Inflammatory responses can be of critical importance in determining both the course and outcome of infectious diseases. Buruli ulcer, a neglected tropical disease caused by Mycobacterium ulcerans (M. ulcerans), has been reported to induce both immunosuppressive and proinflammatory responses in the skin. Here, we found that genetic inactivation of the orphan receptor GPR84 in mice leads to spontaneous healing of ulcerative lesions, recapitulating the rare spontaneous healing observed in human Buruli ulcer. Mechanistically, M. ulcerans infection induced Gpr84 expression through Toll-like receptor 2 engagement, promoting proinflammatory cytokine release through a self-amplifying loop that sustained receptor expression and inflammatory signaling. Moreover, pharmacological inhibition of GPR84 with the antagonist PBI-4050, in combination with antibiotics, accelerated tissue repair in infected GPR84-competent mice, which was associated with attenuation of inflammatory responses. Together, these findings establish GPR84 as a promising target for host-directed therapeutic interventions in Buruli ulcer and its expression as a potential biomarker of lesion activity.

ABSTRACT Primary cutaneous gamma‐delta T‐cell lymphoma has been described as an aggressive entity with a poor prognosis. However, gamma‐delta T‐cell receptor expression has been described in various types of skin lymphoproliferations. Paediatric cases of LyP are increasingly recognized, but paediatric LyP with a gamma‐delta phenotype have been rarely described. We report three paediatric patients with indolent gamma‐delta lymphoproliferation, with a relapsing‐remitting course evoking LyP. These three cases emphasize that TCR gamma‐delta expression in a lymphoproliferation is not a synonym of gamma‐delta lymphoma. Indeed, these cases raise the question of a paediatric variant of CD30‐negative lymphomatoid papulosis with histological features of atypical gamma‐delta‐positive T‐cell lymphoproliferation and underline the necessity of cautious clinico‐histological correlation when facing a gamma‐delta lymphoproliferation to avoid overtreatment.

INTRODUCTION:C3 glomerulopathy is a rare kidney disease resulting from dysregulation of the complement alternative pathway. The mechanistic diversity of alternative pathway activation, the heterogeneous immunological and clinical profiles limit a comprehensive understanding of the disease. METHODS:Here, we characterize mechanisms of complement-mediated immune response within the kidney. We studied a retrospective cohort of 47 patients diagnosed with C3 glomerulopathy and profiled systemic and intra-kidney complement activation and characterized intra-kidney immune infiltrates. RESULTS:The immune infiltrate of the kidney showed distinct compositions between the glomerular and interstitial compartments, with most neutrophils and macrophages in the glomeruli versus a majority of B and T lymphocytes and macrophages in the interstitium. The presence of a neutrophil-rich glomerular infiltrate appeared to be associated with stronger markers of complement activation in both systemic and intra-kidney compartments. However, interstitial immune infiltrates were not associated with a specific complement activation profile. The presence of a neutrophil-rich glomerular infiltrate correlated with a better response of the kidney to treatment and kidney survival, while patients with higher interstitial infiltrate had poor kidney survival. CONCLUSIONS:Our study highlights a link between the intra-kidney immune response, complement activation profile, and the phenotypic expression of the disease, which contributes to improving our understanding of the disease.

Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by ectopic calcification of tissues rich in elastic fibres (OMIM 264800). To date, PXE is considered a metabolic disease linked to an imbalance between pro- and anti-calcifying factors. The occurrence of sporadic erythematous flareups of PXE skin lesions is a complaint that we heard about on several occasions at the French PXE reference centre. However, this rare clinical aspect had never been extensively studied. We have had the opportunity to investigate a 13-year-old patient experiencing an erythematous flareup of his PXE lesions. We conducted this work to identify what type of inflammation was implicated in his lesions. An incisional skin biopsy on a recent erythematous inguinal PXE lesion was performed and sent for histological and transcriptomic analyses. The findings were compared to a non-erythematous PXE-affected skin biopsy obtained from another young PXE patient. Histological examination revealed perivascular T-cell infiltrates with Th1 polarity and elevated expression of cytotoxicity markers in RNAseq and RT-qPCR analyses. There was no increase in Th17 or Th2 markers. Our findings support the previous evidence of a possible inflammatory component in the development of PXE. Whether Th1-dependent inflammation contributes to the pathology as an active process or is an aggravating factor requires further investigations.

