Search

Background: Regulatory T (Treg) cells are pivotal in immune tolerance to allergens. Low-dose IL-2 (IL-2 LD ) activates Treg cells., Objective: Our aim was to assess IL-2 LD efficacy for controlling clinical responses to allergen exposures., Methods: RHINIL-2 was a phase-2a, randomized, double-blind, placebo-controlled trial. Patients with allergic rhinitis to birch pollen (BP) were included; 66% of them had concomitant asthma. All had a total nasal symptom score (TNSS) of 5 or more following nasal exposure to BP in an environmental exposure chamber. Patients received 1 MUI per day of IL-2 (n = 12) or placebo (n = 12) for 5 days, followed by weekly injections for 4 weeks. Clinical responses to subsequent BP exposures in the environmental exposure chamber were evaluated by using TNSS, the rhinitis visual analog scale (VAS), and spirometry. The primary efficacy end point was the difference in TNSS area under the curve (AUC) between inclusion and day 40., Results: IL-2 LD treatment induced a significant expansion of Treg cells. The difference in TNSS AUC between inclusion and day 40 AUC in the IL-2 and placebo groups was not significant. TNSS and visual analog scale AUCs were significantly reduced from baseline to day 40 in the IL-2 LD group only (P = .04 and P = .01, respectively). The ratio of FEV 1 to forced vital capacity (FEV 1P ) and the forced midexpiratory flow (FEF 25%-75% ) showed improvement in the IL-2 LD -treated versus in the groups given placebo at day 40 (P = .04 and P = .04, respectively). However, the short treatment duration used in this study could not have effects on specific IgE or IgG4 levels given their half-life. There were no severe treatment-related adverse events., Conclusion: IL-2 LD is well tolerated in patients with allergy, even in those with asthma, thus clearing the path for further therapeutic development. Our work suggests that Treg cells can safely attenuate an ongoing allergic response. It paves the way for larger studies with longer treatment periods, which are needed to properly evaluate the therapeutic potential of IL-2 in allergy., Competing Interests: Disclosure statement Supported by the Programme Hospitalier de Recherche Clinique, No. P160936J. The Assistance Publique-Hôpitaux de Paris sponsored the study, and ILTOO pharma provided the treatments. Disclosure of potential conflict of interest: M. Rosenzwajg, R. Lorenzon, B. Bellier, and D. Klatzmann are inventors on patent applications related to the therapeutic use of IL-2(LD), which belongs to their academic institutions and has been licensed to ILTOO Pharma. M. Rosenzwajg, B. Bellier, and D. Klatzmann hold shares in ILTOO Pharma. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Type 1 diabetes treatment stands at a crucial and exciting crossroad since the 2022 U.S. Food and Drug Administration (FDA) approval of teplizumab to delay disease development. In this Perspective article, we discuss four major conceptual and practical issues that emerged as key to further advance type 1 diabetes research and therapies. First, collaborative networks leveraging the synergy between the type 1 diabetes research and care community members are key to fostering innovation, know-how and translation into the clinical arena worldwide. Second, recent clinical trials in presymptomatic stage 2 and recent-onset stage 3 disease have shown the promise, and potential pitfalls, of using immunomodulatory and/or beta-cell protective agents to achieve sustained remission or prevention. Third, the increasingly appreciated heterogeneity of clinical, immunological, and metabolic phenotypes and disease trajectories is of critical importance to advance the decision-making process for tailored type 1 diabetes care and therapy. Fourth, the clinical benefits of early diagnosis of beta-cell autoimmunity warrant consideration of general population screening for islet autoantibodies, which requires further efforts to address the technical, organizational and ethical challenges inherent to a sustainable program. Efforts are underway to integrate these four concepts into the future directions of type 1 diabetes research and therapy., (© 2024 by the American Diabetes Association.)

Background: Autoimmune and inflammatory diseases (AIDs) are a heterogeneous group of disorders with diverse etiopathogenic mechanisms. This study explores the potential utility of family history, together with present and past comorbidities, in identifying distinct etiopathogenic subgroups. This approach may facilitate more accurate diagnosis, prognosis and personalized therapy., Methods: We performed a multiple correspondence analysis on patients' comorbidities, followed by hierarchical principal component clustering of clinical data from 48 healthy volunteers and 327 patients with at least one of 19 selected AIDs included in the TRANSIMMUNOM cross-sectional study., Results: We identified three distinct clusters characterized by: 1) the absence of comorbidities, 2) polyautoimmunity, and 3) polyinflammation. These clusters were further distinguished by specific comorbidities and biological parameters. Autoantibodies, allergies, and viral infections characterized the polyautoimmunity cluster, while older age, BMI, depression, cancer, hypertension, periodontal disease, and dyslipidemia characterized the polyinflammation cluster. Rheumatoid arthritis patients were distributed across all three clusters. They had higher DAS28 and prevalence of extra-articular manifestations when belonging to the polyinflammation and polyautoimmunity clusters, and also lower ACPA and RF seropositivity and higher pain scores within the polyinflammation cluster. We developed a model allowing to classify AID patients into comorbidity clusters., Conclusions: In this study, we have uncovered three distinct comorbidity profiles among AID patients. These profiles suggest the presence of distinct etiopathogenic mechanisms underlying these subgroups. Validation, longitudinal stability assessment, and exploration of their impact on therapy efficacy are needed for a comprehensive understanding of their potential role in personalized medicine., Competing Interests: Declaration of competing interest JS declares honoraria from Roche, Chugai, Pfizer, BMS, MSD, AbbVie, Sandoz, Hospira, Janssen, Novartis, Fresenius Kabi, Sanofi Genzyme, Galapagos. PC declares consultancies, honoraria, advisory board, and speakers’ fees from Alnylam, Innotech, Servier and Vifor. PS declares financial support for scientific works from Biocodex, MSD, Takeda, Janssen, and Sandoz, and consultant fees from Abbvie, Merk, MSD, Gilead, Pfizer, Sandoz, Janssen, and Fresenius Kabi. EV declares consulting fees from Abbott, Coloplast and Boston Scientific., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Immune abnormalities including an insufficiency of regulatory T cells (Treg) and increased blood-based inflammatory markers have been observed in bipolar disorders (BD), particularly during depression. As Tregs are pivotal to control inflammation, Treg stimulation by low-dose IL-2 (IL-2 LD ) could have a therapeutic impact on bipolar depression. We performed a randomized, double-blind, placebo-controlled (2 active: 1 placebo) proof-of-concept trial of add-on IL-2 LD in patients with bipolar depression. Patients received a placebo or IL-2 LD (1MIU) once a day for 5 days, and then once a week for 4 weeks starting on week 2. The primary objective was to demonstrate a biological Treg response to IL-2 LD assessed by fold increase in Treg percentage of CD4 + cells from baseline to day 5. Secondary objectives included safety assessment and mood improvement throughout the study period. This trial is registered with ClinicalTrials.gov, number NCT04133233. Fourteen patients with bipolar depression were included, with 4 receiving placebo and 10 IL-2 LD . Baseline clinical and biological characteristics were balanced between groups. The primary evaluation criterion was met, with IL-2 LD expanding 1.17 [95 % CI 1.01-1.34] vs 1.01 [95 % CI 0.90-1.12] (p = 0.0421) and activating Tregs. Secondary evaluation criteria were also met with significant improvements of depressive symptoms and global functioning from day-15 onwards in the IL-2 LD treated patients. The treatment was well-tolerated, with no serious adverse events related to treatment. This proof-of-concept trial shows that stimulating Tregs in patients with bipolar depression is safe and associated with clinical improvements. This supports a pathophysiological role of inflammation in BD and warrants pursuing the evaluation of IL-2 LD as an adjunct treatment of major mood disorders., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MR, RL and DK are inventors for patent applications related to the therapeutic use of IL-2(LD), which belongs to their academic institutions and has been licensed to ILTOO Pharma. MR and DK hold shares in ILTOO Pharma. No other potential conflicts of interest relevant to this article were reported., (Copyright © 2024. Published by Elsevier Inc.)

