Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis

In rheumatoid arthritis (RA), dysfunctional T cells sustain chronic inflammatory immune responses in the synovium. Even unprimed T cells are under excessive replication pressure, suggesting an intrinsic defect in T cell regeneration. In naive CD4 CD45RA+ T cells from RA patients, DNA damage load and apoptosis rates were markedly higher than in controls; repair of radiation-induced DNA breaks was blunted and delayed. DNA damage was highest in newly diagnosed untreated patients. RA T cells failed to produce sufficient transcripts and protein of the DNA repair kinase ataxia telangiectasia (AT) mutated (ATM). NBS1, RAD50, MRE11, and p53 were also repressed. ATM knockdown mimicked the biological effects characteristic for RA T cells. Conversely, ATM overexpression reconstituted DNA repair capabilities, response patterns to genotoxic stress, and production of MRE11 complex components and rescued RA T cells from apoptotic death. In conclusion, ATM deficiency in RA disrupts DNA repair and renders T cells sensitive to apoptosis. Apoptotic attrition of naive T cells imposes lymphopenia-induced proliferation, leading to premature immunosenescence and an autoimmune-biased T cell repertoire. Restoration of DNA repair mechanisms emerges as an important therapeutic target in RA

HLA-B27-Associated Reactive Arthritis: Pathogenetic and Clinical Considerations

Current evidence supports the concept that reactive arthritis (ReA) is an immune-mediated synovitis resulting from slow bacterial infections and showing intra-articular persistence of viable, nonculturable bacteria and/or immunogenetic bacterial antigens synthesized by metabolically active bacteria residing in the joint and/or elsewhere in the body. The mechanisms that lead to the development of ReA are complex and basically involve an interaction between an arthritogenic agent and a predisposed host. The way in which a host accommodates to invasive facultative intracellular bacteria is the key to the development of ReA. The details of the molecular pathways that explain the articular and extra-articular manifestations of the disease are still under investigation. Several studies have been done to gain a better understanding of the pathogenesis of ReA; these constitute the basis for a more rational therapeutic approach to this disease

Superiority of systemic bleomycin to intradermal HOCl for the study of interstitial lung disease

Abstract Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, immune dysregulation, and multi-organ fibrosis. Interstitial lung disease (ILD) is a complication of SSc and a leading cause of SSc-death. The administration of hypochlorous acid (HOCl) intradermally in the mouse (HOCl-SSc) purportedly shows several features typical of SSc. We studied the model by injecting BALB/c mice daily intradermally with HOCl for 6-weeks, an exposure reported to induce lung fibrosis. On day 42, the skinfold thickness and the dermal thickness were two and three times larger respectively in the HOCl group compared to controls. HOCl treatment did not result in histological features of pulmonary fibrosis nor significant changes in lung compliance. Automated image analysis of HOCl mice lungs stained with picrosirius red did not show increased collagen deposition. HOCl injections did not increase pulmonary mRNA expression of pro-fibrotic genes nor induced the production of serum advanced oxidation protein products and anti-topoisomerase 1 antibodies. Immune cells in bronchoalveolar lavage fluid (BALF) and whole lung digests were not increased in HOCl-treated animals. Since lung fibrosis is proposed to be triggered by oxidative stress, we injected HOCl to Nrf2−/− mice, a mouse deficient in many antioxidant proteins. Lung compliance, histology, and BALF leukocyte numbers were comparable between Nrf2−/− mice and wild-type controls. We conclude that the HOCl-SSc model does not manifest SSc-lung disease

Frequency and spectrum of outpatient musculoskeletal diagnoses at a pediatric hospital in Kenya

Chronic pediatric musculoskeletal (MSK) conditions are a major cause of morbidity. The burden of pediatric rheumatic diseases in East Africa is largely unknown. The purposes of this study were to estimate frequencies and assess the spectrum of MSK-related diagnoses using ICD-10 diagnostic codes among outpatients at a pediatric hospital in Kenya and to evaluate the accuracy of the assigned codes used for the \u27arthropathies\u27 category. All pediatric outpatient diagnoses classified under the ICD-10 codes for \u27diseases of the MSK system and connective tissue\u27 (M00-M99) recorded between January and December 2011 were extracted from the electronic medical record system at Gertrude\u27s Children\u27s Hospital (GCH). For each of the ten MSK disease categories, frequencies were calculated. The assigned ICD10 code for cases in the \u27arthropathies\u27 (M00-M25) category was assessed by two rheumatologists. MSK diagnoses (n = 1078) accounted for 0.5% of all GCH outpatient consults available for analysis. \u27Soft tissue disorders\u27 were the most frequent MSK diagnoses (n = 614, 57%), followed by \u27arthropathies\u27 (n = 332, 30.8%), \u27dorsopathies\u27 (n = 81, 7.5%), \u27osteopathies and chondropathies\u27 (n = 39, 3.6%), and \u27other\u27 disorders (n = 12, 1.1%). No patients were classified in the category of \u27systemic connective tissue disorders\u27. In cases classified as \u27arthropathies\u27, there was poor agreement (Kappa 0.136) between the ICD10 code assigned by the treating physicians and that assigned by the rheumatologists. However, when the rheumatologists\u27 classification was loosened, agreement was moderate (Kappa 0.533). This study provides estimates of the frequency of outpatient MSK diagnoses at a pediatric hospital in Kenya in 2011. MSK diagnoses were not rare. Despite limitations of administrative databases to estimate frequencies of specific diagnoses, they provide a snapshot of the overall burden and spectrum of MSK conditions