Sifalimumab had a safety profile that supports further clinical development. This trial demonstrated that overexpression of type I IFN signature in SLE is at least partly driven by IFNα, and exploratory analyses suggest that IFNα inhibition may be associated with clinical benefit in SLE. Trial registration number NCT00299819.

Crossover events within the MHC indicated a susceptibility locus for IgAD/CVID between the class III markers D821/D823 and HLA-B8, a region populated by 21 genes that include tumor necrosis factor alpha and lymphotoxins alpha and beta. Inheritance of at least this fragment of haplotype 1 appears to be necessary for the development of IgAD/CVID in this family.

Active episodes of the inflammatory bowel diseases (IBD) are associated with the infiltration of large numbers of myeloid cells including neutrophils, monocytes and macrophages. The objective of this study was to systematically characterize and define the different populations of myeloid cells generated in a mouse model of chronic gut inflammation. Using the T cell transfer model of chronic colitis, we found that induction of disease was associated with enhanced production of myelopoietic cytokines (IL-17, G-CSF), increased production of neutrophils and monocytes and infiltration of large numbers of myeloid cells into the MLNs and colon. Detailed characterization of these myeloid cells revealed three major populations including Mac-1+Ly6ChighGr-1low/neg cells (monocytes), Mac-1+Ly6CintGr-1+ cells (neutrophils) and Mac-1+Ly6Clow/negGr-1low/neg leukocytes (macrophages, dendritic cells, and eosinophils). In addition, we observed enhanced surface expression of MHC class II and CD86 on neutrophils isolated from the inflamed colon when compared to neutrophils obtained from the blood, MLNs and spleen of colitic mice. Furthermore, we found that colonic neutrophils had acquired antigen-presenting cell (APC) function that enabled these granulocytes to induce proliferation of ovalbumin-specific CD4+ T cells in an antigen- and MHC class II-dependent manner. Finally, we observed a synergistic increase in pro-inflammatory cytokine and chemokine production following co-culture of T cells with neutrophils in vitro. Taken together, our data suggest that extravasated neutrophils acquire APC function within the inflamed bowel where they may perpetuate chronic gut inflammation by inducing T cell activation and proliferation as well as by enhancing production of pro-inflammatory mediators.

Some patients with Plasmodium falciparum infections develop cerebral malaria, acute respiratory distress, and shock and ultimately die even though drug therapy has eliminated the parasite from the blood, suggesting that a systemic inflammatory response contributes to malarial pathogenesis. Plasmodium berghei-infected mice are a well-recognized model of severe malaria (experimental severe malaria [ESM]), and infected mice exhibit a systemic inflammatory response. Because platelets are proposed to contribute to ESM and other systemic inflammatory responses, we determined whether platelet adherence contributes to experimental malarial pathogenesis. Indeed, a significant (P < 0.005) increase in the number of rolling and adherent platelets was observed by intravital microscopy in brain venules of P. berghei-infected mice compared with the number in uninfected controls. P-selectin-or ICAM-1-deficient mice exhibit increased survival after P. berghei infection. We observed a significant (P < 0.0001) reduction in the morbidity of mice injected with anti-CD41 (␣ IIb or gpIIb) monoclonal antibody on day 1 of P. berghei infection compared with the morbidity of infected controls injected with rat immunoglobulin G. Additionally, platelet rolling and adhesion in brain venules were reduced in P. berghei mice lacking either P-selectin or ICAM-1 or when the platelets were coated with anti-CD41 monoclonal antibody. Unlike other inflammatory conditions, we did not detect platelet-leukocyte interactions during P. berghei malaria. Because (i) leukocyte adhesion is not markedly altered in the absence of P-selectin or ICAM-1 and (ii) CD41 is not an adhesion molecule for parasitized erythrocytes, these findings support the hypothesis that inhibition of platelet adhesion to the brain microvasculature protects against development of malarial pathogenesis.

No abstract