Buruli ulcer is a chronic infectious disease caused by Mycobacterium ulcerans. The pathogen persistence in host skin is associated with the development of ulcerative and necrotic lesions leading to permanent disabilities in most patients. However, few of diagnosed cases are thought to resolve through an unknown self-healing process. Using in vitro and in vivo mouse models and M. ulcerans purified vesicles and mycolactone, we showed that the development of an innate immune tolerance was only specific to macrophages from mice able to heal spontaneously. This tolerance mechanism depends on a type I interferon response and can be induced by interferon beta. A type I interferon signature was further detected during in vivo infection in mice as well as in skin samples from patients under antibiotics regiment. Our results indicate that type I interferon-related genes expressed in macrophages may promote tolerance and healing during infection with skin damaging pathogen.

Abstract Background and Aims Antineutrophil-cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) with kidney involvement (AAV-GN) frequently evolves to end-stage kidney disease (ESKD) despite aggressive immunosuppressive treatment. Several risk scores have been used to assess renal prognosis. We aimed to determine whether kidney function and markers of AAV-GN activity after 6 months could improve the prediction of ESKD. Method This retrospective and observational study included adult patients with AAV-GN recruited from 6 French nephrology centers (including from the Maine-Anjou AAV registry). The primary outcome was kidney survival. Analyses were conducted in the whole population and in a sub-population that did not develop ESKD early in the course of the disease. Results 241 patients were included in the whole cohort, with a median follow-up of 59 months. At diagnosis, Berden classification and Renal Risk Score (RRS) were not found better than kidney function (eGFR) alone, at predicting ESKD (C-index = 0.70, 0.79, 0.82, respectively). At 6 months, 20 patients reached ESKD. In the sub-population of 221 patients, 6 months eGFR outperformed Berden classification and RRS (C-index = 0.88, 0.62, 0.69, respectively) to predict ESKD. RRS performed better when it was updated with the eGFR at 6 months instead of the baseline eGFR. While 6-months proteinuria was associated with ESKD and improved ESKD prediction, hematuria and serological remission did not. Conclusion This work suggests the interest of the reassessment of the renal prognosis 6 months after AAV-GN diagnosis. Kidney function at this time remains the most reliable for predicting renal outcome. To improve the long-term prediction of ESKD, there may be a place for repeated kidney biopsy following induction treatment, in order to obtain a precise evaluation of disease activity, discuss the immunosuppressive treatment strategy and improve prognosis scores.

ABSTRACT Background Anti-neutrophil cytoplasmic antibody (ANCA) kinetic in ANCA-associated vasculitis with glomerulonephritis (AAV-GN) has been suggested to be associated with AAV relapse. Few studies have focused on its association with renal prognosis. Thus we aimed to investigate the relationship between ANCA specificity and the evolutive profile and renal outcomes. Methods This multicentric retrospective study included patients diagnosed with ANCA-GN since 1 January 2000. Patients without ANCA at diagnosis and with fewer than three ANCA determinations during follow-up were excluded. We analysed estimated glomerular filtration rate (eGFR) variation, renal-free survival and relapse-free survival according to three ANCA profiles (negative, recurrent and persistent) and to ANCA specificity [myeloperoxidase (MPO) or proteinase 3 (PR3)]. Results Over a follow-up of 56 months [interquartile range (IQR) 34–101], a median of 19 (IQR 13–25) ANCA determinations were performed for the 134 included patients. Patients with a recurrent/persistent ANCA profile had a lower relapse-free survival (P = .019) and tended to have a lower renal survival (P = .053) compared with those with a negative ANCA profile. Patients with a recurrent/persistent MPO-ANCA profile had the shortest renal survival (P = .015) and those with a recurrent/persistent PR3-ANCA profile had the worst relapse-free survival (P = .013) compared with other profiles. The negative ANCA profile was associated with a greater eGFR recovery. In multivariate regression analysis, it was an independent predictor of a 2-fold increase in eGFR at 2 years [odds ratio 6.79 (95% confidence interval 1.78–31.4), P = .008]). Conclusion ANCA kinetic after an ANCA-GN diagnosis is associated with outcomes. MPO-ANCA recurrence/persistence identifies patients with a lower potential of renal recovery and a higher risk of kidney failure, while PR3-ANCA recurrence/persistence identifies patients with a greater relapse risk. Thus ANCA kinetics may help identify patients with a smouldering disease.

