The "French Germinal Center Club" of the French Society for Immunology: a dynamic collaboration between researchers passionate about the germinal center reaction

International audienceThe antibody response and B cell memory development are major effector arms of the immune system. They both rely on the selection of B cells in specific anatomical structures called germinal centers (GC). GCs are not only sites for clonal B cell expansion but also the places where the antibody repertoire diversifies following somatic hypermutations and class switch recombination. CD4+ T cells that are present in GCs guide the stringent cell selection of high-affinity B cell variants. They can be divided in two functional cell subsets: T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. Furthermore, follicular B and T cell subsets are in close contact with specialized stromal cells allowing cell migration, adhesion, and participating in B cell selection mechanisms. Importantly, on top of their essential role as orchestrators of protective immune responses against infections, GCs have also been involved in diverse pathological conditions including autoimmunity, allergy, and cancer. The great complexity of these structures means that GC aficionados encompass researchers working on a very large palette of topics including in depth analysis of the immune cell types cited above, characterization of cell interactions between GC immune and/or mesenchymal cell subsets, as well as deciphering disease physiopathology. The great versatility of these research foci means that the GC field is extremely dynamic and multidisciplinary. However, because there are many scientific topics addressed when studying GC and despite a consequent number of teams interested in this field, events centered only on GCs allowing researcher interactions are quite rare

Cutting Edge

Host resistance to Trypanosoma cruzi infection depends on a type 1 response characterized by a strong production of IL-12 and IFN-γ. Amplifying this response through CD40 triggering results in control of parasitemia. Two newly synthesized molecules (<3 kDa) mimicking trimeric CD40L (mini CD40Ls-1 and -2) bind to CD40, activate murine dendritic cells, and elicit IL-12 production. Wild-type but not CD40 knockout mice exhibited a sharp decrease of parasitemia and mortality when inoculated with T. cruzi mixed with miniCD40Ls. Moreover, the immunosuppression induced by T. cruzi infection was impaired in mice treated with miniCD40Ls, as shown by proliferation of splenic lymphocytes, percentage of CD8+ T cells, and IFN-γ production. Mice surviving T. cruzi infection in the presence of miniCD40L-1 were immunized against a challenge infection. Our results indicate that CD40L mimetics are effective in vivo and promote the control of T. cruzi infection by overcoming the immunosuppression usually induced by the parasites

Achieving SVR Does Not Prevent From Fibrosis Progession In Patients With FCH Results From A Large French Prospective Multicentric ANRS CO23 Cupilt Cohort

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HCV eradication does not protect from fibrosis progression in patients with fibrosing cholestatic hepatitis after liver transplantation

International audienceINTRODUCTION: Hepatitis C virus (HCV) may recur after liver transplantation (LT) in the severe form of fibrosing cholestatic hepatitis (FCH). The prognosis dramatically improved by the use of direct acting antivirals (DAAs). The aim of the present study was to describe the change in histological features of FCH after virological eradication. METHODS: From the ANRS CUPILT cohort we included 17 patients who presented FCH and at least two graft biopsies, one before DAA-treatment and one after. A single expert pathologist, blinded for clinical outcome, retrospectively confirmed the diagnosis of FCH and progression of fibrosis. RESULTS: Diagnosis of FCH was made after a median [IQR] 6.0 [3.1-11.8] months after LT, and the median interval between diagnosis and onset of treatment was 1.2 [0.7-6.1] months. The rate of viral eradication was 94.1%. The median delay between the pre-treatment and the treatment biopsies was 12.5 [11.1-20.0] months. Between the end of treatment and the second biopsy, the delay was 5.3 [0.6-7.4] months. Fibrosis stage worsened in 10 patients (58.8%); 6 patients had cirrhosis (35.3%). Chronic rejection appeared in 4 (23.5%) patients. CONCLUSION: Our results suggest that, despite viral eradication in patients presenting FCH after LT, fibrosis progression was observed in half of patients. This should encourage monitoring fibrosis progression despite HCV cure

Sofosbuvir and NS5A inhibitors without Ribavirin during 12 weeks are efficient to treat hepatitis C recurrence after liver transplantation only in genotype 1. Results from the CO23 ANRS CUPILT study.

International audienceMeeting Abstract: 92

Sofosbuvir and NS5A inhibitors without Ribavirin during 12 weeks are efficient to treat hepatitis C recurrence after liver transplantation only in genotype 1. Results from the CO23 ANRS CUPILT study.

International audienceMeeting Abstract: 92

Patients Treated for HCV Infection and Listed for Liver Transplantation in a French Multicenter Study: What Happens at Five Years?

International audienceBackground: Direct-acting antiviral (DAA) agents for the treatment of hepatitis C virus (HCV) infection have been proven safe and effective in cirrhotic patients awaiting liver transplantation (LT). However, in the long term, data remain minimal regarding the clinical impact of viral eradication on patients listed for decompensated cirrhosis or hepatocellular carcinoma (HCC). We aimed to elucidate the clinical outcomes of patients regarding delisting and the evolution of HCC during the long-term follow-up. Methods: An observational, multicenter, retrospective analysis was carried out on prospectively collected data from HCV-positive patients treated with an interferon-free regimen while awaiting LT in 18 French hospitals. Results: A total of 179 patients were included in the study. The indication for LT was HCC in 104 (58.1%) patients and cirrhosis in 75 (41.9%) patients. The sustained virological response was 84.4% and the treatment was well tolerated. At five years, among 75 patients with cirrhosis treated for HCV, 19 (25.3%) were delisted following improvement after treatment. Predictive factors for delisting highlighted an absence of ascites, MELD score ≤ 15, and Child–Pugh score ≤ 7. No patients with refractory ascites were delisted. Among patients with HCC, 82 (78.9%) were transplanted. The drop-out rate was low (6.7%) and few recurrences of HCC after LT were observed. Conclusions: DAAs are safe and effective in patients awaiting LT for cirrhosis or HCC. A quarter of patients with cirrhosis can be delisted because of clinical improvement. Predictive factors for delisting, as a result of improvement, may assist prescribers, before initiating HCV infection therapy in the long-term perspective

Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (T(reg)) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with T(reg) cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of T(reg) cells and particularly follicular T(reg) cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on T(reg) cells induced a down-regulation of the transforming growth factor-β axis, altering the phenotype of T(reg) cells and limiting their immunosuppressive responses. In patients with SLE, we found an up-regulation of P- and E-selectin both on microparticles and in their soluble forms that correlated with disease activity. Last, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease, such as anti-dsDNA antibody concentrations and kidney pathology. Overall, our results identify a P-selectin-dependent pathway that is active in patients with SLE and validate it as a potential therapeutic avenue