Antibodies to Cartilage Oligomeric Matrix Protein Are Pathogenic in Mice and May Be Clinically Relevant in Rheumatoid Arthritis

Objective. Cartilage oligomeric matrix protein (COMP) is an autoantigen in rheumatoid arthritis (RA) and experimental models of arthritis. This study was undertaken to investigate the structure, function, and relevance of anti-COMP antibodies. Methods. We investigated the pathogenicity of monoclonal anti-COMP antibodies in mice using passive transfer experiments, and we explored the interaction of anti-COMP antibodies with cartilage using immunohistochemical staining. The interaction of the monoclonal antibody 15A11 in complex with its specific COMP epitope P6 was determined by x-ray crystallography. An enzyme-linked immunosorbent assay and a surface plasma resonance technique were used to study the modulation of calcium ion binding to 15A11. The clinical relevance and value of serum IgG specific to the COMP P6 epitope and its citrullinated variants were evaluated in a large Swedish cohort of RA patients. Results. The murine monoclonal anti-COMP antibody 15A11 induced arthritis in naive mice. The crystal structure of the 15A11-P6 complex explained how the antibody could bind to COMP, which can be modulated by calcium ions. Moreover, serum IgG specific to the COMP P6 peptide and its citrullinated variants was detectable at significantly higher levels in RA patients compared to healthy controls and correlated with a higher disease activity score. Conclusion. Our findings provide the structural basis for binding a pathogenic anti-COMP antibody to cartilage. The recognized epitope can be citrullinated, and levels of antibodies to this epitope are elevated in RA patients and correlate with higher disease activity, implicating a pathogenic role of anti-COMP antibodies in a subset of RA patients.</p

Winter

The film has won various documentary prizes in in China. It is located at the edge of the Minshan mountain ranges in southwest China. It looks at a peasant farming family over one winter. The credits at the end give the details. Permission has been given by the producer and director LIANG Bibo. Uploaded by Alan Macfarlane.A film called 'Winter' made by the important Chinese documentary film maker LIANG Bib

Peasant Woman

The film was made in the spring of 1995. Er Niang is a fifty-eight year old woman looking after four family members who are paralysed. The credits give the details of those involved. Permission was given to put this up by LIANG Bibo. Submitted by Alan MacfarlaneA film entitled 'A Peasant Woman - Er Niang' made by the important Chinese documentary film-maker, LIANG Bibo, who works for Chengdu Television

Film on San Jie Cao

With the permission of Liang Bibo, and put up by Alan MacfarlaneFilm 'San Jie Cao - Home-coming of a grand-daughter' made by LIANG Bibo, a Chinese documentary film-maker, about an arranged marriage near Lugu Lake in South West China

The Buddhist Nun of Emei Mountain

With permission of the producer, made in the late 1990's and put up by Alan MacfarlaneA film by LIANG Bibo about a Buddhist nunnery in southwest China, the Fuhu temple. Liang works for Chengdu televisio

Interview of Liang Bibo

LIANG Bibo interviewed by Alan Macfarlane in China on 28th July 2008, edited by Sarah HarrisonAn interview with the film-maker LIANG Bibo in 200

Pony Express

The film is set round Lugu lake in south-western China where the Mosuo people live. They have sent messages by horse for many centuries. The film describes this ancient form. The credits give the details of those involved. With the permission of LIANG Bibo, and submitted by Alan MacfarlaneA film called 'Pony Express' made by the important Chinese documentary film-maker, LIANG Bibo in the late 1990's. Liang works for Chengdu television

A Shared Epitope of Collagen Type XI and Type II Is Recognized by Pathogenic Antibodies in Mice and Humans with Arthritis

BackgroundCollagen XI (CXI) is a heterotrimeric molecule with triple helical structure in which the α3(XI) chain is identical to the α1(II) chain of collagen II (CII), but with extensive posttranslational modifications. CXI molecules are intermingled in the cartilage collagen fibers, which are mainly composed of CII. One of the alpha chains in CXI is shared with CII and contains the immunodominant T cell epitope, but it is unclear whether there are shared B cell epitopes as the antibodies tend to recognize the triple helical structures.MethodsMice expressing the susceptible immune response gene Aq were immunized with CII or CXI. Serum antibody responses were measured, monoclonal antibodies were isolated and analyzed for specificity to CII, CXI, and triple helical collagen peptides using bead-based multiplex immunoassays, enzyme-linked immunosorbent assays, and Western blots. Arthritogenicity of the antibodies was investigated by passive transfer experiments.ResultsImmunization with CII or CXI leads to a strong T and B cell response, including a cross-reactive response to both collagen types. Immunization with CII leads to severe arthritis in mice, with a response toward CXI at the chronic stage, whereas CXI immunization induces very mild arthritis only. A series of monoclonal antibodies to CXI were isolated and of these, the L10D9 antibody bound to both CXI and CII equally strong, with a specific binding for the D3 epitope region of α3(XI) or α1(II) chain. The L10D9 antibody binds cartilage in vivo and induced severe arthritis. In contrast, the L5F3 antibody only showed weak binding and L7D8 antibody has no binding to cartilage and did not induce arthritis. The arthritogenic L10D9 antibody bound to an epitope shared with CII, the triple helical D3 epitope. Antibody levels to the shared D3 epitope were elevated in the sera from mice with arthritis as well as in rheumatoid arthritis.ConclusionCXI is immunologically not exposed in healthy cartilage but contains T and B cell epitopes cross-reactive with CII, which could be activated in both mouse and human arthritis and could evoke an arthritogenic response

Antibodies to Cartilage Oligomeric Matrix Protein Are Pathogenic in Mice and May Be Clinically Relevant in Rheumatoid Arthritis

Objective Cartilage oligomeric matrix protein (COMP) is an autoantigen in rheumatoid arthritis (RA) and experimental models of arthritis. This study was undertaken to investigate the structure, function, and relevance of anti-COMP antibodies. Methods We investigated the pathogenicity of monoclonal anti-COMP antibodies in mice using passive transfer experiments, and we explored the interaction of anti-COMP antibodies with cartilage using immunohistochemical staining. The interaction of the monoclonal antibody 15A11 in complex with its specific COMP epitope P6 was determined by x-ray crystallography. An enzyme-linked immunosorbent assay and a surface plasma resonance technique were used to study the modulation of calcium ion binding to 15A11. The clinical relevance and value of serum IgG specific to the COMP P6 epitope and its citrullinated variants were evaluated in a large Swedish cohort of RA patients. Results The murine monoclonal anti-COMP antibody 15A11 induced arthritis in naive mice. The crystal structure of the 15A11-P6 complex explained how the antibody could bind to COMP, which can be modulated by calcium ions. Moreover, serum IgG specific to the COMP P6 peptide and its citrullinated variants was detectable at significantly higher levels in RA patients compared to healthy controls and correlated with a higher disease activity score. Conclusion Our findings provide the structural basis for binding a pathogenic anti-COMP antibody to cartilage. The recognized epitope can be citrullinated, and levels of antibodies to this epitope are elevated in RA patients and correlate with higher disease activity, implicating a pathogenic role of anti-COMP antibodies in a subset of RA patients

Elevated triglycerides level in hospital stay as a risk factor of mortality in patients with severe acute pancreatitis.

Hypertriglyceridaemia is one of the most common causes of severe acute pancreatitis (SAP). However, the association between elevated triglycerides (TG) level in hospital stay and outcome in SAP patients with normal TG level at admission has not been clearly demonstrated. This retrospective study assessed the serum TG levels of patients with SAP admitted to the intensive care unit (ICU) in 2017. Variables with a statistically significant association with the incidence of in-hospital TG elevation, as determined by univariate analysis, were analysed using a logistic regression model to predictors. Of the 99 patients included in the study, TG levels were within the normal range in 59 (59.59%) patients at admission. Among patients with normal TG level when admitted to ICU, 28 (47.46%) experienced at least one episode of TG level elevation during their ICU stay. Elevated TG level in hospitalization is associated with an increased length of ICU stay, as well as increased mortality. In addition to other factors, propofol usage was independently associated with the occurrence of in-hospital-TG elevation. To conclude, we retrospectively investigated the incidence, outcome, and risk factors for in-hospital TG elevation events in SAP patients admitted to the ICU. We found a high incidence of both preexisting and in-hospital-acquired TG elevation in SAP patients admitted to the ICU. The TG elevation that occurred during the ICU stay was associated with worse outcomes and long-term hospitalization of the ICU. Propofol usage was independently associated with the TG elevation occurrence in the ICU