Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis

Antibodies to citrulline-modifi ed proteins have a high diagnostic value in rheumatoid arthritis (RA). However, their biological role in disease development is still unclear. To obtain insight into this question, a panel of mouse monoclonal antibodies was generated against a major triple helical collagen type II (CII) epitope (position 359 – 369; ARGLTGRPGDA) with or without arginines modifi ed by citrullination. These antibodies bind cartilage and synovial tissue, and mediate arthritis in mice. Detection of citrullinated CII from RA patients ’ synovial fl uid demonstrates that cartilage-derived CII is indeed citrullinated in vivo. The structure determination of a Fab fragment of one of these antibodies in complex with a citrullinated peptide showed a surprising beta -turn conformation of the peptide and provided information on citrulline recognition. Based on these findings, we propose that autoimmunity to CII, leading to the production of antibodies specific for both native and citrullinated CII, is an important pathogenic factor in the development of RA

Identification of Natural Bispecific Antibodies against Cyclic Citrullinated Peptide and Immunoglobulin G in Rheumatoid Arthritis

BACKGROUND: Previous studies indicate that natural bispecific antibodies can be readily produced in vivo when the body is simultaneously stimulated with 2 distinct antigens. Patients with rheumatoid arthritis (RA) usually exhibit persistent immune responses to various autoantigens, raising the possibility that natural bispecific antibodies against 2 distinct autoantigens might exist. METHODOLOGY/PRINCIPAL FINDINGS: We identified the presence of natural bispecific antibodies against cyclic citrullinated peptide (CCP) and immunoglobulin G (IgG) in RA patients' sera by means of a double-antigen sandwich enzyme-linked immunosorbent assay (ELISA). The spontaneous emergence of bispecific antibodies was confirmed by mixing different proportions of 1 anti-CCP-positive serum and 1 rheumatoid factor (RF)-positive serum in vitro. Among the tested samples, positive correlations were found between the presence of bispecific antibodies and both IgG4 anti-CCP antibodies and IgG4 RF (r = 0.507, p<0.001 and r = 0.249, p = 0.044, respectively), suggesting that the IgG4 subclass is associated with this phenomenon. Furthermore, bispecific antibodies were selectively generated when several anti-CCP- and RF-positive sera were mixed pairwise, indicating that factors other than the monospecific antibody titers may also contribute to the production of the natural bispecific antibodies. CONCLUSIONS/SIGNIFICANCE: We successfully identified the presence of natural bispecific antibodies. Our results suggest that these antibodies originate from anti-CCP and RF in the sera of RA patients. The natural occurrence of bispecific antibodies in human diseases may provide new insights for a better understanding of the diseases. Further investigations are needed to elucidate their precise generation mechanisms and explore their clinical significance in disease development and progression in a larger study population

Found in translation: Integrating laboratory and clinical oncology research

Translational research in medicine aims to inform the clinic and the laboratory with the results of each other’s work, and to bring promising and validated new therapies into clinical application. While laudable in intent, this is complicated in practice and the current state of translational research in cancer shows both striking success stories and examples of the numerous potential obstacles as well as opportunities for delays and errors in translation. This paper reviews the premises, promises, and problems of translational research with a focus on radiation oncology and suggests opportunities for improvements in future research design

Local microbleeding facilitates IL-6– and IL-17–dependent arthritis in the absence of tissue antigen recognition by activated T cells

Local microbleeding induces the accumulation of Th17 cells and the development of IL-17– and IL-6–dependent arthritis in the absence of cognate antigen recognition by CD4+ T cells