Ann Rheum Dis

Objective This study was conducted with sera from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and arthritis and lupus-like disease animal models to identify innate immune system-dependent and -independent autoantigens

Immunomics in inflammatory rheumatic diseases

Autoimmune diseases such as rheumatoid arthritis (RA) are characterized by autoantibodies to different autoantigenic proteins. Using proteomic 2D immunoblots, we identified a new 40 kDa autoantigen – hnRNP A3 – from HeLa nuclear extracts, which is frequently (30%) detected by RA. Moreover, we used a set of protein arrays of about 50 000 proteins derived from a human foetal brain cDNA expression library for screening with patient sera. Additionally, we utilized a human foetal brain cDNA library in a robot-based T7 phage display screening system with RA patient sera. To determine the diversity of the enriched library, we amplified the cDNA inserts and hybridized them onto the custom-made human ENSEMBL cDNA array. By these methods, over 80 clones were identified to bind patient immunoglobulins. Moreover, nine clones show only IgA-specific reactivity. We have now evaluated two different clones thoroughly: the carboxyl-terminal half of the nucleolar phosphoprotein p130 (NOPP 130) and a clone representing a 41-amino-acid mimetic peptide showing homology to calreticulin, a previously reported autoantigen. The remaining proteins are still undergoing thorough investigation. Applying state-of-the-art proteomic techniques, such as protein array and phage display, we have succeeded in identifying more than 80 potentially autoantigenic marker molecules, of which we have characterized a subset for RA specificity by screening with large numbers of patient and control sera. However, none of the molecules characterized thus far is exclusively discriminatory for RA and they all exhibit overlap with other autoimmune diseases

Trajectories and predictors of response in youth anxiety CBT:Integrative data analysis

OBJECTIVE: Integrative data analysis was used to combine existing data from nine trials of cognitive-behavioral therapy (CBT) for anxious youth (N = 832) and identify trajectories of symptom change and predictors of trajectories.METHOD: Youth- and parent-reported anxiety symptoms were combined using item-response theory models. Growth mixture modeling assessed for trajectories of treatment response across pre-, mid-, and posttreatment and 1-year follow-up. Pretreatment client demographic and clinical traits and treatment modality (individual- and family-based CBT) were examined as predictors of trajectory classes.RESULTS: Growth mixture modeling supported three trajectory classes based on parent-reported symptoms: steady responders, rapid responders, and delayed improvement. A 4-class model was supported for youth-reported symptoms: steady responders, rapid responders, delayed improvement, and low-symptom responders. Delayed improvement classes were predicted by higher number of diagnoses (parent and youth report). Receiving family CBT predicted membership in the delayed improvement class compared to all other classes and membership in the steady responder class compared with rapid responders (youth report). Rapid responders were predicted by older age (parent report) and higher number of diagnoses (parent report). Low-symptom responders were more likely to be male (youth report).CONCLUSIONS: Integrative data analysis identified distinct patterns of symptom change. Diagnostic complexity, age, gender, and treatment modality differentiated response classes. (PsycINFO Database Record (c) 2018 APA, all rights reserved).</p

Myelin Basic Protein as a Novel Genetic Risk Factor in Rheumatoid Arthritis—A Genome-Wide Study Combined with Immunological Analyses

Rheumatoid arthritis (RA) is a major cause of adult chronic inflammatory arthritis and a typical complex trait. Although several genetic determinants have been identified, they account for only a part of the genetic susceptibility. We conducted a genome-wide association study of RA in Japanese using 225,079 SNPs genotyped in 990 cases and 1,236 controls from two independent collections (658 cases and 934 controls in collection1; 332 cases and 302 controls in collection2), followed by replication studies in two additional collections (874 cases and 855 controls in collection3; 1,264 cases and 948 controls in collection4). SNPs showing p<0.005 in the first two collections and p<10−4 by meta-analysis were further genotyped in the latter two collections. A novel risk variant, rs2000811, in intron2 of the myelin basic protein (MBP) at chromosome 18q23 showed strong association with RA (p = 2.7×10−8, OR 1.23, 95% CI: 1.14–1.32). The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001). We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease. Circulating autoantibody against MBP derived from human brain was quantified by ELISA between patients with RA, other connective tissue diseases and healthy controls. As a result, the titer of anti-MBP antibody was markedly higher in plasma of RA patients compared to healthy controls (p<0.001) and patients with other connective tissue disorders (p<0.001). ELISA experiment using citrullinated recombinant MBP revealed that a large fraction of anti-MBP antibody in RA patients recognized citrullinated MBP. This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease

A SARS-CoV-2 neutralizing antibody protects from lung pathology in a COVID-19 hamster model

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from ten COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb CV07-209 neutralized authentic SARS-CoV-2 with IC(50) of 3.1 ng/ml. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 A revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2 neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy

A therapeutic non-self-reactive SARS-CoV-2 antibody protects from lung pathology in a COVID-19 hamster model

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from 10 COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb, CV07-209, neutralized authentic SARS-CoV-2 with an IC(50) value of 3.1 ng/mL. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2-neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss, and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy