immune deficiencies

Question 1

chronic granulomatous disease

Answer 1

• defect in innate immunity
• reduced NADPH oxidase in phagocytes => defective killing of catalase-positive microbes => chronic inflammatory response to these microbes => granuloma formation and severe skin/bone infection

Question 2

leukocyte adhesion defect (LAD)

Answer 2

• innate immunity defect
• impaired trafficking of phagocytes from circulation into tissues via mutations in integrins or ligands for selectins
• sx: umbilical cord separation > 4-6 weeks, increased neutrophils

Question 3

chediak-higashi

Answer 3

• defect of innate immunity
• defect in gene whose product is involved in phagosome/lysosome fusion => impaired intracellular killing => infection, albinism, abnormal platelets, defective NK cells

Question 4

complement defects

Answer 4

• defect of innate immunity
• C2 and C4 deficiency => autoimmune disease like lupus
• C2 and C3 deficiency => increased risk of infection by encapsulated bugs
• C5-C9 deficiency => recurrent, invasive neisseria infection

Question 5

TLR defects

Answer 5

• defect of innate immunity
• defective TLR signalling => reduced pro-inflammatory cytokine production => increased risk of viral or pyogenic infections w/o significant response

Question 6

SCID

Answer 6

• defect of adaptive immunity
• no T lymphocytes +/- B lymphocytse +/- NK cells => no cell mediated immunity and reduced antibody production
• early onset of infection (pneymocystis jirovecci, adenovirus, RSV, CMV, parainfluenza, etc), chronic diarrhea, failure to thrive
• many causative defects:
• Cytokine signalling: X linked SCID = mutation to X-linked gamma chain gene => mutated receptors for IL2, 4, 7, 9, 15, 12 => defective T and NK cell development (IL7 and IL15)
• Purine metabolism: Adenosine deaminase and purine nucleotide phosphorylase deficiencies => accumulation of nucleotide metabolites that are toxic to developing T, B, and NK cells
• VDJ recombination: defects in RAG1 or RAG2 => no recombination => no B or T cells. Residual RAG activity => Omenn syndrome with rogue T cells
• T cell positive selection: bare lymphocyte syndrome = no MHC II expressed on APC’s due to TF loss => no CD4 T cell development
• T cell signalling: effect on expression of TCR/CD3 or T cell activation signal cascade (ZAP70, Lck)

Question 7

22q11 delection / DiGeorge

Answer 7

• defect of adaptive immunity
• developmental defect in 3rd and 4th pharyngeal pouches => impaired formation of thymus, parathyroid, and heart => spectrum of T cell deficiency

Question 8

hyper IgM

Answer 8

• defect of adaptive immunity
• multiple causes and phenotypes:
• mutation in CD40L: X-linked hyper IgM = normal or increased IgM with low/no other isoytpes => risk of opportunistic infection, neutropenia, liver disease, tumors of liver
• defects in CD40: AR hyper IgM = similar phenotype as X-linked
• mutations to enzymes involved in isotype switching/affinity maturation - activation induced cytidine deaminase (AID) and uracyl N-glycosylase (UNG): AR IgM => no T cell immunodeficiency or increased opportunistic infection but lymphoid hyperplasia and autoimmune disease

Question 9

X-linked agammaglobulinemia (XLA)

Answer 9

• defect of adaptive immunity
• defects in Bruton tyrosine kinase, involved in the pre B cell receptor => very few B cells => infection by encapsulated bugs with recurrent otitis media/sinusitis/pneumonia and by enteroviruses

Question 10

selective IgA deficiency

Answer 10

• defect of adaptive immunity
• common and usually asymptomatic; may have recurrent sinopulmonary infection, autoimmunity, or allergy

Question 11

common variable immune deficiency

Answer 11

• defect of adaptive immunity
• most common symptomatic PID
• genetic cause 90% unknown
• impaired antibody production in response to vaccines/infections, low IgG and at least one other isotype, recurrent infection by encapsulated bugs, lymphoid hyperplasia, autoimmune disease, granulomas, lymphoma, etc
• dx after 2-4 years

Question 12

Wiskott-Aldrich syndrome

Answer 12

• defect in adaptive immunity
• X-linked, mutation in WASP, which binds targets in hematopoietic cells => abnormal platelets and leukocytes, defective T cells, impaired B cells (low IgM, high IgA), impaired phagocytosis and chemotaxis
• eczema, thrombocytopenia, immunodeficiency

Question 13

hyper IgE

Answer 13

• defect of adaptive immunity
• mutations in STAT3 => Th17 differentiation defects
• recurrent infection, retention of primary teeth, severe neonatal rash

Question 14

PID dx from CBC:

lymphopenia

high WBC

thrombocytopenia

neutropenia

morphology

Answer 14

• lymphopenia => SCID
• high WBCs => LAD
• thrombocytopenia => WAS, CVID, or IgA deficiency
• neutropenia => X-linked hyper IgM
• morphology => chediak-higashi

Question 15

PID dx from quantitative immunoglobulin concentrations

Answer 15

• IgG, IgM, IgA deficiencies
• functional adequecy of humoral immunity

Question 16

PID dx from flow

Answer 16

• low B cells => agammaglobulinemia, SCID
• low memory B cells => CVID, hyper IgM
• no T cells => SCID (+/-B and +/- NK)

Question 17

tx for congenital immunodeficiencies

Answer 17

• enzyme replacement therapy: complement deficiency, SCID due to ADA/PNP
• passive immunization: gamma globulin to treat XLA
• stem cell transplant: SCID, LAD, WAS, X-linked hyper IgM
• gene therapy: