Abstract
We have previously shown that B6 congenic mice with a New Zealand Black chromosome 1 (c1) 96-100 cM interval produce anti-nuclear Abs and that at least two additional genetic loci are required to convert this subclinical disease to fatal glomerulonephritis in mice with a c1 70-100 cM interval (c1(70-100)). Here we show that the number of T follicular helper and IL-21-, IFN-γ-, and IL-17-secreting CD4+ T cells parallels disease severity and the number of susceptibility loci in these mice. Immunization of pre-autoimmune mice with OVA recapitulated these differences. Differentiation of naïve T cells in-vitro under polarizing conditions and in-vivo following adoptive transfer of OVA-specific TCR transgenic cells into c1(70-100) or B6 recipient mice, revealed T cell functional defects leading to increased differentiation of IFN-γ- and IL-17-producing cells in the 96-100 cM and 88-96 cM intervals, respectively. However, in-vivo enhanced differentiation of pro-inflammatory T cell subsets was predominantly restricted to c1(70-100) recipient mice, which demonstrated altered dendritic cell function, with increased production of IL-6 and IL-12. The data provide support for the role of pro-inflammatory T cells in the conversion of subclinical disease to fatal autoimmunity and highlight the importance of synergistic interactions between individual susceptibility loci in this process.
Highlights
Systemic Lupus Erythematosus (SLE) is a generalized autoimmune disease characterized by the production of autoantibodies, those directed against nuclear antigens, which form immune complexes that deposit in tissues
Consistent with the increases in T follicular helper (Tfh), and our previous findings, there was a trend to increased proportions of germinal centers (GC) B cells in all three congenic mouse strains with the greatest increase seen in c1(70-100) mice (Figure S1A& B)
To determine whether the increased production of IL-21, IL-17, and IFN-γ in c1 congenic mice was a consequence of the breakdown in tolerance to nuclear antigens, or resulted from intrinsically altered immune function leading to skewed Tfh, Th17 and Th1 development, we investigated the immune response to OVA as a representative exogenous antigen
Summary
Systemic Lupus Erythematosus (SLE) is a generalized autoimmune disease characterized by the production of autoantibodies, those directed against nuclear antigens, which form immune complexes that deposit in tissues. Studies of SLE in humans and lupus-prone mice indicate that multiple genetic polymorphisms affecting diverse immune populations interact with each other to produce the lupus phenotype. Among these populations are T helper (Th) cells. Early studies demonstrated a predominant role for Th1 cells in lupus, several recent studies suggest that two other pro-inflammatory Th cell subsets, T follicular helper (Tfh) and Th17 cells, are pathogenic [1]. Tfh cells are a distinct subset of Th cells that provide help for antigen specific B cell responses in the context of germinal centers (GC) and produce high levels of IL-21 [2,3]. A potential role for this population in the pathogenesis of lupus was first suggested by the observation that lupus-prone mice with a homozygous point mutation in the Roquin gene, demonstrated expansion of their Tfh population, and subsequently supported by demonstration of similar expansions in MRLlpr and BXSB/ Yaa lupus-prone mice [4]
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