Identification of IgA autoantibodies targeting mesangial cells redefines the pathogenesis of IgA nephropathy.

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis, often progressing to renal failure. IgAN is triggered by IgA deposition in the glomerular mesangium by an undefined mechanism. Here, we show that grouped ddY (gddY) mice, a spontaneous IgAN model, produce serum IgA against mesangial antigens, including ßII-spectrin. Most patients with IgAN also have serum anti-ßII-spectrin IgA. As in patients with IgAN, IgA+ plasmablasts accumulate in the kidneys of gddY mice. IgA antibodies cloned from the plasmablasts carry substantial V-region mutations and bind to ßII-spectrin and the surface of mesangial cells. These IgAs recognize transfected and endogenous ßII-spectrin exposed on the surface of embryonic kidney-derived cells. Last, we demonstrate that the cloned IgA can bind selectively to glomerular mesangial regions in situ. The identification of IgA autoantibody and its antigen in IgAN provides key insights into disease onset and redefines IgAN as a tissue-specific autoimmune disease.

T-cell deficiency induces deficits in social behavior and dyslipidemia in mice.

Patients with neuropsychiatric disorders often exhibit an altered metabolic status. However, the underlying factors that induce behavioral and metabolic dysfunctions remain poorly understood. Therefore, we investigated whether behavioral and metabolic alterations could be induced in immunodeficient conditions. We found that T-cell-deficient Cd3e-/- mice exhibit deficits in social behavior associated with dyslipidemia. Cd3e-/- mice exhibited abnormal social novelty preference, but normal anxiety-like behavior. We also detected decreases in the concentrations of plasma triglyceride and the lipid transporter molecule fatty acid-binding protein 2. Furthermore, the adoptive transfer of T-cells to Cd3e-/- mice ameliorated the deficits in social behavior and recovered plasma triglyceride concentration. Thus, we found that T-cell disruption can induce defects in social behavior and systemic lipid homeostasis in mice. Given these findings, we believe that Cd3e-/- mice represent a useful tool for investigating the mechanisms of causal relationships among immune dysfunction, behavior, and metabolism.

A novel cancer immunotherapy using tumor-infiltrating B cells in the APCmin/+ mouse model.

Accumulating evidence has suggested a correlation of tumor infiltrating B cells (TiBcs) and a good prognosis of cancer diseases. In some cases, TiBcs appear to have experienced antigen stimulation since they have undergone class-switching and somatic hypermutation and formed tertiary lymphoid structures around tumors together with T cells. Assuming TiBcs include those that recognize some tumor antigens, we sought to investigate their possible usefulness for cell-mediated immunotherapies. To expand usually small number of TiBcs in vitro, we modified our B cell culture system: we transduced B cells with ERT2-Bach2 so that they grow unlimitedly provided with tamoxifen, IL-21 and our original feeder cells. Such cells differentiate into plasma cells and produce antibodies upon withdrawal of tamoxifen, and further by addition of a Bach2-inhibitor in vitro. As a preliminary experiment, thus expanded splenic B cells expressing a transgenic antigen receptor/antibody against hen egg lysozyme were intravenously injected into mice pre-implanted with B16 melanoma cells expressing membrane-bound HEL in the skin, which resulted in suppression of the growth of B16 tumors and prolonged survival of the recipient mice. To test the usefulness of TiBcs for the immunotherapy, we next used APCmin/+ mice as a model that spontaneously develop intestinal tumors. We cultured TiBcs separated from the tumors of APCmin/+ mice as above and confirmed that the antibodies they produce recognize the APCmin/+ tumor. Repeated injection of such TiBcs into adult APCmin/+ mice resulted in suppression of intestinal tumor growth and elongation of the survival of the recipient mice. Serum antibody from the TiBc-recipient mice selectively bound to an antigen expressed in the tumor of APCmin/+ mice. These data suggest a possibility of the novel individualized cancer immunotherapy, in which TiBcs from surgically excised tumor tissues are expanded and infused into the donor patients.

Bacteria-immune cells dialog and the homeostasis of the systems.

The dialog between microbes and immune cells is critical for the establishment and maintenance of immune homeostasis. Bacterial-derived metabolites or structural components initiate immune signaling pathways and transcriptional factors, inducing a broad range of specificities and functional repertoires of the immune cells. Conversely, the immune system regulates the composition and function of bacterial communities. Elements of the adaptive immunity, including maternal antibodies and mucosal antibody responses, play crucial roles in protecting the hosts from pathogens in addition to promoting colonization of symbiotic bacteria at mucosal surfaces. The complex interactions set from an early stage in life between the microbiota and adaptive immunity, impact other major physiological systems. In this review, we summarize recent advances in our understanding of how gut bacteria regulate systemic homeostasis by highlighting the finely orchestrated interactions between gut bacteria, immune responses and the nervous system.