Rheumatoid arthritis (RA) management leans toward achieving remission or low disease activity. In this study, we conducted single-cell RNA sequencing (scRNA-Seq) of peripheral blood mononuclear cells (PBMCs) from 36 individuals (18 patients with RA and 18 matched controls, accounting for age, sex, race, and ethnicity), to identify disease-relevant cell subsets and cell type-specific signatures associated with disease activity. Our analysis revealed 18 distinct PBMC subsets, including an IFN-induced transmembrane 3-overexpressing (IFITM3-overexpressing) IFN-activated monocyte subset. We observed an increase in CD4+ T effector memory cells in patients with moderate-high disease activity (DAS28-CRP ≥ 3.2) and a decrease in nonclassical monocytes in patients with low disease activity or remission (DAS28-CRP < 3.2). Pseudobulk analysis by cell type identified 168 differentially expressed genes between RA and matched controls, with a downregulation of proinflammatory genes in the γδ T cell subset, alteration of genes associated with RA predisposition in the IFN-activated subset, and nonclassical monocytes. Additionally, we identified a gene signature associated with moderate-high disease activity, characterized by upregulation of proinflammatory genes such as TNF, JUN, EGR1, IFIT2, MAFB, and G0S2 and downregulation of genes including HLA-DQB1, HLA-DRB5, and TNFSF13B. Notably, cell-cell communication analysis revealed an upregulation of signaling pathways, including VISTA, in both moderate-high and remission-low disease activity contexts. Our findings provide valuable insights into the systemic cellular and molecular mechanisms underlying RA disease activity.

Maternal autoimmune diseases (AID) are risk factors for Attention Deficit Hyperactivity Disorder (ADHD). Animal studies suggest that maternal immune activation (MIA) is a disease primer for ADHD, with second environmental factor precipitating the onset of the disease. Prematurity is also a major risk factor for ADHD. In this study, we sought to explore the interaction between parental AID and prematurity on ADHD risk in a community sample. Children of AID parents born prematurely appeared at increased odds of ADHD but these two risk factors do not appear to be additive (OR 1.39 [95 CI 0.75; 2.46]). Longitudinal studies with larger numbers of participants are needed., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Antibody production and the generation of memory B cells are regulated by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in germinal centers. However, the precise role of Tfr cells in controlling antibody production is still unclear. We have previously shown that both Tfh and Tfr cells express the IL-1R1 agonist receptor, whereas only Tfr cells express the IL-1R2 decoy and IL-1Ra antagonist receptors. We aimed to investigate the role of IL-1 receptors in the regulation of B cell responses by Tfh and Tfr., Methods: We generated mice with IL-1 receptors inactivated in Tfh or Tfr and measured antibody production and cell activation after immunisation., Results: While IL-1β levels are increased in the draining lymph node after immunisation, antigen-specific antibody levels and cell phenotypes indicated that IL-1β can activate both Tfh and Tfr cells through IL-1R1 stimulation. Surprisingly, expression of IL-1R2 and IL-1Ra on Tfr cells does not block IL-1 activation of Tfh cells, but rather prevents IL-1/IL-1R1-mediated early activation of Tfr cells. IL-1Rs also regulate the antibody response to autoantigens and its associated pathophysiology in an experimental lupus model., Discussion: Collectively, our results show that IL-1 inhibitory receptors expressed by Tfr cells prevent their own activation and suppressive function, thus licensing IL-1-mediated activation of Tfh cells after immunisation. Further mechanistic studies should unravel these complex interactions between IL-1β and follicular helper and regulatory T cells and provide new avenues for therapeutic intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Belbezier, Engeroff, Fourcade, Vantomme, Vaineau, Gouritin, Bellier, Brocheriou, Tchitchek, Graff-Dubois and Klatzmann.)

