Immunology L3: Immunodef Flashcards
Hypogammaglobulinemia/Ab def
- Defect in B cell development: BTK, m, l5/14.1, Iga, BLNK
- Defect in B cell function: ICOS, AID/UNG, NEMO, CD40
- Defect in B/T interactions: SH2D1A (SAP), CD40L
- Unknown: IgA deficiency, some causes of CVID
Bruton’s X-Linked Agammaglobulinemia (XLA)
- Caused by a mutation in the BTK gene (Xq21.22)
- The Bruton’s or B cell tyrosine kinase (Btk) protein is associated with the B cell antigen receptor
- – Drives maturation signals
- – Without Btk, maturation stops after heavy chain rearrangement
- Failure of B cell precursors to mature into functional B cells
- – Usually limited to males
- – Affected patients become Symptomatic begin at ~6 mo, when maternal Ig is depleted
- Recurrent pyogenic infections
- – Organisms normally cleared by opsonization and phagocytosis
Infections in XLA
- Sinopulmonary infections: H. flu, S. pneumoniae, Staph. aureus
- Enteroviral infections, including encephalitis and meningitis: Echovirus, poliovirus, coxsackievirus
- Giardia (normally resisted by IgA)
Dx
- Absent circulating B cells (nl = 8-10%)
- CD19+ B cell precursors present in marrow
- Cytoplasmic heavy chain, with absence of surface and secreted Ig
- Rudimentary germinal centers in lymphoid organs (small/no tonsils, LN)
- Plasma cells are absent
- Decreased serum Ig (all subclasses)
Pathways Causing Agammaglobulinemia
- XLA (BTK mutation)
- Autosomal recessive (Very rare)
- – mu heavychain
- – l5/14.1surrogate light chain
- – Iga
- – BLNK (B cell linker)
Common Variable Immunodeficiency (CVID)
- B cells present but low; antibody production is impaired
- – “Wastebasket” diagnosis
- Two forms identified to date
- – SH2D1A/SAP (SLAM-associated protein)
- – ICOS/CD278 (inducible co-stimulator)
- Must rule out known causes of hypogammaglobulinemia
- Most individuals have low to normal numbers of B cells: Defective differentiation into plasma cells
- Known genetic causes result in defective T cell-B cell interactions.
Sx
- Recurrent infections
- – Sinopulmonary (pyogenic bacteria)
- – Herpesvirus
- – Enterovirus (meningoencephalitis)
- – Giardia lamblia
- 20% develop autoimmunity (RA)
- ↑ risk of lymphoma & gastric CA
Isolated IgA Deficiency
- Characterized by very low levels of both serum & secretory IgA
- Prevalence varies from 1:223 to 1:3000 in different populations
- Usually asymptomatic
- May have increased sinopulmonary infections, allergy, or autoimmune disease (RA, SLE)
- Differentiation of naïve B cells to IgA- secreting plasma cells is impaired.
- Molecular basis is still unclear
Hyper IgM Syndrome
- Normal numbers of B cells, but abnormal function
- – Normal or increased serum IgM
- – IgG, IgE, & IgA absent
- Due to mutations in genes that affect Ig class switching
Genes Mutated in Hyper IgM Syndrome
X-linked
– CD40L (CD154)
– NEMO (NF-kB essential modulator): Required for CD40-induced NF-kB activation
Autosomal recessive
– Activation-Induced cytidine Deaminase
– Uracil-DNA glycosylase (UNG)
– CD40
Sx
- >50% diagnosed by 1 yr of age: Pneumonia, URI, otitis, diarrhea
- Infections with encapsulated bacteria, Pneumocystis, CMV, Cryptosporidium, Cryptococcus, Candida, Histoplasma, Bartonella
Hyper-IgE Syndrome (Job Syndrome)
severe chronic skin infections.
