The Complexity of Soluble Checkpoint Molecules in Modulating Immune-Mediated Diseases and Autoimmunity

For many decades, the regulation of immune responses, namely, the maintenance of self-tolerance and the prevention of pro-inflammatory processes, was attributed to the suppressive function of T and/or B regulatory cells. However, the field of immune regulation was recently expanded to include not only many membrane-bound regulatory molecules on immune cells but also the release of many soluble molecules playing a role in the modulation of immune responses. Soluble checkpoint molecules are the subject of many recent studies, in which they were reported to function as both regulatory and stimulatory molecules. They are involved in the pathogenesis of immune-mediated disorders, infections, and cancer, and are involved in balancing immune effector responses with regulatory reactions. Many of them have become relevant targets in treating these diseases. In this review, we chose to focus on those soluble molecules whose role is attributed to immune-mediated diseases, namely in modulating autoimmunity by enhancing mechanisms of self-tolerance and immunosuppressive signals. The understanding of these mechanisms might facilitate the development of future therapeutic approaches.