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CD59 is a GPI-anchored membrane regulator of complement expressed on blood cells as well as peripheral tissues. It protects host cells from complement injury by inhibiting formation of the membrane attack complex. Recent studies in mice have suggested also a role of CD59 in T cell immune response that was mechanistically independent of complement. In the present study, we investigated the function of CD59 in the MRL/lpr model of murine lupus. We backcrossed the Cd59a knockout (Cd59a(-/-)) mouse onto the MRL/lpr background and compared Cd59a(+/+)-MRL/lpr and Cd59a(-/-)-MRL/lpr littermates for the development of systemic autoimmunity. We found that CD59a deficiency significantly exacerbated the skin disease and lymphoproliferation characteristic of MRL/lpr mice. It also increased autoantibody titers and caused a higher level of proteinuria in male MRL/lpr mice. Bone marrow transfer experiments indicated that CD59a expression on both bone marrow-derived cells and peripheral tissues played a role in lymphoproliferation, whereas the skin disease phenotype is determined mainly by local CD59a expression. Importantly, C3 gene deletion or C5 neutralization with a blocking mAb in Cd59a(-/-)-MRL/lpr mice did not rescue the proautoimmune phenotype associated with CD59a deficiency. These results together suggest that CD59a inhibits systemic autoimmunity in MRL/lpr mice through a complement-independent mechanism.

The chronic graft-versus-host disease (cGVHD) in mice is characterized by the production of autoantibodies and immunopathology characteristic of systemic lupus erythematosus (lupus). The basic pathogenesis involves the cognate recognition of foreign MHC class II of host B cells by alloreactive CD4 T cells from the donor. CD4 T cells of the host are also necessary for the full maturation of host B cells before the transfer of donor T cells. CD8 T cells play critical roles as well. Donor CD8 T cells that are highly cytotoxic can ablate or prevent the lupus syndrome, in part by killing recipient B cells. Host CD8 T cells can reciprocally downregulate donor CD8 T cells, and thus prevent them from suppressing the autoimmune process. Thus, when the donor inoculum contains both CD4 T cells and CD8 T cells, the resultant syndrome depends on the balance of activities of these various cell populations. For example, in one cGVHD model (DBA/2(C57BL/6xDBA/2)F1, the disease is more severe in females, as it is in several of the spontaneous mouse models of lupus, as well as in human disease. The mechanism of this female skewing of disease appears to depend on the relative inability of CD8 cells of the female host to downregulate the donor CD4 T cells that drive the autoantibody response. In general, then, the abnormal CD4 T cell help and the modulating roles of CD8 T cells seen in cGVHD parallel the participation of T cells in genetic lupus in mice and human lupus, although these spontaneous syndromes are presumably not driven by overt alloreactivity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Receptor editing is the process that replaces the heavy chain or light chain variable region genes in a B cell immunoglobulin receptor that is already productively rearranged. It is a major mechanism in the bone marrow for maintaining B cell tolerance to autoantigens. We propose that a pathological autoimmune process can use receptor editing to induce the de novo creation and activation of B cells with autoreactive receptors in the peripheral immune system., (Copyright © 2012. Published by Elsevier B.V.)

Inflammatory arthritis presents in a variety of diseases, from rheumatoid arthritis to hepatitis. Antibodies to autoantigens or to microbial constituents are commonly associated with these conditions. In some cases, the antibodies have diagnostic and prognostic relevance. It cannot as yet be determined definitively that any of them mediate joint damage, although the evidence from animal models indicates that this mechanism is likely. The purpose of this article is to give an overview of the spectrum of antibodies found in a variety of inflammatory arthritides. The relevant animal models are also discussed.

The Mer receptor tyrosine kinase mediates apoptotic cell phagocytosis and modulates macrophage cytokine production. Mer(-/-) mice have defective clearance of apoptotic debris and develop a systemic lupus erythematosus-like autoimmune syndrome. It was surprising then that B6-Mer(-/-) recipients of bm12 spleen cells failed to develop anti-dsDNA and anti-chromatin autoantibodies, whereas B6 hosts produced the expected autoimmune chronic graft-vs-host (cGVH) reaction. The lack of autoantibody formation in cGVH was not due to the failure of Mer-deficient hosts to provoke alloreactivity, because Mer(-/-) spleen cells were recognized by bm12 T cells in MLR. Cell transfer experiments in Rag-knockout mice indicated that the lack of autoantibody production in Mer(-/-) cGVH disease hosts was due to an intrinsic B cell defect. This defect did not cause a global inability to produce autoantibodies, because in vivo exposure to LPS stimulated production of autoantibodies in both B6 and Mer(-/-) mice. We further observed that wild-type B6 B cells up-regulated Mer upon activation in cGVH, and that B cells from mice lacking Mer showed a decreased up-regulation of activation-associated cell surface markers. These findings indicate that Mer serves an important role in the activation of self-reactive B cells in systemic autoimmunity.

The basic function of the adaptive immune system is to distinguish self from foreign. The failure of self tolerance can result in autoimmunity, which comes in many forms but still targets a limited selection of the total available autologous determinants. This selectivity must reflect the underlying mechanisms of the autoimmune reaction, as well as the particular features of the autoantigens that are targeted. Here I discuss the overall paradigm of autoimmunity, and what kinds of mechanisms might play a role. It is likely that multiple different pathways are critical in various diseases, and even in a single condition.

The encounter of developing B cells in the bone marrow with soluble hen egg lysozyme (sHEL) self antigen induces anergy and endogenous kappa light chain rearrangements ('receptor editing'). We have previously shown that induction of chronic graft-versus-host reaction (GVH) in tolerant Ig/sHEL mice results in prevention of B cell anergy in the bone marrow and the spleen. We now report that in chronic GVH, immature self-reactive B cells also show reduced levels of receptor editing in the bone marrow. This is evidenced by the following observations: (a) a small population of'receptor-edited' B cells, which is found in tolerant mice, is markedly reduced in mice that have lost tolerance in chronic GVH; (b) self-reactive B cells in GVH mice have reduced levels of endogenous kappa chain rearrangements; and (c) recombinase-activating gene (RAG)-2 expression is markedly decreased in immature self-reactive B cells in the bone marrow of chronic GVH mice. These results suggest that in chronic GVH newly emerging B cells escape tolerance, in part because of decreased receptor editing in the bone marrow. Thus, the autoimmunity induced by chronic GVH may ultimately result from the failure of B cell tolerance at multiple checkpoints.

The injection of spleen cells from bm12 mice into C57BL/6 recipients induces a chronic graft-vs-host reaction characterized by systemic autoimmunity, including anti-double-stranded DNA (anti-dsDNA) autoantibodies and immune complex-type proliferative glomerulonephritis. If the B6 recipient mice express an anti-DNA Vh site-directed transgene, the repertoire is skewed even more toward the anti-DNA response. Over a period of several weeks, high titers of serum anti-DNA antibodies appear and the mice develop renal damage. This permits the examination of the role of somatic immunoglobulin genetics and B-cell tolerance in a model of systemic lupus erythematosus.

B cell autoreactivity is a component of chronic graft versus host (GVH) disease in humans and mice. Chronic GVH driven by I-A disparity results in loss of B cell tolerance in Ig/sHEL tolerant mice. In these mice, B cell anergy is characterized by down-modulation of sIgM mediated by intracellular retention in the endoplasmic reticulum (ER) and/or a block in post-ER processing of IgM receptors. Here, we report that GVH induces a selective increase in post-ER processing of the micro chain and trafficking to the cell surface of IgM receptors in B cells that bind HEL self-antigen. The increase in sIgM was detectable as early as 6 days post-GVH, before the appearance of circulating autoantibodies, and was particularly prominent in B cells that up-regulated surface I-A. A further increase in sIgM was found at later time points, along with circulating anti-HEL autoantibodies and a marked decrease in serum-free HEL, but no significant change in the amounts of HEL bound to B cells in vivo. These findings suggest that (i) abrogation of ER retention of IgM receptors in self-reactive B cells is an early event triggered by allogeneic T cells and (ii) at later stages of GVH disease the appearance of autoantibodies reduces the availability of free autoantigen, which may further escalate anergy escape of self-reactive B cells, and lead to exacerbation and perpetuation of autoimmunity.

Autoimmunity results from the failure of self-tolerance of the adaptive immune system. The reactivity of antibodies and T cells against endogenous antigens frequently causes organ damage, and consequent autoimmune disease. Systemic lupus erythematosus (SLE) is an extreme example of such a breakdown of tolerance. Our studies with spontaneous genetic mouse models of SLE and an experimentally induced model have elucidated many of the underlying cellular and genetic mechanisms of this immune dysregulation. We find that the B cell plays a key central role in this process and represents an attractive target for therapeutic intervention.

Receptor editing is the process of ongoing antibody gene rearrangement in a lymphocyte that already has a functional antigen receptor. The expression of a functional antigen receptor will normally terminate further rearrangement (allelic exclusion). However, lymphocytes with autoreactive receptors have a chance at escaping negative regulation by 'editing' the specificities of their receptors with additional antibody gene rearrangements. As such, editing complicates the Clonal Selection Hypothesis because edited cells are not simply endowed for life with a single, invariant antigen receptor. Furthermore, if the initial immunoglobulin gene is not inactivated during the editing process, allelic exclusion is violated and the B cell can exhibit two specificities. Here, we describe the discovery of editing, the pathways of receptor editing at the heavy (H) and light (L) chain loci, and current evidence regarding how and where editing happens and what effects it has on the antibody repertoire. [ABSTRACT FROM AUTHOR]

Abstract: B-cells play a major role in the immunopathogenesis of autoimmune diseases. Not only do they produce autoantibodies, but they regulate other cell types, secrete cytokines, and present antigens. They are thus potential targets for therapeutic intervention. CD20 is a B-cell specific cell surface molecule of uncertain function. An anti-CD20 chimeric mAb (rituximab) has been FDA approved for treatment of B-cell lymphomas since 1997. Rituximab also depletes normal B-cells by several mechanisms, including ADCC. Over the past seven years, it has shown promise in a number of autoimmune diseases in phase I trials and anecdotal reports. Efficacy in rheumatoid arthritis has already been demonstrated in randomized control trials (RCTs), and RCTs in SLE, inflammatory myositis, and ANCA associated vasculitis are under way. Safety does not appear to be a major problem, but continued vigilance is warranted. The increased use of rituximab, other anti-CD20 agents, and other B-cell targeting therapies holds great promise for substantial clinical benefits, as well as providing special opportunities to understand better disease pathogenesis. [Copyright &y& Elsevier]

Abstract: Control of lymphocyte homeostasis is essential to ensure efficient immune responses and to prevent autoimmunity. Splenic marginal zone B cells are important producers of autoantibodies, and are subject to stringent tolerance mechanisms to prevent autoimmunity. In this paper, we explore the role of the Mer tyrosine kinase (Mertk) in regulating autoreactive B cells. This receptor tyrosine kinase serves to bind apoptotic cells, to mediate their phagocytosis, and to regulate subsequent cytokine production. Mice lacking Mertk suffer from impaired apoptotic cell clearance and develop a lupus-like autoimmune syndrome. Here we show that such Mertk-KO mice have expanded numbers of splenic marginal zone B cells. Mertk-KO mice bearing a DNA-specific immunoglobulin heavy-chain transgene (3H9) produced anti-DNA antibodies that appeared to be secreted largely by marginal zone B cells. Finally, Mertk-KO mice developed greater antibody responses after NP-Ficoll immunization than their B6 counterparts. Taken together, our data show that Mertk has a major effect on the development of the marginal zone B-cell compartment. Mertk is also important in establishing DNA-specific B-cell tolerance in 3H9 anti-DNA transgenic mice. [Copyright &y& Elsevier]

Abstract: The accelerated development of atherosclerosis with increased risk of cardiovascular disease in systemic lupus erythematosus (SLE) patients is not well understood. An appropriate mouse model would greatly help to understand the mechanisms of this association. We have therefore combined the ApoE−/− model of atherosclerosis with three different murine models of SLE. We found that induction of cGVH in B6.ApoE −/− mice, breeding a Fas null gene onto the B6.ApoE −/− mice, and breeding the ApoE−/− defect onto MRL/lpr mice all caused a modest increase of atherosclerosis at 24 weeks of age compared to B6.ApoE −/− controls. B cells in B6.ApoE −/− mice had certain phenotypic differences compared to congenic C57BL/6 mice, as indicated by high expression of MHC II, Fas, CD86, and by increased number of cells bearing marginal zone phenotype. Furthermore, B6ApoE−/− mice had significant titers of anti-oxLDL and anti-cardiolipin autoantibodies compared to their B6 counterparts. Our studies also indicate that, following induction of cGVH, marginal zone B cells in B6.ApoE −/− are depleted, and there is considerable increase in anti-oxLDL and anti-cardiolipin abs along with secretion of lupus-specific autoantibodies, such as anti-dsDNA and anti-chromatin abs. Histological sections showed that cGVH and/or Fas deficiency could exacerbate atherosclerosis. The production of anti-oxLDL and anti-cardiolipin in ApoE−/− mice was also increased. These observations define a connection between induction of lupus-like symptoms and development of severe atherosclerosis in ApoE deficient lupus mouse models. [Copyright &y& Elsevier]

Abstract: Identifying factors associated with B lymphocyte depletion and recovery may aid the development of individualized treatment regimens, optimizing therapy for patients with autoimmune disease. In this study, 12 patients with active SLE were monitored at baseline and monthly following treatment with rituximab. The number and phenotype of peripheral blood B lymphocytes, T lymphocytes and natural killer cells were correlated with the extent and longevity of B lymphocyte depletion. This analysis generated three candidate biomarkers for lymphocyte monitoring in patients with autoimmune disease who are treated with rituximab: circulating transitional B cells, the κ:λ ratio and natural killer cells. Further refinement of these potential biomarkers may lead to a better understanding of the role of B cells in disease pathogenesis and a more rational use of B cell depletion therapies. [Copyright &y& Elsevier]