Background/Purpose:

Systemic sclerosis (SSc) is a connective tissue disorder that is characterized by fibrosis and vascular damage in the skin and other visceral organs, with an autoimmune background. One of the cause of vasculopathy is thought to be the repair dysfunction of damaged vessels. Actually, endothelial progenitor cells in peripheral blood mononuclear cells (PBMCs) of SSc were reported to be reduced. However, the mechanism of these reduction is unclear. Recent studies have indicated that B cells play critical roles in systemic autoimmunity and disease expression through various functions such as activation of other immune cells in addition to autoantibody production. Several studies have also shown that B cells activated in SSc produce IL-6, which induces fibrosis. Indeed, Rituximab (RTX), a B cell depleting antibody, or Tocilizumab (TCZ), anti-IL-6 receptor (IL-6R) antibody, can ameliorate many autoimmune diseases including SSc. Here, we focused on the relationships between endothelial colony forming cells (ECFCs), and autoantigen-reactive B cells in SSc.

Methods:

In SSc patients treated with RTX, TCZ, or oral steroid, we analyzed nailfold capillary changes over time. We also compared the number of ECFCs in PBMCs before and one year after treatment. In mouse study, we assessed the relationship between Topo I reactive B cells and ECFCs with or without contact, using topo I and complete Freund’s adjuvant-induced SSc model mice (Topo I model). We also analyzed activated signaling pathway after contact with Topo I reactive B cells and ECFCs. Finally, the effect of B cell depletion treatment or anti-IL-6R antibody treatment to vasculopathy and ECFCs in Topo I model mice was assessed.

Results:

Both B cell depletion treatment and anti-IL-6R antibody treatment improved ulcer healing, promoting neovascularization. The number of ECFCs in PBMCs of SSc patients, which was reduced before treatment, increased after one year of RTX treatment or TCZ treatment. In particular, the number of ECFCs after RTX treatment increased as many as healthy controls. In Topo I model mice, the number of ECFCs was reduced compared with controls. The experiment with recombinant cytokines or neutralizing antibody revealed that this reduction of ECFCs is caused by cytokines such as IL-6, TNF-α, CCL3, and CCL4 from Topo I reactive B cells, which were activated by direct interaction with ECFCs. In contract, IL-10 production, which promotes colony formation of ECFCs, from Topo I reactive B cells was reduced compared with Topo I non-reactive B cells. This direct interaction activates B cell receptor (BCR) pathway such as SYK, BTK, PLCγ2, TRAF6, and NF-κB. In Topo I reactive B cells, IL-6-JAK2-STAT3 pathway is also activated. These results suggest that activated both BCR pathway and IL-6-JAK2-STAT3 pathway are crucial in activation of Topo I reactive B cells and suppression of ECFCs. Finally, both B cell depletion and anti-IL-6R antibody treatment also increased ECFCs, suppressing vasculopathy in Topo I model mice.

Conclusion:

Decreased number of ECFCs is closely related to vasculopathy of SSc. Autoreactive B cells, these signaling pathways, cytokines, and drugs which can increase ECFCs can be novel therapeutic targets in vasculopathy of SSc.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/direct-interaction-between-autoreactive-b-cells-and-endothelial-colony-forming-cells-induces-cytokine-production-from-b-cells-through-b-cell-receptor-and-il-6-jak2-stat3-signaling-pathway-suppressing/