13 research outputs found
Intrinsic NLRP3 inflammasome activity is critical for normal adaptive immunity via regulation of IFN-Îł in CD4+ T cells
The NLRP3 inflammasome controls interleukin-1b maturation in antigen-presenting cells, but
a direct role for NLRP3 in human adaptive immune cells has not been described.We found that
the NLRP3 inflammasome assembles in human CD4+ Tcells and initiates caspase-1–dependent
interleukin-1b secretion, thereby promoting interferon-g production and T helper 1 (TH1)
differentiation in an autocrine fashion. NLRP3 assembly requires intracellular C5 activation and
stimulation of C5a receptor 1 (C5aR1), which is negatively regulated by surface-expressed
C5aR2. Aberrant NLRP3 activity in Tcells affects inflammatory responses in human
autoinflammatory disease and in mouse models of inflammation and infection. Our results
demonstrate that NLRP3 inflammasome activity is not confined to “innate immune cells” but is
an integral component of normal adaptive TH1 responses
Bacillus anthracis Spore Surface Protein BclA Mediates Complement Factor H Binding to Spores and Promotes Spore Persistence
Spores of Bacillus anthracis, the causative agent of anthrax, are known to persist in the host lungs for prolonged periods of time, however the underlying mechanism is poorly understood. In this study, we demonstrated that BclA, a major surface protein of B. anthracis spores, mediated direct binding of complement factor H (CFH) to spores. The surface bound CFH retained its regulatory cofactor activity resulting in C3 degradation and inhibition of downstream complement activation. By comparing results from wild type C57BL/6 mice and complement deficient mice, we further showed that BclA significantly contributed to spore persistence in the mouse lungs and dampened antibody responses to spores in a complement C3-dependent manner. In addition, prior exposure to BclA deletion spores (ΔbclA) provided significant protection against lethal challenges by B. anthracis, whereas the isogenic parent spores did not, indicating that BclA may also impair protective immunity. These results describe for the first time an immune inhibition mechanism of B. anthracis mediated by BclA and CFH that promotes spore persistence in vivo. The findings also suggested an important role of complement in persistent infections and thus have broad implications
The C3aR promotes macrophage infiltration and regulates ANCA production but does not affect glomerular injury in experimental anti-myeloperoxidase glomerulonephritis
<div><p>The anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides are autoimmune diseases associated with significant morbidity and mortality. They often affect the kidney causing rapidly progressive glomerulonephritis. While signalling by complement anaphylatoxin C5a though the C5a receptor is important in this disease, the role of the anaphylatoxin C3a signalling via the C3a receptor (C3aR) is not known. Using two different murine models of anti-myeloperoxidase (MPO) glomerulonephritis, one mediated by passive transfer of anti-MPO antibodies, the other by cell-mediated immunity, we found that the C3aR did not alter histological disease severity. However, it promoted macrophage recruitment to the inflamed glomerulus and inhibited the generation of MPO-ANCA whilst not influencing T cell autoimmunity. Thus, whilst the C3aR modulates some elements of disease pathogenesis, overall it is not critical in effector responses and glomerular injury caused by autoimmunity to MPO.</p></div