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Systemic and mucosal humoral immune responses are crucial to fight respiratory viral infections in the current pandemic of COVID-19 caused by the SARS-CoV-2 virus. During SARS-CoV-2 infection, the dynamics of systemic and mucosal antibody infections are affected by patient characteristics, such as age, sex, disease severity, or prior immunity to other human coronaviruses. Patients suffering from severe disease develop higher levels of anti-SARS-CoV-2 antibodies in serum and mucosal tissues than those with mild disease, and these antibodies are detectable for up to a year after symptom onset. In hospitalized patients, the aberrant glycosylation of anti-SARS-CoV-2 antibodies enhances inflammation-associated antibody Fc-dependent effector functions, thereby contributing to COVID-19 pathophysiology. Current vaccines elicit robust humoral immune responses, principally in the blood. However, they are less effective against new viral variants, such as Delta and Omicron. This review provides an overview of current knowledge about the humoral immune response to SARS-CoV-2, with a particular focus on the protective and pathological role of humoral immunity in COVID-19 severity. We also discuss the humoral immune response elicited by COVID-19 vaccination and protection against emerging viral variants.

Reliable immunoassays are essential to early predict and monitor vaccine efficacy against SARS-CoV-2. The performance of an Interferon Gamma Release Assay (IGRA, QuantiFERON® SARS-CoV-2), and a current anti-spike serological test, compared to a plaque reduction neutralization test (PRNT) taken as gold standard were compared. Eighty vaccinated individuals, whose 16% had a previous history of COVID-19, were included in a longitudinal prospective study and sampled before and two to four weeks after each dose of vaccine. In non-infected patients, 2 doses were required for obtaining both positive IGRA and PRNT assays, while serology was positive after one dose. Each dose of vaccine significantly increased the humoral and cellular response. By contrast, convalescent subjects needed a single dose of vaccine to be positive on all 3 tests. Both IGRA and current serology assay were found predictive of a positive titer of neutralizing antibodies that is correlated with vaccine protection. Patients over 65 or 80 years old had a significantly reduced response. The response tended to be better with the heterologous scheme (vs. homologous) and with the mRNA-1273 vaccine (vs. BNT162b2) in the homologous group, in patients under 55 and under 65 years old, respectively. Finally, decrease intensity or absence of IGRA response and to a less extent of anti-spike serology were also correlated to reinfection which has occurred during the follow up. In conclusion, both IGRA and current anti-spike serology assays could be used at defined thresholds to monitor the vaccine response against SARS-CoV-2 and to simply identify non-responding individuals after a complete vaccination scheme. Two available specific tests (IGRA and anti-spike antibodies) could early assess the vaccine-induced immunity against SARS-CoV-2 at the individual scale, to potentially adapt the vaccination scheme in non-responder patients.

Bordetella bronchiseptica (Bb) is a Gram-negative bacterium responsible for canine infectious respiratory disease complex (CIRDC). Several vaccines targeting this pathogen are currently licensed for use in dogs, but their mechanism of action and the correlates of protection are not fully understood. To investigate this, we used a rat model to examine the immune responses induced and the protection conferred by a canine mucosal vaccine after challenge. Wistar rats were vaccinated orally or intranasally on D0 and D21 with a live attenuated Bb vaccine strain. At D35, the rats of all groups were inoculated with 103 CFU of a pathogenic strain of B. bronchiseptica. Animals vaccinated via either the intranasal or the oral route had Bb-specific IgG and IgM in their serum and Bb-specific IgA in nasal lavages. Bacterial load in the trachea, lung, and nasal lavages was lower in vaccinated animals than in non-vaccinated control animals. Interestingly, coughing improved in the group vaccinated intranasally, but not in the orally vaccinated or control group. These results suggest that mucosal vaccination can induce mucosal immune responses and provide protection against a Bb challenge. This study also highlights the advantages of a rat model as a tool for studying candidate vaccines and routes of administration for dogs.

Following severe adverse reactions to the AstraZeneca ChAdOx1-S-nCoV-19 vaccine1,2, European health authorities have recommended that patients under the age of 55 who received one dose of ChAdOx1-S-nCoV-19 vaccine receive a second dose of Pfizer BNT162b2 vaccine as a booster. However, the effectiveness and the immunogenicity of this vaccination regimen have not been formally tested. Here, we show that the heterologous ChAdOx1-S-nCoV-19/BNT162b2 combination confers better protection against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection than the homologous BNT162b2/BNT162b2 combination in a real-world observational study of healthcare workers (n=13121). To understand the underlying mechanism, we conducted a longitudinal survey of the anti-spike immunity conferred by each vaccine combination. Both combinations induced strong anti-spike antibody (Ab) responses but sera from heterologous vaccinated individuals displayed a stronger neutralizing activity, regardless of the SARS-CoV-2 variant. This enhanced neutralizing potential was correlated with increased frequencies of switched and activated memory B cells recognizing the SARS-CoV-2 Receptor Binding Domain (RBD). The ChAdOx1-S-nCoV-19 vaccine induced a weaker IgG response but a stronger T cell response than the BNT162b2 vaccine after the priming dose, which could explain the complementarity of both vaccines when used in combination. The heterologous vaccination regimen could therefore be particularly suitable for immune compromised individuals.

Background and aimsWe aimed to analyze circulating CD4+T cell subsets and cytokines during the course of Crohn’s disease (CD).Methods and resultsCD4+T cell subsets, ultrasensitive C-reactive protein (usCRP), and various serum cytokines (IL-6, IL-8, IL-10, IL-13, IL-17A, IL-23, TNFα, IFNγ, and TGFβ) were prospectively monitored every 3 months for 1 year, using multicolor flow cytometry and an ultrasensitive Erenna method in CD patients in remission at inclusion. Relapse occurred in 35 out of the 113 consecutive patients (31%). For patients in remission within 4 months prior to relapse and at the time of relapse, there was no significant difference in Th1, Th17, Treg, and double-positive CD4+T cell subsets co-expressing either IFNγ and FOXP3, IL-17A and FOXP3, or IFNγ and IL-17A. On the contrary, in patients who remained in remission, the mean frequency and number of double-positive IL-17A+FOXP3+CD4+T cells and the level of usCRP were significantly higher (p≤ 0.01) 1 to 4 months prior to relapse. At the time of relapse, only the IL-6 and usCRP levels were significantly higher (p≤ 0.001) compared with those patients in remission. On multivariate analysis, a high number of double-positive IL-17A+FOXP3+CD4+T cells (≥1.4 cells/mm3) and elevated serum usCRP (≥3.44 mg/L) were two independent factors associated with risk of relapse.ConclusionsDetection of circulating double-positive FOXP3+IL-17A+CD4+T cell subsets supports that T cell plasticity may reflect the inflammatory context of Crohn’s disease. Whether this subset contributes to the pathogenesis of CD relapse needs further studies.

