Immune deficient mice, reconstituted with human stem cells, have been used to analyze human immune responses in vivo. Although they have been used to study immune responses to xenografts, allografts, and pathogens, there have not been models of autoimmune disease in which the mechanisms of the pathologic process can be analyzed. We have found that reconstituted “humanized” mice treated with anti-CTLA-4 antibody (ipilimumab) develop autoimmune disease characterized by hepatitis, adrenalitis, sialitis, ANAs, and weight loss. Induction of autoimmunity involved activation of T cells and cytokine production and increased infiltration of antigen presenting cells. When anti-CTLA-4 mAb treated mice were co-treated with anti-CD3 mAb (teplizumab) hepatitis and ANAs were no longer seen and weight loss did not occur. The anti-CD3 blocked proliferation and activation of T cells, release of IFNγ and TNF, macrophage infiltration and release of IP-10 that was induced with anti-CTLA-4 mAb. We also found increased levels of Tregs (CD25+CD127-) in the spleen and mesenteric lymph nodes in the mice treated with both antibodies and greater constitutive phosphorylation of STAT5 in Tregs in spleen cells compared to mice treated with anti-CTLA-4 mAb alone. We describe the first model of human autoimmune disease in vivo. Humanized mice may be useful for understanding the mechanisms of biologics that are used in patients. Hepatitis, lymphadenopathy, and other inflammatory sequelae are side effects of ipilumimab treatment in humans and the present study may provide insights into this pathogenesis and the effects of immunologics on autoimmunity.

It is clear that lupus autoimmunity is marked by a variety of abnormalities, including those found at a macroscopic scale, cells and tissues, as well as more microenvironmental influences, originating at the individual cell surface through to the nucleus. The convergence of genetic, epigenetic, and perhaps environmental influences all lead to the overt clinical expression of disease, reflected by the presences of autoantibodies and tissue pathology. This review will address several specific areas that fall among the non-genetic factors that contribute to lupus autoimmunity and related syndromes. In particular, we will discuss the importance of understanding various protein post-translational modifications (PTMs), mechanisms that mediate the ability of "modified self" to trigger autoimmunity, and how these PTMs influence lupus diagnosis. Finally, we will discuss altered pathways of autoantigen presentation that may contribute to the perpetuation of chronic autoimmune disease.

Background: Scavenger receptor A (SR-A) is implicated in the development of autoimmunity. Results: Deficiency of SR-A, anti-SR-A antibody, and small molecule inhibitors (SMIs) block antigen processing. Conclusion: Two SMIs (sennoside B and tannic acid) that reduce antigen transfer and T cell immunity were identified. Significance: SR-A-mediated antigen trafficking is blocked by SMIs, leading to reduced T cell responses.

The cooperation of B lymphocytes with other antigen presenting cells (APCs) is often necessary in the efficient processing and presentation of antigen. Herein, we describe a mechanism by which B cells physically interact with dendritic cells (DCs) resulting in the transfer of B cell receptor (BCR)-enriched antigen to these APCs. Antigen transfer involves direct contact between the two cells followed by the capture of B cell derived membrane and intracellular components. Strikingly, DCs acquire greater amounts of antigen by transfer from B cells than by endocytosis of free antigen. Blocking scavenger receptor A, a DC surface receptor involved in membrane acquisition, abrogates these events. We propose that antigen transfer from B cells to DCs results in a more focused immunologic response due to the selective editing of Ag by the BCR.

Conclusions This study identifies a novel SR-A dependent pathway of antigen presentation between human B cells and MFs and DCs. Inhibition of this pathway reduces T cell activation, reduces the production of autoantibodies, and ameliorates kidney and skin pathology of SLE in a murine model.