Targeting the chemokine receptor CXCR4 with histamine analog to reduce inflammation in juvenile arthritis

IntroductionAmong immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies, particularly in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. The uncontrolled activation of monocytes and excessive production of inflammatory factors contribute to the damage of bone-cartilage joints. Despite the moderate beneficial effect of current therapies and clinical trials, there is still a need for alternative strategies targeting monocytes to treat RA.MethodsTo explore such an alternative strategy, we investigated the effects of targeting the CXCR4 receptor using the histamine analog clobenpropit (CB). Monocytes were isolated from the blood and synovial fluids of JIA patients to assess CB's impact on their production of key inflammatory cytokines. Additionally, we administered daily intraperitoneal CB treatment to arthritic mice to evaluate its effects on circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, as indicators of disease progression.ResultsOur findings demonstrated that CXCR4 targeting with CB significantly inhibited the spontaneous and induced-production of key inflammatory cytokines by monocytes isolated from JIA patients. Furthermore, CB treatment in a mouse model of collagen-induce arthritis resulted in a significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, leading to a reduction in disease progression.DiscussionIn conclusion, targeting CXCR4 with the small amino compound CB shows promise as a therapeutic option for chronic and viral-induced inflammatory diseases, including RA. CB effectively regulated inflammatory cytokine production of monocytes, presenting a potential targeted approach with potential advantages over current therapies. These results warrant further research and clinical trials to explore the full therapeutic potential of targeting CXCR4 with CB-like molecules in the management of various inflammatory diseases

History and Outcome of Febrile Neutropenia Outside the Oncology Setting: A Retrospective Study of 76 Cases Related to Non-Chemotherapy Drugs

International audienceBACKGROUND: Despite major advances in its prevention and treatment, febrile neutropenia remains a most concerning complication of cancer chemotherapy. Outside the oncology setting, however, only few data are currently available on febrile neutropenia related to non-chemotherapy drugs. We report here data on 76 patients with febrile neutropenia related to non-chemotherapy drugs, followed up in a referral center within a university hospital. PATIENTS AND METHODS: Data from 76 patients with idiosyncratic drug-induced febrile neutropenia were retrospectively reviewed. All cases were extracted from a cohort study on agranulocytosis conducted at the Strasbourg University Hospital (Strasbourg, France). RESULTS: Mean patient age was 52.2 years old (range: 18-93) and gender ratio (F/M) 1.6, with several comorbidities present in 86.8% of patients. The most common causative drugs were: antibiotics (37.4%), antithyroid drugs (17.2%), neuroleptic and anti-epileptic agents (13.1%), non-steroidal anti-inflammatory agents and analgesics (8%), and platelet aggregation inhibitors (8%). Main clinical presentations upon hospitalization included isolated fever (30%), sore throat, acute tonsillitis and sinusitis (18.4%), documented pneumonia (18.4%), septicemia (14.5%), and septic shock (6.6%). Mean neutrophil count at nadir was 0.13 × 10(9)/L (range: 0-0.48). While in hospital, 22 patients (28.9%) worsened clinically and required intensive care unit placement. All patients were promptly treated with broad-spectrum antibiotics, and 45 (59.2%) with hematopoietic growth factors. Mean duration of hematological recovery (neutrophil count ≥1.5 × 10(9)/L) was 7.5 days (range: 2-21), which was reduced to 0.7 days (range: 2-16) (p = 0.089) with hematopoietic growth factors. Outcome was favorable in 89.5% of patients, whereas eight died. CONCLUSIONS: Like in oncology and myelosuppressive chemotherapy settings, idiosyncratic febrile neutropenia is typically serious, about 40% of patients exhibiting severe pneumonia, septicemia, and septic shock, with a mortality rate of 10%. Like in febrile, chemotherapy-related neutropenia, modern and timely management (immediate broad spectrum antibiotherapy, hematopoietic growth factors) may reduce infection-related mortality. All practitioners should be aware of this potential side-effect that may even occur in the event of "daily medication" exposur

Fatigue is independently associated with disease activity assessed using the Physician Global Assessment but not the SLEDAI in patients with systemic lupus erythematosus

Objectives To analyse whether reported fatigue, one of the most challenging manifestations of systemic lupus erythematosus (SLE), may bias the assessment of disease activity in SLE according to the Physician Global Assessment (PGA). Methods Patients from the Lupus BioBank of the upper Rhein database, a cross-sectional multicentre collection of detailed clinical and biological data from patients with SLE, were included. Patients had to fulfil the 1997 American College of Rheumatology criteria for SLE and the PGA (0-3 scale) at the time of inclusion had to be available. Fatigue was assessed according to the Fatigue Scale for Motor and Cognitive Functions. Univariate and multivariate regression models were built to determine which variables were associated with the PGA. Results A total of 350 patients (89% female; median age: 42 years, IQR: 34-52) were included. The median Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score was 4 (IQR: 2-6). Of these 350 patients, 257 (73%) reported significant fatigue. The PGA (p=0.004) but not the SELENA-SLEDAI (p=0.43) was significantly associated with fatigue. Both fatigue and SELENA-SLEDAI were independently associated with the PGA in two different multivariate models. Conclusion Fatigue is independently associated with disease activity assessed using the PGA but not the SLEDAI. These findings highlight the fact that the PGA should capture only objectively active disease manifestations in order to improve its reliability

