Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of synovial membranes and progressive joint destruction. In RA, B cells produce large amounts of IgM as well as class switched IgG and IgA that, by accumulating in the joints as highly reactive immunocomplexes, play a central role in the pathogenesis of synovitis. The mechanisms underlying the dysregulation of Ig class switching and antibody production in RA patients remain elusive. Human B cells initiate class switch DNA recombination (CSR) and antibody production upon engagement of CD4O by CD154 (CD4O ligand), a molecule expressed by T cells a few hours after activation by antigen. Later on, T cells express CD3O, a TNF receptor family member that negatively modulates both T and B cell immune responses. Engagement of T cell CD30 by B cell CD153 (CD30 ligand) inhibits CD40-mediated CSR and antibody production in two ways: by interfering with the CD40 signaling pathway and by hampering the CD3-mediated up-regulation of CD154. Dendritic cells reverse the CSR-inhibitory activity of CD3O+ suppressor T cells by inducing metalloprotease (MP)-dependent down-regulation of CD30. The long-term objective of this project is to assess the role of CD30:CD153 interaction in the pathogenesis of RA. We hypothesize that, in RA patients, the increased production of pathogenic antibodies stems from the profound dysregulation of the CD30:CD153-dependent inhibitory pathway. This may result from the ability of DC-like RA synoviocytes to impair the synovial pool of CD30 suppressor T cells by eliciting rapid MP-dependent cleavage of CD30. The relevance of this phenomenon in the pathogenesis of RA is supported by the observation that RA patients display increased levels of synovial soluble CD3O that positively correlate with the levels of circulating rheumatoid factor as well as with the disease activity. The following specific aims will address the role of CD30:CD153 interaction in the pathogenesis of RA.
Aim 1. Analyze the expression, requirements and function of CD30 in RA T cells, and evaluate the mechanisms by which CD30 signaling down-regulates CD154.
Aim 2. Analyze the ability of CD30:CD153 interaction to inhibit Ig class switching in CD154-activated B cells, and evaluate its possible dysregulation in RA.
Aim 3. Analyze the ability of CD30:CD153 interaction to inhibit the CD154-mediated activation of RA synoviocytes, and evaluate the ability of synoviocytes to reverse the inhibitory activity of CD30+ T cells. In addition to elucidating the pathogenesis of RA, the experiments outlined in this application should allow to devise new strategies aimed at reducing the production of pathogenic antibodies, including rheumatoid factors.
|Boiocchi, Leonardo; Witter, Rosanny Espinal; He, Bing et al. (2012) Composite chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma are biclonal lymphomas: a report of two cases. Am J Clin Pathol 137:647-59|
|Cerutti, Andrea; Qiao, Xugang; He, Bing (2005) Plasmacytoid dendritic cells and the regulation of immunoglobulin heavy chain class switching. Immunol Cell Biol 83:554-62|
|He, Bing; Qiao, Xugang; Cerutti, Andrea (2004) CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J Immunol 173:4479-91|
|He, Bing; Chadburn, Amy; Jou, Erin et al. (2004) Lymphoma B cells evade apoptosis through the TNF family members BAFF/BLyS and APRIL. J Immunol 172:3268-79|
|Schaffer, Andras; Kim, Edmund C; Wu, Xiaoping et al. (2003) Selective inhibition of class switching to IgG and IgE by recruitment of the HoxC4 and Oct-1 homeodomain proteins and Ku70/Ku86 to newly identified ATTT cis-elements. J Biol Chem 278:23141-50|
|He, Bing; Raab-Traub, Nancy; Casali, Paolo et al. (2003) EBV-encoded latent membrane protein 1 cooperates with BAFF/BLyS and APRIL to induce T cell-independent Ig heavy chain class switching. J Immunol 171:5215-24|
|Litinskiy, Mikhail B; Nardelli, Bernardetta; Hilbert, David M et al. (2002) DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol 3:822-9|
|Cerutti, Andrea; Zan, Hong; Kim, Edmund C et al. (2002) Ongoing in vivo immunoglobulin class switch DNA recombination in chronic lymphocytic leukemia B cells. J Immunol 169:6594-603|