The major goals are to define the defects in lymphocyte differentiation or function associated with immune deficiency diseases, lymphoid malignancies, and disorders of immunoregulation. The underlying thesis is that some of the gaps in knowledge about the human immune system can be addressed by the comparative analysis of the normal ontogeny of the immune system and the immune system defects in primary immunodeficiency diseases. Emphasis is on (1) the ontogeny of B cell development in humans, (2) the genetic basis of immunodeficiency, and (3) the influence of gene defects on the differentiation of immunocompetent cells. X- linked agamma-globulinemia (XLA) remains the prototype of primary immunodeficiency diseases. Although the affected gene underlying XLA has been identified, the molecular mechanisms that lead to the disruption of B cell development is poorly understood. The hypothesis to be tested is that the block in XLA is not an abrupt termination of cells between the pre-B and B cell stage, but that deviant development is apparent at earlier stages in pre-B cell development. In previously supported work, evidence of a genetic link between the two most common primary immunodeficiency diseases, IgA deficiency (IgAD) and common variable immunodeficiency (CVID), was obtained. Genetic susceptibility for IgAD or CVID in a large subgroup of patients may be associated with a gene or genes located in the class III MHC region. The disease phenotype and prevalence of immunodeficiency in the offspring of IgAD/CVID patients differ in individuals who lack the susceptibility MHC haplotype. Analysis of MHC haplotypes in patients and their families to elucidate which gene in the MHC region is associated with these diseases will be continued. A population of memory B cells that is acquired in the bone marrow after birth has been identified. Based upon preliminary results suggesting an arrest of the normal progression of memory B cell activation in CVID, the hypothesis that this population of memory B cells may not be acquired normally in CVID patients will be tested.
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