Accurate characterization and comparison of T cell receptor (TCR) repertoires from small biological samples present significant challenges. The main challenge is the low material input, which compromises the quality of bulk sequencing and hinders the recovery of sufficient TCR sequences for robust analyses. We aimed to address this limitation by implementing a strategic approach to pool homologous biological samples. Our findings demonstrate that such pooling indeed enhances the TCR repertoire coverage, particularly for cell subsets of constrained sizes, and enables accurate comparisons of TCR repertoires at different levels of complexity across T cell subsets with different sizes. This methodology holds promise for advancing our understanding of T cell repertoires in scenarios where sample size constraints are a prevailing concern., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Based on genetic associations, McGonagle and McDermott suggested a classification of autoimmune and autoinflammatory diseases as a continuum ranging from purely autoimmune to purely autoinflammatory diseases and comprising diseases with both components. We used deep immunophenotyping to identify immune cell populations and molecular targets characterising this continuum., Methods: We collected blood from 443 patients with one of 15 autoimmune or autoinflammatory diseases and 71 healthy volunteers. Deep phenotyping was performed using 13 flow cytometry panels characterising over 600 innate and adaptive cell populations. Unsupervised and supervised analyses were conducted to identify disease clusters with their common and specific cell parameters., Results: Unsupervised clustering categorised these diseases into five clusters. Principal component analysis deconvoluted this clustering into two immunological axes. The first axis was driven by the ratio of LAG3+ to ICOS+ in regulatory T lymphocytes (Tregs), and segregated diseases based on their inflammation levels. The second axis was driven by activated Tregs and type 3 innate lymphoid cells (ILC3s), and segregated diseases based on their types of affected tissues. We identified a signature of 23 cell populations that accurately characterised the five disease clusters., Conclusions: We have refined the monodimensional continuum of autoimmune and autoinflammatory diseases as a continuum characterised by both disease inflammation levels and targeted tissues. Such classification should be helpful for defining therapies. Our results call for further investigations into the role of the LAG3+/ICOS+ balance in Tregs and the contribution of ILC3s in autoimmune and autoinflammatory diseases., Trial Registration Number: NCT02466217., Competing Interests: Competing interests: JS: honoraria from Roche, Chugai, Pfizer, BMS, MSD, AbbVie, Sandoz, Hospira, Janssen, Novartis, Fresenius Kabi, Sanofi Genzyme, Galapagos; research grants from Roche, Pfizer, MSD, Schwa Medico, BMS. FB is an editorial board member of ARD., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ on behalf of EULAR.)

Background: Systemic sclerosis (SSc) is a chronic autoimmune disease, with impaired immune response, increased fibrosis and endothelial dysfunction. Regulatory T cells (Tregs), which are essential to control inflammation, tissue repair and autoimmunity, have a decreased frequency and impaired function in SSc patients. Low-dose interleukin-2 (IL-2 LD ) can expand and activate Tregs and has, therefore, a therapeutic potential in SSc., Objective: We aimed to assess the safety and biological efficacy of IL-2 LD in patients with SSc., Methods: As part of the TRANSREG open-label phase IIa basket trial in multiple autoimmune diseases, we studied nine patients with SSc without severe organ involvement. Patients received 1 million international units (MIU)/day of IL-2 for 5 days, followed by fortnightly injections for 6 months. Laboratory and clinical evaluations were performed between baseline and month 6., Results: At day 8, the primary endpoint (Treg frequency) was reached with a 1.8±0.5-fold increase of Treg levels among CD4 + T lymphocytes (p=0.0015). There were no significant changes in effector T cells nor in B cells. IL-2 LD was well tolerated, and no serious adverse events related to treatment occurred. There was a globally stable measurement in the modified Rodnan skin score and Valentini score at month 6. Disease activity and severity measures, the quality of life evaluated by EuroQL-5D-5L and pulmonary function test parameters remained stable during the study period., Conclusion: IL-2 LD at a dosage of 1 MIU/day safely and selectively activates and expands Tregs. Clinical signs remain stable during the study period. This opens the door to properly powered phase II efficacy trials investigating IL-2 LD therapeutic efficacy in SSc., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A Tregs insufficiency is central to autoimmune and inflammatory diseases pathophysiology and low dose interleukin-2 (IL-2 LD ) can specifically activate Tregs., Objective: To assess IL-2 LD therapeutic potential and select diseases for further clinical development, we performed an open-label, phase 2a, disease-finding, "basket trial" involving patients with one of 13 different autoimmune diseases., Methods: 81 patients treated with IL-2 LD (1 million IU/day) for 5 days, followed by fortnightly injections. The first 48 patients received diluted Proleukin®, while the subsequent 33 received ready-to-use ILT-101®. The primary endpoint was the change in Tregs at day-8 compared to baseline. Key secondary endpoints included clinical efficacy assessments using the Clinical Global Impression (CGI) scale, disease-specific scores, and EuroQL-5D-5L., Results: Our study unveiled a universal and significant expansion and activation of Tregs, without concomitant Teffs activation, across all 13 autoimmune diseases. Both Proleukin® and ready-to-use ILT-101® demonstrated identical effects on Tregs. CGI scores reflecting activity, severity, and efficacy were significantly reduced in the overall patient population. Disease-specific clinical scores improved in five of the six disease cohorts with at least six patients, namely ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease, Sjögren's syndrome, and systemic sclerosis. Urticaria was the only severe adverse event related to treatment., Conclusion: IL-2 LD was well-tolerated, exhibiting specific Treg activation and clinical improvements across the 13 autoimmune diseases., Clinical Implication: Tregs stimulation by IL-2 LD is a promising therapeutic strategy and IL-2 LD holds considerable promise for integration into combinatorial therapeutic approaches., (Copyright © 2024. Published by Elsevier Ltd.)

The adaptive immune response relies on T cells that combine phenotypic specialization with diversity of T-cell receptors (TCRs) to recognize a wide range of pathogens. TCRs are acquired and selected during T-cell maturation in the thymus. Characterizing TCR repertoires across individuals and T-cell maturation stages is important for better understanding adaptive immune responses and for developing new diagnostics and therapies. Analyzing a dataset of human TCR repertoires from thymocyte subsets, we find that the variability between individuals generated during the TCR V(D)J recombination is maintained through all stages of T-cell maturation and differentiation. The interindividual variability of repertoires of the same cell type is of comparable magnitude to the variability across cell types within the same individual. To zoom in on smaller scales than whole repertoires, we defined a distance measuring the relative overlap of locally similar sequences in repertoires. We find that the whole repertoire models correctly predict local similarity networks, suggesting a lack of forbidden T-cell receptor sequences. The local measure correlates well with distances calculated using whole repertoire traits and carries information about cell types.

Maternal immune activation (MIA), related to autoimmune/inflammatory diseases or acute infections, during the two first trimesters of pregnancy is a risk factor for autism spectrum disorders (ASD) in offspring. In mice, MIA has a long-term impact on offspring's immune equilibrium resulting in a pro-inflammatory phenotype. We therefore hypothesized that children with ASD and a history of MIA could display a similar phenotype specifically assessed by a higher neutrophil to lymphocyte ratio (NLR). In this study, we used a retrospective sample of 231 dyads involving children with ASD and their mothers. Among ASD patients, 12% had a history of MIA. The multivariate analysis revealed a significant association between NLR in children with ASD and maternal history of MIA (F = 2.27, p = 0.03). Using a categorical approach, we observed an abnormal NLR (over 3) in 7.4% of children with ASD MIA+ compared to 1.9% for MIA-. Our study supports the hypothesis suggesting an impact of MIA on the risk of ASD. Further studies could contribute to the development of biomarkers in MIA+ ASD and enable the development of targeted immunomodulatory therapies., (© 2023. The Author(s).)