Current Transition Practice for Primary Immunodeficiencies and Autoinflammatory Diseases in Europe: a RITA-ERN Survey

background due to the absence of curative treatments for inborn errors of immunity (IEI), children born with IEI require long-term follow-up for disease manifestations and related complications that occur over the lifespan. effective transition from pediatric to adult services is known to significantly improve adherence to treatment and long-term outcomes. It is currently not known what transition services are available for young people with IEI in europe. objective to understand the prevalence and practice of transition services in europe for young people with IEI, encompassing both primary immunodeficiencies (PID) and systemic autoinflammatory disorders (AID). methods a survey was generated by the european reference network on immunodeficiency, autoinflammatory, and autoimmune diseases transition working group and electronically circulated, through professional networks, to pediatric centers across europe looking after children with IEI. results seventy-six responses were received from 52 centers, in 45 cities across 17 different countries. all services transitioned patients to adult services, mainly to specialist PID or AID centers, typically transferring up to ten patients to adult care each year. the transition process started at a median age of 16-18 years with transfer to the adult center occurring at a median age of 18-20 years. 75% of PID and 68% of AID centers held at least one joint appointment with pediatric and adult services prior to the transfer of care. approximately 75% of PID and AID services reported having a defined transition process, but few centers reported national disease-specific transition guidelines to refer to. conclusions transition services for children with IEI in europe are available in many countries but lack standardized guidelines to promote best practice

Infection et autoimmunité (Approches expérimentale des mécanismes de rupture de la tolérance B lymphocytaire)

Les maladies autoimmunes sont liées à des facteurs génétiques et environnementaux, parmi lesquels les états infectieux semblent tout particulièrement impliqués. Toutefois, les mécanismes par lesquels les infections influencent le développement de ces maladies restent inconnus. Nous avons tenté d approcher ces mécanismes par des modèles transgéniques murins exprimant des facteurs rhumatoïdes (FR) chimériques en présence ou en absence de leur autoantigène (IgG humaines). Dans ce modèle, les cellules B FR restent immunologiquement ignorantes vis-à-vis de leur autoantigène. Toutefois, l infection des souris transgéniques FR par Borrelia burgdorferi (Bb) rompt cet état d ignorance grâce à la formation de complexes immuns Bb/IgG humaines anti-Bb induisant un signal synergique entre le BCR et des récepteurs reconnaissant les antigènes de Bb (probablement des récepteurs Toll-like, TLR). Cette rupture de tolérance nécessite également l intervention d une aide T.En revanche, une infection par le virus de la grippe ne rompt pas l ignorance des cellules B FR dans notre modèle transgénique, malgré la capacité de cette infection à induire une libération d IFN de type I associée par ailleurs à de nombreuses atteintes autoimmunes, même lorsque le transgène est exprimé sur un fond autoimmun NZBxNZW(F1).L infection par Bb provoque une hyperactivation B polyclonale. Ce phénomène mal connu a des conséquences à la fois sur la réponse immunitaire anti-infectieuse et sur la production d autoanticorps potentiellement pathogènes. L infection de souris déficientes pour MyD88 (envisagée au départ pour comprendre le rôle des TLR dans la rupture de tolérance des cellules B FR) nous a permis de mettre en évidence le rôle de cette protéine dans l hyperactivation B polyclonale. MyD88 inhibe le développement d une réponse de type Th2 empêchant ainsi probablement une production accrue d IL-4 capable d activer directement et de manière excessive les cellules B.Autoimmune diseases are associated with genetic and environmental factors. Among the latter, infections have been particularly implicated. However, the mecanisms of such an association between infections and autoimmune diseases are still unknown. We have tried to understand those mecanisms by using transgenic mouse models expressing chimeric rheumatoid factors (RF) in the presence or in the absence of their autoantigen (human IgG). In these models, RF B cells are ignorant towards their autoantigen. However, infection of RF trangenic mice with Borrelia burgdorferi (Bb) breaks this state of tolerance thanks to the formation of Bb/anti-Bb human IgG immune complexes that induce a synergic signal between the BCR and a receptor recognising Bb antigens (probably a Toll-like receptor, TLR). This tolerance breakdown needs T cell help.On the other hand, infection with influenza virus does not break RF B cell tolerance in our tg model although this infection is able to induce type I IFN production, otherwise often associated with autoimmune diseases, and even when the transgene is expressend on an autoimmune background, NZBxNZW(F1).Bb infection induces a polyclonal B cell activation. Ce phenomenon is not well known, it has consequences on the immune response against infections and on the production of potentially harmfull autoantibodies. The infection of MyD88 deficient mice (considered at first to understand the role of TLR in the RF B cell tolerance breakdown) showed that this protein is important for polyclonal B cell activation. MyD88 inhibits the development of a Th2 immune response, thus probably preventing an increased production of IL-4 that can directly and excessively activate B cells.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Scléromyxoedème, physiopathologie et intérêt de l'intensification avec autogreffe de cellules souches.

STRASBOURG-Medecine (674822101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Surdités auto-immunes (à propos de 39 patients atteints de surdité qui ont consulté au service d'immunologie clinique du CHU de Strasbourg depuis 2007 pour suspicion de surdité auto-immune.)

STRASBOURG-Medecine (674822101) / SudocSudocFranceF

Elaboration d'un registre local de recueil et d'étude des déficits immunitaires primitifs d'origine lymphocytaire de l'adulte

STRASBOURG-Medecine (674822101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Lymphocytes B et lupus (Le phénotype lymphocytaire B peut-il être instructif ?)

STRASBOURG-Medecine (674822101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF