The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development

A single nucleotide polymorphism causing constitutive activation of Vav1 results in increased natural Treg generation and is responsible for the imbalance between Vav1 GEF and adaptor functions

A Spontaneous Mutation of the Rat Themis Gene Leads to Impaired Function of Regulatory T Cells Linked to Inflammatory Bowel Disease

Spontaneous or chemically induced germline mutations, which lead to Mendelian phenotypes, are powerful tools to discover new genes and their functions. Here, we report an autosomal recessive mutation that occurred spontaneously in a Brown-Norway (BN) rat colony and was identified as causing marked T cell lymphopenia. This mutation was stabilized in a new rat strain, named BNm for “BN mutated.” In BNm rats, we found that the T cell lymphopenia originated in the thymus, was intrinsic to CD4 T lymphocytes, and was associated with the development of an inflammatory bowel disease. Furthermore, we demonstrate that the suppressive activity of both peripheral and thymic CD4+ CD25bright regulatory T cells (Treg) is defective in BNm rats. Complementation of mutant animals with BN Treg decreases disease incidence and severity, thus suggesting that the impaired Treg function is involved in the development of inflammatory bowel disease in BNm rats. Moreover, the cytokine profile of effector CD4 T cells is skewed toward Th2 and Th17 phenotypes in BNm rats. Linkage analysis and genetic dissection of the CD4 T cell lymphopenia in rats issued from BNm×DA crosses allowed the localization of the mutation on chromosome 1, within a 1.5 megabase interval. Gene expression and sequencing studies identified a frameshift mutation caused by a four-nucleotide insertion in the Themis gene, leading to its disruption. This result is the first to link Themis to the suppressive function of Treg and to suggest that, in Themis-deficient animals, defect of this function is involved in intestinal inflammation. Thus, this study highlights the importance of Themis as a new target gene that could participate in the pathogenesis of immune diseases characterized by chronic inflammation resulting from a defect in the Treg compartment

Is Isocyanate Exposure and Occupational Asthma Still a Major Occupational Health Concern? Systematic Literature Review

Isocyanate, whose disease-inducing mechanism is poorly understood, with poor prognosis, is widely used. Asthma is the most frequent manifestation of prolonged exposure. We assessed the evolution of the incidence of isocyanate-induced occupational asthma over time. PubMed and Cochrane databases were systematically searched for studies published since 1990 that assessed the relationship between occupational exposure to isocyanates and asthma. We identified 39 studies: five retrospective cohort studies, seven prospective cohort studies, three of which were inception cohorts), seven observational cross-sectional studies, five literature reviews, two case series, and 13 registry studies. The incidence of occupational asthma secondary to isocyanate exposure has decreased from more than 5% in the early 1990s to 0.9% in 2017 in the United States. Despite the wide use of optimal collective and individual protection measures, the risk of occupational asthma has stabilized. Occupational asthma risk can be assessed with good sensitivity using self-questionnaires and pulmonary function tests. Occupational avoidance should be implemented as soon as possible after the first symptoms appear because the prognosis becomes increasingly poor with the persistence of exposure. It is now necessary to study specifically cutaneous sensitization to isocyanates and to define what protective equipment is effective against this mode of exposure

Allergic contact dermatitis to diclofenac gel due to propylene glycol sensitization: usefulness of repeated open application tests to determine safer alternatives

Topical non-steroidal anti-inflammatory drugs (NSAIDs) can cause allergic contact dermatitis (ACD) and photocontact dermatitis. Although topical diclofenac is associated with fewer side effects than other topical NSAIDs, rare cases of contact dermatitis have been reported

Role of the occupational disease consultant in the multidisciplinary discussion of interstitial lung diseases

Abstract Background Diffuse interstitial lung diseases (ILD) constitute a heterogeneous group of conditions with complex etiological diagnoses requiring a multidisciplinary approach. Much is still unknown about them, particularly their relationship with occupational exposures. The primary objective of this study was to investigate the distribution of occupational exposures according to type of ILD. The secondary objectives were to estimate the proportion of ILDs possibly related to occupational exposure and to evaluate the added value of the participation of an occupational disease consultant in ILD multidisciplinary discussions (MDD). Methods From May to December 2020, all consecutive patients with ILD whose cases were reviewed during a MDD in a referral centre for ILD were prospectively offered a consultation with an occupational disease consultant. Results Of the 156 patients with ILD whose cases were reviewed in MDD during the study period, 141 patients attended an occupational exposure consultation. Occupational exposure was identified in 97 patients. Occupational exposure to asbestos was found in 12/31 (38.7%) patients with idiopathic pulmonary fibrosis (IPF) and in 9/18 (50.0%) patients with unclassifiable fibrosis. Occupational exposure to metal dust was found in 13/31 (41.9%) patients with IPFs and 10/18 (55.6%) patients with unclassifiable fibrosis. Silica exposure was found in 12/50 (24.0%) patients with autoimmune ILD. The link between occupational exposure and ILD was confirmed for 41 patients after the specialist occupational consultation. The occupational origin had not been considered (n = 9) or had been excluded or neglected (n = 4) by the MDD before the specialised consultation. A total of 24 (17%) patients were advised to apply for occupational disease compensation, including 22 (15.6%) following the consultation. In addition, a diagnosis different from the one proposed by the MDD was proposed for 18/141 (12.8%) patients. Conclusions In our study, we found a high prevalence of occupational respiratory exposure with a potential causal link in patients with ILD. We suggest that a systematic specialised consultation in occupational medicine could be beneficial in the ILD diagnostic approach

