IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) is a major hospital- and communityacquired pathogen, but the mechanisms underlying host-defense to MRSA remain poorly understood. Here, we investigated the role of IL-21 in this process. When administered intratracheally into wild-type mice, IL-21 induced granzymes and augmented clearance of pulmonary MRSA but not when neutrophils were depleted or a granzyme B inhibitor was added. Correspondingly, IL-21 induced MRSA killing by human peripheral blood neutrophils. Unexpectedly, however, basal MRSA clearance was also enhanced when IL-21 signaling was blocked, both in Il21r KO mice and in wild-type mice injected with IL-21R-Fc fusion-protein. This correlated with increased type I interferon and an IFN-related gene signature, and indeed antiIFNAR1 treatment diminished MRSA clearance in these animals. Moreover, we found that IFNb induced granzyme B and promoted MRSA clearance in a granzyme B-dependent fashion. These results reveal an interplay between IL-21 and type I IFN in the innate immune response to MRS

Development and Function of Immune Cells in an Adolescent Patient with a Deficiency in the Interleukin-10 Receptor

OBJECTIVE:: Monogenic defects in the interleukin-10 (IL-10) pathway are extremely rare and cause infantile-onset inflammatory bowel disease (IBD)-like pathology. Understanding how immune responses are dysregulated in monogenic IBD-like diseases can provide valuable insight in “classical” IBD pathogenesis. Here, we studied long-term immune cell development and function in an adolescent IL-10 receptor (IL10RA)-deficient patient who presented in infancy with severe colitis and fistulizing perianal disease and is currently treated with immune suppressants. METHODS:: Biomaterial was collected from the IL10RA-deficient patient, pediatric IBD patients and healthy controls. The frequency and phenotype of immune cells were determined in peripheral blood and intestinal biopsies by flow cytometry and immunohistochemistry. Functional changes in monocyte-derived dendritic cells and T cells were assessed by in vitro activation assays. RESULTS:: The IL10RA-deficient immune system developed normally with respect to numbers and phenotype of circulating immune cells. Despite normal co-stimulatory molecule expression, bacterial lipopolysaccharide-stimulated monocyte-derived dendritic cells from the IL10RA-deficient patient released increased amounts of TNFα compared to healthy controls. Upon T-cell receptor ligation, IL10RA-deficient peripheral blood mononuclear cells released increased amounts of T cell cytokines IFNγ and IL-17 agreeing with high numbers of T-bet and IL-17 cells in intestinal biopsies taken at disease onset. In vitro, the immunosuppressive drug thalidomide used to treat the patient decreased peripheral blood mononuclear cell-derived TNFα production. CONCLUSIONS:: With time and during immunosuppressive treatment the IL10RA- deficient immune system develops relatively normally. Upon activation, IL-10 is crucial for controlling excessive inflammatory cytokine release by dendritic cells and preventing IFNγ and IL-17-mediated T-cell responses

Expression of Plet1 controls interstitial migration of murine small intestinal dendritic cells

Under homeostatic conditions, dendritic cells (DCs) continuously patrol the intestinal lamina propria. Upon antigen encounter, DCs ini

Comparison of skin prick test and prick‐to‐prick test with fruits and vegetables in the diagnosis of food allergy

Abstract Introduction Prick‐to‐prick (PTP) test with fresh food is accepted as a reliable tool for measuring sensitization to fruits and vegetables. Not all fruits and vegetables are available throughout the year. The objective of this study was to investigate whether skin prick test (SPT) performed with frozen juice of fruits and vegetables (FJFV) is a good alternative to PTP tests performed with fresh fruits and vegetables (FFV). Methods Adult patients suspected of having a food allergy to fruits and/or vegetables were included. A questionnaire was used to score symptoms after consumption of apple, kiwi, peach, tomato, and carrot. SPTs with FJFV, and PTP tests with FFV were performed. Intra‐class correlation coefficients (ICC) between the SPT and PTP test results were calculated. The sensitivity and specificity of both diagnostic tests towards food allergen specific symptoms (FASS) were calculated. Results Thirty‐six patients were included. FASS was positive in 75% for apple, 53% for kiwi, 44% for peach, 25% for tomato, and 22% for carrot. ICC between SPT and PTP test results were moderate for apple (0.72) and kiwi (0.71), strong for peach (0.75) and tomato (0.89), and very strong for carrot (0.94). Sensitivity was equal for the SPT and PTP tests for apple (0.93), peach (0.81), and carrot (1.00), and comparable for kiwi (0.50 resp. 0.70), and tomato (0.44 resp. 0.56). Specificity was equal for apple (0.33), peach (0.15), and carrot (0.41), and comparable for kiwi (0.29 resp. 0.21) and tomato (0.80 resp. 0.72). Conclusions Results of SPT with FJFV and PTP test with FFV are comparable. SPT with FJFV is a good alternative in the daily practice of the allergists

Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis

Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3+, and Foxp3neg CD4+ T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4+ T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4+ T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.</p

Tetraspanin CD37 protects against the development of B cell lymphoma

Worldwide, B cell non-Hodgkin lymphoma is the most common hematological malignancy and represents a substantial clinical problem. The molecular events that lead to B cell lymphoma are only partially defined. Here, we have provided evidence that deficiency of tetraspanin superfamily member CD37, which is important for B cell function, induces the development of B cell lymphoma. Mice lacking CD37 developed germinal center-derived B cell lymphoma in lymph nodes and spleens with a higher incidence than Bcl2 transgenic mice. We discovered that CD37 interacts with suppressor of cytokine signaling 3 (SOCS3); therefore, absence of CD37 drives tumor development through constitutive activation of the IL-6 signaling pathway. Moreover, animals deficient for both Cd37 and Il6 were fully protected against lymphoma development, confirming the involvement of the IL-6 pathway in driving tumorigenesis. Loss of CD37 on neoplastic cells in patients with diffuse large B cell lymphoma (DLBCL) directly correlated with activation of the IL-6 signaling pathway and with worse progression-free and overall survival. Together, this study identifies CD37 as a tumor suppressor that directly protects against B cell lymphomagenesis and provides a strong rationale for blocking the IL-6 pathway in patients with CD37- B cell malignancies as a possible therapeutic interventio