Surprisingly, GN still develops in lyn–/–IL-21–/–

mice T

Surprisingly, GN still develops in lyn–/–IL-21–/–

mice. This likely results from the presence of IgG autoantibodies against a limited set of non-DNA Ags. These studies identify a specific role for IL-21 in the class switching of anti-DNA B cells and demonstrate that neither IL-21 nor anti-DNA IgG is required for kidney damage in lyn–/– mice. The autoimmune disease systemic lupus erythematosus (SLE) is driven by the production of autoantibodies and exacerbated by innate immune system hyperactivation. This leads to inflammation and Selleck Ridaforolimus damage to multiple organs, including the kidneys. Genetic studies in humans and mice have identified multiple pathways that contribute to the autoimmune phenotypes associated with lupus [1, 2]. Despite these advances, the majority of current treatments for SLE involve nonspecific immunosuppression. A more thorough understanding of the mechanism(s) responsible for the initial loss of tolerance and the subsequent end organ damage might facilitate the development of more targeted therapies. Lyn-deficient mice lack a critical negative regulator of B-cell and myeloid cell activation [3]. These mice exhibit hyper-active B cells, plasma cell (PC) accumulation, autoantibodies, Mdm2 inhibitor and glomerulonephritis

(GN) [4-6], all features of SLE. Reduced Lyn expression has been observed in B cells from SLE patients [7, 8], and polymorphisms in the lyn gene have been associated with SLE [9, 10]. By defining the requirements for autoantibody production and kidney damage

in lyn–/– mice, we hope to better understand the events that disrupt normal B-cell tolerance checkpoints and the consequences of these for disease pathology. We previously identified two stages in the development of humoral autoimmunity in this model [11]. The first involves the accumulation of PCs and IgM autoantibodies, while the second controls the class switching of autoreactive B cells specific for lupus-associated autoantigens such as dsDNA. The latter step requires IL-6, a proinflammatory cytokine associated with autoimmunity Sulfite dehydrogenase in mice and humans [11, 12]. Understanding how IL-6 promotes autoantibody production in lyn–/– mice may have important clinical applications, as anti-IL6R antibodies are currently in trials as a therapy for SLE [13]. While IL-6 has pleiotropic effects [14], it likely promotes autoantibody production via the cytokine IL-21. IL-6 induces IL-21 expression by multiple subsets of CD4+ T cells [15-17]. IL-21 is a potent stimulator of B-cell differentiation [15, 18-24] and class switching [18, 19, 25-27] and promotes GC maintenance [21, 28]. IL-21 and/or IL-21-producing cells such as T follicular helper (Tfh) cells or extrafollicular T helper cells are elevated in several murine lupus models [18, 29-32]. In BXSB.Yaa [31] and MRL.lpr mice [33, 34], blocking IL-21 signaling can prevent autoimmune pheno-types.

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