Scientific Background

Autoimmune diseases are chronic conditions initiated by the loss of immunological tolerance to self-antigens, leading to self-attack of the immune system on one’s organs. Although differing from each other, autoimmune diseases present several shared common phenotypes: the presence of nonspecific autoantibodies [i.e., antinuclear antibodies and double-strand DNA (dsDNA)], high levels of cytokines, and the presence of infiltrating immune cells. Anti-dsDNA is a known hallmark of lupus and other autoimmune diseases, but it is not only a disease marker, it also promotes autoimmunity. The presence of dsDNA in the cytoplasm has been described as a potent danger signal that activates stimulator of interferon genes (STING), a regulator of the immune response (1). Activating STING leads to a signaling cascade that eventually alters pro-inflammatory molecule production. A defect or unnecessary alert in this mechanism has been described as underpinning the auto-inflammatory process (2). One source of dsDNA is related to the production of neutrophil extracellular traps (NETs). Activated neutrophils extrude their DNA and bactericidal molecules, creating NETs in a unique type of cell death called NETosis (3). Neutrophils from patients with various autoimmune diseases are more likely to undergo NETosis than those of healthy donors (4). Moreover, the presence of autoantibodies promotes the release of NETs.
Adenosine is a potent modulator of lymphocyte development, proliferation, and activity (5-7). There are four types of adenosine receptors, all of which are members of the G protein-coupled receptor family: A1, A2A, A2B, and A3. The A1 (A1R) and A3 receptors (A3R) activate Gi, which inhibits adenylyl cyclase activity and decreases cAMP levels and promote pro-inflammatory response. A2A receptor (A2AR) interacts with Gs, and the A2Breceptor (A2BR) interacts with Gs/Gq to induce adenylyl cyclase activity and elevates cAMP levels, thus, promoting anti-inflammatory responses (3). A1R exerts the highest affinity for adenosine, and it is the first to react in the early phase of inflammation, while Gs-coupled A2AR is related to immunosuppression and resolution of inflammation.
Adenosine receptors expressed on a wide variety of both non-immune and immune cells (8) and all four adenosine receptors have been described on neutrophils (9). A1R stimulation enhances their adherence to endothelium, chemotaxis (8), and their activity (10), while A2AR inhibits neutrophil trafficking and effector functions such as oxidative burst, inflammatory mediator production, and granule release (reviewed in (11, 12)). Multiple reports suggest that the onset of autoimmune disorders is at least in part related to a partial or complete loss of function in the purinergic pathways and to local defective production of adenosine (reviewed in (9)).
In a model of SIRS, we have previously shown that a surge of adenosine desensitizes Gi-coupled adenosine A1R and upregulates Gs-coupled A2AR, an effect that provokes a cAMP-dependent lymphotoxic response. The depletion of lymphocytes and their functional impairment has been thought to be part of the pathology in SIRS that worsens recovery and decreases chances of survival (13). We now suggest that adenosine-dependent lymphocyte depletion observed in SIRS might be a normal physiological mechanism that minimizes lymphocyte exposure to self-antigens to reduce the prevalence of autoimmunity.
In the current study, we aimed to evaluate the protective role A1R and A2AR have in the prevention of autoimmune diseases.