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The aromatic hydrocarbons receptor (AhR) is a ligand‐dependent transcription factor that plays a role in mediating toxicity to xenobiotics. Its key role in immune regulation has been recently demonstrated. Recent data pointed to the efficacy of ITE (2‐(1′H‐indole‐3′‐carbonyl)‐thiazole‐4‐carboxylic acid methyl ester), a nontoxic ligand of AhR, in experimental models of inflammatory diseases. Such effect was mainly through the expansion of regulatory T cells (Tregs). Similarly, TCDD (2,3,7,8‐tetrachlorodibenzo‐p‐dioxin), a toxic ligand of AhR, has been shown to exert comparable effects on Tregs in mice. Herein, we showed that ITE has no effects on natural Tregs. However, it supports the de novo generation of Tregs in humans while promoting their suppressive functions. Our data bring new elements supporting the use of ITE in human therapy of inflammatory diseases. ITE, a non‐toxic endogenous aryl hydrocarbon receptor ligand, enhances de novo generation of regulatory T cells in humans and promotes their suppressive functions. [ABSTRACT FROM AUTHOR]

Nearly two billion people are latently infected with Mtb (LTBI). Detection of LTBI with high risk to develop active tuberculosis (aTB) is considered the cornerstone to control the disease. The current challenge is to identify markers that better classify LTBI versus aTB. It has been previously shown that Rv0140, a reactivation‐associated antigen of Mtb, induces significantly higher IFN‐γ production in LTBI individuals as compared to aTB patients. Herein, we show that Rv0140 induces high granzyme B level by PBMCs derived from LTBI (n = 34) as compared to aTB (n = 18). Receiving operator characteristic (ROC) curves were used to evaluate the capacity of Rv0140 to discriminate between LTBI and aTB by measuring IFN‐γ and granzyme B secretion. Our results show that, in response to Rv0140, granzyme B seems to allow better discrimination of LTBI from aTB with areas under the curve (AUC) of 0.88 (95% CI 0.79–0.98) as compared to IFN‐γ with AUC of 0.85 (95% CI 0.74–0.96) even though CI overlap. Intracellular staining (ICS) experiments and the use of anti‐MHC I antibody showed that granzyme B is mainly produced by CD8+ T cells in response to Rv0140. Thus, we propose granzyme B as a host marker to help identify LTBI individuals. Rv0140‐induced Granzyme B biomarker discriminates TB infection status [ABSTRACT FROM AUTHOR]

Abstract: Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency disease due to impaired Fas‐Fas ligand apoptotic pathway. It is characterized by chronic nonmalignant, noninfectious lymphadenopathy and/or splenomegaly associated with autoimmune manifestations primarily directed against blood cells. Herein, we review the heterogeneous ALPS molecular bases and discuss recent findings revealed by the study of consanguineous patients. Indeed, this peculiar genetic background favored the identification of a novel form of AR ALPS‐FAS associated with normal or residual protein expression, expanding the spectrum of ALPS types. In addition, rare mutational mechanisms underlying the splicing defects of FAS exon 6 have been identified in AR ALPS‐FAS with lack of protein expression. These findings will help decipher critical regions required for the tight regulation of FAS exon 6 splicing. We also discuss the genotype‐phenotype correlation and disease severity in AR ALPS‐FAS. Altogether, the study of ALPS molecular bases in endogamous populations helps to better classify the disease subgroups and to unravel the Fas pathway functioning. [ABSTRACT FROM AUTHOR]

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency disease due to impaired Fas-Fas ligand apoptotic pathway. It is characterized by chronic nonmalignant, noninfectious lymphadenopathy and/or splenomegaly associated with autoimmune manifestations primarily directed against blood cells. Herein, we review the heterogeneous ALPS molecular bases and discuss recent findings revealed by the study of consanguineous patients. Indeed, this peculiar genetic background favored the identification of a novel form of AR ALPS-FAS associated with normal or residual protein expression, expanding the spectrum of ALPS types. In addition, rare mutational mechanisms underlying the splicing defects of FAS exon 6 have been identified in AR ALPS-FAS with lack of protein expression. These findings will help decipher critical regions required for the tight regulation of FAS exon 6 splicing. We also discuss the genotype-phenotype correlation and disease severity in AR ALPS-FAS. Altogether, the study of ALPS molecular bases in endogamous populations helps to better classify the disease subgroups and to unravel the Fas pathway functioning., (©2017 Society for Leukocyte Biology.)