Autism spectrum disorder (ASD) are neurodevelopmental conditions characterised by deficits in social communication and interaction and repetitive behaviours. Maternal immune activation (MIA) during the mid-pregnancy is a known risk factor for ASD. Although reported in 15% of affected individuals, little is known about the specificity of their clinical profiles. Adaptive skills represent a holistic approach to a person's competencies and reflect specifically in ASD, their strengths and difficulties. In this study, we hypothesised that ASD individual with a history of MIA (MIA + ) could be more severely socio-adaptively impaired than those without MIA during pregnancy (MIA - ). To answer this question, we considered two independent cohorts of individuals with ASD (PARIS study and FACE ASD) screened for pregnancy history, and used supervised and unsupervised machine learning algorithms. We included 295 mother-child dyads with 14% of them with MIA + . We found that ASD-MIA + individuals displayed more severe maladaptive behaviors, specifically in their socialization abilities. MIA + directly influenced individual's socio-adaptive skills, independent of other covariates, including ASD severity. Interestingly, MIA + affect persistently the socio-adaptive behavioral trajectories of individuals with ASD. The current study has a retrospective design with possible recall bias regarding the MIA event and, even if pooled from two cohorts, has a relatively small population. In addition, we were limited by the number of covariables available potentially impacted socio-adaptive behaviors. Larger prospective study with additional dimensions related to ASD is needed to confirm our results. Specific pathophysiological pathways may explain these clinical peculiarities of ASD- MIA + individuals, and may open the way to new perspectives in deciphering the phenotypic complexity of ASD and for the development of specific immunomodulatory strategies., (© 2023. Springer Nature Limited.)

Mucosal surfaces serve as the primary entry points for pathogens such as SARS- CoV-2 coronavirus or HIV in the human body. Mucosal vaccination plays a crucial role to successfully induce long-lasting systemic and local immune responses to confer sterilizing immunity. However, antigen formulations and delivery methods must be properly selected since they are decisive for the quality and the magnitude of the elicited immune responses in mucosa. We investigated the significance of using particulate antigen forms for mucosal vaccination by comparing VLP- or protein- based vaccines in a mouse model. Based on a mucosal prime-boost immunization protocol combining (i) HIV- pseudotyped recombinant VLPs (HIV-VLPs) and (ii) plasmid DNA encoding HIV- VLPs (pVLPs), we demonstrated that combination of intranasal primes and intravaginal boosts is optimal to elicit both humoral and cellular memory responses in mucosa. Interestingly, our results show that in contrast to proteins, particulate antigens induce high-quality humoral responses characterized by a high breadth, long-term neutralizing activity and cross-clade reactivity, accompanying with high T follicular helper cell (T FH ) response. These results underscore the potential of a VLP-based vaccine in effectively instigating long-lasting, HIV-specific immunity and point out the specific role of particulate antigen form in driving high-quality mucosal immune responses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Behçet's disease (BD) is a systemic vasculitis with inflammatory lesions mediated by cytotoxic T cells and neutrophils. Apremilast, an orally available small-molecule drug that selectively inhibits phosphodiesterase 4 (PDE4), has been recently approved for the treatment of BD. We aimed to investigate the effect of PDE4 inhibition on neutrophil activation in BD., Methods: We studied surface markers and reactive oxygen species (ROS) production by flow cytometry, and neutrophil extracellular traps (NETs) production and molecular signature of neutrophils by transcriptome analysis before and after PDE4 inhibition., Results: Activation surface markers (CD64, CD66b, CD11b, and CD11c), ROS production, and NETosis were up-regulated in BD patient neutrophils compared to healthy donor neutrophils. Transcriptome analysis revealed 1,021 significantly dysregulated neutrophil genes between BD patients and healthy donors. Among dysregulated genes, we found a substantial enrichment for pathways linked to innate immunity, intracellular signaling, and chemotaxis in BD. Skin lesions of BD patients showed increased infiltration of neutrophils that colocalized with PDE4. Inhibition of PDE4 by apremilast strongly inhibited neutrophil surface activation markers as well as ROS production, NETosis, and genes and pathways related to innate immunity, intracellular signaling, and chemotaxis., Conclusion: We highlight key biologic effects of apremilast on neutrophils in BD., (© 2023 American College of Rheumatology.)

