Immunology: Primary Immunodeficiency Disorders 8

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Immunodeficiency Disease

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Primary: congenital
-manifest infancy bw 6months-2yrs
-genetic: x-linked or autosomal recessive
-affects differentiation & maturation of B & T Cells
-infant has increased suscept. to recurrnet infection
-eval: serum reveals low or no levels of specific Ig isotypes

Secondary: autoimmune diseases

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Immunodeficiency Disease

Back 2

Primary: congenital
-manifest infancy bw 6months-2yrs
-genetic: x-linked or autosomal recessive
-affects differentiation & maturation of B & T Cells
-infant has increased suscept. to recurrnet infection
-eval: serum reveals low or no levels of specific Ig isotypes

Secondary: autoimmune diseases

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DiGeorge Syndrome

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-thymic hypoplasia: deficiency of cell-mediated T-cell
-defective embryological development of 3rd & 4th pharyngeal pouches (thymus & parathyroid)
-total absence of cell-mediated immunity = lack of thymus
-infant prone to viral, parasitic, & fungal infections
-characteristic facial features (microcephaly w/ 40% borderline/mild mental retardation)
-90% cases = deletion of chromosome 22 (TBX1 gene)
-10% cases = aut. dom.
-present in infant w/ heart defect (VSD) & interrupted aortic arch
-hypocalcemia & tetany bc lack of parathyroid
-disease corrected by transplanting normal thymic tissue or bone marrow transplant

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DiGeorge Syndrome

Back 4

-thymic hypoplasia: deficiency of cell-mediated T-cell
-defective embryological development of 3rd & 4th pharyngeal pouches (thymus & parathyroid)
-total absence of cell-mediated immunity = lack of thymus
-infant prone to viral, parasitic, & fungal infections
-characteristic facial features (microcephaly w/ 40% borderline/mild mental retardation)
-90% cases = deletion of chromosome 22 (TBX1 gene)
-10% cases = aut. dom.
-present in infant w/ heart defect (VSD) & interrupted aortic arch
-hypocalcemia & tetany bc lack of parathyroid
-disease corrected by transplanting normal thymic tissue or bone marrow transplant

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Chronic Mucocutaneous Candidiasis

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-yeast infection = congenital lack in Tcell fxn
-suscept. to candidal infections
-assoc endocrinopathy present (DM, Addisons, hypoparathyroidism)
-impaired response to candida Ag (cause unkown, but most other Tcell fxn intact)
-ab skin fold, thrush

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Chronic Mucocutaneous Candidiasis

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-yeast infection = congenital lack in Tcell fxn
-suscept. to candidal infections
-assoc endocrinopathy present (DM, Addisons, hypoparathyroidism)
-impaired response to candida Ag (cause unkown, but most other Tcell fxn intact)
-ab skin fold, thrush

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Congenital X-linked Agammaglobulinemia of Bruton

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-most common forms of primary immunodeficiencies
-absence of ALL serum Igs
-X-linked recessive & restricted to males (infant 5-8 months - when maternal Ab decline)
-recurrent pyogenic infection (Staph, Strep, H. flu) - conjuctivitis, pharyngitis, otitis media, bronchitis, & pneumonia
-normal Tcell (can fight viral & fungal infect)
-enteroviruses can cause GI disease (echo, polie, coxsackievirus)
-immunization w/ live-attenuated poliovirus = paralytic poliomyelitis infection
-gene defect located Xq21 (mut. of gene for Bcell tyrosine kinase - ATK) enzyme critical for Bcell maturation
-absence of mature Bcell in blood & loss of Bcell follicles in lymph tissue (nodes, appendix, & spleen)
-increased freq. of autoimmune: SLE & dermatomyositis
-50% children develop. rheum. arthritis (mycoplasma)
-basis for disease are unknown
-treatment is replace all Igs

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Congenital X-linked Agammaglobulinemia of Bruton

