Mathieu Uzzan

Human Secretory IgM Emerges from Plasma Cells Clonally Related to Gut Memory B Cells and Targets Highly Diverse Commensals

Summary Secretory immunoglobulin A (SIgA) enhances host‐microbiota symbiosis, whereas SIgM remains poorly understood. We found that gut IgM+ plasma cells (PCs) were more abundant in humans than mice and clonally related to a large repertoire of memory IgM+ B cells disseminated throughout the intestine but rare in systemic lymphoid organs. In addition to sharing a gut‐specific gene signature with memory IgA+ B cells, memory IgM+ B cells were related to some IgA+ clonotypes and switched to IgA in response to T cell‐independent or T cell‐dependent signals. These signals induced abundant IgM which, together with SIgM from clonally affiliated PCs, recognized mucus‐embedded commensals. Bacteria recognized by human SIgM were dually coated by SIgA and showed increased richness and diversity compared to IgA‐only‐coated or uncoated bacteria. Thus, SIgM may emerge from pre‐existing memory rather than newly activated naive IgM+ B cells and could help SIgA to anchor highly diverse commensal communities to mucus. Graphical Abstract Figure. No Caption available. HighlightsIgM+ PCs generating SIgM are relatively abundant in human but not mouse gutIgM+ PCs clonally relate to a large gut repertoire of memory IgM+ B cellsGut memory IgM+ B cells express a tissue‐specific signature and can switch to IgAHuman but not mouse SIgM binds a highly diverse microbiota dually coated by SIgA &NA; Magri et al. found that the human gut includes a large memory IgM+ B cell repertoire clonally related to plasma cells mounting SIgM responses against mucus‐embedded commensals co‐targeted by SIgA. Dually coated bacteria are detected in humans but not mice and show increased diversity and richness compared to SIgA‐only‐coated or uncoated bacteria.

Case Series: Does a Combination of Anti-TNF Antibodies and Transient Ileal Fecal Stream Diversion in Severe Crohn's Colitis With Perianal Fistula Prevent Definitive Stoma?

Case Series: Does a Combination of Anti-TNF Antibodies and Transient Ileal Fecal Stream Diversion in Severe Crohns Colitis With Perianal Fistula Prevent Definitive Stoma?

B Cell-Activating Factor (BAFF)-Targeted B Cell Therapies in Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBD) involve dysregulated immune responses to gut antigens in genetically predisposed individuals. While a better elucidation of IBD pathophysiology has considerably increased the number of treatment options, the need for more effective therapeutic strategies remains a pressing priority. Defects of both non-hematopoietic (epithelial and stromal) and hematopoietic (lymphoid and myeloid) cells have been described in patients with IBD. Within the lymphoid system, alterations of the T cell compartment are viewed as essential in the pathogenesis of IBD. However, growing evidence points to the additional perturbations of the B cell compartment. Indeed, the intestinal lamina propria from IBD patients shows an increased presence of antibody-secreting plasma cells, which correlates with enhanced pro-inflammatory immunoglobulin G production and changes in the quality of non-inflammatory IgA responses. These B cell abnormalities are compounded by the emergence of systemic antibody responses to various autologous and microbial antigens, which predates the clinical diagnosis of IBD and identifies patients with complicated disease. It is presently unclear whether such antibody responses play a pathogenetic role, as B cell depletion with the CD20-targeting monoclonal antibody rituximab did not ameliorate ulcerative colitis in a clinical trial. However, it must be noted that unresponsiveness to rituximab is also observed also in some patients with autoimmune disorders usually responsive to B cell-depleting therapies. In this review, we discussed mechanistic aspects of B cell-based therapies and their potential role in IBD with a special interest on BAFF and BAFF-targeting therapies buoyed by the success of anti-BAFF treatments in rheumatologic disorders.

Long-term Follow-up After Ileorectal Anastomosis for Ulcerative Colitis: A GETAID/GETAID Chirurgie Multicenter Retrospective Cohort of 343 Patients.

Objectives: To determine the cumulative incidence and the prognostic factors of ileorectal anastomosis (IRA) failure after colectomy for ulcerative colitis (UC). Background: Although ileal pouch-anal anastomosis is recommended after colectomy for UC, IRA is still performed. Methods: This was a multicenter retrospective cohort study, which included patients with IRA for UC performed between 1960 and 2014. IRA failure was defined as secondary proctectomy and/or rectal cancer occurrence. Uni- and multivariate survival analyses were performed using Cox-proportional hazards models. Results: A total of 343 patients from 13 French centers were included. Median follow up after IRA was 10.6 years. IRA failure rates were estimated at 27.0% (95% confidence interval, CI, 22–32) and 40.0% (95% CI 33–47) at 10 and 20 years, respectively. Median survival time without IRA failure was estimated at 26.8 years. Two thirds of secondary proctectomies were performed for refractory proctitis, and 20% for rectal neoplasia. Univariate analysis identified factors associated with IRA failure: IRA performed after 2005, a longer duration of disease at the time of IRA, indication for colectomy and having received immunomodulative agents before IRA. In multivariate analysis, treatment with both immunosuppressant (IS) and anti-TNF before colectomy was independently associated with IRA failure (HR=2.9, 95% CI 1.2–7.1). Conversely, colectomy for severe acute colitis was associated with decreased risk of IRA failure (HR=0.6, 95% CI 0.4–0.97). Discussion: Patients with UC have a high risk of IRA failure, particularly when colectomy is performed for refractory disease. However, IRA could be discussed after colectomy for severe acute colitis, or in patients naive to IS and anti-TNF.