Sjögren's syndrome (SjS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the salivary and lacrimal glands associated with sicca syndrome. TAFRO syndrome is a systemic inflammatory disease of unknown cause, characterized by Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis, Renal dysfunction and Organomegaly, first reported in 2010 in Japanese patients. Despite their rarity, both conditions have been concurrently reported in several patients during the recent years, hence questioning the existence of shared or related features.A systematic review of the literature regarding SjS associated with TAFRO syndrome (SjS-TAFRO) was performed. The 2019 updated Masaki diagnostic criteria were used for TAFRO syndrome and SjS was considered when the diagnosis was mentioned by the authors, necessarily with either anti-Sjogren's Syndrome A (SSA) ± anti-Sjogren's Syndrome B (SSB) antibodies and/or histological evidence of focal lymphocytic sialadenitis.Ten cases of SjS-TAFRO have been reported in the literature to date. Compared to SjS patients without TAFRO syndrome, these 10 SjS-TAFRO had a lower female predominance (2.3:1 vs 9:1 women to man ratio) and a higher frequency of anti-SSA antibodies (90% vs 70%). All fulfilled the three major Masaki criteria i.e., anasarca, thrombocytopenia, and systemic inflammation. Seven of them (70%) had megakaryocyte hyperplasia or reticulin fibrosis in the bone marrow. Lymph node biopsy was performed in 8 out of 10 cases (80%) and results were consistent with Castleman disease in 6 (75%). Eight of them had developed renal failure (80%) within six months. Nine of them (90%) had organomegaly, with hepatosplenomegaly in 8 cases and splenomegaly alone in 1.This review brings new insights regarding TAFRO syndrome and suggests it could be a severe manifestation of SjS. The identification of shared abnormal signaling pathways could help in the therapeutic management of both diseases, which face an unmet therapeutic need.

Broadly neutralizing antibodies (bNAbs) offer promising opportunities for preventing HIV-1 infection. The protection mechanisms of bNAbs involve the Fc domain, as well as their Fab counterpart. Here, different bNAb isotypes including IgG1, IgA1, IgA2, and IgA122 (IgA2 with the hinge of IgA1) were generated and then produced in CHO cells. Their ability to neutralize pseudovirus and primary HIV-1 isolates were measured, as well as their potential ADCC-like activity using a newly developed assay. In our work, gp41-specific IgA seems to be more efficient than IgG1 in inducing ADCC-like activity, but not in its virus neutralization effect. We show that either gp120-specific IgA or IgG1 isotypes are both efficient in neutralizing different viral strains. In contrast, gp120-specific IgG1 was a better ADCC-like inducer than IgA isotypes. These results provide new insights into the neutralization and ADCC-like activity of different bNAbs that might be taken into consideration when searching for new treatments or antibody-based vaccines.

Antibody-dependent enhancement (ADE) can increase the rates and severity of infection with various viruses, including coronaviruses, such as MERS. Some in vitro studies on COVID-19 have suggested that prior immunization enhances SARS-CoV-2 infection, but preclinical and clinical studies have demonstrated the contrary. We studied a cohort of COVID-19 patients and a cohort of vaccinated individuals with a heterologous (Moderna/Pfizer) or homologous (Pfizer/Pfizer) vaccination scheme. The dependence on IgG or IgA of ADE of infection was evaluated on the serum samples from these subjects (twenty-six vaccinated individuals and twenty-one PCR-positive SARS-CoV-2-infected patients) using an in vitro model with CD16- or CD89-expressing cells and the Delta (B.1.617.2 lineage) and Omicron (B.1.1.529 lineage) variants of SARS-CoV-2. Sera from COVID-19 patients did not show ADE of infection with any of the tested viral variants. Some serum samples from vaccinated individuals displayed a mild IgA-ADE effect with Omicron after the second dose of the vaccine, but this effect was abolished after the completion of the full vaccination scheme. In this study, FcγRIIIa- and FcαRI-dependent ADE of SARS-CoV-2 infection after prior immunization, which might increase the risk of severe disease in a second natural infection, was not observed.

Sjögren’s syndrome (SjS) is a frequent systemic autoimmune disease responsible for a major decrease in patients’ quality of life, potentially leading to life-threatening conditions while facing an unmet therapeutic need. Hence, we assessed the immunogenicity, efficacy, and tolerance of IFN-Kinoid (IFN-K), an anti-IFNα vaccination strategy, in a well-known mouse model of systemic autoimmunity with SjS-like features: MRL/MpJ-Faslpr/lpr (MRL/lpr) mice. Two cohorts (with ISA51 or SWE01 as adjuvants) of 26 female MRL/lpr were divided in parallel groups, “controls” (not treated, PBS and Keyhole Limpet Hemocyanin [KLH] groups) or “IFN-K” and followed up for 122 days. Eight-week-old mice received intra-muscular injections (days 0, 7, 28, 56 and 84) of PBS, KLH or IFN-K, emulsified in the appropriate adjuvant, and blood samples were serially collected. At sacrifice, surviving mice were euthanized and their organs were harvested for histopathological analysis (focus score in salivary/lacrimal glands) and IFN signature evaluation. SjS-like features were monitored. IFN-K induced a disease-modifying polyclonal anti-IFNα antibody response in all treated mice with high IFNα neutralization capacities, type 1 IFN signature’s reduction and disease features’ (ocular and oral sicca syndrome, neuropathy, focus score, glandular production of BAFF) improvement, as reflected by the decrease in Murine Sjögren’s Syndrome Disease Activity Index (MuSSDAI) modelled on EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI). No adverse effects were observed. We herein report on the strong efficacy of an innovative anti-IFNα vaccination strategy in a mouse model of SjS, paving the way for further clinical development (a phase IIb trial has just been completed in systemic lupus erythematosus with promising results).

International audience; IFN-I and IFN-III immunity in the nasal mucosa is poorly characterized during SARS-CoV-2 infection. We analyze the nasal IFN-I/III signature, namely the expression of ISGF-3–dependent IFN-stimulated genes, in mildly symptomatic COVID-19 patients and show its correlation with serum IFN-α2 levels, which peak at symptom onset and return to baseline from day 10 onward. Moreover, the nasal IFN-I/III signature correlates with the nasopharyngeal viral load and is associated with the presence of infectious viruses. By contrast, we observe low nasal IFN-I/III scores despite high nasal viral loads in a subset of critically ill COVID-19 patients, which correlates with the presence of autoantibodies (auto-Abs) against IFN-I in both blood and nasopharyngeal mucosa. In addition, functional assays in a reconstituted human airway epithelium model of SARS-CoV-2 infection confirm the role of such auto-Abs in abrogating the antiviral effects of IFN-I, but not those of IFN-III. Thus, IFN-I auto-Abs may compromise not only systemic but also local antiviral IFN-I immunity at the early stages of SARS-CoV-2 infection.

Maintaining commensal diversity is essential to host homeostasis, because microbial species provide a range of metabolic products and continuously educate the host immune system. The mucosal immune system must actively gather information about the composition of the microbiota, while offering an appropriate response. In mammals, bacterial sensing leads to the production of specific immunoglobulins (Ig), which reach the intestinal lumen as secretory Ig (SIg). Recent work has shed more light on the mechanisms by which SIg can shape bacterial repertoires and contribute to regulating host metabolism. In parallel, bacterial metabolites modulate Ig production and secretion. Here, we present an overview of the current knowledge of the relationship between bacterial metabolites and host SIg, correlating the disruption of this balance with chronic inflammation in humans.

In peripheral neuropathies with antibodies against Myelin Associated Glycoprotein (MAG), an IgM monoclonal gammopathy recognizes a specific epitope called Human Natural Killer 1 (HNK1) shared by NK lymphocytes and several components of the peripheral nerve myelin. Recently an ELISA test has been developed to detect antibodies against HNK1 epitope. Objectives were to determine the usefulness of this assay in the management of anti-MAG neuropathy. Anti-HNK1 antibodies were assessed with the GanglioCombi™ MAG ELISA test (Buhlmann) in 41 anti-MAG neuropathies and in 118 controls: 34 chronic inflammatory demyelinating polyradiculoneuropathies, 3 Miller Fisher syndromes, 12 sensory neuronopathies, 63 length-dependent axonal sensory polyneuropathies, 6 healthy controls. Anti-HNK1 antibody was tested before and 1 year after rituximab therapy in seven patients with anti-MAG neuropathy. Anti-HNK1 antibodies were positive in 40/41 anti-MAG neuropathies, and in 1/118 controls (sensitivity 98%, specificity 99%). Only considering controls with IgM paraprotein, specificity was 96% (23/24). In anti-MAG neuropathies, anti-HNK1 titre was correlated with sensory deficiency evaluated with the INCAT sensory sum score (r = 0.4, p = 0.01) and with disability evaluated with the Rasch-built Overall Disability Scale (r = $$-$$ 0.4, p = 0.01) and Overall Neuropathy Limitation Scale (r = 0.4, p = 0.02). Anti-HNK1 titres were not related to age, disease duration, atypical clinical features and anti-MAG antibodies titres. Anti-MAG titres were not associated with disease severity. Anti-HNK1 titres were decreased by 18% 1 year after rituximab treatment. Anti-HNK1 antibodies have good sensitivity and specificity for the diagnosis of anti-MAG neuropathy. Interestingly, anti-HNK1 titres are related to the disease severity and decrease after rituximab infusions.

Intestinal microfold cells are the primary pathway for translocation of secretory IgA (SIgA)-pathogen complexes to gut-associated lymphoid tissue. Uptake of SIgA/commensals complexes is important for priming adaptive immunity in the mucosa. This study aims to explore the effect of SIgA retrograde transport of immune complexes in Crohn’s disease (CD). Here we report a significant increase of SIgA transport in CD patients with NOD2-mutation compared to CD patients without NOD2 mutation and/or healthy individuals. NOD2 has an effect in the IgA transport through human and mouse M cells by downregulating Dectin-1 and Siglec-5 expression, two receptors involved in retrograde transport. These findings define a mechanism of NOD2-mediated regulation of mucosal responses to intestinal microbiota, which is involved in CD intestinal inflammation and dysbiosis., Trafficking of IgA/commensal complex in the gut has been implicated in inflammatory bowel diseases such as Crohn’s disease, but molecular insights are still lacking. Here the authors show, using mouse model or human cells, that NOD2 mutation increases IgA transport, potentially by altering gut microfold cells from the gut, to impact gut inflammation.

Systemic autoimmune and inflammatory diseases have a complex and only partially known pathophysiology with various abnormalities involving all the components of the immune system. Among these components, antibodies, and especially autoantibodies are key elements contributing to autoimmunity. The interaction of antibody fragment crystallisable (Fc) and several distinct receptors, namely Fc receptors (FcRs), have gained much attention during the recent years, with possible major therapeutic perspectives for the future. The aim of this review is to comprehensively describe the known roles for FcRs (activating and inhibitory FcγRs, neonatal FcR [FcRn], FcαRI, FcεRs, Ro52/tripartite motif containing 21 [Ro52/TRIM21], FcδR, and the novel Fc receptor-like [FcRL] family) in systemic autoimmune and inflammatory disorders, namely rheumatoid arthritis, Sjögren's syndrome, systemic lupus erythematosus, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, Crohn's disease, ulcerative colitis, immunoglobulin (Ig) A vasculitis, Behçet's disease, Kawasaki disease, IgG4-related disease, immune thrombocytopenia, autoimmune hemolytic anemia, antiphospholipid syndrome and heparin-induced thrombocytopenia.

Understanding the immune responses elicited by SARS-CoV-2 infection is critical in terms of protection from re-infection and, thus, for public health policy and for vaccine development against the COVID-19. Here, using either live SARS-CoV-2 particles or retroviruses pseudotyped with the SARS-CoV-2 S viral surface protein (Spike), we studied the neutralizing antibody (nAb) response in serum specimens from a cohort of 140 SARS-CoV-2 qPCR-confirmed patients, including patient with mild symptoms but also more severe form including those that require intensive care. We show that nAb titers were strongly correlated with disease severity and with anti-Spike IgG levels. Indeed, patients from intensive care units exhibited high nAb titers, whereas patients with milder disease symptoms displayed heterogenous nAb titers and asymptomatic or exclusive outpatient care patients had no or poor nAb levels. We found that the nAb activity in SARS-CoV-2-infected patients displayed a relatively rapid decline after recovery, as compared to individuals infected with alternative coronaviruses. We show the absence of cross-neutralization between endemic coronaviruses and SARS-CoV-2, indicating that previous infection by human coronaviruses may not generate protective nAb against SARS-CoV-2 infection. Finally, we found that the D614G mutation in the Spike protein, which has recently been identified as the major variant now found in Europe, does not allow neutralization escape. Altogether, our results contribute to the understanding of the immune correlate of SARS-CoV-2 induced disease and claim for a rapid evaluation of the role of the humoral response in the pathogenesis of SARS-CoV-2.

Human IgA could be from different isotypes (IgA1/IgA2) and/or isoforms (monomeric, dimeric, or secretory). Monomeric IgA mainly IgA1 are considered as an anti-inflammatory isotype whereas dimeric/secretory IgA have clearly dual pro- and anti-inflammatory effects. Here, we show that IgA isotypes and isoforms display different binding abilities to FcαRI, Dectin-1, DC-SIGN, and CD71 on monocyte-derived dendritic cells (moDC). We describe that IgA regulate the expression of their own receptors and trigger modulation of moDC maturation. We also demonstrate that dimeric IgA2 and IgA1 induce different inflammatory responses leading to cytotoxic CD8+ T cells activation. moDC stimulation by dimeric IgA2 was followed by a strong pro-inflammatory effect. Our study highlights differences regarding IgA isotypes and isoforms in the context of DC conditioning. Further investigations are needed on the activation of adaptive immunity by IgA in the context of microbiota/IgA complexes during antibody-mediated immune selection.

BackgroundABP501 is a biosimilar to Reference Adalimumab (HUMIRA®) produced by AMGEN. Adalimumab (ADA) has a marketing authorization for Crohn's disease, ulcerative colitis and other inflammatory or autoimmune diseases. The aim of this study was to evaluate the LISA-TRACKER assays developed by Theradiag (France), for the monitoring of ABP501 and anti-ABP501 antibodies in human serum.Results68 ABP501 clinical samples were measured with the LISA TRACKER Duo Adalimumab assay. LISA TRACKER has been validated as suitable for quantification of ABP501 in human serum samples. Accuracy of the LISA-TRACKER was measured using 3 human serum matrices spiked with known levels of biosimilar, 3 levels spanning the dynamic range. Percentages of recovery were ranged from 90 to 120% for biosimilar batch1, and between 93 and 105% for biosimilar batch2. The acceptance criteria (CV 50% for specificity. Specificity was tested with Biosimilar spiked samples, Biosimilar with Humira® spiked samples, and clinical samples from patients treated with adalimumab biosimilar. All of these samples were spiked with polyclonal antibodies directed against Humira®. Specificity inhibition and specificity detection steps were also part of the validation parameters. Reagents made with ABP501 gave similar results than reagents made with Humira® meeting acceptance criteria.ConclusionsLISA-TRACKER ADA and anti-ADA assays are reliable for the monitoring of patients treated with ABP501.