ABSTRACT Background Antineutrophil-cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with kidney involvement (AAV-GN) frequently evolves to end-stage kidney disease (ESKD) despite aggressive immunosuppressive treatment. Several risk scores have been used to assess renal prognosis. We aimed to determine whether kidney function and markers of AAV-GN activity after 6 months could improve the prediction of ESKD. Methods This retrospective and observational study included adult patients with AAV-GN recruited from six French nephrology centers (including from the Maine-Anjou AAV registry). The primary outcome was kidney survival. Analyses were conducted in the whole population and in a sub-population that did not develop ESKD early in the course of the disease. Results When considering the 102 patients with all data available at diagnosis, Berden classification and Renal Risk Score (RRS) were not found to be better than kidney function [estimated glomerular filtration rate (eGFR)] alone at predicting ESKD (C-index = 0.70, 0.79, 0.82, respectively). Multivariables models did not indicate an improved prognostic value when compared with eGFR alone. When considering the 93 patients with all data available at 6 months, eGFR outperformed Berden classification and RRS (C-index = 0.88, 0.62, 0.69, respectively) to predict ESKD. RRS performed better when it was updated with the eGFR at 6 months instead of the baseline eGFR. While 6-month proteinuria was associated with ESKD and improved ESKD prediction, hematuria and serological remission did not. Conclusion This work suggests the benefit of the reassessment of the kidney prognosis 6 months after AAV-GN diagnosis. Kidney function at this time remains the most reliable for predicting kidney outcome. Of the markers tested, persistent proteinuria at 6 months was the only one to slightly improve the prediction of ESKD.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are a group of multisystemic autoimmune diseases characterized by necrotizing inflammation of small vessels. Kidney involvement is frequent in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and accounts for a significant proportion of the morbidity and mortality related to these diseases. Despite improvement in therapeutic management of ANCA-glomerulonephritis (ANCA-GN), end-stage kidney disease (ESKD) still occurs in up to 30% of affected patients within 5 years following diagnosis. Thus, identifying patients for whom aggressive immunosuppressive therapy will be more beneficial than deleterious is of great importance. Several clinical, biological and histological factors have been proposed as predictors of ESKD. The kidney biopsy is essential not only for the diagnosis, but also for evaluating renal prognosis. In this review, we discuss the prognostic value of renal lesions at the diagnosis of ANCA-GN by analyzing each compartment of the nephron. We also review existing ESKD risk classification in ANCA-GN and finally propose an example of a standardized pathology report that could be used in routine practice.

VEXAS (vacuoles, E1 enzyme, X-linked, auto-inflammatory, somatic) syndrome is an inflammatory disorder with hematological and systemic features. A recent study demonstrated that the dermal infiltrate in neutrophilic dermatosis from VEXAS patients is derived from the pathological UBA1-mutated myeloid clone. Neutrophilic dermatosis is, however, only one of the various skin involvements observed in VEXAS syndrome. We analyzed 10 formalin-fixed paraffin-embedded skin biopsies from genetically confirmed VEXAS syndrome. UBA1 mutation was found in the biopsies related to neutrophilic dermatitis but in none of the other histological patterns (leukocytoclastic vasculitis and septal panniculitis). This could lead to a distinction between clonal and paraclonal cutaneous involvements in VEXAS syndrome, which could in turn improve therapeutic outcomes.

