AIDS is characterized by many immunologic abnormalities. One of the most frequently observed, yet relatively unstudied, is the notable elevation in serum IgA seen in most patients. The human IgA system is unique in that IgA is derived from two relatively independent sources. Serum IgA is primarily produced by plasma cells in the bone marrow, is predominantly monomeric, and is composed primarily (85%) of the IgA1 subclass. On the other hand, secretory or mucosal IgA is produced by plasma cells in mucosal sites (e.g., gastrointestinal or upper respiratory tracts), is composed of dimers or polymers linked by J chain, contains secretory component, and contains IgA1 and IgA2 in approximately equal proportions. This structural compartmentalization of human IgA molecules is mirrored by functional differences: human serum IgA has no known function, while the protective role of secretory IgA at mucosal sites is well documented. The reason for the elevated serum IgA levels in AIDS is unknown, although it seems unlikely that it is a result of random polyclonal activation, since the hypergammaglobulinemia of AIDS is not associated with increases in all isotypes. The objective of the proposed investigation is to utilize the known structural and serologic differences of serum and secretory IgA to determine the origin and function of the elevated IgA in sera of AIDS patients. The molecular form and subclass distribution of total IgA and anti-HTLV-III/LAV antibodies in sera and saliva will be examined, as will be the IgA and specific anti-viral antibodies produced by peripheral blood cells as well as isolated gastrointestinal cells. Further, we shall determine the role of IgA in the composition of circulating immune complexes (CIC) that are also a hallmark of this disease. In preliminary studies we have found that a significant portion of AIDS patients have serum rheumatoid factor of the IgA class (IgA RF); therefore, we shall examine and characterize this IgA RF with respect to structure and subclass composition and determine its contribution to the elevated levels of serum IgA as well as to the CIC. The characterization of IgA, with respect to its specificity for HTLV-III/LAV as well as subclass distribution and molecular form in serum, secretions and CIC, will answer basic questions regarding the pathogenesis of AIDS and the role of IgA, and Ig isotype generally considered incapable of protecting the host by the mechanisms ascribed to other isotypes.
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