International audience; Cytomegalovirus (CMV) infects approximately 40% of adults in France and persists lifelong as a latent agent in different organs, including gut. A close relationship is observed between inflammation that favors viral expression and viral replication that exacerbates inflammation. In this context, CMV colitis may impact the prognosis of patients suffering from inflammatory bowel diseases (IBDs), and notably those with ulcerative colitis (UC). In UC, the mucosal inflammation and T helper cell (TH) 2 cytokines, together with immunomodulatory drugs used for controlling flare-ups, favor viral reactivation within the gut, which, in turn, increases mucosal inflammation, impairs corticoid and immunosuppressor efficacy (the probability of steroid resistance is multiplied by more than 20 in the case of CMV colitis), and enhances the risk for colectomy. This review emphasizes the virological tools that are recommended for exploring CMV colitis during inflammatory bowel diseases (IBD) and underlines the interest of using ganciclovir for treating flare-ups associated to CMV colitis in UC patients.

International audience; Autoimmune diseases are mostly characterized by autoantibodies in the patients' serum or cerebrospinal fluid, representing diagnostic or prognostic biomarkers. For decades, research has focused on single autoantigens or panels of single autoantigens. In this article, we advocate to broaden the focus by addressing the entire autoantigen repertoire in a systemic "omics-like" way. This approach aims to capture the enormous biodiversity in the sets of targeted antigens and pave the way toward a more holistic understanding of the concerted character of antibody-related humoral immune responses. Ongoing technological progress permits high-throughput screenings of thousands of autoantigens in parallel, e.g., via protein microarrays, phage display, or immunoprecipitation with mass spectrometry. We argue that the time is right for combining omics and autoantibody screening approaches into "autoantigenomics" as a novel omics subcategory. In this article, we introduce the concept of autoantigenomics, describe its roots and application options, and demarcate the method from related holistic approaches such as systems serology or immune-related transcriptomics and proteomics. We suggest the following extendable method set to be applied to autoantigen repertoires: (1) principal component analysis, (2) hierarchical cluster analysis, (3) partial least-square discriminant analysis or orthogonal projections to latent structures discriminant analysis, (4) analysis of the repertoire sizes in disease groups and clinical subgroups, (5) overrepresentation analyses using databases like those of Gene Ontology, Reactome Pathway, or DisGeNET, (6) analysis of pathways that are significantly targeted by specific repertoires, and (7) machine learning approaches. In an unsupervised way, these methods can identify clusters of autoantigens sharing certain functional or spatial properties, or clusters of patients comprising clinical subgroups potentially useful for patient stratification. In a supervised way, these methods can lead to prediction models that may eventually assist diagnosis and prognosis. The untargeted autoantigenomics approach allows for the systematic survey of antibody-related humoral immune responses. This may enhance our understanding of autoimmune diseases in a more comprehensive way compared to current single or panel autoantibodies approaches.

Inflammatory bowel disease (IBD) is caused by a dysregulation of the immune system, inducing the production of proinflammatory cytokines and adhesion molecules. A better understanding of the mucosal immune response in IBD has led to the development of new drugs directed at inflammatory cytokines and leukocyte-trafficking molecules. Beyond tumor necrosis factor antagonists and anti-integrin molecules, which act by blocking the interaction between gut-specific lymphocytes and their receptor on vascular endothelium, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway represents a new target in IBD. JAK inhibitors are small molecules able to selectively target the activity of specific JAKs that play a role in signal transmission via interleukins. This review presents an overview of the role of the JAK/STAT signaling pathway and updated information for JAK molecules, which are promising drugs in IBD. Currently developed to treat ulcerative colitis and Crohn's disease, tofacitinib (in a phase III study) and filgotinib (in a phase II study), respectively, are the JAK inhibitors in the most advanced stage of development for IBD. However, the utility of, and adverse events associated with, these new drugs remain to be determined and clarified (in particular, the risk of herpes zoster infections), depending on the efficacy and tolerance determined from definitive studies. The availability of these drugs could enhance the therapeutic approach to IBD in the coming years, and reinforce the concept of personalized medicine for IBD patients.

The homing of lymphocytes to the mucosa is mainly controlled by α4β7 integrin, and it is amplified during gut chronic inflammation, as occurs with HIV and/or inflammatory bowel diseases. We designed and applied an improved immunization strategy based on an innovative selection process to isolate new α4β7 lymphocyte-specific monoclonal antibodies that are able to prevent their migration into inflamed gut tissues and/or to counteract HIV infection in vitro. First, 5 monoclonal antibodies (1 IgA, 1 IgM, and 4 IgGs) were selected based on their capacity to recognize α4 or β7 homodimers and α4β7 heterodimers in transfected human cells. Their ability to block gp120/α4β7 or MAdCAM-1/α4β7 interactions was then measured in vitro with human T and B lymphocytes. In vitro, the anti-α4β7 IgA isotype was found to have the highest affinity for the α4β7 heterodimer, and it significantly reduced HIV replication in retinoic acid-treated α4β7 CD4 human T cells. This α4β7-specific IgA also displayed a high avidity for human and mouse α4β7 lymphocytes in both mouse and human inflammatory colitis tissues. These new antibodies, and in particular those with mucosa-targeting isotypes such as IgA, could therefore be potential novel therapeutic tools for treating HIV and inflammatory bowel disease.

Introduction: Tumor necrosis factor antagonists have revolutionized the therapeutic management of inflammatory bowel disease. Infliximab and adalimumab were the first biological agents used to induce and maintain remission in ulcerative colitis. More recently, a third tumor necrosis factor antagonist, golimumab, was approved, extending the therapeutic approach for moderate-to-severe ulcerative colitis. Areas covered: In this review, the authors review the literature on the efficacy and safety of golimumab in the context of other anti-TNF agents used in the treatment of this disease. The role of therapeutic drug monitoring in the case of loss of response to an anti-TNF agent is also discussed. Expert opinion: Golimumab is currently effective to induce and maintain remission in patients with ulcerative colitis, especially those patients who are naive for an anti-TNF agent. No large studies have evaluated the efficacy of golimumab after failure of a first-line TNF antagonist therapy. In the case of loss of response to a first anti-TNF agent, therapeutic drug monitoring is essential to determine the most suitable therapeutic option.

ObjectivesAssociation between periodontal disease (PD) and rheumatoid arthritis (RA) has been extensively described, but direct evidence of causal involvement of PD in RA is missing. We investigated the priming role of oralPorphyromonas gingivalis(P. gingivalis) in PD and subsequent RA and we assessed biomarkers of bone resorption and arthritis development in rats.MethodsLewis rats were orally exposed to eitherP. gingivalis,Prevotella intermediaor control gel for 1 month and then followed for 8 months. The onset and development of PD was assessed by serology, gingivitis severity and micro-CT (µCT). We investigated arthritis development using circulating proinflammatory markers, anticyclic citrullinated peptide (CCP), anticitrullinated protein antibody (ACPA), ankle histology and µCT.ResultsPD was only observed in theP. gingivalistreated rats, as early as 1 month postexposure. Joint and systemic inflammation were detected only in theP. gingivalisgroup after 4 and 8 months. At 8 months, inflammatory cell infiltrate was observed in ankle joints and paralleled cortical erosions and overall cortical bone reduction. Furthermore, anti-CCP2 correlated with local and systemic bone loss.ConclusionsIn our long-term study, PD induced by oral exposure toP. gingivalistriggered seropositive arthritis, with systemic inflammation and bone erosions. This is the first in vivo demonstration of arthritis induced by oral priming withP. gingivalis.

