Although impressive progress has been made toward understanding the biology of the etiologic agent of AIDs as well as the basis of its pathogenicity, new cases of the disease continue to increase worldwide at logarithmic rates, with no currently available means of either prevention or cure. AIDS is earmarked by a multitude of immune abnormalities, some of which are poorly understood. One of the relatively uncharacteracterized disorders of immune function in AIDS is an apparent dysfunction of IgA regulation. This is typified by inversely affected levels of serum and secretory IgA (often in the absence of alterations in the levels of other immunoglobulin isotypes), as well as elevated levels of IgA- containing immune complexes and IgA rheumatoid factor (RF). Understanding these often IgA-specific immunopathologies as well as the IgA immune system in general is imperative in a disease that is so often mucosally acquired as well as associated with multiple secondary infections at mucosal surfaces. Therefore, we will use the known serological and structural differences of serum and secretory IgA to elucidate the origin and function of IgA produced by the systemic and mucosal IgA systems in AIDS. At the cellular level we will study the immunoglobulin isotypes, including subclasses and molecular form of IgA, produced by peripheral blood lymphocytes, bone marrow, and lymphoid cells of sigmoid colon of AIDS patients; we will perform similar analyses on HIV-specific antibodies produced by the same cell populations. Since serum IgA is normally produced primarily in the bone marrow, we will examine the regulation of IgA synthesis by bone marrow cells of AIDS patients. We will examine the functional role of IgA antibodies, specifically with regard to: antibody-mediated enhancement of HIV infectivity; role in mediation or inhibition of ADCC and HIV neutralization; and identification of IgA autoantibodies. Other Studies will aim at identifying the cellular origins of IgA RF, using the same cell populations defined above. We will also characterize both serum and secretory (salivary) IgA and IgA antibodies specific for HIV with respect to IgA subclass and molecular form. Finally, we will further analyze the IgA- containing immune complexes in the sera of AIDS patients and correlate the composition and levels of these complexes with clinical status. These studies will answer basic questions as to the role of IgA, an immunoglobulin isotype generally considered incapable of protecting the host by classical mechanisms, in the pathogenesis of AIDS, a disease characterized by notable aberrations in IgA regulation.
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