B-cell depletion inhibits arthritis in a collagen-induced arthritis (CIA) model, but does not adversely affect humoral responses in a respiratory syncytial virus (RSV) vaccination model

Abstract

IntroductionThe pathogenesis of autoimmune diseases involves a complicated network of tissue-damaging mechanisms that are governed primarily by recognition of self-antigens and an imbalance in cytokine production. 1,2 In rheumatoid arthritis (RA), major cell types responsible for chronic inflammation and subsequent cartilage destruction and bone erosion in the joints are macrophages, synovial fibroblasts, neutrophils, and lymphocytes. Recent studies demonstrated that T and B lymphocytes that infiltrate inflamed synovial tissues are often organized into structures that resemble lymphoid follicles. [3][4][5][6][7] Normally, in T-dependent immune responses antigen-activated B cells migrate into lymphoid follicles of lymphoid organs and form germinal centers. Within the unique milieu of the germinal center, hypermutation leads to diversification and selection of the B-cell repertoire for high affinity and differentiation into antibody-secreting plasma cells or memory B cells. [8][9][10] Molecular analysis of B cells isolated from synovial follicular structures during rheumatoid arthritis demonstrated the importance of B cells in local antigen-driven specific immune responses and increased production of rheumatoid factor (RF), the high-affinity antibodies with self-reactivity. 5 Positivity for RF is associated with more aggressive articular disease and higher frequency of extraarticular manifestations. 11 Studies using RA synovium-severe combined immunodeficiency (SCID) mouse chimeras showed that activation of synovial germinal center CD4 ϩ T cells required the presence of B cells, but not macrophages and dendritic cells, raising the possibility that B cells provided critical function in T-cell activation or harbored the relevant antigens. 12 The significance of extranodal lymphoid follicle formation in inflamed RA joints is unknown, and it remains to be defined whether the reaction is a bystander effect induced by the local chronic inflammation or results from an autoimmune reaction directly related to the pathogenesis of the disease.Intriguing evidence on the pathogenic contribution of B cells in the development of arthritis was recently provided using K/BxN T-cell receptor (TCR) transgenic mice, which spontaneously develop joint disorders with many of the clinical, histologic, and immunologic characteristics of human RA. 13 The articular manifestations are caused by arthritogenic antibodies directed against glucose-6-phosphate isomerase, which develop at high titers in K/BxN transgenic mice. [14][15][16] More convincing evidence regarding the pathogenicity of B cells in RA was recently obtained from clinical trials in patients with refractory disease by using B-cell ablation with rituximab (Rituxan), a human chimeric anti-CD20 monoclonal antibody (mAb). 17,18 Expression of CD20, a B-cellspecific transmembrane glycoprotein with similar patterns of expression and function in humans and in mice, emerges on late pre-B cells and is extinguished on plasma cells. 19,20 Anti-CD20 therapy has also been tested in several ot...

Targeted Disruption of Leukotriene B4 Receptors BLT1 and BLT2: A Critical Role for BLT1 in Collagen-Induced Arthritis in Mice

“…These data suggest that the method of immunization but not the MHC haplotype might be a critical determinant of CIA incidence in B6 mice. The precise mechanisms whereby immunization with CII leads to a chronic arthritis are not known; however, data have shown that the CIA model is absolutely dependent on B cells and is significantly dependent on CD4 ϩ T cell involvement (35)(36)(37)(38). Our results of comparable levels of anti-CII Ab indicate the normal functioning of B cells in the BLT1…”

B Cell Depletion Delays Collagen-Induced Arthritis in Mice: Arthritis Induction Requires Synergy between Humoral and Cell-Mediated Immunity

“…Likewise, B cell-deficient mice or xid mice with defective humoral immunity do not develop CIA (22,23). In addition, IFN-␥-deficient B6 mice treated with CD22 mAbs conjugated with calicheamicin toxin do not develop CIA (24), implying that B cells play a pivotal role in the disease. Transferring collagen-specific autoantibodies alone leads to transient arthritis, with a histopathology that is somewhat different from that of CIA (19,(25)(26)(27)(28).…”

“…5A) because IgG3 Abs do not interact significantly with Fc␥Rs (54). Although autoantibodies are important for initiating joint inflammation by binding to cartilage and initiating inflammation through Fc␥R-dependent pathways (55), there is little agreement as to whether individual collagen-specific autoantibody isotypes or their titers cause or correlate with disease severity in CIA (24). In fact, collagen-specific IgG1, IgG2a, and IgG2b Abs alone can induce transient arthritis in recipient mice (19,26,27), with collagen-reactive T cells required for normal CIA induction and progression (19).…”

Targeting CD22 Reprograms B-Cells and Reverses Autoimmune Diabetes

“…In humans, the production of autoantibodies to islet antigens is well documented as an early indicator of disease onset (12). These observations render B-cell targeting a particularly attractive and novel strategy for the treatment of type 1 diabetes (13)(14)(15). Unfortunately, this strategy has not been fully described in naïve NOD mice.…”

“…We made use of a newly developed reagent (anti-CD22 calicheamicin-conjugated monoclonal antibody [anti-CD22/cal mAb]) that efficiently depletes mature B-cells in mice (13) to establish a therapeutic approach for type 1 diabetes. Our main hypothesis was that depleting B-cells by targeting CD22 should prevent diabetes onset and restore normoglycemia in newly hyperglycemic NOD mice.…”