INFECTIOUS AGENTS AND B CELL TOLERANCE BREAKDOWN

Oral Communication presented at the "Forum des Jeunes Chercheurs", Brest (France) 2011

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

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

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

Genetic Influences on the End-Stage Effector Phase of Arthritis

K/B×N T cell receptor transgenic mice are a model of inflammatory arthritis, most similar to rheumatoid arthritis, that is critically dependent on both T and B lymphocytes. Transfer of serum, or just immunoglobulins, from arthritic K/B×N animals into healthy recipients provokes arthritis efficiently, rapidly, and with high penetrance. We have explored the genetic heterogeneity in the response to serum transfer, thereby focussing on the end-stage effector phase of arthritis, leap-frogging the initiating events. Inbred mouse strains showed clear variability in their responses. A few were entirely refractory to disease induction, and those which did develop disease exhibited a range of severities. F1 analyses suggested that in most cases susceptibility was controlled in a polygenic additive fashion. One responder/nonresponder pair (C57Bl/6 × NOD) was studied in detail via a genome scan of F2 mice; supplementary information was provided by the examination of knock-out and congenic strains. Two genomic regions that are major, additive determinants of the rapidity and severity of K/B×N serum-transferred arthritis were highlighted. Concerning the first region, on proximal chromosome (chr)2, candidate assignment to the complement gene C5 was confirmed by both strain segregation analysis and functional data. Concerning the second, on distal chr1, coinciding with the Sle1 locus implicated in susceptibility to lupus-like autoimmune disease, a contribution by the fcgr2 candidate gene was excluded. Two other regions, on chr12 and chr18 may also contribute to susceptibility to serum-transferred arthritis, albeit to a more limited degree. The contributions of these loci are additive, but gene dosage effects at the C5 locus are such that it largely dominates. The clarity of these results argues that our focus on the terminal effector phase of arthritis in the K/B×N model will bear fruit

Lineage-specific analysis of Syk function in autoantibody-induced arthritis

Autoantibody production and autoantibody-mediated inflammation are hallmarks of a number of autoimmune diseases. The K/BxN serum-transfer arthritis is one of the most widely used models of the effector phase of autoantibody-induced pathology. Several hematopoietic lineages including neutrophils, platelets, and mast cells have been proposed to contribute to inflammation and tissue damage in this model. We have previously shown that the Syk tyrosine kinase is critically involved in the development in K/BxN serum-transfer arthritis and bone marrow chimeric experiments indicated that Syk is likely involved in one or more hematopoietic lineages during the disease course. The aim of the present study was to further define the lineage(s) in which Syk expression is required for autoantibody-induced arthritis. To this end, K/BxN serum-transfer arthritis was tested in conditional mutant mice in which Syk was deleted in a lineage-specific manner from neutrophils, platelets, or mast cells. Combination of the MRP8-Cre, PF4-Cre, or Mcpt5-Cre transgene with floxed Syk alleles allowed efficient and selective deletion of Syk from neutrophils, platelets, or mast cells, respectively. This has also been confirmed by defective Syk-dependent in vitro functional responses of the respective cell types. In vivo studies revealed nearly complete defect of the development of K/BxN serum-transfer arthritis upon neutrophil-specific deletion of Syk. By contrast, Syk deletion from platelets or mast cells did not affect the development of K/BxN serum-transfer arthritis. Our results indicate that autoantibody-induced arthritis requires Syk expression in neutrophils, whereas, contrary to prior assumptions, Syk expression in platelets or mast cells is dispensable for disease development in this model. © 2018 Németh, Futosi, Szilveszter, Vilinovszki, Kiss-Pápai and Mócsai

NIK Stabilization in Osteoclasts Results in Osteoporosis and Enhanced Inflammatory Osteolysis

Maintenance of healthy bone requires the balanced activities of osteoclasts (OCs), which resorb bone, and osteoblasts, which build bone. Disproportionate action of OCs is responsible for the bone loss associated with postmenopausal osteoporosis and rheumatoid arthritis. NF-κB inducing kinase (NIK) controls activation of the alternative NF-κB pathway, a critical pathway for OC differentiation. Under basal conditions, TRAF3-mediated NIK degradation prevents downstream signaling, and disruption of the NIK:TRAF3 interaction stabilizes NIK leading to constitutive activation of the alternative NF-κB pathway.Using transgenic mice with OC-lineage expression of NIK lacking its TRAF3 binding domain (NT3), we now find that alternative NF-κB activation enhances not only OC differentiation but also OC function. Activating NT3 with either lysozyme M Cre or cathepsinK Cre causes high turnover osteoporosis with increased activity of OCs and osteoblasts. In vitro, NT3-expressing precursors form OCs more quickly and at lower doses of RANKL. When cultured on bone, they exhibit larger actin rings and increased resorptive activity. OC-specific NT3 transgenic mice also have an exaggerated osteolytic response to the serum transfer model of arthritis.Constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption, both in basal conditions and in response to inflammatory stimuli