Étude rétrospective multicentrique de néphropathies à dépôts d’immunoglobuline A associées aux maladies inflammatoires chroniques de l’intestin

Background: clinical, pathological characteristics and kidney outcome of patients with immunoglobulin A nephropathy (IgAN) occurring in a context of inflammatory bowel disease (IBD) (IBD-associated IgAN) have been poorly investigated. This study analyzed IBD pattern, kidney features at IgAN onset, therapeutic management and outcome of these patients. Method: we conducted a multicentric retrospective study with centralized histological review to identify patients with IBD-associated IgAN. We compared their main clinical pathological characteristics and renal survival with a cohort of 134 patients with primary IgAN without IBD. Results: Crohn’s disease accounted for 75% of IBD in this IBD-associated IgAN cohort. IgAN occurred in 23/24 cases after the diagnosis of IBD (median 9±6 years). IBD was considered as active at IgAN onset in 23.6%. Hypertension was present in 41.7% of patients. Urinary protein-to-creatinine ratio was higher than 50 mg/mmol in 95.8% of patients (mean 254 mg/mmol). At the time of renal biopsy, 13/24 patients have eGFR higher than 60 ml/min/1.73m2 and only one patient required renal replacement therapy. Centralized review of kidney biopsies, according to Oxford MEST-C classification, found M1, E1, S1, T1+T2 and C1+C2 lesions in 57%, 48%, 76%, 57% and 38% of cases, respectively. Steroids were used in 50% cases, started intravenously in half of the cases. After an average follow-up of 6.8 years, 4 patients (16.7%) reached a poor kidney outcome defined as end-stagerenal-disease (n=3) or a decline > 50% of initial eGFR (n=1). IBD was not associated with a poor kidney outcome in comparison with IgAN without IBD group (HR = 0.72, 95%CI: [0.3 - 2], p = 0.51). Conclusions: this first case series suggests that IBD-associated IgAN and primary IgAN have similar clinic biological presentation and evolution.Contexte : les caractéristiques sémiologiques et le pronostic rénal des patients atteints de néphropathie à immunoglobuline A (IgAN) survenant dans un contexte de maladies inflammatoires chroniques intestinales (MICI) (IgAN+MICI) ont été peu étudiés. Cette étude a analysé le phénotype des MICI, la présentation néphrologique, la prise en charge thérapeutique et le pronostic des IgAN+MICI. Méthode : nous avons mené une étude rétrospective multicentrique avec analyse histologique centralisée d'IgAN associées aux MICI. Nous avons comparé leurs principales caractéristiques cliniques et histologiques et leur survie rénale avec une cohorte de 134 patients atteints d'IgAN primitives. Résultats : la maladie de Crohn représentait 75 % des MICI dans cette cohorte d'IgAN+MICI. La néphropathie est apparue dans 23/24 cas après le diagnostic de MICI (9±6 ans en moyenne). Les MICI étaient en phase active au moment de l'apparition de la néphropathie chez 23,6 % des sujets. L'hypertension était présente chez 41,7 % des patients. Le rapport protéine/créatinine urinaire était supérieur à 50 mg/mmol chez 95,8 % des patients (254 mg/mmol en moyenne). Au moment de la biopsie rénale, 13/24 patients présentaient un DFGe supérieur à 60 ml/min/1,73 m² et un seul patient a nécessité une épuration extra-rénale. La relecture centralisée des biopsies rénales a révélé des lésions M1, E1, S1, T1+T2 et C1+C2 dans 57 %, 48 %, 76 %, 57 % et 38 % des cas respectivement selon la classification MEST-C d'Oxford. Une corticothérapie a été administrée dans 50 % des cas avec une initiation intraveineuse dans la moitié des cas. Après un suivi moyen de 6,8 ans, 4 patients (16,7 %) ont évolué défavorablement en développant une insuffisance rénale chronique terminale (n = 3) ou une diminution > 50 % du DFGe initial (n = 1). Les MICI n'ont pas été associées à un mauvais pronostic rénal comparativement aux IgAN primitives (HR = 0,72, 95 % IC : [0.3 - 2], p = 0,51). Conclusions : cette première cohorte suggère que les IgAN associées aux MICI et les IgAN primitives possèdent une présentation clinique et une évolution rénale similaires

HLA Desensitization in Solid Organ Transplantation: Anti-CD38 to Across the Immunological Barriers

