Schistosoma mansoni secretes a chemokine binding protein with antiinflammatory activity

The coevolution of humans and infectious agents has exerted selective pressure on the immune system to control potentially lethal infections. Correspondingly, pathogens have evolved with various strategies to modulate and circumvent the host's innate and adaptive immune response. Schistosoma species are helminth parasites with genes that have been selected to modulate the host to tolerate chronic worm infections, often for decades, without overt morbidity. The modulation of immunity by schistosomes has been shown to prevent a range of immune-mediated diseases, including allergies and autoimmunity. Individual immune-modulating schistosome molecules have, therefore, therapeutic potential as selective manipulators of the immune system to prevent unrelated diseases. Here we show that S. mansoni eggs secrete a protein into host tissues that binds certain chemokines and inhibits their interaction with host chemokine receptors and their biological activity. The purified recombinant S. mansoni chemokine binding protein (smCKBP) suppressed inflammation in several disease models. smCKBP is unrelated to host proteins and is the first described chemokine binding protein encoded by a pathogenic human parasite and may have potential as an antiinflammatory agent

Dysregulation of type 2 innate lymphoid cells and TH2 cells impairs pollutant-induced allergic airway responses

Background: Although the prominent role of TH2 cells in type 2 immune responses is well established, the newly identified type 2 innate lymphoid cells (ILC2s) can also contribute to orchestration of allergic responses. Several experimental and epidemiologic studies have provided evidence that allergen-induced airway responses can be further enhanced on exposure to environmental pollutants, such as diesel exhaust particles (DEPs). However, the components and pathways responsible remain incompletely known. Objective: We sought to investigate the relative contribution of ILC2 and adaptive TH2 cell responses in a murine model of DEP-enhanced allergic airway inflammation. Methods: Wild-type, Gata-3+/nlslacZ (Gata-3-haploinsufficient), RAR-related orphan receptor α (RORα)fl/flIL7RCre (ILC2-deficient), and recombination-activating gene (Rag) 2-/- mice were challenged with saline, DEPs, or house dust mite (HDM) or DEP+HDM. Airway hyperresponsiveness, as well as inflammation, and intracellular cytokine expression in ILC2s and TH2 cells in the bronchoalveolar lavage fluid and lung tissue were assessed. Results: Concomitant DEP+HDM exposure significantly enhanced allergic airway inflammation, as characterized by increased airway eosinophilia, goblet cell metaplasia, accumulation of ILC2s and TH2 cells, type 2 cytokine production, and airway hyperresponsiveness compared with sole DEPs or HDM. Reduced Gata-3 expression decreased the number of functional ILC2s and TH2 cells in DEP+HDM-exposed mice, resulting in an impaired DEP-enhanced allergic airway inflammation. Interestingly, although the DEP-enhanced allergic inflammation was marginally reduced in ILC2-deficient mice that received combined DEP+HDM, it was abolished in DEP+HDM-exposed Rag2-/- mice. Conclusion: These data indicate that dysregulation of ILC2s and TH2 cells attenuates DEP-enhanced allergic airway inflammation. In addition, a crucial role for the adaptive immune system was shown on concomitant DEP+HDM exposure

The TNF-family cytokine TL1A promotes allergic immunopathology through group 2 innate lymphoid cells

The TNF-family cytokine TL1A (TNFSF15) costimulates T cells and promotes diverse T-cell dependent models of autoimmune disease through its receptor DR3. TL1A polymorphisms also confer susceptibility to inflammatory bowel disease. Here we find that allergic pathology driven by constitutive TL1A expression depends on IL-13, but not T, NKT, mast cells or commensal intestinal flora. Group 2 innate lymphoid cells (ILC2) express surface DR3 and produce IL-13 and other type 2 cytokines in response to TL1A. DR3 is required for ILC2 expansion and function in the setting of T cell dependent and independent models of allergic disease. By contrast, DR3 deficient ILC2 can still differentiate, expand and produce IL-13 when stimulated by IL-25 or IL-33, and mediate expulsion of intestinal helminths. These data identify costimulation of ILC2 as a novel function of TL1A important for allergic lung disease, and suggest that TL1A may be a therapeutic target in these settings

Inflammation-induced formation of fat-associated lymphoid clusters

Fat-associated lymphoid clusters (FALCs) are a type of lymphoid tissue associated with visceral fat. Here we found that the distribution of FALCs was heterogeneous, with the pericardium containing large numbers of these clusters. FALCs contributed to the retention of B-1 cells in the peritoneal cavity through high expression of the chemokine CXCL13, and they supported B cell proliferation and germinal center differentiation during peritoneal immunological challenges. FALC formation was induced by inflammation, which triggered the recruitment of myeloid cells that expressed tumor-necrosis factor (TNF) necessary for signaling via the TNF receptors in stromal cells. Natural killer T cells (NKT cells) restricted by the antigen-presenting molecule CD1d were likewise required for the inducible formation of FALCs. Thus, FALCs supported and coordinated the activation of innate B cells and T cells during serosal immune responses. © 2015, Nature Publishing Group. All rights reserved