In the 1950s, the discovery of autoantibodies produced by B cells seemed to provide a compelling mechanism underlying autoimmune diseases. The discovery of T regulatory cells and other T helper cell subsets shifted the field back towards a T cell central view. The success of rituxan, a chimeric mAb targeting CD20 on B cells, in the treatment of rheumatoid arthritis forced a review of the role of B cells in autoimmunity. Rituxan was first developed to treat lymphomas, and it also proved effective in treating rheumatoid arthritis, a disease not previously associated with B cells. One of the side effects of rituxan is a pronounced depletion of peripheral blood B cells, an effect that seemed to correlate with effectiveness in preclinical and clinical models of autoimmune diseases. B cell depletion was also shown to affect T cell populations, suggesting an antibody-independent mechanism through which B cells influenced rheumatic disease. Most recently, the identification of cytokine producing B cells (B regulatory and B effector cells) that modulate tolerance has added to our understanding of human health and disease and the mechanisms that break tolerance, as the B cell cytokine network produced by B cell subsets were shown to influence T cell numbers, as well as the polarization of T cell subsets (Tregs/Th1/Th2). Therefore, B cells have once again taken the center stage in tolerance and autoimmunity. Here, we review the role of B cells in autoimmunity, mainly through their ability to produce cytokines.

We describe a novel B cell–associated cytokine, encoded by an uncharacterized gene (C17orf99; chromosome 17 open reading frame 99), that is expressed in bone marrow and fetal liver and whose expression is also induced in peripheral B cells upon activation. C17orf99 is only present in mammalian genomes, and it encodes a small (~27-kDa) secreted protein unrelated to other cytokine families, suggesting a function in mammalian immune responses. Accordingly, C17orf99 expression is induced in the mammary gland upon the onset of lactation, and a C17orf99−/− mouse exhibits reduced levels of IgA in the serum, gut, feces, and lactating mammary gland. C17orf99−/− mice have smaller and fewer Peyer’s patches and lower numbers of IgA-secreting cells. The microbiome of C17orf99−/− mice exhibits altered composition, likely a consequence of the reduced levels of IgA in the gut. Although naive B cells can express C17orf99 upon activation, their production increases following culture with various cytokines, including IL-4 and TGF-β1, suggesting that differentiation can result in the expansion of C17orf99-producing B cells during some immune responses. Taken together, these observations indicate that C17orf99 encodes a novel B cell–associated cytokine, which we have called IL-40, that plays an important role in humoral immune responses and may also play a role in B cell development. Importantly, IL-40 is also expressed by human activated B cells and by several human B cell lymphomas. The latter observations suggest that it may play a role in the pathogenesis of certain human diseases.

We have identified Tspan33 as a gene encoding a transmembrane protein exhibiting a restricted expression pattern including expression in activated B cells. TSPAN33 is a member of the tetraspanin family. TSPAN33 is not expressed in resting B cells, but is strongly induced in primary human B cells following activation. Human 2E2 cells, a Burkitt’s lymphoma-derived B cell model of activation and differentiation, also upregulate TSPAN33 upon activation. TSPAN33 is expressed in several lymphomas including Hodgkin’s and Diffuse large B Cell Lymphoma. TSPAN33 is also expressed in some autoimmune diseases where B cells participate in the pathology, including rheumatoid arthritis patients, systemic lupus erythematosus (SLE), and in spleen B cells from MRL/Faslpr/lpr mice (a mouse model of SLE). We conclude that TSPAN33 may be used as a diagnostic biomarker or as a target for therapeutic antibodies for treatment of certain B cell lymphomas or autoimmune diseases.

During a severe outbreak of bacterial heart rot that occurred in pineapple plantations on Oahu, Hawaii, in 2003 and years following, 43 bacterial strains were isolated from diseased plants or irrigation water and identified as Erwinia chrysanthemi (now Dickeya sp.) by phenotypic, molecular, and pathogenicity assays. Rep-PCR fingerprint patterns grouped strains from pineapple plants and irrigation water into five genotypes (A-E) that differed from representatives of other Dickeya species, Pectobacterium carotovorum and other enteric saprophytes isolated from pineapple. Monoclonal antibodies produced following immunization of mice with virulent type C Dickeya sp. showed only two specificities. MAb Pine-1 (2D11G1, IgG1 with kappa light chain) reacted to all 43 pineapple/water strains and some reference strains (D. dianthicola, D. chrysanthemi, D. paradisiaca, some D. dadantii, and uncharacterized Dickeya sp.) but did not react to reference strains of D. dieffenbachiae, D. zeae, or one of the two Malaysian pineapple strains. MAb Pine-2 (2A7F2, IgG3 with kappa light chain) reacted to all type B, C, and D strains but not to any A or E strains or any reference strains except Dickeya sp. isolated from Malaysian pineapple. Pathogenicity tests showed that type C strains were more aggressive than type A strains when inoculated during cool months. Therefore, MAb Pine-2 distinguishes the more virulent type C strains from less virulent type A pineapple strains and type E water strains. MAbs with these two specificities enable development of rapid diagnostic tests that will distinguish the systemic heart rot pathogen from opportunistic bacteria associated with rotted tissues. Use of the two MAbs in field assays also permits the monitoring of a known subpopulation and provides additional decision tools for disease containment and management practices.

We have identified a novel mouse and human cytokine. IL-40 is normally produced in the bone marrow and fetal liver, and by activated B cells. Its sequence predicts a small (~27kDa) secreted protein unrelated to other cytokine gene families, that we have called Interleukin 40 (IL-40). IL40 is only present in mammalian genomes, suggesting a role in mammalian immune responses. Accordingly, IL-40 expression is induced in the mammary gland upon the onset of lactation, and an IL-40−/− mouse exhibits reduced levels of IgA in the serum, gut, feces, and milk. Furthermore, the IL-40−/− mouse has smaller and fewer Peyer’s patches and IgA secreting cells. The gut microbiome of IL-40−/− mice also exhibits altered composition, reflecting the reduced levels of IgA in the gut. We have also determined that B cell precursor populations are altered in the IL-40−/− mouse. Taken together, these observations indicate that IL-40 represents a novel B cell associated cytokine, that plays an important role in the development of humoral immune responses. IL-40 is also expressed by human activated B cells and by several human B cell lymphomas. The latter observation suggests that it may play a role in the pathogenesis of these diseases.