Eta-1 is a single copy gene encoding a 60 kD glycoprotein secreted by activated T-cells. Studies indicate the Eta-1 gene maps to a locus that confers genetic resistance to lethal infection by intracellular bacterial parasites. Inbred mouse strains bearing the Eta-1a allele display strong and rapid Eta-1 responses after bacterial infection and are resistant to intracellular bacterial growth. Conversely, inbred strains that carry the b allele exhibit delayed and reduced Eta-1 responses and are unable to contain bacterial growth. Studies of the cellular mechanism of genetic resistance conferred by Eta-1 suggest that binding of the Eta-1 protein to specific receptors on macrophages may be responsible for resistance. A second area of study comes from examination of cell surface events and intracellular signalling pathways that lead to cytokine expression in CD4+ T-cells after stimulation by bacterial and retroviral superantigens. Analysis of cytokine gene expression after T-cell activation by the two types of ligand indicates that a putative Ca2+-independent activation pathway triggered by superantigen leads to expression of the Eta-1 gene but not IFN-gamma, IL-2 or IL-3 expression. By contrast, triggering of the same clone by conventional peptide-I-A complexes results in strong induction of all of these cytokines. The proposed studies will further define and distinguish the activation pathway triggered by superantigen resulting in selective Eta-1 gene expression from the pathway coupled to TCR ligation by conventional peptide I-A complexes. A third are of study comes from the identification of an example of dysregulated Eta-1 expression. We screened a panel of inbred mouse strains that develop different types of autoimmune disorders for evidence of elevated levels of constitutive Eta-1 expression. We found that MRL/1pr mice display a selective and substantial elevation of Eta-1 gene expression. Further studies of the interaction between Eta-1 and B-cells indicate that this cytokine promotes IgM and IgG production. These observations open the possibility that dysregulated Eta-1 expression may be responsible for polyclonal B-cell activation, the hallmark of this form of murine lupus. These findings also suggest that a subset of the autoimmune diseases may be marked by dysregulated expression of Eta-1 and thus represent a discreet nosologic entity within the autoimmune disease spectrum. If so, treatment of this biochemical disorder may be directed at correction of Eta-1 overexpression rather than current approaches which employ non-specific immunosuppressive agents.
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