Anti-{alpha}4{beta}7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals

Herein, we present the first human study of anti-α4β7 therapy in a cohort of HIV-1 infected subjects with mild inflammatory bowel disease. α4β7+ gut homing CD4+ T cells are early viral targets and contribute to HIV-1 pathogenesis, likely by seeding the gastrointestinal (GI) tract with HIV. Although, simianized anti-α4β7 monoclonal antibodies (Mab) have shown promise in preventing or attenuating the disease course of SIV in Non-Human Primate studies, the mechanisms of drug action remain elusive and the impact on HIV-1 persistence remains unanswered. By sampling the immune inductive and effector sites of the GI tract, we have discovered that anti-α4β7 therapy led to a significant and unexpected attenuation of lymphoid aggregates, most notably in the terminal ileum. Given that lymphoid aggregates serve as important sanctuary sites for establishing and maintaining viral reservoirs, their attrition by anti-α4β7 therapy has important implications for HIV-1 therapeutics and eradication efforts, and defines a rational basis for the continued evaluation of anti-α4β7 therapy in HIV-1 infection. One Sentence Summary Anti-α4β7 integrin therapy results in attrition of lymphoid aggregates within the gastrointestinal tract of HIV-1 infected individuals

Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1–infected individuals

Anti-α4β7 integrin therapy results in attrition of lymphoid aggregates within the gastrointestinal tract of HIV-1–infected individuals with IBD. Gut check for a promising HIV treatment Eradicating HIV in infected patients likely requires disrupting the reservoir of infected T cells in the gastrointestinal tract. One way to accomplish this is by targeting cells expressing the α4β7, which has been tested in SIV models and is an approved therapy for inflammatory bowel disease. Uzzan and colleagues studied a small cohort of HIV-infected individuals on antiretroviral therapy that began anti-α4β7 treatment for their mild inflammatory bowel disease. The investigators performed colonoscopies before and several months after the anti-integrin treatment, allowing them to assess lymphoid populations and HIV prevalence before and after treatment. They saw that treatment disrupted local lymphoid aggregates and also affected peripheral immune populations. As with non–HIV-infected IBD patients, treatment was well tolerated. Their results are sure to draw interest from scientists and clinicians who believe targeting this integrin could possibly help cure HIV. Gut homing CD4+ T cells expressing the integrin α4β7 are early viral targets and contribute to HIV-1 pathogenesis, likely by seeding the gastrointestinal (GI) tract with HIV. Although simianized anti-α4β7 monoclonal antibodies have shown promise in preventing or attenuating the disease course of simian immunodeficiency virus in nonhuman primate studies, the mechanisms of drug action remain elusive. We present a cohort of individuals with mild inflammatory bowel disease and concomitant HIV-1 infection receiving anti-α4β7 treatment. By sampling the immune inductive and effector sites of the GI tract, we have discovered that anti-α4β7 therapy led to a significant and unexpected attenuation of lymphoid aggregates, most notably in the terminal ileum. Given that lymphoid aggregates serve as important sanctuary sites for maintaining viral reservoirs, their attrition by anti-α4β7 therapy has important implications for HIV-1 therapeutics and eradication efforts and defines a rational basis for the use of anti-α4β7 therapy in HIV-1 infection.

Concise Commentary: Calling in Your Marker—Rectal CD30-Positive Cells Differentiate Ulcerative Colitis from Crohn’s Disease

In both children and adults, the diagnosis of Crohn’s disease (CD) and ulcerative colitis (UC) relies on a combination of clinical, biological, radiological, endoscopic, and histological features. While in many cases, e.g., penetrating disease, distinguishing between these two inflammatory bowel diseases (IBDs) is straightforward, 10–20% of IBD cases affecting the colon remain unclassified, even in the era of molecular pathology and multimodal diagnostic approaches [1–3]. Since most of the pathological features observed in colonic biopsies are shared between CD and UC, new tools are being explored to help the pathologist and the clinician to reach an accurate diagnosis. For many years, cluster-of-differentiation (CD)30 has been proposed as a potential marker differentially expressed between UC and CD [4]. More recently, Flores et al. studied whether CD30 immunostaining in affected colonic segments could be an efficient tool to discriminate between UC and CD in adults. A cutoff of fifteen CD30positive cells/high power field (HPF) yielded a sensitivity of 97.4% and a specificity of 97.4% [6]. In this issue of Digestive Diseases and Sciences, Fabian et al. explored the value of CD30 staining in a pediatric population of IBD studying 74 patients including 33 CD, 30 UC, and 11 IBD-undetermined [5]. They assessed the number of CD30-positive cells in intestinal and colonic segments from the terminal ileum to the rectum, confirming the results previously published in the adult population [6]. Although the median number of CD30-positive cells differed in most segments between UC and CD patients, rectal assessment alone was sufficient to discriminate between CD and UC. They determined that 2.5 positive cells/HPF was the most accurate with a sensitivity of ~ 83% and a specificity of 90%. Interestingly, they found that the number of CD30-positive cells was not dependent on the intensity of endoscopic or microscopic inflammation. Since the main caveat of their study was that CD30 counts may depend on the presence of inflammation and that about half of CD patients did not have rectal inflammation, this observation convincingly addressed this concern. Overall, their study opens to the use of a new easily applicable method in clinical practice. CD30 staining could be optimally used in the context of mild colonic IBD when the clinical and pathological picture does not correspond obviously to CD or UC. For the pathologist, it brings an additional feature that could be used in combination with the “classical signs” such as basal plasmacytosis and eosinophilia. Regarding the bigger picture of the specific pathogenesis of UC, CD30 could be the starting point of fundamental research studying its contribution to intestinal inflammation. CD30 is a plasma membrane protein that belongs to the tumor necrosis factor receptor family which although expressed on several cell types, has been primarily studied in T and B cells and as a marker of some neoplastic diseases such as Hodgkin lymphoma. Although in T cells, CD30 expression is linked to the interleukin (IL)-4 expressing, interferon (IFN)-γ non-expressing CD4 cells that define T helper (Th)2-like cells [7], the biological function of CD30 expressing cells is highly variable, not restricted to a single effect or a unique cell type. Its complex biological functions that are likely to reflect the interplay of many immune subsets could provide fascinating clues to the pathogenesis of IBD.

Colonic microRNA Profiles, Identified by a Deep-learning Algorithm, That Predict Responses of Patients With Acute Severe Ulcerative Colitis to Therapy

BACKGROUND & AIMS: Acute severe ulcerative colitis (ASUC) is a life‐threatening condition managed with intravenous steroids followed by infliximab, cyclosporine, or colectomy (for patients with steroid resistance). There are no biomarkers to identify patients most likely to respond to therapy; ineffective medical treatment can delay colectomy and increase morbidity and mortality. We aimed to identify biomarkers of response to medical therapy for patients with ASUC. METHODS: We performed a retrospective analysis of 47 patients with ASUC, well characterized for their responses to steroids, cyclosporine, or infliximab, therapy at 2 centers in France. Fixed colonic biopsies, collected before or within the first 3 days of treatment, were used for microarray analysis of microRNA expression profiles. Deep neural network‐based classifiers were used to derive candidate biomarkers for discriminating responders from non‐responders to each treatment and to predict which patients would require colectomy. Levels of identified microRNAs were then measured by quantitative PCR analysis in a validation cohort of 29 independent patients—the effectiveness of the classification algorithm was tested on this cohort. RESULTS: A deep neural network‐based classifier identified 9 microRNAs plus 5 clinical factors, routinely recorded at time of hospital admission, that associated with responses of patients to treatment. This panel discriminated responders to steroids from non‐responders with 93% accuracy (area under the curve, 0.91). We identified 3 algorithms, based on microRNA levels, that identified responders to infliximab vs non‐responders (84% accuracy, AUC = 0.82) and responders to cyclosporine vs non‐responders (80% accuracy, AUC = 0.79). CONCLUSION: We developed an algorithm that identifies patients with ASUC who respond vs do not respond to first‐ and second‐line treatments, based on microRNA expression profiles in colon tissues.

Efficient long‐term depletion of CD20+ B cells by rituximab does not affect gut‐resident plasma cells

The vast majority of antibody‐producing B cells are located within the gastrointestinal tract and are key players in maintaining homeostasis. The failure of rituximab, a potent B cell–depleting agent, to ameliorate ulcerative colitis in a single clinical trial has dampened enthusiasm to study B cells in patients with inflammatory bowel disease (IBD). However, several lines of evidence suggest that intestinal B cells may be affected in IBD. Additionally, the pathophysiological mechanisms underlying rituximabs lack of efficacy in IBD remain unclear. Here, on the basis of detailed immunophenotyping of a patient who underwent a colonoscopy 6 months after the end of rituximab‐based therapy, we observed that rituximab did not deplete colon‐resident plasma cells (PCs) while ablating all CD20+ B cells in tissues and in the circulation. On the basis of these observations, we propose that one factor underlying the lack of efficacy of rituximab relates to the fact that it does not affect the entire B cell compartment in tissues, sparing the intestinal‐resident PCs while effectively depleting CD20+ B cell populations. Thus, we contend that, despite the results of the Rituximab study, there is a need for more intensive B cell–oriented research in inflammatory disorders, including IBD.