Secretory IgMs (SIgMs) were amongst the first identified immunoglobulins. However, their importance was not fully understood and recent advances have shown they play a key role in establishing and promoting commensal gut tolerance in mice and humans. The true interactions between SIgMs and the microbiota remain controversial and we aim to consolidate current knowledge in this review. Through comprehensive examination of SIgMs and their corresponding B cell secretors in several different pathological immunological contexts, we review the presumed role of these molecules in gut tolerance, inflammatory bowel diseases, and lung immunity. As SIgMs harbor a mostly tolerogenic function, we posit that their inclusion in further immunological research is paramount.

Mental health is becoming a public health priority worldwide. Anorexia nervosa and autism spectrum disorders are 2 important types of childhood disorders with a bad prognosis. They share cognitive impairments and, in both cases, the microbiota appears to be a crucial factor. Alteration of the microbiota-gut-brain axis is an appealing hypothesis to define new pathophysiological mechanisms. Mucosal immunity plays a key role between the microbiota and the brain. The mucosal immune system receives and integrates messages from the intestinal microenvironment and the microbiota and then transmits the information to the nervous system. Abnormalities in this sensorial system may be involved in the natural history of mental diseases and might play a role in their maintenance. This review aims to highlight data about the relationship between intestinal mucosal immunity and these disorders. We show that shared cognitive impairments could be found in these 2 disorders, which both present dysbiosis. This literature review provides details on the immune status of anorexic and autistic patients, with a focus on intestinal mucosal factors. Finally, we suggest future research hypotheses that seem important for understanding the implication of the gut-brain-axis in psychiatric diseases.

International audience; BACKGROUND:Early steps of HIV infection are mediated by the binding of the envelope to mucosal receptors as α4β7 and the C-type lectins DC-SIGN and langerin. Previously Env-specific B-cell responses have been reported in highly exposed seronegative individuals (HESN).METHOD:Here, we studied gp120-specific antibodies ability to block HIV interaction with α4β7, DC-SIGN and/or langerinin HESN. New cell-based assays were developed to analyze whether antibodies that can alter gp120 binding to α4β7, DC-SIGN and/or langerin are induced in HESN. A mucosal blocking score (MBS) was defined based on the ability of antibodies to interfere with gp120/α4β7, gp120/DC-SIGN, and gp120/langerin binding. A new MBS was evaluated in a cohort of 86 HESN individuals and compared with HIV+ patients or HIV- unexposed healthy individuals.RESULTS:Antibodies reducing gp120 binding to both α4β7 and DC-SIGN were present in HESN serum but also in mucosal secretions, whereas antibodies from HIV+ patients facilitated gp120 binding to DC-SIGN. Any correlation was observed between MBS and the capacity of antibodies to neutralize infection of α4β7 CD4+ T cells with primary isolates.CONCLUSIONS:MBS is significantly associated with protection in HESN and might reflect altered HIV spreading to mucosal-associated lymphoid tissues.

Background:Idiopathic juvenile arthritis (JIA) is a heterogeneous group of pathologies whose origin remains unknown at present (1). They are characterised by a systemic inflammatory and joint disease affecting children under 16 years of age. The current classification groups the different forms of JIA into 7 distinct entities (systemic forms, polyarticular forms with or without rheumatoid factors, oligoarticular forms, inflammatory arthritis associated with enthesopathies (ERA), arthritis associated with psoriasis and unclassifiable arthritis). Exact etiology of JIA is still unknown. To date, the various hypotheses put forward on the occurrence of JIAs integrate the genetic and environmental framework.The link between periodontal disease and rheumatoid arthritis (RA) is largely reported. Recently, Porphyromonas gingivalis (P. gingivalis) infection explained the occurrence of arthritis in rodent and in RA (2). Several studies mention the beneficial effect of P. gingivalis treatment on disease activity.Currently, there are very few studies on the prevalence of P. gingivalis in patients with JIA and the possible involvement of the germ in the development of inflammatory joint diseases in the pediatric population(3)(4).Objectives:The objective of our study is to determine presence of high IgG antibodies against P. gingivalis and Prevotella Intermedia in a cohort of patients with JIA compared to a control population and to determine variation of level according to sub-classes of JIA.Methods:Sera were obtained from 101 patients satisfying the ILAR classification criteria for JIA and in 25 patients with two other dysimmune disorders (type 1 diabetes and juvenile inflammatory bowel disease). Level of IgG antibodies against P. gingivalis and Prevotella Intermedia were obtained by homemade ELISA already used previously (5).Results:In the JIA group, major children were oligarthritis (47.5%), polyarthritis represents 31.7% of JIAs, ERA and systemic forms of JIA are respectively 9 and 11%. For the control group, 10 (40%) children had diabetes and 15 (60%) had IBD.Levels of anti-P. gingivalis anti-Prevotella Intermedia antibodies were higher in AJI group compared at control groups (PP. gingivalis and Prevotella Intermedia.Figure 1.Relative titer of antibodies to P. gingivalis and anti Prevotella intermedia. *: PConclusion:We confirmed high level of anti-P. gingivalis and anti-Prevotella intermedia antibodies in JIA compared to other inflammatory disorders. For the first time, we observed that this high level was mainly in oligoarthritis and ERA. Further investigations are required to investigate involvement of oral dysbiosis in AJI pathogenesis. As observed in RA, it could be a new way to integrate in JIA therapy management.References:[1]Thatayatikom A, De Leucio A. Juvenile Idiopathic Arthritis (JIA). StatPearls Publishing; 2020[2]Cheng Z, Meade J, Mankia K, Emery P, Devine DA. Periodontal disease and periodontal bacteria as triggers for rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2017;31(1):19–30.[3]Romero-Sánchez C, Malagón C, Vargas C, Fernanda Torres M, Moreno LC, Rodríguez C, et al. Porphyromonas Gingivalis and IgG1 and IgG2 Subclass Antibodies in Patients with Juvenile Idiopathic Arthritis. J Dent Child Chic Ill. 2017 May 15;84(2):72–9.[4]Lange L, Thiele GM, McCracken C, Wang G, Ponder LA, Angeles-Han ST, et al. Symptoms of periodontitis and antibody responses to Porphyromonas gingivalis in juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2016 Feb 9[5]Rinaudo-Gaujous M, Blasco-Baque V, Miossec P, Gaudin P, Farge P, Roblin X, et al. Infliximab Induced a Dissociated Response of Severe Periodontal Biomarkers in Rheumatoid Arthritis Patients. J Clin Med. 2019 May 26;8(5).Disclosure of Interests:None declared.