Riverscape approaches in practice: perspectives and applications

Landscape perspectives in riverine ecology have been undertaken increasingly in the last 30 years, leading aquatic ecologists to develop a diverse set of approaches for conceptualizing, mapping and understanding ‘riverscapes’. Spatiotemporally explicit perspectives of rivers and their biota nested within the socio-ecological landscape now provide guiding principles and approaches in inland fisheries and watershed management. During the last two decades, scientific literature on riverscapes has increased rapidly, indicating that the term and associated approaches are serving an important purpose in freshwater science and management. We trace the origins and theoretical foundations of riverscape perspectives and approaches and examine trends in the published literature to assess the state of the science and demonstrate how they are being applied to address recent challenges in the management of riverine ecosystems. We focus on approaches for studying and visualizing rivers and streams with remote sensing, modelling and sampling designs that enable pattern detection as seen from above (e.g. river channel, floodplain, and riparian areas) but also into the water itself (e.g. aquatic organisms and the aqueous environment). Key concepts from landscape ecology that are central to riverscape approaches are heterogeneity, scale (resolution, extent and scope) and connectivity (structural and functional), which underpin spatial and temporal aspects of study design, data collection and analysis. Mapping of physical and biological characteristics of rivers and floodplains with high-resolution, spatially intensive techniques improves understanding of the causes and ecological consequences of spatial patterns at multiple scales. This information is crucial for managing river ecosystems, especially for the successful implementation of conservation, restoration and monitoring programs. Recent advances in remote sensing, field-sampling approaches and geospatial technology are making it increasingly feasible to collect high-resolution data over larger scales in space and time. We highlight challenges and opportunities and discuss future avenues of research with emerging tools that can potentially help to overcome obstacles to collecting, analysing and displaying these data. This synthesis is intended to help researchers and resource managers understand and apply these concepts and approaches to address real-world problems in freshwater management

Impaired suppressive function of BN^m Treg is involved in the development of intestinal lesions.

<p>(A) Absolute numbers of Foxp3+ CD4+ T cells in thymus, spleen and mLN from BN (n = 7) and BN^m (n = 13) rats. Data are representative of three independent experiments. (B) Suppressive activity of thymic CD25^bright CD4+ SP cells (top panel) and peripheral CD25^bright CD4+ T cells (bottom panel) from BN or BN^m rats was assessed in co-culture experiments with CFSE-labeled naive LEW CD4 T cells as effector cells. Proliferation was assessed by CFSE dilution (percentages indicate the proportion of CFSE^low cells). Data are representative of three independent experiments. (C, D) Disease frequency (C) and duodenum microscopic scores (D) in 12 week-old BN^m rats injected with PBS (white column or symbols; n = 21) or with 4.10⁶ BN CD25^bright CD4+ T cells (grey columns or symbols; n = 12) at 4 weeks of age. (E) Cytokine protein expression in duodenum from control BN^m rats with microscopic intestinal scores (white columns; n = 8) and from BN^m rats transferred with CD25^bright CD4+ T cells (grey columns; n = 12).</p

BN^m rats develop inflammatory bowel disease.

<p>(A) Small intestine and colon from 12 week-old BN and BN^m rats. (B, C) Length of small intestine and colon (B) and thickness of the duodenum, jejunum, ileum and colon (C) of BN (n = 10) and BN^m rats with macroscopic signs of intestinal lesions (n = 7). (D) Hematoxylin-eosin staining of duodenum, jejunum and colon from 8 to 10 week-old BN and BN^m rats. Images are representative of microscopic lesions observed in all affected BN^m rats (original magnification: 100 X). Stars indicate granulomas; arrows point to infiltration and double head arrows indicate the thickness of the intestinal wall. (E) CD68, CD3 and B220 immunoperoxydase staining on sections of jejunum from 8 week-old BN^m rats. Positive staining results in a brown reaction product. HE: hematoxylin-eosin staining showing the presence of polymorphonuclear leucocytes (original magnification: 400 X). (F) Myeloperoxidase (MPO) activity in the duodenum, jejunum, ileum and colon tissue samples from BN (n = 30) and BN^m rats with macroscopic lesions (n = 21). (G) Cytokine and chemokine protein expression in duodenum from BN (n = 7) and BN^m rats with macroscopic lesions (n = 7). (H) Relative mRNA expression of IL-2 and IL-17A in duodenum from BN (n = 4) and BN^m rats exhibiting intestinal macroscopic lesions (n = 7). (BN: black columns, BN^m: white columns).</p