Background: Multiple sclerosis (MS) is associated with regulatory T cells (Tregs) insufficiency while low-dose interleukin-2 (IL2 LD ) activates Tregs and reduces disease activity in autoimmune diseases., Methods: We aimed at addressing whether IL2 LD improved Tregs from MS patients. MS-IL2 was a single-center double-blind phase-2 study. Thirty patients (mean [SD] age 36.8 years [8.3], 16 female) with relapsing-remitting MS with new MRI lesions within 6 months before inclusion were randomly assigned in a 1:1 ratio to placebo or IL-2 at 1 million IU, daily for 5 days and then fortnightly for 6 months. The primary endpoint was change in Tregs at day-5., Results: Unlike previous trials of IL2 LD in more than 20 different autoimmune diseases, Tregs were not expanded at day-5 in IL2 LD group, but only at day-15 (median [IQR] fold change from baseline: 1.26 [1.21-1.33] in IL2 LD group; 1.01 [0.95-1.05] in placebo group, p < 0.001). At day-5, however, Tregs had acquired an activated phenotype (fold change of CD25 expression in Tregs: 2.17 [1.70-3.55] in IL2 LD versus 0.97 [0.86-1.28] in placebo group, p < 0.0001). Regulator/effector T cells ratio remained elevated throughout treatment period in the IL2 LD group (p < 0.001). Number of new active brain lesions and of relapses tended to be reduced in IL2 LD treated patients, but the difference did not reach significance in this trial not powered to detect clinical efficacy., Conclusion: The effect of IL2 LD on Tregs in MS patients was modest and delayed, compared to other auto-immune diseases. This, together with findings that Tregs improve remyelination in MS models and recent reports of IL2 LD efficacy in amyotrophic lateral sclerosis, warrants larger studies of IL2 LD in MS, notably with increased dosages and/or modified modalities of administration., Trial Registration Information: ClinicalTrials.gov: NCT02424396; EU Clinical trials Register: 2014-000088-42., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Giant cell arteritis (GCA) causes severe inflammation of the aorta and its branches and is characterized by intense effector T-cell infiltration. The roles that immune checkpoints play in the pathogenesis of GCA are still unclear. Our aim was to study the immune checkpoint interplay in GCA., Methods: First, we used VigiBase, the World Health Organization international pharmacovigilance database, to evaluate the relationship between GCA occurrence and immune checkpoint inhibitors treatments. We then further dissected the role of immune checkpoint inhibitors in the pathogenesis of GCA, using immunohistochemistry, immunofluorescence, transcriptomics, and flow cytometry on peripheral blood mononuclear cells and aortic tissues of GCA patients and appropriated controls., Results: Using VigiBase, we identified GCA as a significant immune-related adverse event associated with anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein-4) but not anti-PD-1 (anti-programmed death-1) nor anti-PD-L1 (anti-programmed death-ligand 1) treatment. We further dissected a critical role for the CTLA-4 pathway in GCA by identification of the dysregulation of CTLA-4-derived gene pathways and proteins in CD4 + (cluster of differentiation 4) T cells (and specifically regulatory T cells) present in blood and aorta of GCA patients versus controls. While regulatory T cells were less abundant and activated/suppressive in blood and aorta of GCA versus controls, they still specifically upregulated CTLA-4. Activated and proliferating CTLA-4 + Ki-67 + regulatory T cells from GCA were more sensitive to anti-CTLA-4 (ipilimumab)-mediated in vitro depletion versus controls., Conclusions: We highlighted the instrumental role of CTLA-4 immune checkpoint in GCA, which provides a strong rationale for targeting this pathway., Competing Interests: Disclosures None.