Back 8

-most common forms of primary immunodeficiencies
-absence of ALL serum Igs
-X-linked recessive & restricted to males (infant 5-8 months - when maternal Ab decline)
-recurrent pyogenic infection (Staph, Strep, H. flu) - conjuctivitis, pharyngitis, otitis media, bronchitis, & pneumonia
-normal Tcell (can fight viral & fungal infect)
-enteroviruses can cause GI disease (echo, polie, coxsackievirus)
-immunization w/ live-attenuated poliovirus = paralytic poliomyelitis infection
-gene defect located Xq21 (mut. of gene for Bcell tyrosine kinase - ATK) enzyme critical for Bcell maturation
-absence of mature Bcell in blood & loss of Bcell follicles in lymph tissue (nodes, appendix, & spleen)
-increased freq. of autoimmune: SLE & dermatomyositis
-50% children develop. rheum. arthritis (mycoplasma)
-basis for disease are unknown
-treatment is replace all Igs

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Selective IgA Deficiency

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-most common primary immunodeficiency disease (1:600)
-low serum & secretory [IgA]
-asymptomatic but present w/ GI or respiratory infect of varying severity
-stron predilection for allergies & mucosal defense weakened
-normal #s of Iga-bearing Bcells but defect in terminal differentiation of Bcells to IgA
-rare assoc. w/ autoimmune SLE & rheum. arthritis

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Selective IgA Deficiency

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-most common primary immunodeficiency disease (1:600)
-low serum & secretory [IgA]
-asymptomatic but present w/ GI or respiratory infect of varying severity
-stron predilection for allergies & mucosal defense weakened
-normal #s of Iga-bearing Bcells but defect in terminal differentiation of Bcells to IgA
-rare assoc. w/ autoimmune SLE & rheum. arthritis

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Common Variable Immunodeficiency

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-group of disorders char. by hypogammaglobulinemia (defect in BCell maturation or ability of Tcell to send approp. activation signal to Bcell matur)
-recurrent pyogenic infections (pneumonias) & diarrhea (amoebic parasite = giardia)
-manifests later in life (~15-20yrs), affects both sexes equally
-inheritance pattern variable (1 in 50-100,000)
-histologically: Bcell areas are hyperplastic (proliferate in response to Ag, but no production of Ab)
-50x increase of CVID & stomach cancer
-higher incidence of lymphomas in women than men
-assoc. of acquired autoimmune disorders like rheum. arthritis & inflam. bowel disease

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Wiskott-Aldrich Syndrome

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-rare X-linked recessive Xp11
-recurrent infection, hemorrhages secondary to thrombocytopenia & exzema (usually leads to death at an early age)
-typ. present in boys w/in 1st few months of life (petechiae & infect otitis media)
-infec. range from strep pneumonia to H flu & C. albicans to P. carinii
-thrombocytopenia severe, char. by small platelets
-1/3 patients bleed is cause of death
-syndrome caused by mut. of x chrom (protein called WASP) -> cause defects in cell & humarl immunity (lymphocytes & megakaryocytes) mxn unknown
-IgM extrememly low/absent (essential for combat encapsulated bacterial/viral infect)
-selective deficiencies in Tcells (suscept to Candida, Herpes, CMV)
-autoimmune complicate: polyarthritis & casculitis of coronary or cerebral vessels
-increase incidence of lymphoproliferative malignancies
-bone marrow transplant cure over 90%

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Severe Combined Immunodeficiency

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-swiss-type agammablobulinemia
-affects both Tcell & Bcells
-recurrent viral, bacterial, fungal, & protozoan infections
-related to defect in all lymph stem cells
-thymus = hypoplastic (lymph nodes & appendix lacks germinal centers)
-x-linked & aut. rec. (before 6mnth age)
-60% x-linked (boys) defect: receptor for various cytokines (needed for prolif. of lymphoid stem cells)
-aut rec: def. of enzyme adenosine deaminase (ADA) - accum of deoxyadenosine (toxic to immature lymphocytes)
-treatment = bone marrow transplant