Lack of the Long Pentraxin PTX3 Promotes Autoimmune Lung Disease but not Glomerulonephritis in Murine Systemic Lupus Erythematosus

The long pentraxin PTX3 has multiple roles in innate immunity. For example, PTX3 regulates C1q binding to pathogens and dead cells and regulates their uptake by phagocytes. It also inhibits P-selectin-mediated recruitment of leukocytes. Both of these mechanisms are known to be involved in autoimmunity and autoimmune tissue injury, e.g. in systemic lupus erythematosus, but a contribution of PTX3 is hypothetical. To evaluate a potential immunoregulatory role of PTX3 in autoimmunity we crossed Ptx3-deficient mice with Fas-deficient (lpr) C57BL/6 (B6) mice with mild lupus-like autoimmunity. PTX3 was found to be increasingly expressed in kidneys and lungs of B6lpr along disease progression. Lack of PTX3 impaired the phagocytic uptake of apoptotic T cells into peritoneal macrophages and selectively expanded CD4/CD8 double negative T cells while other immune cell subsets and lupus autoantibody production remained unaffected. Lack of PTX3 also aggravated autoimmune lung disease, i.e. peribronchial and perivascular CD3+ T cell and macrophage infiltrates of B6lpr mice. In contrast, histomorphological and functional parameters of lupus nephritis remained unaffected by the Ptx3 genotype. Together, PTX3 specifically suppresses autoimmune lung disease that is associated with systemic lupus erythematosus. Vice versa, loss-of-function mutations in the Ptx3 gene might represent a genetic risk factor for pulmonary (but not renal) manifestations of systemic lupus or other autoimmune diseases

Increased Levels of Circulating Cytokines with HIV-Related Immunosuppression

Cytokines may contribute to the severity of CD4 cell depletion with human immunodeficiency virus (HIV) infection, but quantitative relationships are not well defined. Serum and plasma from 181 HIV-infected individuals were tested with Millipore 30-plex Luminex cytokine assays. Within-individual correlations among cytokines were summarized by two-dimensional hierarchical cluster analysis. Associations with age, sex, race, CD4 count, and HIV viral load were determined with linear regression models. Tests for statistical significance were corrected for multiple comparisons, using a false discovery rate of 0.1. African-Americans had significantly higher levels than whites of six cytokines (IL-2, IL-5, IL-7, IL-15, fractalkine, and IFN-γ), and lower levels of MCP-1. Females had higher fractalkine levels than males. Age was not associated with levels of any cytokine. Six cytokines, including the T-helper (Th) type 1 cytokine IL-15, the Th2 cytokines IL-1ra and IL-10, the chemokines fractalkine and MCP-1, and the growth factor G-CSF were each inversely associated with CD4 count; no cytokine was directly associated with CD4 count. Fractalkine was directly associated with HIV viral load, adjusted for CD4 count. Cytokines clustered by primary function (e.g., Th1, Th2, proinflammatory, chemokines, or growth factors) whereas individuals clustered according to cytokine levels (generally high, intermediate, or low) had significantly different CD4 counts [medians (interquartile range) of 60 (17–162), 131 (62–321), and 155 (44–467), respectively; p<0.0001]. CD4 deficiency is associated with generalized increases in cytokines of various functions. Racial differences in cytokine response to HIV infection could contribute to disparities in disease progression