Variants in the Late Cornified Envelope Gene Locus Are Associated With Elevated T-helper 17 Responses in Patients With Postinfectious Lyme Arthritis.

BACKGROUND: Postinfectious Lyme arthritis (LA) is associated with dysregulated immunity and autoreactive T- and B-cell responses in joints. Here we explored the role of host genetic variation in this outcome. METHODS: The frequency of 253 702 single-nucleotide polymorphisms (SNPs) was determined in 147 patients with LA (87 with postinfectious LA and 60 with antibiotic-responsive LA), and for comparison in 90 patients with erythema migrans or the general population (n = 2504). Functional outcome of candidate SNPs was assessed by evaluating their impact on clinical outcome and on immune responses in blood and synovial fluid in patients with LA. RESULTS: Six SNPs associated with late cornified envelope (LCE3) genes were present at greater frequency in patients with postinfectious LA compared to those with antibiotic-responsive LA (70% vs 30%; odds ratio, 2; P < .01). These SNPs were associated with heightened levels of inflammatory Th17 cytokines in serum but lower levels of interleukin 27, a regulatory cytokine, implying that they may contribute to dysregulated Th17 immunity in blood. Moreover, in patients with postinfectious LA, the levels of these Th17 mediators correlated directly with autoantibody responses in synovial fluid, providing a possible link between LCE3 SNPs, maladaptive systemic Th17 immunity, and autoreactive responses in joints. CONCLUSIONS: Variation in the LCE3 locus, a known genetic risk factor in psoriasis and psoriatic arthritis, is associated with dysregulated systemic Th17 immunity and heightened autoantibody responses in joints. These findings underscore the importance of host genetic predisposition and systemic Th17 immunity in the pathogenesis of postinfectious (antibiotic-refractory) Lyme arthritis.

Clinical features and treatment outcomes of bone and joint nontuberculous mycobacterial infections according to immune status: a 9-year retrospective observational cohort.

OBJECTIVES: Nontuberculous mycobacteria (NTM) bone and joint infections (BJIs) are uncommon. We evaluated the characteristics of BJIs and identified differences according to immune status. METHODS: We performed a multicenter retrospective study in France involving patients with documented NTM BJI over a 9-year period. We collected the clinical and microbiological characteristics, management, and clinical outcomes of the patients. RESULTS: Overall, 95 patients were included, of whom 50.5% (48/95) were immunosuppressed. Tenosynovitis was more frequent in the immunocompetent group, and native arthritis more common in the immunosuppressed group. Mycobacerium marinum and M. abscessus complex were significantly more frequent in the immunocompetent group, and M. avium and M. xenopi were significantly more frequent in the immunosuppressed group. The combination of antibiotherapy with surgery tended to be more frequent in the immunocompetent than the immunosuppressed group (63.8% (30/47) vs 47.8% (22/46), respectively); of the latter, 45.7% (21/46) received antimicrobial therapy alone, a higher frequency than in the immunocompetent group (23.4%, 11/47). The median duration of antimicrobial treatment was similar in the two groups (11 months). Mortality was significantly higher in the immunosuppressed group. CONCLUSIONS: Although the clinical presentations and the NTM species involved in BJI differed according to immune status, most recovered completely after treatment.

Case Report: Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne: A Single-Center Experience and Literature Review.

Objectives: This study aims to describe the characteristics of patients diagnosed with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome at a single center in China and provide an up-to-date literature review. Methods: The clinical data and genotype of three Chinese Han patients were carefully documented and studied. We also conducted a systematic literature review on PAPA syndrome. Results: A total of three patients were diagnosed with PAPA syndrome at our center from 2018 to 2020. Arthritis was observed in all three patients, while pyoderma gangrenosum (PG) was found in two patients and acne in one patient. Other manifestations included pathergy reaction, intermittent fever, oral ulcer, keratitis, proteinuria, and hematuria. The PSTPIP1 A230T mutation was identified in two patients, and a novel Y119C variation was revealed in a sporadic patient. A total of 76 patients with PAPA syndrome reported in 29 articles were included in our literature review. The classical triad of arthritis, PG, and acne was visible in only 16 (25.4%) patients, while 24 (38.1%) exhibited only one major symptom. Skin lesions were more commonly seen in patients with adult-onset disease than those with childhood-onset disease (100 vs. 83%), whereas arthritis was less common (50 vs. 98.1%). Steroid and/or biological agents were effective in most patients. Conclusions: The rarity and phenotypic heterogeneity associated with PAPA syndrome make the diagnosis a huge challenge to physicians, especially in adult patients. A significant portion of patients did not exhibit the full spectrum of the classical triad. Accordingly, gene testing is critically helpful for diagnosis.

Neutralization of IL-17 and treatment with IL-2 protects septic arthritis by regulating free radical production and antioxidant enzymes in Th17 and Tregs: An immunomodulatory TLR2 versus TNFR response.

Septic arthritis is a destructive joint disease caused by Staphylococcus aureus. Synovial inflammation involved Th17 proliferation and down regulation of Treg population, thus resolution of inflammation targeting IL-17 may be important to control arthritis. Endogenous inhibition of IL-17 to regulate arthritic inflammation correlating with Th17/Treg cells TLR2 and TNFRs are not done. The role of SOD, CAT and GRx in relation to ROS production during arthritis along with expression of TLR2, TNFR1/TNFR2 in Th17/Treg cells of mice treated with IL-17A Ab/ IL-2 were studied. Increased ROS, reduced antioxidant enzyme activity was found in Th17 cells of SA infected mice whereas Treg cells of IL-17A Ab/ IL-2 treated group showed opposite effects. Neutralization of IL-17 after arthritis cause decreased TNFR1 and increased TNFR2 expression in Treg cells. Thus, neutralization of IL-17 or IL-2 treatment regulates septic arthritis by enhancing anti-inflammatory properties of Treg via antioxidant balance and modulating TLR2/TNFR response.

Selective Activation of MST1/2 Kinases by Retinoid Agonist Adapalene Abrogates AURKA-Regulated Septic Arthritis.

Septic arthritis is a chronic inflammatory disorder caused by Staphylococcus aureus invasion of host synovium, which often progresses to impairment of joint functions. Although it is known that disease progression is intricately dependent on dysregulated inflammation of the knee joint, identification of molecular events mediating such imbalance during S. aureus-induced septic arthritis still requires detailed investigation. In this article, we report that Aurora kinase A (AURKA) responsive WNT signaling activates S. aureus infection-triggered septic arthritis, which results in inflammation of the synovium. In this context, treatment with adapalene, a synthetic retinoid derivative, in a mouse model for septic arthritis shows significant reduction of proinflammatory mediators with a simultaneous decrease in bacterial burden and prevents cartilage loss. Mechanistically, adapalene treatment inhibits WNT signaling with concomitant activation of HIPPO signaling, generating alternatively activated macrophages. Collectively, we establish adapalene as a promising strategy to suppress S. aureus-induced irreversible joint damage.

Ureaplasma septic polyarthritis in a young woman with neuromyelitis optica receiving rituximab.

We report a case of septic polyarthritis caused by Ureaplasma urealyticum in a woman with neuromyelitis optica who was receiving rituximab. Her case exemplifies some of the unique characteristics of invasive Ureaplasma infections that can lead to delayed diagnosis as well as treatment challenges including recurrence following antibiotic discontinuation.

The Immunologists' Guide to Pandemic Preparedness.

Immunologists are central to fighting any pandemic. From pathogenesis to disease modeling, pharmaceuticals to vaccines, immunologists play a crucial role in translating basic science into effective response strategies. This article describes our view on how lessons from the coronavirus disease 2019 (COVID-19) pandemic can be developed into an immunologists' guide for preparedness for future pandemics.

CXCL10 Signaling Contributes to the Pathogenesis of Arthritogenic Alphaviruses.

