Plasma cell development and survival.

Plasma cells have long been recognized as the basis of humoral immunity, yet we are only now beginning to appreciate the complexities of plasma cell development and the fact that not all plasma cells are created equal. In vivo, plasma cells can arise from two developmental routes: one occurring outside the follicle and another within the germinal center. A B cell's decision to follow one of these pathways is in part determined by the phenotypic subset to which it belongs and is also influenced by the nature of the antigen eliciting the response and the affinity of the B-cell receptor for that antigen. Once a plasma cell has chosen one of these pathways, the outcome of differentiation is relatively hard-wired. However, the phenotype of the plasma cells arising from these two pathways is distinct in terms of survival, location, and the quantity and quality of antibody they secrete. The extra-follicular pathway represents a relatively unchecked route to differentiation resulting in the generation of short-lived plasma cells that secrete low-affinity antibody. The germinal center response, however, allows the integration of external signals to delay plasma cell differentiation, eventually generating a plasma cell that secretes high-affinity antibody of an appropriate class, and that persists for a lifetime. The means by which these varying properties are conferred to a developing plasma cell are the subject of intense investigation.

Autoimmune disease in Lyn-deficient mice is dependent on an inflammatory environment established by IL-6.

Lyn-deficient mice develop Ab-mediated autoimmune disease resembling systemic lupus erythematosus where hyperactive B cells are major contributors to pathology. In this study, we show that an inflammatory environment is established in Lyn(-/-) mice that perturbs several immune cell compartments and drives autoimmune disease. Lyn(-/-) leukocytes, notably B cells, are able to produce IL-6, which facilitates hyperactivation of B and T cells, enhanced myelopoiesis, splenomegaly, and, ultimately, generation of pathogenic autoreactive Abs. Lyn(-/-) dendritic cells show increased maturation, but this phenotype is independent of autoimmunity as it is reiterated in B cell-deficient Lyn(-/-) mice. Genetic deletion of IL-6 on a Lyn-deficient background does not alter B cell development, plasma cell accumulation, or dendritic cell hypermaturation, suggesting that these characteristics are intrinsic to the loss of Lyn. However, hyperactivation of B and T cell compartments, extramedullary hematopoiesis, expansion of the myeloid lineage and autoimmune disease are all ameliorated in Lyn(-/-)IL-6(-/-) mice. Importantly, our studies show that although Lyn(-/-) B cells may be autoreactive, it is the IL-6-dependent inflammatory environment they engender that dictates their disease-causing potential. These findings improve our understanding of the mode of action of anti-IL-6 and B cell-directed therapies in autoimmune and inflammatory disease treatment.

CTLA4Ig alters the course of autoimmune disease development in Lyn-/- mice.

Lyn-deficient (Lyn(-/-)) mice develop an age-dependent autoimmune disease similar to systemic lupus erythematosus, characterized by the production of IgG anti-nuclear Ab. To determine the extent to which this autoimmune phenotype is driven by T cell costimulation, we generated Lyn(-/-) mice expressing a soluble form of the T cell inhibitory molecule, CTLA4 (CTLA4Ig). Surprisingly, although CTLA4Ig prevented myeloid hyperplasia, splenomegaly and IgG anti-nuclear Ab production in Lyn(-/-) mice, it did not inhibit immune complex deposition and tissue destruction in the kidney. In fact, regardless of CTLA4Ig expression, Lyn(-/-) serum contained elevated titers of IgA anti-nuclear Ab, although generally IgA deposition in the kidney was only revealed in the absence of self-reactive IgG. This demonstrated that activation of autoreactive B cell clones in Lyn(-/-) mice can still occur despite impaired costimulation. Indeed, CTLA4Ig did not alter perturbed Lyn(-/-) B cell development and behavior, and plasma cell frequencies were predominantly unaffected. These results suggest that when self-reactive B cell clones are unimpeded in acquiring T cell help, they secrete pathogenic IgG autoantibodies that trigger the fulminant autoimmunity normally observed in Lyn(-/-) mice. The absence of these IgG immune complexes reveals an IgA-mediated axis of autoimmunity that is not sufficient to cause splenomegaly or extramedullary myelopoiesis, but which mediates destructive glomerulonephritis. These findings have implications for the understanding of the basis of Ab-mediated autoimmune diseases and for their treatment with CTLA4Ig.