Impaired B Cell Apoptosis Results in Autoimmunity That Is Alleviated by Ablation of Btk

While apoptosis plays a role in B-cell self-tolerance, its significance in preventing autoimmunity remains unclear. Here, we report that dysregulated B cell apoptosis leads to delayed onset autoimmune phenotype in mice. Our longitudinal studies revealed that mice with B cell-specific deletion of pro-apoptotic Bim (BBimfl/fl) have an expanded B cell compartment with a notable increase in transitional, antibody secreting and recently described double negative (DN) B cells. They develop greater hypergammaglobulinemia than mice lacking Bim in all cells and accumulate several autoantibodies characteristic of Systemic Lupus Erythematosus (SLE) and related Sjögren’s Syndrome (SS) including anti-nuclear, anti-Ro/SSA and anti-La/SSB at a level comparable to NODH2h4 autoimmune mouse model. Furthermore, lymphocytes infiltrated the tissues including submandibular glands and formed follicle-like structures populated with B cells, plasma cells and T follicular helper cells indicative of ongoing immune reaction. This autoimmunity was ameliorated upon deletion of Bruton’s tyrosine kinase (Btk) gene, which encodes a key B cell signaling protein. These studies suggest that Bim-mediated apoptosis suppresses and B cell tyrosine kinase signaling promotes B cell-mediated autoimmunity.

Using the K/BxN mouse model of endogenous, chronic, rheumatoid arthritis for the evaluation of potential immunoglobulin-based therapeutic agents, including IVIg and Fc-μTP-L309C, a recombinant IgG1 Fc hexamer

Background High-dose intravenous immunoglobulin (IVIg), and more recently, subcutaneously-delivered Ig (SCIg), are used to treat a variety of autoimmune diseases; however, there are challenges associated with product production, availability, access and efficacy. These challenges have provided incentives to develop a human recombinant Fc as a more potent alternative to IVIg and SCIg for the treatment of autoimmune diseases. Recently, a recombinant human IgG1 Fc hexamer (Fc-μTP-L309C) was shown to be more efficacious than IVIg in a variety of autoimmune mouse models. We have now examined its efficacy compared to IVIg and SCIg in the K/BxN mouse model of endogenous, chronic rheumatoid arthritis (RA). Result Using the serum-transfer K/BxN model and the endogenous autoimmune model, amelioration of the arthritis was achieved. Effective treatment required high and frequent doses of IVIg, SCIg and Fc-μTP-L309C. However, Fc-μTP-L309C was efficacious at 10-fold lower doses that IVIg/SCIg. Also, arthritis could be prevented when Fc-μTP-L309C was given prior to onset of the arthritis in both the endogenous model and in the serum transfer model. Conclusions Our results show that Fc-μTP-L309C is a powerful treatment for the prevention and amelioration of severe, chronic arthritis in a true autoimmune mouse model of RA. Thus, the K/BxN endogenous arthritis model should be useful for testing potential therapeutics for RA. Our findings provide rationale for further examination of the treatment efficacy of immunoglobulin-based therapeutics in rheumatoid arthritis.

Strong selection of a few dominant CD8 clones in a TLR7-dependent autoimmune mouse model

Systemic lupus disease is characterized by the expansion of a self-reactive repertoire of B cells that, with the help of CD4 cells, generate IgG antibodies against common nuclear antigens. Meanwhile, the functional state and posible clonal selection of CD8 cells in lupus remain poorly defined. We previously described the activated but non-pathogenic phenotype of CD8+ T cells, some of which accumulate in the brain, in a model of systemic autoimmune disease triggered by increased copy number of the tlr7 gene (TLR7tg mice). Here we report, through the analysis of TCRβ sequences, that CD8+ cells from TLR7tg are strongly selected for a small number of clones, some of them reaching 30% of the repertoire, compared to less than 0.4% for a single top clone in wild type cells. High frequency clones are variable in sequence among individual TLR7tg mice and are distinct from top clones in WT, while cells from spleen and brain-resident cells from the same animals have perfect concordance. These results suggest that top CD8 clones are selected in stochastic fashion in each animal but limit further diversification, and that brain infiltrating CD8 cells in TLR7tg are not selected by a tissue specific antigen. This kind of extreme clonal dominance and narrowing of the CD8+ T cell repertoire coud potentially impair anti-viral responses and should be considered as an additional detrimental feature of chronic autoimmune disease.