Primary Immunodeficiencies With Defects in Innate Immunity: Focus on Orofacial Manifestations.

The field of primary immunodeficiencies (PIDs) is rapidly evolving. Indeed, the number of described diseases is constantly increasing thanks to the rapid identification of novel genetic defects by next-generation sequencing. PIDs are now rather referred to as "inborn errors of immunity" due to the association between a wide range of immune dysregulation-related clinical features and the "prototypic" increased infection susceptibility. The phenotypic spectrum of PIDs is therefore very large and includes several orofacial features. However, the latter are often overshadowed by severe systemic manifestations and remain underdiagnosed. Patients with impaired innate immunity are predisposed to a variety of oral manifestations including oral infections (e.g., candidiasis, herpes gingivostomatitis), aphthous ulcers, and severe periodontal diseases. Although less frequently, they can also show orofacial developmental abnormalities. Oral lesions can even represent the main clinical manifestation of some PIDs or be inaugural, being therefore one of the first features indicating the existence of an underlying immune defect. The aim of this review is to describe the orofacial features associated with the different PIDs of innate immunity based on the new 2019 classification from the International Union of Immunological Societies (IUIS) expert committee. This review highlights the important role played by the dentist, in close collaboration with the multidisciplinary medical team, in the management and the diagnostic of these conditions.journal articleresearch support, non-u.s. gov'treview20202020 06 18importe

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

Recommendations for Transitioning Young People with Primary Immunodeficiency Disorders and Autoinflammatory Diseases to Adult Care

Purpose: Significant improvements in the prognosis for young patients with Primary Immunodeficiency Diseases (PID) and Autoinflammatory Disorders (AID), which together make up the majority of Inborn Errors of Immunity (IEI), have resulted in the need for optimisation of transition and transfer of care to adult services. Effective transition is crucial to improve health outcomes and treatment compliance among patients. Evaluations of existing transition programmes in European health centres identified the absence of disease-specific transition guidelines for PID and AID, as a challenge to the transition process. This research aimed to establish expert consensus statements for the transition of young patients with PID and AID to adult services. Methods: This project used the Delphi method to establish mutual agreement for the proposed recommendations. A draft set of statements was developed following a literature review of existing transition programmes. Then the ERN RITA Transition Working Group convened to review the drafted recommendations and develop them into a survey. This survey was circulated among healthcare professionals to determine consensus using a five-point Likert scale, with the level of agreement set to 80% or greater. Statements that did not reach consensus were revised by the Working Group and recirculated among respondents. Results: The initial survey received 93 responses from 68 centres across 23 countries, while the following survey outlining revised recommendations received 66 responses. The respondents agreed upon recommendations detailing the structure and administration of transition programmes, collaborative working with social systems, and contraindications to transfer of care. Conclusion: This paper sets out a comprehensive set of recommendations to optimise transitional care for PID and AID

Overexpression of Fkbp11, a feature of lupus B cells, leads to B cell tolerance breakdown and initiates plasma cell differentiation

Systemic Lupus Erythematosus (SLE) is a severe systemic autoimmune disease, characterized by multi-organ damages, triggered by an autoantibody-mediated inflammation, and with a complex genetic influence. It is today accepted that adult SLE arises from the building up of many subtle gene variations, each one adding a new brick on the SLE susceptibility and contributing to a phenotypic trait to the disease. One of the ways to find these gene variations consists in comprehensive analysis of gene expression variation in a precise cell type, which can constitute a good complementary strategy to genome wide association studies. Using this strategy, and considering the central role of B cells in SLE, we analyzed the B cell transcriptome of quiescent SLE patients, and identified an overexpression of FKBP11, coding for a cytoplasmic putative peptidyl-prolyl cis/trans isomerase and chaperone enzyme. To understand the consequences of FKBP11 overexpression on B cell function and on autoimmunity's development, we created lentiviral transgenic mice reproducing this gene expression variation. We showed that high expression of Fkbp11 reproduces by itself two phenotypic traits of SLE in mice: breakdown of B cell tolerance against DNA and initiation of plasma cell differentiation by acting upstream of Pax5 master regulator gene

Neurol-Neuroimmunol

Objective To report the association of JC virus infection of the brain (progressive multifocal encephalopathy [PML]) during the course of sarcoidosis and the challenging balance between immune reconstitution under targeted cytokine interleukin 7 (IL7) therapy for PML and immunosuppression for sarcoidosis. Methods Original case report including deep sequencing (whole-exome sequencing) to exclude a primary immunodeficiency (PID) and review of the literature of cases of PML and sarcoidosis. Results We report and discuss here a challenging case of immune reconstitution with IL7 therapy for PML in sarcoidosis in a patient without evidence for underling PID or previous immunosuppressive therapy. Conclusions New targeted therapies in immunology and infectiology open the doors of more specific and more specialized therapies for patients with immunodeficiencies, autoimmune diseases, or cancers. However, before instauration of these treatments, the risk of immune reconstitution inflammatory syndrome and potential exacerbation of an underlying disease must be considered. It is particularly true in case of autoimmune disease such as sarcoidosis or lupus

Front Immunol

Context Disseminated infections due to Mycobacterium bovis Bacillus Calmette-Guerin (BCG) are unusual and occur mostly in patients with inborn error of immunity (IEI) or acquired immunodeficiency. However, cases of secondary BCGosis due to intravesical BCG instillation have been described. Herein, we present a case of severe BCGosis occurring in an unusual situation. C ase Description We report one case of severe disseminated BCG disease occurring after hematological malignancy in a 48-year-old man without BCG instillation and previously vaccinated in infancy with no complication. Laboratory investigations demonstrated that he was not affected by any known or candidate gene of IEI or intrinsic cellular defect involving IFN gamma pathway. Whole genome sequencing of the BCG strain showed that it was most closely related to the M. bovis BCG Tice strain, suggesting an unexpected relationship between the secondary immunodeficiency of the patient and the acquired BCG infection.& nbsp; Conclusion This case highlights the fact that, in addition to the IEI, physicians, as well as microbiologists and pharmacists should be aware of possible acquired disseminated BCG disease in secondary immunocompromised patients treated in centers that administrate BCG for bladder cancers.</p