Though few, plasma cells secrete large amounts of antibodies, and are thus crucial to the body’s fight against pathogens. To maintain its small but potent plasma cell cadres, the body relies on signaling molecules to sustain plasma cell production. Signaling molecules also influence the long-term survival of plasma cells. By identifying these signaling molecules, scientists hope to improve the design of vaccines. Tapping into the body’s signaling pathways could also point to therapies for autoimmune diseases.

Scientists from A*STAR’s Bioprocessing Technology Institute (BTI) recently uncovered details about two signaling molecules with previously unknown functions in maintaining plasma cell differentiation and long-term survival. One of these signaling molecules, the adaptor Downstream-of-Kinase 3 (DOK3), was known to participate in early B-cell development. Now, however, it has been shown to promote the production of plasma cells.

This result appeared August 5 in the Proceedings of the National Academy of Sciences, in an article entitled “Adaptor protein DOK3 promotes plasma cell differentiation by regulating the expression of programmed cell death 1 ligands.” Interestingly, the article unraveled a mechanism that relied, in part, on the effects of calcium signaling.

While calcium signaling typically controls a wide range of cellular processes that allow cells to adapt to changing environments, it was found to inhibit the expression of the membrane proteins essential for plasma cell formation. These membrane proteins include programmed cell death ligands (PDL1 and PDL2), and represent some of the key targets for the development of immunotherapy by pharmaceutical companies. DOK3 was able to promote the production of plasma cells by reducing the effects of calcium signaling on these membrane proteins.

“Abrogation of calcium signaling in B cells by deleting BTK or PLCγ2 or inhibiting calcineurin with cyclosporine A leads to increased expression of PD-1 ligands,” wrote the authors. “Thus, our study reveals DOK3 as a nonredundant regulator of PC differentiation by up-regulating PD-1 ligand expression through the attenuation of calcium signaling.”

In another study, BTI scientists discovered the importance of SHP1 signaling to the long-term survival of plasma cells. While the molecule SHP1 has a proven role in prevention of autoimmune diseases, it was found that the absence of SHP1 would result in the failure of plasma cells to migrate from the spleen, where they are generated to the bone marrow, a survival niche where they are able to survive for much longer periods.

This finding appeared June 30 in Nature Communications, in an article entitled, “Shp1 signaling is required to establish the long-lived bone marrow plasma cell pool.”

“We have deleted Shp1 specifically in activated B cells, and this leads to hyperactivation of Src family kinase and PI3-kinase signaling and manifests exaggerated α4β1 binding affinity,” wrote the authors. “Both kinases are important in mediating cell migration, and dysregulation of these kinases might be responsible for the PC defects seen in Ptpn6f/fAicdaCre/+ mice. Dysregulated integrin signaling deters PCs from migrating from the site of generation to the long-lived niche in the bone marrow.”

Such dysregulation, the researchers noted, could result in a reduction of the body’s immune response and thus, an increased susceptibility to infections and diseases. To rectify a defective immune response caused by an absence of SHP1, the researchers applied antibody injections. This approach might advance the development of therapeutics. Alternatively, the researchers indicated, targeting SHP1 might be a strategy to treat multiple myeloma where the accumulation of cancerous plasma cells in the bone marrow survival niches is undesirable.

The DOX3 and SHP1 discoveries suggest new targets for modulating the antibody response and may advance the development of novel therapeutic strategies for patients with autoimmune diseases and cancer. Understanding the mechanism that governs plasma cell differentiation is also critical for the optimal design of vaccines and adjuvants, which are added to vaccines to boost the body's immune response.

Professor Lam Kong Peng, executive director of BTI, said, “These findings allow better understanding of plasma cells and their role in the immune system. The identification of these targets not only paves the way for development of therapeutics for those with autoimmune diseases and multiple myeloma, but also impacts the development of immunological agents for combating infections.”