON SCID
• IL-2Ry gene deficiency (T-Cell growth receptor)
• B cells present but no functional (no T help = very low Ig)

Question 13

IL-7R Alpha Chain Deficiency

Answer 13

• autosomal recessive
• Ig levels lows (no T help to activate B cells)
• B and NK cells present

Question 14

Bare Lymphocyte Syndrome II

Answer 14

• autosomal recessive
• no MHC class II expression on professional APCs
• no CD4+ T Cells, CD8+ fine
• variable hypogammaglobulinaemia

Question 15

MHC Class I Deficiency

Answer 15

• autosomal recessive
• mutation in TAP1 molecules
• CD8+ deficient (recurring viral infections)
• CD4+ normal, normal Abs, normal DTH

Question 16

CD3 Complex Deficiency

Answer 16

• autosomal recessive
• present in infancy = lymophenia, dec. T Cell numbers
• classically present in infancy

Question 17

Defect in IFNy/IL-12 Axis

Answer 17

• mutation in receptor genes, or p40 subunit of IL-12
• macrophages/DCs -> IL-12 to T and NK cells, which produce IFNy
• susceptible to nontuberculous mycobacteria

IL-12 = Th1 cell differentiation

Question 18

Th17 Deficiency

Answer 18

• susceptible to chronic mucocutaneous candidiasis
• mutations in IL-17, IL-17R, STAT1/3, AIRE
• prior autosomal recessive Hyper IgE Syndrome

Question 19

IPEX

Answer 19

• X-linked
• self-reactive T effector cells are NOT inhibited
• mutation in FOXP3 prevents Treg inhibition

Question 20

ALPS

Answer 20

• resistance of effector T Cells to apoptosis

- defects in Fas, FasL, caspase-8/10

Question 21

Wiskott-Aldrich Syndrome (WAS)

Answer 21

• X-linked
• WASP mutations
• T cell lymphopenia, dec. NK cytotoxicity
• low IgM, normal IgG, high IgA/IgE
• recurrent bacterial infections (ENCAPSULATED BACTERIA)

Question 22

Chronic Granulomatous Disease (CGD)

Answer 22

• most common in MALES
• tendency to form Granulomas
• deficiency of NADPH oxidase (no superoxide)
• defective extracellular pathogen elimination

Question 23

G6PD Deficiency

Answer 23

• X-linked recessive
• lack of NADPH substrate
• usually asymptomatic
• same manifestation as CGD

Question 24

Leukocyte Adhesion Deficiency (LAD)

Answer 24

• neutrophil count twice normal lvl (unable to aggregate)
• do NOT bind to intercellular adhesion molecules on endothelial cells
• delayed attachment of umbilical cord, no pus, severe bacterial infection, slow wound healing

Question 25

LAD-1 vs LAD-2

Answer 25

LAD-1 = B2 integrin (CD11/18) mutations LAD-2 = impaired P selectin ligand

Question 26

Chediak-Higashi Syndrome

Answer 26

- autosomal recessive - abnormal giant granules in neutrophils - no cathepsin G/elastase in granules - chemotaxis/degranulation problems - NO NK ACTIVITY

Question 27

C8 Complement Deficiencies

Answer 27

- autosomal recessive | - late complement protein deficiencies (Neisserial infections)

Question 28

C1-INH Deficiency

Answer 28

- Hereditary Angioedema (HAE) - swelling in face, larynx, GI tract, extremities - Bradykinin = swelling

Question 29

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Answer 29

- failure to regulate MAC formation - deficiency of glycosylphosphatidylinositol - lack DAF (CD55) and CD59 on RBCs - most likely cause of intravascular hemolysis

Question 30

MyD88 Deficiency

Answer 30

- impaired signaling of all TLRs but TLR3 - frequent and severe infections by pyogenic bacteria - normally resistant to other common bacteria, viruses, bacteria, parasites - lack fevers (low TNF-a, IL-1, IL-6)

Question 31

TLR3 Deficiency

Answer 31

- autosomal dominant | - increased susceptibility to HSV encephalitis