CD4 + T cells regulate adaptive responses to pathogens by secreting unique subsets of cytokines that mediate inflammatory processes. The innate cytokines IL-12 and IFN-α/β regulate type I responses and promote acute IFN-γ secretion through the activation of the STAT4 transcription factor. Although IL-12-induced STAT4 activation is a conserved pathway across species, IFN-α/β-dependent STAT4 phosphorylation does not occur as efficiently in mice as it does in human T cells. In order to understand this species-specific pathway for IFN-α/β-dependent STAT4 activation, we have examined the molecular basis of STAT4 recruitment by the human IFNAR. In this report, we demonstrate that the N-domain of STAT4 interacts with the cytoplasmic domain of the human, but not the murine IFNAR2 subunit. This interaction mapped to a membrane-proximal segment of the hIFNAR2 spanning amino acids 299-333. Deletion of this region within the hIFNAR2 completely abolishes IFN-α/β-dependent STAT4 tyrosine phosphorylation when expressed in human IFNAR2-deficient fibroblasts. Thus, the human IFNAR2 cytoplasmic domain serves to link STAT4 to the IFNAR as a pre-assembled complex that facilitates cytokine-driven STAT4 activation.

IgG antinuclear antibodies (ANAs) are elevated in patients with systemic lupus erythematosus (SLE) compared with patients with discoid lupus erythematosus (DLE). To provide an expanded immunologic view of circulating ANAs in lupus patients, we compared the expressions of IgG, IgM, and IgA ANAs in DLE and SLE patients. In this cross-sectional study, sera from age-, gender-, and ethnic-matched SLE (N = 35), DLE (N = 23), and normal patients (N = 22) were tested for IgG, IgM, and IgA ANAs using enzyme-linked immunosorbent assays (ELISAs) and indirect immunofluorescence (IIF) with monkey esophagus as substrate. ELISAs showed elevated levels of IgG ANA, IgM ANA, and IgG/IgM ANA ratios in SLE patients compared with DLE and normal patients. IgA ANA expression was higher in SLE and DLE patients versus normal patients. IIF studies showed higher percentages of patients positive for IgG, IgM, and IgA ANAs in the SLE group. Higher IgG/IgM ANA ratios in SLE than DLE show enhanced class-switching and a more sustained humoral response in SLE. They also suggest a potential connection of IgM ANAs with disease containment.

CD4+ T cells directly participate in bacterial clearance through secretion of proinflammatory cytokines. Although viral clearance relies heavily on CD8+ T cell functions, we sought to determine whether human CD4+ T cells could also directly influence viral clearance through cytokine secretion. We found that IFN-γ and TNF-α, secreted by IL-12-polarized Th1 cells, displayed potent antiviral effects against a variety of viruses. IFN-γ and TNF-α acted directly to inhibit hepatitis C virus replication in an in vitro replicon system, and neutralization of both cytokines was required to block the antiviral activity that was secreted by Th1 cells. IFN-γ and TNF-α also exerted antiviral effects against vesicular stomatitis virus infection, but in this case, functional type I IFN receptor activity was required. Thus, in cases of vesicular stomatitis virus infection, the combination of IFN-γ and TNF-α secreted by human Th1 cells acted indirectly through the IFN-α/β receptor. These results highlight the importance of CD4+ T cells in directly regulating antiviral responses through proinflammatory cytokines acting in both a direct and indirect manner.

Importance Anti-type VII collagen autoantibodies are often detectable in patients with bullous systemic lupus erythematosus (BSLE); however their timing of appearance preceding onset of disease is unknown. Observations We report the case of a 50-year-old female with a history of systemic lupus erythematosus who presented with vesicles and bullae around her lips, trunk, axillae, arms, and thighs. Histologic analysis as well as immunofluorescence and immunoblot studies confirmed the diagnosis of BSLE. Immunoblotting and ELISA studies of the patient’s serum obtained three months prior to the onset of BSLE showed presence of anti-type VII collagen autoantibodies. Levels of anti-type VII collagen IgG increased after bullous lesions appeared. Within one month after initiating dapsone and increasing the dose of prednisone, skin lesions promptly resolved. A year after onset of BSLE, her anti-type VII collagen IgG decreased below levels observed prior to the inception of her bullous lesions. Conclusions and Relevance This study shows that anti-type VII collagen autoantibodies can precede the clinical appearance of BSLE. The subsequent increase and decrease in the levels of circulating anti-type VII collagen autoantibodies, which mirrored skin disease activity, support a potential role in their initiation of disease.

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