Meeting report, COMBINE Scientific Meeting, Karolinska University Hospital, October 2011

Text by: Aurélie Ambrosi


The 2011 COMBINE scientific meeting took place on October 17th at the Karolinska University Hospital in Stockholm. The COMBINE project is a network of scientists, clinicians, industrial representatives and patients whose aim is to develop better prevention and treatment of chronic inflammatory diseases by drawing together the actors of academic research, health care and industry, and by favouring close interactions between these different partners.
The annual COMBINE scientific meeting is an integral part of the program’s strong aim to facilitate rapid transfer of knowledge between its different acting partners and wish to offer an open dialogue about its activities to all participants and the general public. On October 17th, Lars Klareskog, project coordinator, welcomed about 80 participants to the COMBINE meeting. The day was filled by a succession of presentations from scientists involved in the different COMBINE work packages and was concluded by a poster session, giving an opportunity to all to discuss recent advances in the various projects.


Understanding the cellular and molecular mechanisms underlying inflammatory and autoimmune responses is crucial to the development of effective therapies. The last decade has seen many improvements in the treatment of chronic inflammatory conditions, succeeding in slowing disease progression, reducing the severity of associated co-morbidities and ameliorating the daily life of patients. However, facing diseases for which there is currently no definite cure, clinicians and scientists are redoubling efforts to increase their knowledge of the pathogenic mechanisms initiating and maintaining disease, as well as to identify genetic and environmental factors that contribute to establishment of disease. In sessions 1 and 3 of the 2011 COMBINE scientific meeting, advances in various projects were discussed, ranging from genetic studies in animal models and humans to molecular and cellular investigations of immune mechanisms implicated in chronic inflammatory autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus.
An essential objective of COMBINE is to promote advances not only at the bench, but also at the bedside. Session 2 offered the audience examples of how patients can be involved via questionnaires and interviews to generate data that will be used to further improve treatment options and implementation as well as interactions between patients and medical staff. Information thus gathered from patients is however not for the sole benefit of care science, as the last presentation of session 2 highlighted, but has also led to important discoveries on how certain environmental factors influence disease development.

Session 1: Mechanisms and therapeutic mechanisms

Opening the first session of the day, Håkan Westerblad raised the question whether the decreased muscle strength observed in RA is solely due to the lack of physical activity, itself caused by the pain experienced by RA patients. He presented data recently generated in his group, where, using a collagen-induced arthritis model in mice, he and his colleague have observed an increased presence of reactive oxygen and nitric oxide species in muscle fibers from affected mice.
Christian Lood, a PhD student in Gunnar Sturfelt’s group, then described his work on the bacterial enzyme EndoS in the context of immune activation by immune complexes in SLE. EndoS is known to modify the Fc part of immunoglobulins, and C. Lood showed that incubation of serum from SLE patients containing immune complexes with EndoS abrogated the serum’s ability to activate complement, attract polymorphonuclear cells or induce IFNα production by plasmacytoid dendritic cells (pDCs).
Following up on the subject of type I IFN production by pDCs, an important pathway implicated in SLE pathogenesis, Olof Berggren, a PhD student in Lars Rönnblom’s group, shared his findings on the capacity of B cells to enhance IFNα production by pDCs. Indeed, while the effect of pDC-derived IFNα on B cells maturation and differentiation is well studied, less is known about the reverse, that is, about potential influence of B cells on pDCs. O. Berggren and colleagues are currently trying to elucidate the mechanisms by which B cells seem to modulate the production of type I IFN by pDCs.

Velmurugesan Arulampalam, a researcher in Sven Pettersson’s group, opened the second part of the session by introducing the audience to the question of how the gut microbiota may influence host physiology. How commensal bacteria living in an organism’s gut may influence the organism’s physiological responses, and in particular how it affects its immune system, has attracted the attention of an increasing part of the scientific community in the last few years. Within the COMBINE program, members of Sven Pettersson’s group will study the interaction host-microbiota in the context of chronic inflammatory diseases.
Taking the audience back to the detailed study of pathogenic mechanisms in RA, Sabrina Haag, a post-doctoral fellow in Rikard Holmdahl’s group, presented her recent work on citrulline-immunity in collagen-induced arthritis (CIA) in mice. While the presence of autoantibodies to citrullinated antigens is well recognized and well studied in humans, little is known about the existence and relative importance of a citrulling-specific immune response in animal models of RA. Sabrina Haag and colleagues showed that citrulline-specific antibodies were indeed raised during the course of CIA, indicating that a prominent feature of human RA is also present in this animal model of arthritis. These interesting findings open new avenues to analyse in detail the development of anti-citrulline responses in relation to disease progression, but also for the study of how environmental factors may impact anti-citrullinated peptide antibodies development in a controlled animal model.
Finally, Hans Carlsten Ulrika Islander, Anna Börjesson and Marie Lagerquist discussed the use of selective estrogen receptor modulators (SERMs) to potentially treat post-menopausal RA, as they are currently testing the effect of new SERMs on arthritis severity in animal models and investigating the molecular pathways involved.

