The role of B-cells in the pathogenesis of osteoarthritis
Ageing is a complex phenomenon. It affects cells and tissues, diminishes homeostasis and increases vulnerability. Many pathways have been shown to be involved in ageing and age-related diseases, including osteoarthritis (OA). In elders, infectious diseases are the primary cause of death, underpinning the role of the immune system. The acquired immune responses decline with age (increased susceptibility to infection, poor responses to vaccination, higher prevalence of cancers). In addition, there is intrinsic difficulty in dealing with common pathogens and a disproportionate inflammatory response. Paradoxically, this decline is accompanied by an increase in auto-reactivity (generation of autoantibodies) and chronic low-grade inflammation, which acts as predictor of mortality. Inflammatory response are so prevalent in driving tissue damage associated with age-related diseases that the term "Inflammageing" has been coined to explain the underlining inflammatory changes common to most age-associated diseases.
OA is a degenerative joint disease whose prevalence increases with age, and includes a group of pathologies involving structural degeneration of the joint resulting in pain and disability. Treatment is currently limited to the management of pain, exercise and lifestyle modification, and ultimately joint replacement surgery. There is evidence of OA in all individuals over the age of 60 but symptomatic OA, (disease that requires medical treatment), occurs in only 15%. The reasons why OA only becomes symptomatic in some people remain unexplained.
Recent magnetic resonance imaging studies have highlighted a very high frequency of pathology involving cartilage, bone and synovium (soft tissue lining of the joints), with relevance in structure-pain associations. Inflammation of the synovium (synovitis) is a well-recognised feature of OA, notably with an important role for interleukin-1beta (IL-1β). Many of the age-related defects of the immune system highlighted above are involved in the pathogenesis of OA. Furthermore, mechanical forces which produce cartilage damage breakdown products have been proposed as a source of immune stimulation, promoting persistent low-grade inflammation. Antigen-driven stimuli using collagen breakdown products as neo-antigens were suggested to lead to specific T/B-cell responses. Innate immune responses to calcium crystal deposition were shown to initiate IL-1β production.
Our project hypothesizes that the interactions between the musculoskeletal and the immune system are important sources of divergence between healthy people and patients with OA. We postulate that they can be used to better understand the pathology of OA by distinguishing ageing specific changes from those that are OA specific. We recently showed that the immune cell composition of the blood of OA patients is quite divergent from that of aged-matched controls notably with major changes in CD4/CD8 T-cells, loss of regulatory T-cells and alteration in the T to B-cell ratio. Synovitis has been proposed as niche for B-cell maturation and the production of auto-antibodies in OA. However, B-cell infiltration in OA is quite independent of T-cells and the presence of germinal centre like structures is rarely observed.
We are proposing to investigate the mechanism of auto-reactive B-cell development in OA under the hypothesis that it is T-cell independent and uses alternative maturation signals brought in by the innate immune system. The IgM repertoire is quite broadly developed (targeting many auto-antigens in health even at a younger age), however maturation of IgG is achieved with the help of T-cells. In ageing (and OA) T-cell help is defective and alternative signals can be used to mature B-cells. These include signals from the innate immune system, such as those provided by the activation of TLR on B-cells which result in the expression of the XBP-1 transcription factor, an essential regulator of B-cell maturation.
The events leading to B-cell maturation and isotype switching are known and steps are reproducible in vitro. B-cell cultures will be used to establish the role of TLR activation on B-cell maturation and effect on the activation of XBP-1. Gene expression profiling will address the pathways implicated in this alternative maturation process including XBP-1 and genes of the B-cell receptor and immunoglobulin rearrangement pathways. These profiles will be compared to those obtained from B-cell cultures stimulated with T-cell help signals (CD40::CD40L). Selected genes will then be tested in B-cells purified from the blood from healthy controls and OA patients and from OA synovial tissue to assess the mean by which B-cells mature and produce IgGs (i.e. T-cell dependent or independent pathways).
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Applications will also be considered from Self-Funded Students. If you have the correct qualifications and access to your own funding, either from your home country or your own finances, your application will be considered for this project. However, tuition and bench fees will be payable for this project.
F Ponchel, AN Burska, EA Hensor R Raja, M Campbell, P Emery, PG Conaghan. Changes in peripheral blood immune cell composition in osteoarthritis. Osteoarthritis and Cartilage, in press, doi: 10.1016/j.joca.2015.06.018