Emerging and re-emerging arthritogenic alphaviruses, such as Chikungunya virus (CHIKV) and O'nyong nyong virus, cause acute and chronic crippling arthralgia associated with inflammatory immune responses. Approximately 50% of CHIKV-infected patients suffer from rheumatic manifestations that last 6 months to years. However, the physiological functions of individual immune signaling pathways in the pathogenesis of alphaviral arthritis remain poorly understood. Here, we report that a deficiency in CXCL10, which is a chemoattractant for monocytes/macrophages/T cells, led to the same viremia as wild-type animals, but fewer immune infiltrates and lower viral loads in footpads at the peak of arthritic disease (6-8 days post infection). Macrophages constituted the largest immune cell population in footpads following infection, and were significantly reduced in Cxcl10-/- mice. The viral RNA loads in neutrophils and macrophages were reduced in Cxcl10-/- compared to wild-type mice. In summary, our results demonstrate that CXCL10 signaling promotes the pathogenesis of alphaviral disease and suggest that CXCL10 may be a therapeutic target for mitigating alphaviral arthritis.

Inflammatory Joint Disease Is a Risk Factor for Streptococcal Sepsis and Septic Arthritis in Mice.

Septic arthritis is a medical emergency associated with high morbidity and mortality, yet hardly any novel advances exist for its clinical management. Despite septic arthritis being a global health burden, experimental data uncovering its etiopathogenesis remain scarce. In particular, any interplay between septic arthritis and preceding joint diseases are unknown as is the contribution of the synovial membrane to the onset of inflammation. Using C57BL/6 mice as a model to study sepsis, we discovered that Group A Streptococcus (GAS) - an important pathogen causing septic arthritis - was able to invade the articular microenvironment. Bacterial invasion resulted in the infiltration of immune cells and detrimental inflammation. In vitro infected fibroblast-like synoviocytes induced the expression of chemokines (Ccl2, Cxcl2), inflammatory cytokines (Tnf, Il6), and integrin ligands (ICAM-1, VCAM-1). Apart from orchestrating immune cell attraction and retention, synoviocytes also upregulated mediators impacting on bone remodeling (Rankl) and cartilage integrity (Mmp13). Using collagen-induced arthritis in DBA/1 × B10.Q F1 mice, we could show that an inflammatory joint disease exacerbated subsequent septic arthritis which was associated with an excessive release of cytokines and eicosanoids. Importantly, the severity of joint inflammation controlled the extent of bone erosions during septic arthritis. In order to ameliorate septic arthritis, our results suggest that targeting synoviocytes might be a promising approach when treating patients with inflammatory joint disease for sepsis.

Differential Accumulation and Activation of Monocyte and Dendritic Cell Subsets in Inflamed Synovial Fluid Discriminates Between Juvenile Idiopathic Arthritis and Septic Arthritis.

Despite their distinct etiology, several lines of evidence suggest that innate immunity plays a pivotal role in both juvenile idiopathic arthritis (JIA) and septic arthritis (SA) pathophysiology. Indeed, monocytes and dendritic cells (DC) are involved in the first line of defense against pathogens and play a critical role in initiating and orchestrating the immune response. The aim of this study was to compare the number and phenotype of monocytes and DCs in peripheral blood (PB) and synovial fluid (SF) from patients with JIA and SA to identify specific cell subsets and activation markers associated with pathophysiological mechanisms and that could be used as biomarkers to discriminate both diseases. The proportion of intermediate and non-classical monocytes in the SF and PB, respectively, were significantly higher in JIA than in SA patients. In contrast the proportion of classical monocytes and their absolute numbers were higher in the SF from SA compared with JIA patients. Higher expression of CD64 on non-classical monocyte was observed in PB from SA compared with JIA patients. In SF, higher expression of CD64 on classical and intermediate monocyte as well as higher CD163 expression on intermediate monocytes was observed in SA compared with JIA patients. Moreover, whereas the number of conventional (cDC), plasmacytoid (pDC) and inflammatory (infDC) DCs was comparable between groups in PB, the number of CD141+ cDCs and CD123+ pDCs in the SF was significantly higher in JIA than in SA patients. CD14+ infDCs represented the major DC subset in the SF of both groups with potent activation assessed by high expression of HLA-DR and CD86 and significant up-regulation of HLA-DR expression in SA compared with JIA patients. Finally, higher activation of SF DC subsets was monitored in SA compared with JIA with significant up-regulation of CD86 and PDL2 expression on several DC subsets. Our results show the differential accumulation and activation of innate immune cells between septic and inflammatory arthritis. They strongly indicate that the relative high numbers of CD141+ cDC and CD123+ pDCs in SF are specific for JIA while the over-activation of DC and monocyte subsets is specific for SA.

In vivo synthesis of bacterial amyloid curli contributes to joint inflammation during S. Typhimurium infection.

Reactive arthritis, an autoimmune disorder, occurs following gastrointestinal infection with invasive enteric pathogens, such as Salmonella enterica. Curli, an extracellular, bacterial amyloid with cross beta-sheet structure can trigger inflammatory responses by stimulating pattern recognition receptors. Here we show that S. Typhimurium produces curli amyloids in the cecum and colon of mice after natural oral infection, in both acute and chronic infection models. Production of curli was associated with an increase in anti-dsDNA autoantibodies and joint inflammation in infected mice. The negative impacts on the host appeared to be dependent on invasive systemic exposure of curli to immune cells. We hypothesize that in vivo synthesis of curli contributes to known complications of enteric infections and suggest that cross-seeding interactions can occur between pathogen-produced amyloids and amyloidogenic proteins of the host.

Role of different Th17 and Treg downstream signalling pathways in the pathogenesis of Staphylococcus aureus infection induced septic arthritis in mice.

Septic arthritis is a condition of bone disorder caused predominantly by Staphylococcus aureus. Following the bacterial entry activated immune cells specially macrophages and dendritic cells release pro-inflammatory mediators such as IL-6, TNF-α, IL-1ß etc., which not only create an inflammatory microenvironment but also play crucial roles in the proliferation of different CD+ T cell subsets. Among them, Th17 and Tregs are of major concern in recent times because of their potential roles in regulating the ongoing inflammation in many diseases including experimental arthritis. But the downstream signalling mechanism of these cells in regulating the severity of inflammation in case of septic arthritis is not known yet. So, here we have established a murine model of S. aureus induced septic arthritis and kept the animal upto 15 days post-infection. To examine the signalling mechanism, Th17 and Treg cells were isolated from blood, spleen and synovial joints of control and infected mice and observed the expression of JNK, NFκB and RANKL in the lysate of isolated Th17 and Tregs. We have also estimated the levels of serum IL-21 and TGF-ß. NFκB, JNK and RANKL expression was found to be higher at 3 and 15 days post-infection along with serum IL-21 levels. On the other hand, maximum TGF-ß level was observed at 9 days post-infection along with increased Treg population. In conclusion it was hypothesized that bone resorption is related with downstream signalling pathways of Th17 cells, which stimulate osteoclast generation via NFκB/JNK-RANKL axis and helps in the persistence of the disease.

Mycoplasma bovis induces matrix metalloproteinase-3 expression in bovine synovial cells via up-regulation of interleukin-1ß expression in mononuclear cells.