Background:Porphyromonas gingivalis (PG) and Prevotella Intermedia (PI) are two oral pathogens involved in the pathophysiology of chronic periodontopathies. Several studies have determined a role of these periodontal pathologies in the pathophysiology of rheumatoid arthritis (1) while the link with spondyloarthritis is not clearly established with currently contradictory studies (2,3,4).Objectives:The purpose of this work is to investigate a link between spondylarthritis and the presence of chronic periodontopathy evaluated by PG and IP serologies.Methods:The positivity and quantity of anti-PG and anti-PI antibodies were determined by ELISA method in patients from the DESIR cohort with one of the spondyloarthritis phenotypes compared to patients with common low back pain (n=50) (population control). Patients with spondyloarthritis were classified according to the following phenotypes (diagnosis chosen at 3 years in the DESIR cohort): axial spondylarthritis (n=126), psoriatic rheumatism (n=101), spondyloarthritis associated with chronic inflammatory bowel disease (n=36), undifferentiated spondylitis (n=241), reactive arthritis (n=2), SAPHO (acronym for Synovite, Acne, Pustulose, Hyperostosis and Osteitis. Correlations between patients’ serological status, and smoking status, body mass index and age were sought.Results:According to the general characteristics, the control group was significantly older than the axial spondylarthritis (pConclusion:Our results therefore suggest the absence of a link between periodontal germs involved in chronic periodontopathies and spondyloarthritis, provided that the two phenotypes involving germs in their pathophysiology could not be analyzed. Our results from a population of beginner spondylitis are therefore not in favour of the involvement of oral flora in the pathophysiology of spondyloarthritis, as is the case in rheumatoid arthritis (1). The associations found previously could therefore be favoured by a systemic inflammatory phenomenon. In conclusion, our study suggests no link between chronic periodontopathy and the occurrence of spondyloarthritis. However, the effect of chronic periodontopathy on the evolution of spondylarthritis remains to be explored.References:[1]Detert J, Pischon N, Burmester GR, Buttgereit F. The association between rheumatoid arthritis and periodontal disease. Arthritis Res Ther. 2010;12(5):218.[2]Ratz T, Dean LE, Atzeni F, Reeks C, Macfarlane GJ, Macfarlane TV. A possible link between ankylosing spondylitis and periodontitis: a systematic review and meta-analysis. Rheumatology. 2015;54(3):500-10.[3]Pischon N, Pischon T, Gülmez E, Kröger J, Purucker P, Kleber B-M, et al. Periodontal disease in patients with ankylosing spondylitis. Ann Rheum Dis. janv 2010;69(01):34-8.[4]Sezer U, Erciyas K, Pehlivan Y, Üstün K, Tarakçioğlu M, Şenyurt SZ, et al. Serum cytokine levels and periodontal parameters in ankylosing spondylitis: Ankylosing spondylitis and periodontal diseases. J Periodontal Res. juin 2012;47(3):396-401.Disclosure of Interests:None declared

SummaryBackground Anti-adalimumab antibodies (AAA) are associated with loss of clinical response (LOR). Addition of an immunomodulator has been shown to reverse immunogenicity and regain response with infliximab monotherapy. Similar data on adalimumab are lacking. Aim To study the impact of immunomodulator addition on the emergence of AAA and LOR among adalimumab therapy patients. Methods The databases of three tertiary medical centres were reviewed to identify patients who developed AAA during adalimumab monotherapy with resultant LOR, and received an immunomodulator as a salvage combination therapy. All sera were prospectively analysed using previously described ELISA assays. Clinical response was determined using appropriate clinical scores. Elimination of AAA, designated as ‘sero-reversal’, elevation of drug levels and regained clinical response were the sought outcomes. Results Twenty-three patients (21 Crohn's disease, and 2 ulcerative colitis) developed AAA with subsequent LOR and were thereafter prescribed an immunomodulator as salvage therapy (thiopurine n = 14, methotrexate n = 9). Eleven patients (48%) underwent sero-reversal with gradual elimination of AAA, increase in drug trough levels and restoration of clinical response (median time to sero-reversal 5 months). In 12 patients (52%), immunogenicity and loss of response could not be reversed. There was no difference between responders and nonresponders in the type of immunomodulators used or baseline clinical characteristics. Conclusions In almost half of inflammatory bowel disease patients developing anti-adalimumab antibodies and loss of response, established immunogenicity of adalimumab can be gradually reversed by the addition of immunomodulator therapy with restoration of a clinico-biological response. However, these observations need to be confirmed with larger studies.

Background Indirect immunofluorescence plays a major role in the detection of antinuclear antibodies (ANAs) and follow-up of their titers in the context of connective tissue diseases. Given the numerous unfavorable features of the conventional manual reading of HEP2 slides (need of time and expert morphologists for the reading, lack of standardization, subjectivity of the interpretation), the biomedical industry has developed automated techniques of slide preparation and microscope reading. Methods We collected 49 sera beforehand analyzed by the conventional reading of slides. They were prepared again by QUANTA-Lyser® and reanalyzed in four different conditions: two dilutions of screening (1/40 and 1/80), two different systems of analysis, NOVA View® automated reading (INOVA Diagnostics), then confirmation by the operator, and conventional manual reading by two different qualified operators. The analysis was realized in blind of the first interpretation and clinical diagnosis. The sera were classified in four groups, on the basis of the results of the first analysis: negative sera (titer < 1/160; 11 patients), low positives (titer at 1/160; 18 patients), moderated positives (titers between 1/320 and 1/640; 10 patients), and strong positives (titers between 1/1,280 and 1/2,560; 10 patients). Results Among the 49 patients, 13 presented a connective tissue disease including 4 systemic scleroderma (SS), 3 rheumatoid arthritis (RA), 2 Goujerot-Sjogren (GS), 2 systemic lupus erythematosus (SLE), 1 polymyositis (PM), 1 Raynaud's syndrome (RS), and 1 CREST syndrome. One patient presented both an SLE and an SS. Regarding the screening dilution, the 1/40 dilution is less specific than the 1/80 dilution for both the systems of analysis (5.6% vs. 16.7% for the manual reading, and 27.8% vs. 50% for the automated reading). It also generates statistically more false positives (P = 0.037 for the conventional analysis and P = 0.003 for the automated system). The automated NOVA View® reading of slides allows a gain in specificity for both dilutions, and also statistically less false positives (P = 0.002 at the 1/40 and P = 0.0006 at the 1/80), and detriment of the sensitivity at the highest dilution (84.6% vs. 92.3% with manual reading). Thus, according to our analysis of 49 sera, the automated NOVA View® system of reading of slides at the dilution 1/80 seems to be a successful condition for the detection of ANAs on HEP2 cells, close to the significance (P = 0.067). Conclusion The automated NOVA View® reading of slides allows saving time, and an improvement in the standardization. Nevertheless, it requires a confirmation by a qualified operator, to interpret mixed patterns in particular.

The association of small cell lung cancer with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is rare. We report a 62 year old patient who developed psychiatric disorders followed by epilepsy, movement disorders, mutism and hypoventilation. Flair weighted brain MRI sequences showed diffuse high signals in the limbic system. Anti-NMDAR antibodies were detected in the serum and CSF. The patient's IgGs reacted with the patient's own tumor cells and with 2 out of 4 small cell lung cancers of patients without neurological syndrome.

Patients with Down syndrome are more susceptible to autoimmune pathologies, in particular endocrine or digestive diseases such as celiac disease. Autoimmune enteropathy is another form of digestive autoimmune disease, non-gluten-dependant, more often diagnosed in male neonates with immunodysregulation and polyendocrinopathy such as the Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome. It also exists in the adult, but this pathology is less known and therefore frequently under-diagnosed. Clinical manifestations are similar to celiac disease, but not improved after a gluten-free diet. Autoimmune enteropathy is frequently associated with other autoimmune diseases, such as thyroiditis, myasthenia gravis, lupus or immune deficiencies, as Common Variable Immunodeficiency. Pathological analysis of intestinal biopsies can frequently distinguish autoimmune enteropathy and celiac disease. Autoimmune enteropathy usually has an important lymphoplasmacytic infiltration of the mucosa and a lack of intraepithelial lymphocytes in the gastrointestinal mucosal surface, while celiac disease usually has a polymorph infiltration of the mucosa and an important intraepithelial lymphocytes infiltration. Nevertheless, the two pathological patterns may overlap. Here we report the first case of a patient with Down syndrome associated to autoimmune enteropathy (initially diagnosed as celiac disease), chronic pancreatitis and cutaneous lupus erythematosus. Even if autoimmune pathologies are much more common in patients with Down syndrome, we would like to report on this rare and original association found in our patient.