Session 2: Early RA, ethics and patient involvement

Taking up the first theme of the day, physical activity in RA patients, but leaving the molecular level to turn towards patients’ health management, Åsa Revenäs, a PhD student in Christina Opava’s group, presented her project on health care intervention for the maintenance of physical activity in patients with RA. Her project will build on patients’ innovations and aims at identifying specific tools used by patients to change behaviour and implement a physical activity program, highlighting the importance of the involvement of patients in the development of better treatment strategies.
Continuing in the theme of health care, Anita Domargård described the benefits of coaching to implement changes in the health care system and help all the people involved, from patient to medical staff, to commit to the changes and together improve the value and the quality of health care.
Joanna Tingström, a PhD student in Marie Wahren-Herlenius’ group, offered yet another example of how researchers can reach out to patients, collect and analyze the information obtained from the patients’ experiences, with the final aim of reaching back to the patients and medical staff with suggestions and means for the improvement of health care. Through her interviews of women giving birth to a child with heart block, she identified lacks in the current health care system as experienced by these women, and generated information that will guide the changes to be implemented to offer better help and information to both patients and health care professionals.

Closing the session with the topic of early RA, Karin Lundberg presented data generated through the use of the EIRA cohort, which is comprised of individuals newly diagnosed with RA. The EIRA project, initiated in 1996, has allowed the investigation of the influence of genetic and environmental factors on RA development in the Swedish population. More particularly, the HLA-DRB1 shared epitope and smoking are now known to associate with ACPA (anti-citrullinated peptide antibody)-positive RA. Karin Lundberg is now focusing her investigations on unravelling the different specificities of ACPAs to progress further in the understanding of RA ethiopathology. The long-term hope of scientists like K. Lundberg is to render interventions earlier in the course of disease development possible and develop means to control potentially dangerous immune responses before they turn out pathogenic.

Session 3: Ethiology and genetics

Gunnel Normark opened the last session of the day by discussing candidate susceptibility genes in primary Sjögren’s syndrome (pSS). Besides HLA genes, which show the highest association, genes encoding the transcription factors IRF5 and STAT4 as well as the tyrosine kinase BLK have been confirmed to be associated with pSS. Recently, additional susceptibility genes have been uncovered, including genes encoding EBF1 and TNFSF4 (also denoted Ox40L), molecules known to be involved in B cell differentiation and activation.
Rikard Holmdahl then presented data from a large-scale genetic study performed on heterogeneous stock and aimed at identifying loci implicated in experimental arthritis and osteoporosis. The use of heterogeneous stock is a powerful method to identify haplotype loci controlling specific features, such as bone mineral density. Following the identification of candidate genes associated with arthritis and osteoporosis development and severity, the role of these genes in the development of these pathologies will be studied in detail.

Leaving the world of genetics, Malin Erlandsson, a scientist in Maria Bokarewa’s group, talked about the use of the S100A4 protein as a marker of active arthritis.
Finally, Vivianne Malmström ended the annual COMBINE meeting by presenting recent data generated in her group that open new avenues to investigate the pathogenicity of anti-citrullinated peptide antibodies (ACPAs). Specific ACPAs are known to be enriched in the rheumatic joint compared to serum from the same patients, but the questions so far remain, whether these antibodies are a cause or consequence of RA pathogenesis, and if indeed pathogenic, whether all specificities contribute to disease. Monoclonal antibodies derived from memory B cells present in the joint of RA patients and reactive to citrullinated peptides have now been generated by Khaled Amara, a postdoctoral fellow in V. Malmström’s group. Further characterization of these antibodies as well as use in animal transfer experiment offer exciting possibilities to advance in the understanding of the role of ACPA in RA development.

Concluding remarks

Over the course of the day, the participants to the 2011 COMBINE scientific meeting had the opportunity to hear of recent advances in many of the projects supported by the COMBINE initiative. Topics ranging from basic experimental research to care science, from animal models to human biology, from genetics to cellular immunology, were discussed. Altogether, the meeting highlighted the diversity of approaches supported by COMBINE to improve the current understanding of how inflammatory diseases develop and how new therapies for these diseases can be developed and implemented.