Mycoplasma bovis causes chronic arthritis in calves, presenting as osteolysis in affected joints. Matrix metalloproteinase-3 (MMP-3), an enzyme involved in cartilage degradation, is produced by synovial cells. Production of this proteinase is regulated by interleukin (IL)-1ß, which is produced by mononuclear cells. Both factors are known to play important roles in osteolysis in human autoimmune and bacterial arthritis. However, the pathophysiology of Mycoplasma arthritis (MA) has not been elucidated. In this study, we evaluated the levels of MMP-3 and IL-1ß in synovial fluid (SF) from MA calves and examined the effect of IL-1ß on MMP-3 expression in bovine synovial cells in vitro. Levels of MMP-3 and IL-1ß in SF from MA calves were significantly higher than those of clinically healthy calves. Mycoplasma bovis induced significant increases in the expression of IL-1ß mRNA and protein in mononuclear cells, compared with cells not exposed to M. bovis. Interestingly, the supernatant of mononuclear cells stimulated with M. bovis contained high levels of IL-1ß, which induced higher expression of MMP-3 mRNA and protein in synovial cells than direct stimulation by M. bovis. Recombinant bovine IL-1ß also induced increased MMP-3 mRNA and protein expression in synovial cells. Our results indicate that M. bovis induces IL-1ß expression by bovine mononuclear cells, and this cytokine then promotes MMP-3 production by synovial cells. These findings suggest that MMP-3 and IL-1ß are key factors in the development of osteolysis in MA calves.

Post-traumatic Curvularia sp. arthritis in an immunocompetent adult.

A 44-year-old woman, victim of a road accident in Mali was diagnosed with left knee arthritis. Joint effusion aspiration and subcutaneous surgical biopsies were positive for a melanized asexual ascomycete. Using microscopy and molecular biology, the fungus was identified as Curvularia sp. In vitro antifungal susceptibility was determined by the EUCAST broth microdilution reference technique and by E-test. The patient was treated with liposomal amphotericin B before posaconazole relay. Mycological samples obtained 10 days after starting the antifungal therapy by liposomal amphotericin B were negative in culture. Curvularia spp. are environmental fungi which can under certain conditions be pathogenic for humans.

Impact of simultaneous neutralization of IL-17A and treatment with recombinant IL-2 on Th17-Treg cell population in S.aureus induced septic arthritis.

The contribution of Th17 and Treg in the pathogenesis of septic arthritis is well known. The imbalance of Th17/Treg ratio, especially the skewed CD4+ T cell differentiation towards pathogenic Th17 lineage is a major reason that mediates bone damage through one of its prime cytokine member IL-17A. The neutralization of released IL-17A, as well as exogenous administration of IL-2 at a lower dose, was seen to be potent in dampening the inflammatory response in many cases. Interestingly the effect of IL-17A neutralization to limit IL-17 mediated inflammation and induction of Tregs by the administration of IL-2 has not been studied in experimental arthritis. So in this study, we have treated arthritic mice with IL-17A Ab and recombinant mouse IL-2 either alone or in combination at 3, 9 and 15 days post-infection. We have found a marked decrease in Th17 cell population and their related pro-inflammatory cytokine levels at 15DPI in arthritic mice after IL-17 neutralization. An increased Treg cell population was also observed in mice after application of rIL-2 with a significantly heightened TGF-ß level in serum and synovial joints compared to the untreated one. However, in the case of combination therapy of IL-17A Ab and rIL-2 we have observed a beneficial effect in ameliorating the disease outcome as the arthritic index was decreased maximally at 15DPI with a significant reduction of arthritis compared to individual treatment. Overall the inflammatory microenvironment was counterbalanced most effectively in combination treatment by lowering the Th17/Treg ratio and their related cytokines that resulted in reducing the immunopathogenesis of the destructive arthritis.

A novel mouse model for septic arthritis induced by Pseudomonas aeruginosa.

