8/25/10 Introduction To Immune Deficiencies And Antibody Investigations

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Describe immune deficiencies that lead to recurrent infections in children and adults, and categorize them as: primary (inherited) or secondary (acquired); innate or adaptive; defects in lymphocyte maturation or activation/function

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IgG is transferred to fetus late in pregnancy

Transient hypogammaglobulinemia of infancy occurs even in normal infants at ~ 3-6 months of age (IgG drops)

Severe primary immune deficiencies often first present with infections at this same age (3-6 months)

Innate immunity: IL-12/complement/neutrophil defects

Adaptive: B/T cell defects
SCID, NK cell defects

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B cell deficiencies

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Absent or reduced follicles in lymphoid organs

Reduced serum Ig

Result: Pyogenic bacterial infections

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T cell deficiencies

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Reduced in T Cell Zones

Reduced DTH reactions to common antigens

Result: viral/intracellular microbe infections + virus-associated malignancies

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Innate immune deficiencies

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variable, dependent on branch of innate immunity

Result: pyogenic bacterial infections

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Blocks in Lymphocyte maturation

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defiencincy of adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) enzymes (purines=toxic metabolites), RAG1/2 (VDJ recombinase)

gamma chain deficiency, a component of receptors for many cytokines

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X-linked SCID (defect in lymphocyte maturation)

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marked decrease in T cells, normal or increased B cells, reduced serum Ig

Mechanism: gamma chain defective, T cell maturation defective due to lack of IL-7 signals

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Autosomal recessive SCID (defect in lymphocyte maturation)

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progressive decrease in T and B cells (mostly T) due to ADA or PNP deficiency

reduced serum Ig in ADA
normal B cells and serum Ig in PNP

Mechanism: ADA/PNP deficiencies lead to accumulation of toxic metabolites in lymphocytes

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Autosomal recessive CID (other causes) (defect in lymphocyte maturation)

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decreased T and B and serum Ig

Mechanism: genetic defective maturation of T and B, may be caused by defective RAG genes

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X-linked agammaglobulinemia aka Bruton's Disease (a B cell immunodeficiency) (defect in lymphocyte maturation)

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decrease in all serum Ig isotypes, reduced B cells

Mechanism: block in matruation beyond Pre-B cells because of a mutation in a B cell Tyr-Kin

Stem cell->ProB->PreB->immature B->mature B

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Ig heavy chain deletions (defect in lymphocyte maturation)

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IgG1/G2/G4 absent. chromosomal deletion at heavy chain locus

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DiGeorge syndrome (T cell immunodeficiency) (defect in lymphocyte maturation)

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decreased T cells, normal B cells, normal or decreased Ig

Thymus hypoplasia

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X-linked hyper IgM syndrome (defect in lymphocyte activation)

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Defect in helper T cell-dependent B cell/macrophage activation

Cause: mutation of CD40 ligand

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Common variable immunodefiency (defect in lymphocyte activation)

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reduced/no production of selective isotypes of Ig. Susceptibility to bacterial infections.

Cause: Mutations in receptor for B cell growth factors/costimulators

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Defective MHC2 expression: Bare lymphocyte syndrome (defect in lymphocyte activation)

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Lack of MHC2 expression and impared CD4+ activation. Defective cell-mediated immunity and T-dependent humoral immunity

Cause: mutations in TF genes for MHC gene

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Defect in T cell receptor complex expression or signalling

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Decreased T cells or abnormal ratio of CD4 to CD8; decreased cell-mediated immunity

Cause: mutations in CD3 proteins

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List the common causes of acquired (secondary) immunodeficiency

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HIV: depletion of CD4+ helper T cells

irradiation from chemo: decreased bone marrow precursors for all leukocytes

Bone marrow cancers: reduced leukocyte development

Protein/calorie malnutrition: inhibit lymphocyte maturation/function

removal of spleen: decreased phagocytosis by microbes

Front 17

Define the major components of serum gamma globulin

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Antibodies are in g-globulin band (this is why they are called g-globulins)--rightmost band

The g-globulin band actually contains all the immunoglobulins (IgG, IgA and IgM)

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Define immune complex and describe methods for measuring immunoglobulins and complement components in serum that depend on the formation of immune complexes

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Front 19

Explain the use of the enzyme linked immunosorbent assay (ELISA) and Western blot assay in the diagnosis of infection

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ELISA: wells coated with antigen. then serum added, bind to antigen. then anti-antibody added. add substrate (pigment)

Western Blot for HIV:
Positive: antibodies in patient’s serum react with at least two of these three proteins: p24 (capsid protein), gp41 (mediates fusion) and gp160 (envelope protein which is cleaved into gp120 and gp41)

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Describe the significance of an IgM vs IgG response or a rise in the titer of an IgG antibody in the diagnosis of an infection

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IgM = recent infection
IgG = chronic/recurrent infection

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Describe the principles that govern precipitation reactions by defining the three zones in an antigen-antibody precipitin curve and defining the term prozone

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