Iid - Immunodeficiency

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General clinical presentations of T cell deficiencies

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Recurrent opportunistic infections

Absence or deficiency of T cells

Functional deficiencies in T cells

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Thymic hypoplasia

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Pathogenesis: Abnormalities in embryogenesis of the 3rd or 4th pharyngeal pouches lead to incomplete or absent development of the thymus, resulting in a failure of mature T cells to develop

Disease caused: DiGeorge Syndrome

Diagnosis: Presence in infants with characteristic abnormalities in facial features, heart, and parathyroids of severe infections of all types, decreased T cell with normal B cell numbers

Therapy: If a remnant of the thymus remains, the individual that survives can recover with time. Severe cases are treated with a thymus graft. Live or attenuated viral vaccinations need to be avoided.

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Mutations in Recombination Activating Genes (RAG1 or RAG2)

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Pathogenesis: Mutations in RAG2 or RAG2 prevent the normal functioning of the VDJ recombinase in TCR gene recombinations, resulting in a failure to develop antigen receptors.

Disease caused: SCID

Diagnosis: Presence in an infant with recurrent infections of severely decreased numbers of lymphocytes, complete absence of T or B cells, absent responsiveness to mitogens and polyclonal activators, and severe hypogammaglobulinemia

Therapy: Aggressive early treatment of infections, stem cell transplantation. Gene therapy is being tried experimentally.

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Mutation resulting in defective gamma chain in the common cytokine receptor

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Pathogenesis: X-linked mutations in the common gamma chain, a signaling subunit of receptors for numerous cytokines, including IL-2, IL-4, etc. prevent these cytokines from promoting the precursor expansion and survival. In humans, the defect affects mainly T cell maturation; however, B cell responses are affected because of the lack of T cell help

Disease caused: SCID (half of SCID cases)

Diagnosis: Males, presents in infancy with recurrent infections, decreased lymphocytes (specially T cell) and decreased responses to T cell mitogens with normal B cells but reduced serum Ig

Therapy: Agressive and early treatment of infections; stem cell transplantation; gene therapy is being tried experimentally

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Mutation resulting in deficiency of adenosine deaminase (ADA or purine nucleoside phosphorylase (PNP)

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Pathogenesis: Mutations in ADA and PNP, enzymes involved in degrading purines, lead to buildup of toxic metabolites of pruines that are produced by actively dividing cells. These defects affect T cells (and therefore cell-mediated immunity) more than B cells; however, humoral immunity is also affected because of the deficiency of T cell help.

Disease caused: SCID

Diagnosis: Male and female; recurrent opprotunistic infections since infancy; depressed lymphocyte numbers with a progressive decrease in T and B cells (mostly T), decreased skin reactions and responsiveness to mitogens or polyclonal activators; and decreased (ADA defect) or normal (PNP defect) serum Ig.

Therapy: Aggressive and early treatment of infections and stem cell transplantation. Gene therapy is being tried.

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Mutations resulting in defective MHC class II expression

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Pathogenesis: Failure to express MHC class II on antigen presenting cells results in a failure of CD4+ T cells to mature in the thymus.

Disease caused: Bare lymphocyte syndrome

Diagnosis: Rare, autosomal recessive defect resulting in recurrent infections from infancy, especially of the GI tract; flow cytometry of peripheral blood mononuclear cells shows absence of CD4+ and MHC Class II+ cells.

Therapy: Aggressive and early treatment of infections and stem cell transplantation.

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Wiskott-Aldrich syndrome

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Pathogenesis: Malfunction of protein that binds to varous adapter molecules and cytoskeletal components. Malfunction leads to altered morphology of T cells as well as other hematopoietic cells and a failure of T cells to develop normally. Both cellular and humoral immunity is impaired.

Clinical presentation: Eczema and susceptibility to infection with encapsulated organisms, such as Streptococcus pneumonia

Therapy: Aggressive and early treatment of infections and stem cell transplantation

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Ataxia-telangiectasia

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Pathogenesis: Mutations in a gene involved in DNA repair. May lead to abnormal DNA repair during TCR and Ig gene recombination, resulting in defective lymphocyte maturation.

Clinical immune presentation: Variable deficiency in cell mediated immunity and IgA, IgG2 and IgG4.

Therapy: Early and aggressive treatment of infections.

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Chronic Mucocutaneous Candidiasis

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Individuals mount Th2 response when a Th1 response would be more appropriate

Ineffective responses to Candida albicans

Absense of T cell reactivity to Candida antigens

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Autoimmune Lymphoproliferative Syndrome (ALPS)

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Defects in either Fas or FasL result in defects in activation induced cell death

Mutations in FoxP3 result in a failure of regulatory T cells to develop, leading to multiple autoimmune syndromes

Caused by IPEX (x-linked)

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General clinical presentations of B cell deficiencies

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Recurrent bacterial infections

Onset is detected after 5-6 months of age

Absence of mature B cells and serum Ig isotypes

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Bruton's Agammaglobulinemia

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X-linked mutation inactivates the BTK enzyme, which is critical to maturation of B cells beyond the pre-B cell stage

Mature B cells and Ig absent

Therapy: Repeated infusions of gamma globulin preparations, prompt treatment of infections.

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Hyper IgM syndrome

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Mutation in CD40 ligand; T cell does not provide the co-stimulatory necessary for class switching in B cells and there is a build-up of IgM positive B cells or T cell dependent activation of macrophages

Pyogenic bacteria infections, high levels of IgM, low levels of IgA and IgG

B cells only express surface IgM and IgD

Treatment: Aggressive treatment of infections

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Selective IgA deficiency

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Patients have normal or increased numbers of B cells with surface IgA, suggesting a defect in maturation of these B cells into antibody secreting plasma cells.

MOST COMMON IMMUNODEFICIENCY DISORDER

20% also deficient for IgG2 and 4

Recurrent respiratory and GI infections; many will also develop type 3 hypersensitivity

do NOT treat with gamma globulin

Aggressive and early treatment of infections

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Hereditary Angioneurotic Edema (HAE)

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The C1 inhibitor is responsible for dissociated of activated C, thus inhibiting the classical complement pathway. The inhibitor is inactive.

Causes swelling, most commonly in lips and upper airways and the GI tract

Therapy: When the upper airway is severely involved, emergency treatment is required (epinephrine / steroids, or, in some cases, tracheostomy)

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Chronic Granulomatous Disease

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Ineffectiveness of phagocyte oxidases in killing and elimination of intracellular microbes allows persistence of these microbial antigens that result in persistent cell-mediated responses to these organisms

Presentation: Localized granulomas (type IV hypersensitivity), pneumonia, infections in the lymph nodes, abscesses in skin, liver, other organs

Therapy: Rapid and aggressive antibiotic treatment of infections