|M.Sc Student||Sela Sapir|
|Subject||The Role of Scavenger Receptor-B1 in the Regulation of|
Autoimmunity in the Gut
|Department||Department of Medicine||Supervisor||Professor Nathan Karin|
|Full Thesis text|
Inflammatory bowel disease is an autoimmune syndrome of the gastrointestinal tract. While the etiology remains unclear, studies have indicated that it is caused by an immunological disorder in which the immune response towards commensally bacteria and/or luminal antigens is dysregulated. During this chronic inflammation, the balance between pro and anti-inflammatory cells is dysregulated, as regulatory T cells and M2 macrophages fail to inhibit the activity of effector T cells and M1 macrophages.
Our laboratory previously showed that during autoimmune diseases the immune system develops an autoantibody based immune response to key chemokines and cytokines that participate in the regulation of these diseases. Others in the lab observed an autoantibody response to several cell surface molecules, among them scavenger receptor Class B type 1 (SR-B1). These autoantibodies showed anti-inflammatory properties. Epitope mapping showed that these autoantibodies bind a single 11AA epitope within the SR-BI receptor, with no cross-reactivity to other known epitopes.
Scavenger receptors (SRs) are a group of transmembrane proteins that bind to a large variety of ligands including HDL and unmodified lipoproteins, as well as conserved microbial structures such as bacterial lipopolysaccharide. SR-B1 has a vital role in the uptake of HDL cholesterol in many tissues as well as in pathogen recognition.
Based on the above, our laboratory generated a mAb to the 11AA epitope recognized by the anti SR-B1 autoantibodies. We named it E12 mAb. Preliminary observations in our lab suggested that E12 mAb holds an agonistic function on macrophages and CD4 T cells, while directing their polarization into Tr1 cells and M2c like macrophages. In a set-up of experimental autoimmune encephalomyelitis (EAE) these cells could be identified at the site of inflammation in the CNS, which may well explain the therapeutic effect of E12 mAb.
In this study, we used DSS-induced IBD mouse model in order to explore the role of E12 mAb in the polarization of macrophages In-vitro, as well as the therapeutic potential and mechanism of action of the mAb. In this study, we have shown that E12 mAb treatment of macrophages In-vitro shifts the polarization of macrophages from M1 to M2 in a MAPK/ERK pathway, suggesting an agonistic effect of the mAb on SR-B1. We have also demonstrated a strong therapeutic effect of E12 mAb on IBD bearing mice. Finally, we have shown that this effect is correlated with activation of Tr1 cells and the polarization of M2c macrophages in lymphoid tissues of treated mice. Interestingly, my study shows that in IBD the therapeutic effect of E12 mAb is not necessarily associated with the accumulation of these cells at the site of inflammation. It is therefore likely that Tr1 cells may suppress T effector cells via producing IL-10 at the spleen and MLN from which effector T cells migrate to the site of inflammation. Here, we report a robust clinical effect of E12 mAb on IBD-bearing mice, implying the protective role of SR-B1 in gut autoimmunity, and suggest a possible mechanism for the suppressive function of E12 mAb treatment.