Studies on triggering of autoimmunity at mucosal sites
We have recruited patients to characterize autoimmunity in the lungs, gingival tissue and bone marrow. Using this unique material, we analyzed cells and the antibody repertoire in the mucosal environment in both individuals at risk for and those having RA, showing that local inflammation associate with increased expression of citrullinated targets and antibody-producing cells. We have cloned a large array of monoclonal antibodies from cells obtained from different tissues and characterized these for antigen specificity, binding affinity, cross reactivity with bacterial and viral derived antigens and functional capacities. We were able to isolate monoclonal ACPAs from the lung, demonstrating mucosal production of ACPAs in very early stages of disease development and more importantly already before the onset of joint inflammation. Monoclonal ACPAs cloned from the lungs are able to modulate important cellular functions such as osteoclast activation many can bind to neutrophils. We have further characterized the presence and specificities of autoantibodies showing that specific patterns of ACPAs associate with presence of lung abnormalities in RA.
In summary, we provided new data linking immune activation, breach of tolerance and initiation of autoimmunity at mucosal sites in RA.
Studies on longitudinal development of autoimmunity
In this study, we focused on two cohorts: a retrospective cohort of serum samples donated by RA patients before disease onset (pre-RA cohort) and one prospective cohort of ACPA-positive individuals at risk for developing RA (RISK RA cohort). We show that ACPAs can be detected as early as 30 years before RA, with an increasing level towards disease onset. The asymptomatic autoimmunity phase proved to be sometimes longer than expected, which points to the importance of additional biomarkers for predicting disease development in a reasonable time perspective. To address this, we use the prospective RISK RA cohort where we generated an extensive characterization of the clinical status, patient reported outcomes, as well as large omics data (genome wide scanning, antibody profiling and proteomics biomarkers). From 400 recruited participants ca. 30% developed arthritis during a 2-year follow-up. The ones progressing to arthritis are more likely to present with tendon inflammation, certain ACPA reactivities, genetic risk factors and proteomics biomarkers. We are validating new patient-orientated tools to allow earlier diagnosis and better incorporation of patient outcomes. In summary, we implemented a new health program for individuals at risk for RA and identified new ways of risk estimation and communication.
Studies on joint targeting
Our working hypothesis is that ACPAs generated at mucosal sites can target joints through recognition of identical PTMs in the osteoclasts located in the bone and bone marrow. We have shown that ACPAs can induce activation of osteoclasts, synovial fibroblast migration and cause pain-like behavior and bone loss after injection in otherwise healthy mice. More recently we showed that passive transfer of ACPA in mice also induces subclinical tendon inflammation (resembling the clinical presentation of the at-risk individuals that eventually develop arthritis). The ACPAs effects are mediated by osteoclast, interleukin-8 and citrullination dependent pathways. Based on these finding we conduct a clinical study with osteoclasts inhibitor bisphosphonates, in ACPA-positive individuals at risk for developing RA. We have also established collaborations to test additional therapeutic strategies targeting IL-8 or citrullination.
Studies on perpetuation of chronic inflammation in established disease
We have characterized several early and late disease mechanisms in epidemiological and experimental studies and we have initiated novel projects to link these mechanisms and reconstruct experimentally the disease components that bridge the earliest symptoms with subsequent chronic joint inflammation.