Etiopath
Defects in Th17 function
– Hypomorphic mutations in STAT3
– Null mutation in Tyk2 (Tyr kinase)
– DOCK8 mutations
Defective signal transduction for multiple cytokines, including IL-6 and IL-23
Sx
- Persistent skin infection & abcesses: “Cold”: no pain, heat, redness
- Recurrent sinusitis
- Eczema
- Eosinophilia and high IgE
- Bone defects, including fractures (57%)
- Late or absent shedding of baby teeth (72%): double layer of teeth (fig)
LAD, Type 1 (CD18 mutation)
CD18 is required for neutrophil aggregation and extravasation
– Elevated blood neutrophils
– Few neutrophils in tissues
Recurrent infections of skin, soft tissues, respiratory and GI tracts
– Gram negative bacteria
– Staph. aureus
– Candida
– Aspergillus
Sx
- Delayed separation of the umbilical cord
- Poor wound healing
- Peridontal disease
Dx
- Flow cytometry to show lack of CD18
- DNA sequencing
Rx
– Neutrophil infusions
– Stem cell transplantation
• Requires chemotherapy; GVHD common
LAD, Type 2
- Very rare disorder of leukocyte adhesion
- Elevated blood neutrophil count
- Recurrent infections: Particularly periodontal disease
- Severe mental retardation
- Short stature and distinctive facies
- E-selectin ligands (sialyl-LewisX or CD15s) and other cell surface molecules that contain fucose are absent.
Chediak-Higashi syndrome
Autosomal recessive
Mutations in the CHS1/LYST gene affect microtubule function.
– Defective granule formation
– Defective degranulation leads to delayed release of bacteriocidal enzymes.
– Defective formation of melanin granules leads to albinism, visual defects
Sx
- Recurrent pyogenic infections: Mean survival 10 yrs
- Partial oculocutaneous albinism
- Impaired vision
- Neurologic abnormalities
- **Bone marrow transplant corrects the immunologic but not the neurologic abnormalities of CHS **
Chronic Granulomatous Disease
- Due to dysfunction of the NADPH oxidase complex
- Phagocytes cannot generate sufficient H2O2 to counteract microbial catalase
- Results in recurrent infections with catalase-positive organisms
- – Staph. aureus
- – Burkholderia cepacia
- – Serratia marcescens
- – Aspergillus species
- – Nocardia species
Sx
- Repeated infections
- Severe acne
- Nasal inflammation
- Granuloma formation
- Gingivitis
- Lymphadenopathy in CGD can be massive
Dx
- Respiratory Burst Assay
- Flow cytommetry
Rx
- Anti-microbial prophylaxis with trimethoprim-sulfa, itraconazole, and/or IFN-g
- Stem cell or gene therapies await optimal myeloablation and vectors
Wiskott Aldrich Syndrome
- X-linked recessive
- Due to mutations in the WAS gene (protein = WASp)
- Normal thymus early in disease: Progressive T cell depletion in periphery
- Minimal to no Ab responses to polysaccharide and protein Ags: Low IgM; nl IgG; high IgA, IgE
- Autoimmunity (40-72%): Vasculitis, cytopenias, arthritis
Etiopath
WASp is involved in dynamic cytoskeleton rearrangement.
– Cell migration
– Phagocytosis
– Ag presentation
– Immunological synapse
– Cytotoxic effector function
Sx
- Thrombocytopenia
- Eczema
- Recurrent infections
Ataxia Telangiectasia
Autosomal recessive
Due to mutation in the ATM gene
Etiopath:
ATM is a kinase with a critical role in repair of ds DNA breaks, activation of NF-kB, and cell cycle progression.
Mutation causes defective:
– TCR & Ig rearrangement
– T cell activation
– Lymphocyte proliferation
Sx
- dilated small blood vessels
- Ataxia due to cerebellar Purkinje cell degeneration
- Telangiectasias
- Recurrent sinopulmonary infections
- – Decreased serum Igs
- – Poor T cell function
- Predisposition to cancer
Deficiency of C2, C1[q,r,s], C4
Defects in early components of the classical pathway causes little to no increase in infections.
– Alternative pathway sufficient for infection control
– Predisposes to SLE
– C2 deficiency most common