International audienceThe presence of anti-human leucocyte antigen (HLA) antibodies in the potential solid organ transplant recipient’s blood is one of the main barriers to access to a transplantation. The HLA sensitization is associated with longer waitlist time, antibody mediated rejection and transplant lost leading to increased recipient’s morbidity and mortality. However, solid organ transplantation across the HLA immunological barriers have been reported in recipients who were highly sensitized to HLA using desensitization protocols. These desensitization regimens are focused on the reduction of circulating HLA antibodies. Despite those strategies improve rates of transplantation, it remains several limitations including persistent high rejection rate and worse long-term outcomes when compare with non-sensitized recipient population. Currently, interest is growing in the development of new desensitization approaches which, beyond targeting antibodies, would be based on the modulation of alloimmune pathways. Plasma cells appears as an interesting target given their critical role in antibody production. In the last decade, CD38-targeting immunotherapies, such as daratumumab, have been recognized as a key component in the treatment of myeloma by inducing an important plasma cell depletion. This review focuses on an emerging concept based on targeting CD38 to desensitize in the field of transplantation

Immunoglobulin A Nephropathy in Association with Inflammatory Bowel Diseases: Results from a National Study and Systematic Literature Review

International audienceAbstract Background Little is known about clinical characteristics and kidney outcomes in patients with biopsy-proven immunoglobulin A nephropathy (IgAN) in a context of inflammatory bowel disease (IBD). Methods We conducted a retrospective multicentre study with a centralized histological review to analyse the presentation, therapeutic management and outcome of 24 patients suffering from IBD-associated IgAN relative to a cohort of 134 patients with primary IgAN without IBD. Results Crohn's disease and ulcerative colitis accounted for 75 and 25% of IBD-associated IgAN cases, respectively. IBD was diagnosed before IgAN in 23 cases (a mean of 9\,years previously) and was considered active at IgAN onset in 23.6% of patients. Hypertension was present in 41.7% of patients. The urinary protein:creatinine ratio exceeded 100\,mg/mmol in 70.8% of patients (mean 254\,mg/mmol). Estimated glomerular filtration rate (eGFR) was >60\,mL/min/1.73\,m2 in 13/24 patients and only 1 patient required dialysis. In the Oxford mesangial hypercellularity, endocapillary cellularity, segmental sclerosis and interstitial fibrosis/tubular atrophy with crescents classification of renal biopsies, 57% were M1, 48% E1, 76% S1, 57% T1\textendash 2 and 38% C1\textendash 2. Steroids were administered in 50% of cases. After a mean follow-up of 7.2\,years, 4 patients (16.7%) had a poor kidney outcome: end-stage renal disease (n\,=\,3) or a >50% decrease in eGFR from initial values (n\,=\,1). A similar evolution was observed in patients with primitive IgAN. Conclusions This first case series suggests that IBD-associated IgAN has frequent inflammatory lesions at onset and variable long-term outcomes

TLR9 signalling in HCV-associated atypical memory B cells triggers Th1 and rheumatoid factor autoantibody responses

International audienceBackground & aims: Hepatitis C virus (HCV) infection contributes to the development of autoimmune disorders such as cryoglobulinaemia vasculitis (CV). However, it remains unclear why only some individuals with HCV develop HCV-associated CV (HCV-CV). HCV-CV is characterized by the expansion of anergic CD19+CD27+CD21low/- atypical memory B cells (AtMs). Herein, we report the mechanisms by which AtMs participate in HCV-associated autoimmunity.Methods: The phenotype and function of peripheral AtMs were studied by multicolour flow cytometry and co-culture assays with effector T cells and regulatory T cells in 20 patients with HCV-CV, 10 chronicallyHCV-infected patients without CV and 8 healthy donors. We performed gene expression profile analysis of AtMs stimulated or not by TLR9. Immunoglobulin gene repertoire and antibody reactivity profiles of AtM-expressing IgM antibodies were analysed following single B cell FACS sorting and expression-cloning of monoclonal antibodies.Results: The Tbet+CD11c+CD27+CD21- AtM population is expanded in patients with HCV-CV compared to HCV controls without CV. TLR9 activation of AtMs induces a specific transcriptional signature centred on TNFα overexpression, and an enhanced secretion of TNFα and rheumatoid factor-type IgMs in patients with HCV-CV. AtMs stimulated through TLR9 promote type 1 effector T cell activation and reduce the proliferation of CD4+CD25hiCD127-/lowFoxP3+ regulatory T cells. AtM expansions display intraclonal diversity with immunoglobulin features of antigen-driven maturation. AtM-derived IgM monoclonal antibodies do not react against ubiquitous autoantigens or HCV antigens including NS3 and E2 proteins. Rather, AtM-derived antibodies possess rheumatoid factor activity and target unique epitopes on the human IgG-Fc region.Conclusion: Our data strongly suggest a central role for TLR9 activation of AtMs in driving HCV-CV autoimmunity through rheumatoid factor production and type 1 T cell responses.Lay summary: B cells are best known for their capacity to produce antibodies, which often play a deleterious role in the development of autoimmune diseases. During chronic hepatitis C, self-reactive B cells proliferate and can be responsible for autoimmune symptoms (arthritis, purpura, neuropathy, renal disease) and/or lymphoma. Direct-acting antiviral therapy clears the hepatitis C virus and eliminates deleterious B cells