Septic arthritis is one of the most aggressive joint diseases. Although caused predominantly by S. aureus, Gram-negative bacteria, Pseudomonas aeruginosa among them, account for a significant percentage of the causal agents of septic arthritis. However, septic arthritis caused by P. aeruginosa has not been studied thus far, due to lack of an animal model. NMRI mice were inoculated with different doses of P. aeruginosa. The clinical course of septic arthritis and radiological changes of joints were examined. Furthermore, the host molecular and cellular mechanisms involved in P. aeruginosa-induced septic arthritis were investigated. Inoculation of mice with P. aeruginosa caused septic arthritis in a dose-dependent manner. Neutrophil depletion led to higher mortality and more severe joint destruction (p < 0.01). In contrast, monocyte depletion resulted in higher mortality (p < 0.05) but similar arthritis severity compared to controls. Mice depleted of CD4+ T-cells inoculated with P. aeruginosa displayed less severe bone damage (p < 0.05). For the first time, a mouse model for P. aeruginosa septic arthritis is presented. Our data demonstrate that neutrophils play a protective role in P. aeruginosa septic arthritis. Monocytes/macrophages, on the other hand, are only essential in preventing P. aeruginosa-induced mortality. Finally, CD4+ T-cells are pathogenic in P. aeruginosa septic arthritis.

The clinical presentation of Legionella arthritis reveals the mode of infection and the bacterial species: case report and literature review.

BACKGROUND: While Legionella is a common cause of pneumonia, extrapulmonary infections like arthritis are scarce. Here, we describe a case of monoarthritis due to Legionella bozemanii, with no history of pneumonia. We provide a literature review of the 9 previously published Legionella arthritis and highlight a dichotomous epidemiology suggesting different physiopathological pathways leading to joint infection. CASE PRESENTATION: A 56-year old woman under immunosuppressive treatment by oral and intra-articular corticosteroids, methotrexate, and tocilizumab for an anti-synthetase syndrome was hospitalized for worsening pain and swelling of the left wrist for 3 days. Clinical examination showed left wrist synovitis and no fever. The arthritis occurred a few days after an accidental fall on wet asphalt responsible for a cutaneous wound followed by a corticosteroid intra-articular injection. Due to both the negativity of conventional culture of articular fluid and suspicion of infection, 16S rRNA and specific PCRs were performed leading to the identification of L. bozemanii. Legionella-specific culture of the articular fluid was performed retrospectively and isolated L. bozemanii. The empiric antibiotic therapy was switched for oral levofloxacin and rifampin and the patient recovered after a 12-week treatment. CONCLUSION: We report a case of L. bozemanii monoarthritis in an immunosuppressed woman, following a fall on wet asphalt and intra-articular corticosteroid injection. The review of the literature found that the clinical presentation reveals the mode of infection and the bacterial species. Monoarthritis more likely occurred after inoculation in patients under immunosuppressive therapy and were associated with non-Legionella pneumophila serogroup 1 (Lp1) strains that predominate in the environment. Polyarthritis were more likely secondary legionellosis localizations after blood spread of Lp1, the most frequently found in pneumonia. In both settings, 16S rRNA and Legionella-specific PCR were key factors for the diagnosis.

Two cases of severe neutropenia in patients on low-dose methotrexate and ceftriaxone.

PURPOSE: There are limited data on the effect of ceftriaxone on methotrexate clearance, with results of some studies indicating altered methotrexate pharmacokinetics with the administration of ceftriaxone. We describe 2 possible cases demonstrating an interaction between methotrexate and ceftriaxone, resulting in profound neutropenia. SUMMARY: The decision to continue methotrexate therapy in the setting of surgery or during treatment of an active infection continues to be a topic of debate due to perceived negative effects on the healing process. Methotrexate is typically administered at a lower dose for inflammatory arthritis than for hematologic indications, thus having less immunosuppression potential. However, if methotrexate is continued during treatment of infection, drug interactions along with effects on the healing process should be considered. Ceftriaxone is commonly considered safe for long-term therapy due to its favorable adverse effect and drug interaction profile. Ceftriaxone is partially eliminated via organic anion transporters in the kidneys, leading to potential competition with methotrexate clearance in the renal tubules. Clinicians using these drugs concurrently should be aware of the potential for development of neutropenia and monitor patients receiving this combination closely. CONCLUSION: Two patients receiving ceftriaxone therapy in the setting of a joint infection developed profound neutropenia after resuming oral methotrexate therapy for inflammatory arthritis.