Background Lymphopaenia is commonly observed in autoimmune diseases, where it has been associated with disease activity or prognosis. However, in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) only a few small-scale studies have been targeted towards this issue. Research has not yet focused on AAV with renal involvement (AAV-RI). Thus the aim of this study was to analyse the association between lymphocyte counts and outcomes in a large cohort of AAV-RI patients. Methods We used the Maine-Anjou AAV registry that retrospectively gathers data on consecutive patients affected by AAV in four French nephrology centres, recorded since January 2000. We analysed clinical, biological and histological data at diagnosis of AAV-RI. Risk factors for end-stage kidney disease (ESKD) were analysed. Event-free survival was also assessed. Results Among the 145 patients included in the study, those with lymphopaenia at diagnosis had a lower renal function at baseline [estimated glomerular filtration rate (eGFR) 13 versus 26 mL/min; P = 0.002] and were more likely to require kidney replacement therapy (51% versus 25%; P = 0.003). Lymphopaenia was correlated with histological lesions and especially with the percentage of sclerotic glomeruli (P = 0.0027). ESKD-free survival was lower in lymphopaenic patients (P < 0.0001). In multivariate Cox analysis, lymphopaenia was an independent risk factor for ESKD [hazard ratio 4.47 (95% confidence interval 2.06-9.72), P < 0.001]. Conclusions Lymphopaenia correlates with the severity of AAV glomerulonephritis at diagnosis and predicts poor renal outcome. In this view, lymphopaenia could be used as a simple and cost-effective biomarker to assess renal prognosis at AAV-RI diagnosis.

IntroductionThe “Renal Risk Score” (RRS) and the histopathological classification have been proposed to predict the risk of end-stage kidney disease (ESKD) in ANCA-associated glomerulonephritis (ANCA-GN). Besides, factors associated with kidney function recovery after ANCA-GN onset remain to be more extensively studied. In the present study, we analyzed the value of the RRS and of the histopathological classification for ESKD prediction. Next, we analyzed factors associated with eGFR change within the first 2 years following ANCA-GN diagnosis.Materials and MethodsWe included patients from the Maine–Anjou ANCA-associated vasculitis registry with at least 6 months of follow-up. The values of ANCA-GN, histopathological classification, and RRS, and the factors associated with eGFR variations between ANCA-GN diagnosis and 2 years of follow-up were assessed.ResultsThe predictive values of the histopathological classification and RRS were analyzed in 123 patients. After a median follow-up of 42 months, 33.3% patients developed ESKD. The predictive value of RRS for ESKD was greater than that of the histopathological classification. Determinants of eGFR variation were assessed in 80/123 patients with complete eGFR measurement. The median eGFR increased from ANCA-GN diagnosis to month 6 and stabilized thereafter. The only factor associated with eGFR variation in our study was eGFR at ANCA-GN diagnosis, with higher eGFR at diagnosis being associated with eGFR loss (p<0.001).ConclusionThe RRS has a better predictive value for ESKD than the histopathological classification. The main determinant of eGFR variation at 2 years was eGFR at ANCA-GN diagnosis. Thus, this study suggests that eGFR recovery is poorly predicted by histological damage at ANCA-GN diagnosis.

Objective Ovarian mature teratoma (OMT) is a common ovarian tumor found in the pediatric population. In 10% to 20% of cases, OMT occurs as multiple synchronous or metachronous lesions on ipsi- or contralateral ovaries. Ovarian sparing surgery (OSS) is recommended to preserve fertility, but total oophorectomy (TO) is still performed. This study reviews the clinical data of patients with OMT, and analyzes risk factors for second events. Design A retrospective review of all girls under 18 years of age with OMTs was performed. Data on clinical features, imaging, laboratory studies, surgical reports, follow-up second events and their management were retrieved. Results Overall, 350 children were identified. Eighteen patients (5%) presented with a synchronous bilateral form at diagnosis. Surgery was performed by laparotomy (85%) and laparoscopy (15%). OSS and TO were performed in 59% and 41% of cases respectively. Perioperative tumor rupture occurred in 23 cases, independently of the surgical approach. Twenty-nine second events occurred (8.3%) in a median time of 30.5 months from diagnosis (ipsilateral: 8 cases including one malignant tumor, contralateral: 18 cases, both ovaries: 3 cases). A large palpable mass, bilateral forms at diagnosis and perioperative rupture had a statistical impact on the risk of second event, whereas type of surgery or approach did not. Conclusion This study is a plea in favor of OSS as the first choice of treatment of OMT when possible. Close follow-up during the first five years is mandatory considering the risk of 8.3% of second events especially in cases with risk factors.

Ovarian mature teratoma (OMT) is a common ovarian tumor found in the pediatric population. In 10%–20% of cases, OMT occurs as multiple synchronous or metachronous lesions on ipsi‐ or contralateral ovaries. Ovarian‐sparing surgery (OSS) is recommended to preserve fertility, but total oophorectomy (TO) is still performed.

CONTEXT:Radioiodine-refractory thyroid cancers have poor outcomes and limited therapeutic options (tyrosine kinase inhibitors) due to transient efficacy and toxicity of treatments. Therefore, combinatorial treatments with new therapeutic approaches are needed. Many studies link G protein-coupled receptors (GPCRs) to cancer cell biology.OBJECTIVE:To perform a specific atlas of GPCR expression in progressive and refractory thyroid cancer to identify potential targets among GPCRs aiming at drug repositioning.METHODS:We analyzed samples from tumor and normal thyroid tissues from 17 patients with refractory thyroid cancer (12 papillary thyroid cancers [PTCs] and 5 follicular thyroid cancers [FTCs]). We assessed GPCR mRNA expression using NanoString technology with a custom panel of 371 GPCRs. The data were compared with public repositories and pharmacological databases to identify eligible drugs. The analysis of prognostic value of genes was also performed with TCGA datasets.RESULTS:With our transcriptomic analysis, 4 receptors were found to be downregulated in FTC (VIPR1, ADGRL2/LPHN2, ADGRA3, and ADGRV1). In PTC, 24 receptors were deregulated, 7 of which were also identified by bioinformatics analyses of publicly available datasets on primary thyroid cancers (VIPR1, ADORA1, GPRC5B, P2RY8, GABBR2, CYSLTR2, and LPAR5). Among all the differentially expressed genes, 22 GPCRs are the target of approved drugs and some GPCRs are also associated with prognostic factors.DISCUSSION:For the first time, we performed GPCR mRNA expression profiling in progressive and refractory thyroid cancers. These findings provide an opportunity to identify potential therapeutic targets for drug repositioning and precision medicine in radioiodine-refractory thyroid cancer.

Ketogenic diets have been used to treat diverse conditions, and there is growing evidence of their benefits for tissue repair and in inflammatory disease treatment. However, their role in infectious diseases has been little studied. Buruli ulcer (Mycobacterium ulcerans infection) is a chronic infectious disease characterized by large skin ulcerations caused by mycolactone, the major virulence factor of the bacillus. In the current study, we investigated the impact of ketogenic diet on this cutaneous disease in an experimental mouse model. This diet prevented ulceration, by modulating bacterial growth and host inflammatory response. β-hydroxybutyrate, the major ketone body produced during ketogenic diet and diffusing in tissues, impeded M. ulcerans growth and mycolactone production in vitro underlying its potential key role in infection. These results pave the way for the development of new patient management strategies involving shorter courses of treatment and improving wound healing, in line with the major objectives of the World Health Organization.

Abstract Background and Aims Lymphopenia is commonly observed in various autoimmune diseases, such as systemic lupus erythematosus, where it has been associated with disease activity or prognosis. However, in ANCA-associated vasculitis (AAV) only few, small-scale studies have been targeted to this issue. Research has not yet focused on ANCA-glomerulonephritis (ANCA-GN) patients. Thus, the aim of this study was to analyze the association between lymphocyte counts and outcomes in a large cohort of ANCA-GN patients. Method We used the Maine-Anjou AAV registry that retrospectively gathers data on consecutive patients affected by AAV in four French Nephrology Centers, recorded since January 2000. We analyzed clinical, biological, and histological data at diagnosis of ANCA-GN. Biological data, including lymphocyte counts, were collected before the administration of any immunosuppressive treatment. Risk factors for end-stage kidney disease (ESKD) were analyzed. Event-free survival was also assessed. Results Among the 145 patients included in the study, 53 (37%) patients presented with lymphopenia at ANCA-GN diagnosis. Lymphopenic patients were older (72 [63–79] vs 66 [56–73] years old, p = 0.010), had a lower renal function at baseline (eGFR 13 mL/min vs 26 mL/min, p = 0.002), and a higher proteinuria (1.86 [1.21–3.52] g/g vs 1.30 [0.75–2.65] g/g, p = 0.042). There was a trend for a higher BVAS (18 [14–22] vs 15 [12–20], p = 0.076) in lymphopenic patients. Therapeutic management between the two groups was similar. There was no difference in relapse rate between the two groups but lymphopenic patients were more likely to require kidney replacement therapy (51% vs 25%, p = 0.003) and were more likely to die (34% vs 17%, p = 0.039). Lymphopenia was correlated with histological lesions and especially with the percentage of sclerotic glomeruli (p = 0.0027). ESKD-free survival and overall survival were lower in lymphopenic patients (p < 0.0001 and 0.0051 respectively). In multivariate Cox analysis, lymphopenia, but not death, was an independent risk factor for ESKD (HR 4.47 (95% confidence interval: [2.06–9.72], p < 0.001). Conclusion Lymphopenia correlates with severity of ANCA-GN at diagnosis and predicts poor renal outcome. In this view, lymphopenia could be used as a simple and cost-effective biomarker to assess renal prognosis at ANCA-GN diagnosis.

&lt;title xmlns=&quot;https://jats.nlm.nih.gov/ns/archiving/1.2/&quot; xmlns:xsi=&quot;http://www.w3.org/2001/XMLSchema-instance&quot; xmlns:ali=&quot;http://www.niso.org/schemas/ali/1.0/&quot; xmlns:mml=&quot;http://www.w3.org/1998/Math/MathML&quot; xmlns:xlink=&quot;http://www.w3.org/1999/xlink&quot;&gt;Abstract&lt;/title&gt; &lt;p xmlns=&quot;https://jats.nlm.nih.gov/ns/archiving/1.2/&quot; xmlns:xsi=&quot;http://www.w3.org/2001/XMLSchema-instance&quot; xmlns:ali=&quot;http://www.niso.org/schemas/ali/1.0/&quot; xmlns:mml=&quot;http://www.w3.org/1998/Math/MathML&quot; xmlns:xlink=&quot;http://www.w3.org/1999/xlink&quot;&gt;Skins symptoms during COVID‐19 have been recently described but their relation to SARS‐CoV‐2 is unclear while results for real‐time reverse transcriptase polymerase chain reaction (rRT‐PCR) testing were variable. Recalcati et al. reported 14 cases of patients with skin symptoms consistent with previous described COVID‐19 lesions but all the patients were tested negative. They asked for a serology to validate the hypothesis that these lesions are related to COVID‐19.&lt;/p&gt;