Immunoregulatory Mechanisms in Systemic Lupus
In lupus, immune cells known as B cells release proteins called antibodies that attack patients’ own tissues. But several types of immune cells, including regulatory T and B cells, can block production of these antibodies and prevent lupus development in mice. Dr. Kuchroo and his colleagues had previously found that regulatory T and B cells make a protein called fibrinogen-like protein 2 (Fgl2) that curbs B cells’ production of destructive antibodies. In their new study supported with the Distinguished Innovator Award, they will determine how Fgl2 prevents B cells from making antibodies that target patients’ tissues and how it protects against lupus. In addition, regulatory T and B cells carry proteins on their surface, including one known as TGIT, that act as on-off switches. TGIT also stimulates regulatory T and B cells to make Fgl2. Another aim of their study is to determine whether TGIT and similar protein switches have a role in the development of lupus. Their findings could suggest new approaches for treating lupus by stimulating regulatory T and B cells, possibly through TGIT.
What this study means for people with lupus
Harmful immune cells cause the symptoms of lupus, but helpful immune cells called regulatory T and B cells may prevent them. Dr. Kuchroo wants to find out more about how certain types of regulatory T and B cells work, which might reveal whether we can use them for lupus treatment.
Lupus is caused by dysregulated self-reactive T and B cell responses and characterized by high titer autoantibodies against nuclear antigens, which affects multiple end-organs. A defect in clearing apoptotic bodies in induction of lupus has been well documented but we are postulating that a defect in regulatory mechanisms that are induced by sensing apoptotic bodies may be equally at fault in the disease. Besides effector T cells, a specialized subset of FoxP3 Treg cells called follicular Tregs (TFR) is critical in regulating antibody production. In addition, we have identified a sub-population of B cells that expresses cell surface molecule Tim-1 that not only identifies a regulatory population of B cells but is also required for their function. Of note, Tim-1 is a cell surface molecule that binds to Phosphatidyl serine (PS) on apoptotic bodies and induces IL-10 production. Mice with a Tim-1 defect display impaired B cell regulatory function and develop a lupus-like disease. By RNAseq analysis we identified that both TFR and Tim-1+ Bregs highly express a soluble suppressive molecule called Fibrinogen-Like protein 2 (Fgl2). Consistent with this data, we found that Fgl2-/- mice with age develop a lupus-like disease with increased production of autoantibodies against multiple nuclear antigens. Therefore, we hypothesize Fgl2 from both TFH and Tim-1+ B cells is critical in regulating autoantibody production and lupus development by acting through inhibitory Fc receptors. In addition to the production of Fgl2, both TFH and Tim1+ B cells highly express a panel of co-inhibitory “checkpoint” molecules including TIGIT. Interestingly, our preliminary data suggests that TIGIT in both TFR and Tim1+ B cells may regulate production of Fgl2, suggesting that TIGIT besides directly suppressing effector T cells in a cell-intrinsic manner can also promote induction of Fgl2 to suppress other cells in the micro-environment. Our preliminary data therefore suggests that TIGIT-Fgl2 forms an axis to regulate autoreactive T and B cells by cell-intrinsic and cell extrinsic mechanisms. Based on our preliminary data, we hypothesize that TFR and Tim-1+ B cells may synergize and used shared mechanisms to regulate autoantibody production and development of lupus. We propose two major aims to understand the mechanisms by which TFR and Tim-1+ B cells regulate Lupus: 1. Study the Role of Fgl2 in TFR and Tim-1+ B cells in regulating autoantibody production and lupus development; 2) study the role of checkpoint receptors especially TIGIT expressed on TFR and Tim-1+ B cells in the disease development. Understanding the mechanisms by which Fgl2 suppresses autoantibody responses and how check-point molecules like TIGIT can be activated to promote cell intrinsic and cell-extrinsic inhibitory functions will provide means by which to promote peripheral tolerance and identify novel therapeutic strategies for treating lupus.