This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Antinuclear antibodies of particular specificities (e.g. anti-DNA, anti-Sm) are highly associated with systemic lupus erythematosus (SLE). Why these specificities are produced in lupus, but not other autoimmune diseases, is unexplained. Similar autoantibodies can be induced in non-autoimmune prone mice by pristane. Preliminary studies strongly implicate IL-4 and the proinflammatory cytokines IL-6, IL-12, and IFNy in the formation of different subsets of autoantibodies. Altering the cytokine milieu from Th2 to Th1 can change the autoantibodies produced by a given strain of mouse. Thus, cytokine overproduction may be a key factor determining the autoantibody phenotype. We have found that autoantibody phenotypes in SLE patients also can change. We hypothesize that, as in the mouse, cytokine overproduction may be a critical factor determining autoantibody specificity, i.e. autoantibody phenotypes in SLE may be markers for different forms of SLE mediated by different cytokines. Several predictions of this model will be evaluated. We will look for human autoantibody phenotypes , defined as groups of autoantibodies produced together more frequently than predicted by chance (Aim 1). For instance, anti-Sm and anti-Ku are strongly associated with one another. We expect to find additional examples. The frequencies of these phenotypes will be determined in African-American, Caucasian, and other SLE cohorts. We will then determine whether the autoantibody phenotypes correlate with certain patterns of cytokine overproduction (Aim 2). A variety of cytokines, some of them contributing to autoantibody formation in mice, will be measured directly in the blood and indirectly in affected tissues through the use of surrogate markers. Finally, we will carry out prospective studies to explore the possibility that the overproduction of IFNy, which drives anti-nRNP/Sm autoantibody production in mice, increases the risk of developing a subset of autoantibodies in human lupus (Aim 3). We hypothesize that there may be certain lupus patients, including many African-Americans, who overproduce IFNy. Another group of SLE patients, most commonly Caucasians, may overproduce a different set of cytokines. This may help explain some of the striking serological differences between races. Thus, like murine lupus, human SLE may be several diseases with overlapping clinical manifestations but a different pathogenesis. If so, there could be significant implications for the early diagnosis of autoimmunity and its treatment.
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