Objective: To investigate host and gut-microbiota related Tryptophan metabolism in hand osteoarthritis (HOA)., Methods: The baseline serum concentration of 20 Tryptophan metabolites was measured in 416 HOA patients in a cross-sectional analysis of the DIGICOD cohort. Tryptophan metabolites levels, metabolite-ratios and metabolism pathway activation were compared between erosive (N = 141) and non-erosive HOA (N = 275) by multiple logistic regressions adjusted on age, BMI and sex. The association between Tryptophan metabolite levels and HOA symptoms was investigated by a Spearman's rank correlation analysis., Results: Four serum Tryptophan metabolites, eight metabolite ratios and one metabolism pathway were associated with erosive HOA. Erosive HOA was negatively associated with Tryptophan (odds ratio (OR) = 0.41, 95% confidence interval [0.24-0.70]), indole-3-aldehyde (OR = 0.67 [0.51-0.90]) and 3-OH-anthranilic acid (OR = 1.32 [1.13-1.54]) and positively with 5-OH-Tryptophan levels (OR = 1.41 [1.13-1.77]). The pro-inflammatory kynurenine-indoleamine 2,3-dioxygenase pathway was upregulated in erosive HOA (OR = 1.60 [1.11-2.29]). Eleven metabolites were correlated with HOA symptoms and were mostly pain-related. Serotonin and N-acetyl serotonin levels were negatively correlated with number of tender joints. Indole-3-aldehyde level was negatively correlated and 3-OH-anthranilic acid, 3-OH-kynurenine and 5-OH-Tryptophan levels were positively correlated with number of patients-reported painful joints. Quinolinic acid and 3-OH-kynurenine levels correlated positively with AUSCAN pain., Conclusions: Tryptophan metabolites disturbance is associated with erosive HOA and pain and emphasize the role of low-grade inflammation and gut dysbiosis in HOA., (Copyright © 2023 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: We aimed to delineate phenotypes in hand osteoarthritis (HOA) based on cardinal symptoms (pain, functional limitation, stiffness, and aesthetic discomfort)., Methods: With data from the Digital Cohort Design (DIGICOD), we performed a hierarchical agglomerative clustering analysis based on Australian/Canadian Osteoarthritis Hand Index (AUSCAN) subscores for pain, physical function, stiffness, and visual analog scale for aesthetic discomfort. Kruskal-Wallis and post hoc analyses were used to assess differences between clusters., Results: Among 389 patients, we identified 5 clusters: cluster 1 (n = 88) and cluster 2 (n = 91) featured low and mild symptoms; cluster 3 (n = 80) featured isolated aesthetic discomfort; cluster 4 (n = 42) featured a high level of pain, stiffness, and functional limitation; and cluster 5 (n = 88) had the same features as cluster 4 but with high aesthetic discomfort. For clusters 4 and 5, AUSCAN pain score was >41 of 100, representing only one-third of our patients. Aesthetic discomfort (clusters 3 and 5) was significantly associated with erosive HOA and a higher number of nodes. The highly symptomatic cluster 5 was associated but not significantly with metabolic syndrome, and body mass index and C-reactive protein level did not differ among clusters. Symptom intensity was significantly associated with joint destruction as well as with physical and psychological burden. Patients' main expectations differed among clusters, and function improvement was the most frequent expectation overall., Conclusion: The identification of distinct clinical clusters based on HOA cardinal symptoms suggests previously undescribed subtypes of this condition, warranting further study of biological characteristics of such clusters, and opening a path toward phenotype-based personalized medicine in HOA., (© 2022 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4β7 + CD4 + regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4β7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1-α4β7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation., Significance: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027., (©2023 American Association for Cancer Research.)

T-cell receptors (TCRs) are formed by stochastic gene rearrangements, theoretically generating >10 19 sequences. They are selected during thymopoiesis, which releases a repertoire of about 10 8 unique TCRs per individual. How evolution shaped a process that produces TCRs that can effectively handle a countless and evolving set of infectious agents is a central question of immunology. The paradigm is that a diverse enough repertoire of TCRs should always provide a proper, though rare, specificity for any given need. Expansion of such rare T cells would provide enough fighters for an effective immune response and enough antigen-experienced cells for memory. We show here that human thymopoiesis releases a large population of clustered CD8 + T cells harboring α/β paired TCRs that (i) have high generation probabilities and (ii) a preferential usage of some V and J genes, (iii) which CDR3 are shared between individuals, and (iv) can each bind and be activated by multiple unrelated viral peptides, notably from EBV, CMV, and influenza. These polyspecific T cells may represent a first line of defense that is mobilized in response to infections before a more specific response subsequently ensures viral elimination. Our results support an evolutionary selection of polyspecific α/β TCRs for broad antiviral responses and heterologous immunity., Competing Interests: VQ Valentin Quiniou is affiliated with Parean biotechnologies. The author has no financial interests to declare, PB, VM, PS, HV, ZZ, FM, NC, MB, BC, HV, MS, AS, BB, RM, EM, DK No competing interests declared, HP Hang-Phuong Pham is affiliated with ILTOO pharma and Parean biotechnologies. The author hasno financial interests to declare, (© 2023, Quiniou et al.)