49 research outputs found
Amplified B Lymphocyte CD40 Signaling Drives Regulatory B10 Cell Expansion in Mice
Aberrant CD40 ligand (CD154) expression occurs on both T cells and B cells in human lupus patients, which is suggested to enhance B cell CD40 signaling and play a role in disease pathogenesis. Transgenic mice expressing CD154 by their B cells (CD154(TG)) have an expanded spleen B cell pool and produce autoantibodies (autoAbs). CD22 deficient (CD22(-/-)) mice also produce autoAbs, and importantly, their B cells are hyper-proliferative following CD40 stimulation ex vivo. Combining these 2 genetic alterations in CD154(TG)CD22(-/-) mice was thereby predicted to intensify CD40 signaling and autoimmune disease due to autoreactive B cell expansion and/or activation.CD154(TG)CD22(-/-) mice were assessed for their humoral immune responses and for changes in their endogenous lymphocyte subsets. Remarkably, CD154(TG)CD22(-/-) mice were not autoimmune, but instead generated minimal IgG responses against both self and foreign antigens. This paucity in IgG isotype switching occurred despite an expanded spleen B cell pool, higher serum IgM levels, and augmented ex vivo B cell proliferation. Impaired IgG responses in CD154(TG)CD22(-/-) mice were explained by a 16-fold expansion of functional, mature IL-10-competent regulatory spleen B cells (B10 cells: 26.7×10(6)±6 in CD154(TG)CD22(-/-) mice; 1.7×10(6)±0.4 in wild type mice, p<0.01), and an 11-fold expansion of B10 cells combined with their ex vivo-matured progenitors (B10+B10pro cells: 66×10(6)±3 in CD154(TG)CD22(-/-) mice; 6.1×10(6)±2 in wild type mice, p<0.01) that represented 39% of all spleen B cells.These results demonstrate for the first time that the IL-10-producing B10 B cell subset has the capacity to suppress IgG humoral immune responses against both foreign and self antigens. Thereby, therapeutic agents that drive regulatory B10 cell expansion in vivo may inhibit pathogenic IgG autoAb production in humans
Poorly controlled type 2 diabetes is accompanied by significant morphological and ultrastructural changes in both erythrocytes and in thrombin-generated fibrin: implications for diagnostics
We have noted in previous work, in a variety of inflammatory diseases, where iron dysregulation occurs, a strong
tendency for erythrocytes to lose their normal discoid shape and to adopt a skewed morphology (as judged by
their axial ratios in the light microscope and by their ultrastructure in the SEM). Similarly, the polymerization of
fibrinogen, as induced in vitro by added thrombin, leads not to the common ‘spaghetti-like’ structures but to dense
matted deposits. Type 2 diabetes is a known inflammatory disease. In the present work, we found that the axial
ratio of the erythrocytes of poorly controlled (as suggested by increased HbA1c levels) type 2 diabetics was
significantly increased, and that their fibrin morphologies were again highly aberrant. As judged by scanning
electron microscopy and in the atomic force microscope, these could be reversed, to some degree, by the addition
of the iron chelators deferoxamine (DFO) or deferasirox (DFX). As well as their demonstrated diagnostic significance,
these morphological indicators may have prognostic value.Biotechnology and Biological Sciences Research Council (grant
BB/L025752/1) as well as the National Research Foundation (NRF) of South
Africa.http://www.cardiab.com/hb201