Translational Rheumatology Research Program
We pursue excellence in outstanding patient care through innovative research and education for the benefit of people affected by rheumatic diseases. Translational Rheumatology is focused on the innate and adaptive immune mechanisms that contribute to the onset, progression, persistence and regulation of systemic autoimmune diseases.
By seeking better understanding mechanism and novel treatment approaches for rheumatic diseases, we also create an environment for rewarding creativity and learning for the next generation of rheumatologist, ultimately improving quality of service and patient outcomes.
T cell homeostasis in the pathogenesis of Autoimmune Disease
Systemic lupus erythematosus (SLE) or Rheumatoid Arthritis (RA) are chronic autoimmune diseases characterized by the production of autoantibodies, binding with self-antigens and potentially causing tissue damage. These high affinity autoantibodies are usually present prior to clinical manifestations, indicating the breakdown of B cell tolerance which causes the expansion of autoreactive B cells and generation of autoreactive plasmablasts. Although there have been many recent advances in the development of therapies for SLE and RA, inadequate responses and therapy resistance are common (30-40%), remission is rarely achieved or sustained. The main root of inadequate or non-responsive outcome is incomplete killing of self-reactive B cells residing in the synovium, B cell-infiltrated tissue, and plasmablasts/plasma cells in the peripheral sites (such as synovium and blood). With the cognate help from T cells, these B cells and plasmablasts are able to survive, expand and differentiate in synovial membranes and the peripheral blood, ultimately produce antibodies and cause tissue/joint damage.
Effective immunologic homeostasis relies on a continual balance in helper T cell activation and regulatory T cell suppression. When homeostasis is disrupted and immune system tips in favor of activation, the host becomes susceptible to autoimmunity. Although it is traditionally believed that many autoimmune are resulted from an aberrant Th1 response via interferon-γ. However, several studies in mice demonstrated the resistance to interferon-γ treatment in autoimmune disorders, which put the role of Th1 lineage in autoimmune pathogenesis into question. Furthermore, discoveries the other T cell subsets (such as Tfh, Th17, and Treg cells) finally break the long accepted concept about T cells subsets in autoimmunity.
Follicular helper T cells (Tfh), recently identified as a special T cell subset expressing master transcription factor Bcl-6, is responsible for autoimmunity by helping memory B cell proliferation to produce self-reacting high affinity antibodies. Studies from our group have contributed significantly to the new field of Tfh cells on autoimmune diseases, such as SLE or RA. We demonstrated that circulating T follicular helper cells (Tfh cells) in SLE and RA patients shared similar phenotype and functional properties with normal Tfh cells resides on the secondary lymphoid tissue. The accumulated Tfh cells in the peripheral blood and synovial fluid of active SLE and RA patients correlated with the high level of plasmablasts, titer of specific autoantibody, and disease severity in RA and SLE patients. Our in vivo experiments showed that the circulating Tfh cells not only increased in SLE and RA patients, functionally support B cells differentiation to antibody secreting plasma cells. Our studies break down old paradigms concerning the dominant role of Th1 cells in autoimmune disorders, and bridge the knowledge gap of T cell lineages on SLE/RA pathogenesis, and will lead to design customized specific therapies targeting Tfh cells that provide foster environment for auto-reactive B cells.
In summary, our research goal is to address the cellular and molecular mechanism responsible for the survival of autoreactive B cells, the modulation of autoantibody production, and persistent inflammation, ultimately lead to design customized specific therapies targeting foster environment for auto-reactive B cells and give hope to those patients unresponsive to traditional treatment.
- The role of T cell subsets (especially Tfh cells) in the pathogenesis of SLE and RA.
- Develop specific biological therapy targeting Tfh cells and block autoantibody production in SLE and RA
- The role of Tfh and Th17 cells in obesity-associated lupus pathogenesis
Support the Research Work
A gift to our Experimental Rheumatology laboratory helps support our research and develop novel treatment to patients with SLE, RA, or other autoimmune diseases.