The gut associated lymphoid tissue (GALT) is the site of numerous immunological disturbances during HIV-1 infection. It constitutes the largest reservoir for HIV, not or very poorly susceptible to antiretroviral therapy (ART), making it a major obstacle to HIV cure. Moreover, the GALT is involved in systemic immune activation in HIV-infected individuals: intestinal damage due to viral replication and severe CD4(+) T cell depletion in the GALT leads to microbial translocation, a key driver of immune activation, and in turn, disease progression. In this review, we describe the role of the GALT in HIV infection and we discuss therapeutic options to decrease the intestinal viral reservoir and to preserve immune function in the gut of HIV-infected people. Achieving these goals is necessary for a long-term infection control after the interruption of ART.

Cytotoxic CD8+ T-cells are key players of the immune responses against viruses. During the priming of a CD8+ T-cell response, the activation of a naïve T-cell by a professional antigen presenting cell (APC) involves the induction of various intracellular and metabolic pathways. The modulation of these pathways at the level of APCs or T-cells offers great potential to enhance the induction of robust effector cells and the generation of long-lived memory cells. On the one hand, signaling through pathogen recognition receptors (PRRs) expressed by APCs can greatly influence T-cell priming, and the potential of several PRR ligands as adjuvants are being studied. On the other hand, the engagement of several metabolic processes, at play in APCs and T-cells upon stimulation, implies that modulating cellular metabolism can impact on priming efficacy. Here, we review recent efforts to understand the interplay between PRR mediated signaling and metabolic pathway modulation in this context, through three examples: interplay between TLR4 and fatty acid metabolism, between TLR9 and IDO, and between STING and autophagy. These initial works highlight the potential for harnessing the induction of antiviral CD8+ T-cell responses using synergistic modulation of metabolic and PRR pathways.

International audience; Traditionally, IBD diagnosis is based on clinical, radiological, endoscopic, and histological criteria. Biomarkers are needed in cases of uncertain diagnosis, or to predict disease course and therapeutic response. No guideline recommends the detection of antibodies (including ASCA and ANCA) for diagnosis or prognosis of IBD to date. However, many recent data suggest the potential role of new serological markers (anti-glycan (ACCA, ALCA, AMCA, anti-L and anti-C), anti-GP2 and anti-GM-CSF Ab). This review focuses on clinical utility of these new serological markers in diagnosis, prognosis and therapeutic monitoring of IBD. Literature review of anti-glycan, anti-GP2 and anti-GM-CSF Ab and their impact on diagnosis, prognosis and prediction of therapeutic response was performed in PubMed/MEDLINE up to June 2014. Anti-glycan, anti-GP2 and anti-GM-CSF Ab are especially associated with CD and seem to be correlated with complicated disease phenotypes even if results differ between studies. Although anti-glycan Ab and anti-GP2 Ab have low sensitivity in diagnosis of IBD, they could identify a small number of CD patients not detected by other tests such as ASCA. Anti-glycan Abs are associated with a progression to a more severe disease course and a higher risk for IBD-related surgery. Anti-GP2 Ab could particularly contribute to better stratify cases of pouchitis. Anti-GM-CSF Ab seems to be correlated with disease activity and could help predict relapses. These new promising biomarkers could particularly be useful in stratification of patients according to disease phenotype and risk of complications. They could be a valuable aid in prediction of disease course and therapeutic response but more prospective studies are needed.

HIV transmission and spread in the host are based on the survival of the virus or infected cells present in mucosal secretions, and the virus' ability to cross the epithelial barrier and access immune target cells, which leads to systemic infection. Therefore, HIV-specific immunity at mucosal sites is critical for control of infection. Although mucosal delivery would ensure the best onset of protective immunity, most candidate vaccines are administered through the parenteral route. Remarkably, secretory IgA (SIgA) interacts specifically with mucosal microfold (M) cells present in gut-associated lymphoid tissues. Here we evaluate the feasibility of delivering chemically bound p24HIV antigen via SIgA into the intestinal mucosae in mice. After oral administration, p24-SIgA complexes are quickly delivered into the tissue and selectively captured by CX3CR1(+) dendritic cells. Oral immunization with p24gag linked to SIgA (p24-SIgA) adjuvanted with E. coli heat labile enterotoxin (HLT) elicits both humoral and cellular immune responses against p24 at the systemic and mucosal levels and induces efficient protection against rectal challenge with a recombinant vaccinia virus encoding gag. This is the first study which underscores the remarkable potential of SIgA to serve as a vaccine carrier for an HIV antigen in mucosal administration targeting the gastrointestinal environment.

TLR ligands are critical activators of innate immunity and are being developed as vaccine adjuvants. However, their usefulness in conjunction with NOD-like receptor agonists remains poorly studied. In this study, we evaluated a new ligand that targets both TLR2 and NOD2 receptors. We assessed its ability to enhance dendritic cell maturation in vitro in addition to improving systemic and mucosal immune responses in mice. The chimeric NOD2/TLR2 ligand induced synergistic upregulation of dendritic cell maturation markers, costimulatory molecules, and secretion of proinflammatory cytokines compared with combinations of separate ligands. Furthermore, when coadministered with biodegradable nanoparticles carrying a model Ag, the ligand was able to induce high Ag-specific IgA and IgG titers at both systemic and mucosal sites after parenteral immunizations. These findings point out the potential utility of chimeric molecules TLR/NOD as adjuvants for vaccines to induce systemic and mucosal immune responses.

SUMMARY Salmonella enterica subspecies enterica includes several serovars infecting both humans and other animals and leading to typhoid fever or gastroenteritis. The high prevalence of associated morbidity and mortality, together with an increased emergence of multidrug-resistant strains, is a current global health issue that has prompted the development of vaccination strategies that confer protection against most serovars. Currently available systemic vaccine approaches have major limitations, including a reduced effectiveness in young children and a lack of cross-protection among different strains. Having studied host-pathogen interactions, microbiologists and immunologists argue in favor of topical gastrointestinal administration for improvement in vaccine efficacy. Here, recent advances in this field are summarized, including mechanisms of bacterial uptake at the intestinal epithelium, the assessment of protective host immunity, and improved animal models that closely mimic infection in humans. The pros and cons of existing vaccines are presented, along with recent progress made with novel formulations. Finally, new candidate antigens and their relevance in the refined design of anti- Salmonella vaccines are discussed, along with antigen vectorization strategies such as nanoparticles or secretory immunoglobulins, with a focus on potentiating mucosal vaccine efficacy.

International audience; BACKGROUND: Immunosuppressed patients are at risk of severe viral infections-related complications. National and international vaccination guidelines have been developed to decrease the mortality risk associated with these infections. However, a summary of these guidelines and the value of immunisation in this population is missing. OBJECTIVES: To summarize specific guidelines regarding vaccination in immunosuppressed patients. METHODS: We performed a literature search based on last update vaccine guidelines in immunosuppressed adult patients published between 1/1/2005-1/31/2016 in English or French language using PubMed, Cochrane and Embase, as well as relevant medical society websites. RESULTS: Of the 389 citations identified, 12 guidelines were selected Three additional guidelines were selected by searching on the websites from medical societies of each specialty. 15 guidelines were included, involving 19 medical societies issued from the US (n~=~6), international collaboration (n~=~3), UK (n~=~2), Canada (n~=~1), Australia (n~=~1), France (n~=~1), and Germany (n~=~1). These guidelines provide recommendations on vaccination in asplenic patients (n~=~5), cancer patients (n~=~4), HIV patients (n~=~5), hematopoietic stem cell recipients (n~=~4), inflammatory bowel diseases patients (n~=~5), psoriasis patients (n~=~4), primary immunocompromised patients (n~=~3), inflammatory rheumatic diseases patients (n~=~6), and solid organ transplant recipients (n~=~5). All guidelines recommended pneumococcal and injectable influenza vaccines. Other inactivated vaccines were recommended only in high risk patients. Live vaccines were usually contraindicated in patients under immunosuppressive therapy and/or in HIV patients with a CD4 count under 200/mm3. CONCLUSION: Pneumococcal and injectable influenza are the two essential vaccines recommended in all immunocompromised patients. Other inactivated vaccines are only indicated in high risk patients. Live vaccines are usually contraindicated.

Anti-p17 antibodies are able to neutralize human immunodeficiency virus (HIV) entry in a mouse model. In this study, we identified a region of sequence similarity between the epitopes of anti-p17 neutralizing antibodies and anti-gp41 neutralizing 2F5 antibody and verified cross-reactivity between p17 and 2F5 in vitro. The p17 sequence was modified to increase sequence identity between the p17 and 2F5 epitopes, which resulted in enhanced cross-reactivity in vitro. Immunogenicity of wild-type and modified p17 was characterized in a rabbit model. Both wild-type and mutated p17 induced anti-gp41 responses in rabbits; sera from these animals reacted with gp41 from different HIV clades. Moreover, introduction of the 2F5 sequence in p17 resulted in induction of antibodies with partially neutralizing activity. Based upon these data, we suggest that the natural cross-reactivity between HIV-1 p17 protein and 2F5 antibody can be exploited to induce antibodies with neutralizing activity in an animal model.

Most new HIV infections occur via sexual routes. The induction of protective anti-HIV antibodies in genital mucosa is an important step toward reducing HIV transmission. Mucosal anti-HIV antibodies may play a dual role by either protecting against HIV transmission or facilitating it. Protective properties against HIV of mucosal IgGs and IgAs exhibiting neutralizing or antibody-dependent cell-mediated cytotoxicity activities have been described in highly exposed seronegative individuals. Conversely, some IgGs may facilitate the crossing of HIV free-particles through epithelial barriers by transcytosis. Hence knowledge of the mechanisms underlying anti-HIV antibody production in the genital tract and their exact role in sexual transmission may help to develop appropriate preventive strategies based on passive immunization or mucosal vaccination approaches. Our review focuses on the characteristics of the humoral immune responses against HIV in the male genital tract and related prevention strategies.

Objectives. To evaluate methotrexate effect on tumor necrosis factor (TNF) alpha bioactivity during infliximab (IFX) therapy in rheumatoid arthritis (RA) patients and to correlate TNF bioactivity with antibody towards IFX (ATI) development and RA clinical response. Materials and Methods. Thirty-nine active women RA patients despite conventional synthetic disease modifying antirheumatic drugs (csDMARDs) requiring IFX therapy were enrolled, and clinical data and blood samples were recorded at baseline (W0) and at 6 weeks (W6), W22, and W54 of IFX treatment. TNF bioactivity as well as IFX trough and ATI concentrations were assessed on blood samples. Results. TNF bioactivity decreased from W0 to W54 with a large range from W22 at the time of ATI detection. From W22, TNF bioactivity was lower in presence of methotrexate as csDMARD compared to other csDMARDs. IFX trough concentration increased from W0 to W54 with a large range from W22, similarly to TNF bioactivity. Methotrexate therapy prevented ATI presence at W22 and reduced TNF bioactivity compared to other csDMARDs (p=0.002). Conclusion. This suggests that methotrexate plays a key role in TNF bioactivity and against ATI development.

TLR agonists are currently being developed and tested as adjuvants in various formulations to optimize the immunogenicity and efficacy of vaccines. The aim of this study was to evaluate the immunostimulatory properties of a novel compound incorporating covalently linked moieties designed to stimulate both TLR2 and TLR7. This dual TLR2/TLR7 agonist induced the maturation of dendritic cells and primed substantial populations of cytolytic and highly polyfunctional effector CD8+ T cells in vitro, and safely potentiated the immunogenic properties of a nanoparticulate Ag in vivo, eliciting humoral responses with a balanced TH1/TH2 profile in mice. Collectively, these data reveal the potential utility of chimeric adjuvants with synergistic activities mediated via TLRs.

To the Editor: We read with great interest the editorial by Mavragani and Moutsopoulos1, questioning the historical classification of Sjogren syndrome (SS) as primary or secondary. Few authors2 have published papers in line with these criticisms, but this editorial was of particular interest to us, because Dr. Moutsopoulos and his team were the ones who coined the concept of secondary SS more than 35 years ago. The authors remind us that it was specifically coined for patients with SS in a rheumatoid arthritis (RA) background, because of the clinical, serological, and genetic differences they observed between SS and SS/RA patients1. The same kind of observations were made only in patients with primary biliary cirrhosis presenting with sicca syndrome1; however, the concept of secondary SS has been improperly expanded to include the other systemic autoimmune diseases, especially systemic lupus erythematosus (SLE). We think that this expansion occurred because SS, especially secondary SS, is … Address correspondence to M. Killian, Groupe Immunite des Muqueuses et Agents Pathogenes, Faculte de Medecine Jacques Lisfranc, Pole Sante Innovations, 10 rue de la Marandiere, 42270 Saint-Priest-en-Jarez, France. E-mail: martin.killian{at}chu-st-etienne.fr

We appreciate the comments by Hillion et al 1 on our original paper.2 The data presented are very interesting and suggest that P. gingivalis serology positive was not associated to early rheumatoid arthritis (RA) severity in the ESPOIR cohort. They …

We read with interest the paper by l’Ami et al 1 reporting the safety of a single step-down strategy without flare-up of disease in rheumatoid arthritis (RA) patients treated with adalimumab associated with high trough concentrations. At the time of personalised medicine, prediction of the absence of relapse during tapering strategy is a huge challenge to improve this approach. Furthermore, EULAR recommendations proposed in RA patients in remission without glucocorticoids to first step down the bDMARDs.2 So, we investigated the interest of TNF blocker blood concentration assessment in order to predict the absence of relapse during tapering in the STRASS study.3 The STRASS study demonstrated the feasibility of step-down therapeutic strategy compared with maintenance strategy in RA patients in clinical remission treated with adalimumab or etanercept. In contrast to l’Ami study, which performed a single tapering, successive tapering step every 3 months in RA patient …

Staphylococcal disease represents a universal burden including acute, life-threatening infections as well as chronic infections usually associated with foreign materials. Infections occur notably in permanent carriers of Staphylococcus aureus. To date, all the attempts to develop an efficacious vaccine against S. aureus have failed. Failures in vaccine clinical trials might be related to a focus on single targets and development of humoral-based vaccines rather than vaccines with a combination of antigens stimulating both humoral and cellular immunity. The end points of these unsuccessful trials were a reduction in mortality or bacteremia, whereas the patient's decolonization was not assessed. Adopting the latter point of view, the aim of this article is to discuss nasal mucosal decolonization as a complementary marker of vaccine efficacy for clinical research in vaccine development.