The adaptive immune system consists of two types of lymphocytes: T and B cells. These two lymphocytes originate from a common precursor, yet are fundamentally different with B cells mediating humoral immunity while T cells mediate cell mediated immunity. In cytokine production, naïve T cells produce multiple cytokines upon activation while naïve activated B cells do not. B cells are capable of producing cytokines, but their cytokine production depends on their differentiation state and activation conditions. Hence, unlike T cells that can produce a large amount of cytokines upon activation, B cells require specific differentiation and activation conditions to produce cytokines. Many cytokines act on B cells as well. Here, we discuss several cytokines and their effects on B cells including: Interleukins, IL-7, IL-4, IL-6, IL-10, and Interferons, IFN-α, IFN-β, IFN-γ. These cytokines play important roles in the development, survival, differentiation and/or proliferation of B cells. Certain chemokines also play important roles in B cell function, namely antibody production. As an example, we discuss CCL28, a chemokine that directs the migration of plasma cells to mucosal sites. We conclude with a brief overview of B cells as cytokine producers and their likely functional consequences on the immune response.

Cytokines are involved in many functions of the immune system including initiating, amplifying and resolving immune responses. Through bioinformatics analyses of a comprehensive database of gene expression (BIGE: Body Index of Gene Expression) we observed that a small secreted protein encoded by a poorly characterized gene called meteorin-like (METRNL), is highly expressed in mucosal tissues, skin and activated macrophages. Further studies indicate that Metrnl is produced by Alternatively Activated Macrophages (AAM) and M-CSF cultured bone marrow macrophages (M2-like macrophages). In the skin, METRNL is expressed by resting fibroblasts and IFNγ-treated keratinocytes. A screen of human skin-associated diseases showed significant over-expression of METRNL in psoriasis, prurigo nodularis, actinic keratosis and atopic dermatitis. METRNL is also up-regulated in synovial membranes of human rheumatoid arthritis. Taken together, these results indicate that Metrnl represents a novel cytokine, which is likely involved in both innate and acquired immune responses.

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.

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