A topical medication combining calcipotriol (Cal) and betamethasone dipropionate (BDP) has proven effective in a number of randomized controlled trials performed in patients with psoriasis, but its mechanism of action has not been fully elucidated. We investigated whether the combination of Cal and BDP (Cal/BDP) in this topical medication had a synergistic effect on psoriasis-like dermatitis and explored the underlying immunological mechanisms in a murine psoriasis model induced by application of imiquimod. Cal/BDP synergistically inhibited ear thickening induced by imiquimod compared to monotherapy with either Cal or BDP. In addition, Cal/BDP significantly suppressed the interleukin (IL)-23/IL-17-producing T (T17) pathogenic axis, including expression of IL-17a, IL-23a, IL-22 and TNF-α mRNA in skin lesions and expansion of CCR6+ γδ T17 cells in the draining lymph nodes. Notably, Cal/BDP synergistically induced regulatory CD8+ T cells and also improved the balance between regulatory CD8+ or CD4+ T cells and proinflammatory CCR6+ γδ T17 cells in the draining lymph nodes. These results suggest synergistic anti-psoriatic activity of Cal/BDP with normalization of the imbalance between regulatory CD8+ or CD4+ T cells and proinflammatory CCR6+ γδ T17 cells, which contributes to successful control of psoriasis by Cal-BDP combination therapy.

Genome-wide association studies have identified risk loci associated with the development of inflammatory bowel disease, while epidemiological studies have emphasized that pathogenesis likely involves host interactions with environmental elements whose source and structure need to be defined. Here, we identify a class of compounds derived from dietary, microbial, and industrial sources that are characterized by the presence of a five-membered oxazole ring and induce CD1d-dependent intestinal inflammation. We observe that minimal oxazole structures modulate natural killer T cell-dependent inflammation by regulating lipid antigen presentation by CD1d on intestinal epithelial cells (IECs). CD1d-restricted production of interleukin 10 by IECs is limited through activity of the aryl hydrocarbon receptor (AhR) pathway in response to oxazole induction of tryptophan metabolites. As such, the depletion of the AhR in the intestinal epithelium abrogates oxazole-induced inflammation. In summary, we identify environmentally derived oxazoles as triggers of CD1d-dependent intestinal inflammatory responses that occur via activation of the AhR in the intestinal epithelium.
Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.

Biologic drugs, including enzyme-replacement therapies, can elicit anti-drug Abs (ADA) that may interfere with drug efficacy and impact patient safety. In an effort to control ADA, we focused on identifying regimens of immune tolerance induction that may be readily available for clinical use. Data generated in both wild-type mice and a Pompe disease mouse model demonstrate that single-cycle, low-dose methotrexate can be as effective as three cycles of methotrexate in providing a long-lived reduction in alglucosidase alfa-specific ADA. In addition, we show that methotrexate induces Ag-specific tolerance as mice generate similar Ab responses to an irrelevant Ag regardless of prior methotrexate treatment. Methotrexate-induced immune tolerance does not seem to involve cell depletion, but rather a specific expansion of IL-10- and TGF-β-secreting B cells that express Foxp3, suggesting an induction of regulatory B cells. The mechanism of immune tolerance induction appears to be IL-10 dependent, as methotrexate does not induce immune tolerance in IL-10 knockout mice. Splenic B cells from animals that have been tolerized to alglucosidase alfa with methotrexate can transfer tolerance to naive hosts. We hypothesize that methotrexate induction treatment concomitant with initial exposure to the biotherapeutic can induce Ag-specific immune tolerance in mice through a mechanism that appears to involve the induction of regulatory B cells.
Copyright © 2014 by The American Association of Immunologists, Inc.

The key role of TRAF6 in TLR signaling pathways is well known. More recent evidence has implicated TRAF3 as another TRAF family member important to certain TLR responses of myeloid cells. Previous studies demonstrate that TRAF3 functions are highly context-dependent, displaying receptor and cell-type specificity. We thus examined the TLR responses of TRAF3(-/-)mouse B lymphocytes to test the hypothesis that TRAF3 plays distinct roles in such responses, depending on cell type. TRAF3(-/-) DC are known to have a defect in type 1 IFN production and here, showed diminished production of TNF and IL-10 and unaltered IL-6. In marked contrast, TRAF3(-/-) B cells made elevated amounts of TNF and IL-6 protein, as well as IL-10 and IP-10 mRNA, in response to TLR ligands. Also, in contrast to TRAF3(-/-) DC, the type 1 IFN pathway was elevated in TRAF3(-/-) B cells. Increased early responses of TRAF3(-/-) B cells to TLR signals were independent of cell survival or proliferation but associated with elevated canonical NF-κB activation. Additionally, TRAF3(-/-) B cells displayed enhanced TLR-mediated expression of AID and Ig isotype switching. Thus, TRAF3 plays varied and cell type-specific, biological roles in TLR responses.

The importance of regulated AP-1 activity during T cell development was assessed using transgenic mice overexpressing BATF, a basic leucine zipper transcription factor and an AP-1 inhibitor. BATF transgenic animals possess normal thymic cellularity and all major T cell subsets, but show impaired thymocyte proliferation in vitro and no induction of IL-2, IL-4, IL-5, IL-10, and IL-13 expression. Since NKT cells are largely responsible for cytokine production in the thymus, this population was examined by detection of the V alpha 14-J alpha 281 TCR, flow cytometry of NK1.1(+) TCR beta(+) cells, and analysis of cytokine production by heat-stable Ag(low) thymocytes and peripheral NKT cells stimulated in vivo. Results show a severe under-representation of NKT cells in BATF transgenic animals, providing the first evidence that the precise control of AP-1-mediated transcription is critical for the proper emergence of thymus-derived NKT cells in the mouse.