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Austin Mircheff, Yanru Wang; Positive- and Negative Regulation of Transcripts Associated with Formation of Sjögren’s Lesions. Invest. Ophthalmol. Vis. Sci. 2013;54(15):963.
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© ARVO (1962-2015); The Authors (2016-present)
Sjögren’s immunopathology involves ectopic lymphoid tissues that generate autoantigen-specific IgG+ B cells. CCL21 recruits T cells to the lesions; CXCL13 recruits B cells; IL−4 and IL−10 induce B cell activation and differentiation; and BAFF and IL−6 support T cell and B cell proliferation. Once formed, the lesions are self-sustaining.
Transcript abundances were measured in individual lacrimal glands from groups of rabbits that had experienced five different environmental conditions: cool, temperate, hot, dry, and hot and dry. Transcripts were sorted into clusters on the basis of deviations from heuristics for quantitative relationships to the environmental variables and on the basis of strong and significant correlations.
The abundances of mRNAs for IL−4, IL−6, BAFF, and IL−10 increased exponentially with increasing dryness. IL−6 and IL−10 were consistently associated with CTLA-4 and CD8, but IL−4 and BAFF were associated with the T cell surface proteins only above a threshold of dryness. Each of the four cytokine transcripts sorted to a different cluster, suggesting that each was expressed by a different T cell type. Heat augmented BAFF above the exponential growth heuristic, but in the hot setting BAFF associated with IL−4 inversely (ρ = −0.961, P = 0.038). The combination of heat and dryness augmented IL−4 above the exponential growth heuristic, and in that setting BAFF associated with IL−4 positively (ρ = 0.789, P = 0.020). mRNAs for CCL21 and CXCL13 were associated with mRNAs for CD4, CD3ε, and CD3ζ, but they sorted to different clusters. CCL21 mRNA increased exponentially with increasing heat. Dryness suppressed CCL21 below the exponential growth heuristic. The relationship between CXCL13 and heat was biphasic; it was suppressed below the exponential growth heuristic in the hot and hot and dry settings.
Non-diseased lacrimal glands host populations of T cells expressing transcripts for chemokines and cytokines that may come to be involved in ectopic lymphoid tissue formation. The cytokine- and chemokine-expressing cells are regulated differently, and environmental stresses promoting exponential expansion of one type or the other would produce quite different immunopathologies. Negative feedback interactions prevent formation of B cell inductive tissue. It may be that Sjögren’s pathogenesis depends on abrogation of the negative regulatory signals.
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