Dysregulation of Adenosinergic Signaling in Systemic and Organ-Specific Autoimmunity

Abstract

Exact causes for autoimmune diseases remain unclear and no cures are available. Breakdown of immunotolerance could set the stage for unfettered immune responses that target self-antigens. Impaired regulatory immune mechanisms could have permissive roles in autoreactivity. Abnormal regulatory immune cell function, therefore, might be a major determinant of the pathogenesis of autoimmune disease. All current treatments are associated with some level of clinical toxicity. Treatment to specifically target dysregulated immunity in these diseases would be a great advance. Extracellular adenosine is a signaling mediator that suppresses inflammation through activation of P1 receptors, most active under pathological conditions. Mounting evidence has linked alterations in the generation of adenosine from extracellular nucleotides by ectonucleotidases, and associated perturbations in purinergic signaling, to the immunological disruption and loss of immunotolerance in autoimmunity. Targeted modulation of the purinergic signaling by either targeting ectonucleotidases or modulating P1 purinergic receptors could therefore restore the balance between autoreactive immune responses; and thereby allow reestablishment of immunotolerance. We review the roles of CD39 and CD73 ectoenzymes in inflammatory states and with the dysregulation of P1 receptor signaling in systemic and organ-specific autoimmunity. Correction of such perturbations could be exploited in potential therapeutic applications.

Keywords: T-cell; adenosine; adenosine receptor; autoimmunity; ectonucleotidase.

Figure 1

Immune and purinergic dysregulation in systemic lupus erythematosus (SLE) and autoimmune hepatitis (AIH). (A) In SLE, defects in ENTPD1/CD39 expression and impaired Treg function have been associated with loss of peripheral tolerance. Studies conducted in active SLE patients have indicated impaired suppression of B-cell differentiation and identified the abnormal generation of regulatory T-cells (Treg) as result of limited transition from inducer/helper to suppressor phenotype. Upregulation of A2AR is detectable in SLE patients, likely being linked to activation of compensatory pathways. (B) In type 1 autoimmune hepatitis (AIH-1), CD39⁺ Treg cells display impaired suppression of IL-17 production by CD4⁺ effectors. Acute AIH patients present a low ratio between Tregs and NK bright cells, a specific NK subset with activated effector phenotype. Activated memory phenotype and signs of exhaustion, including increased CTLA-4 and PD-1 levels are also typical of AIH Tregs. Reduced CD39⁺ Treg and CD39⁺ Th17-cell frequencies positively correlate with the disease progression and might result from cell instability upon pro-inflammatory challenge, with increased rate of conversion into effector lymphocytes. The reduction in CD39⁺ Th17-cell numbers, also associates with lower A2AR expression (see text below).

Figure 2

Purinergic-based therapeutic strategies. (A) Administration of exogenous apyrase strongly ameliorates dextran-sulfate-sodium (DSS) colitis in ENTPD1/CD39^−/− mice. (B) In experimental murine diabetes models, treatment with the nonselective adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) prevents diabetes development by suppressing expression of pro-inflammatory cytokines by activated splenic cells. (C) In rat models of adjuvant-induced arthritis, administration of the A2AR agonist CGS 21680 shows anti-inflammatory and analgesic properties. Similarly, orally administrated, low doses of the A3R agonist CF502 significantly ameliorate clinical condition. (D) On the other hand, A2AR agonists have also been described as highly effective vasodilators, having, as a major side effect, hypotension. An improved and promising therapeutic approach might be the use of phosphorylated A2AR agonists (prodrugs) that need the ecto-5′-nucleotidase(CD73)-mediated de-phosphorylation in order to be activated. As an example, in a murine model of collagen-induced arthritis, the prodrug 2-(cyclohexylethylthio)adenosine 5′-monophosphate (chet-AMP), showed potent immunosuppressive properties, with negligible vasodilatory side effects. (E) In rheumatoid arthritis (RA) patients, anti-TNF-α agents, rituximab or methotrexate (MTX) reduce the compensatory and protective increase in A2AR expression in peripheral blood lymphocytes. However, studies reveal that in vitro stimulation with the receptor agonist CGS 21680 significantly promotes immunoregulatory responses, increasing IL-10 production. Administration of CF101, an A3R specific agonist, is currently being tested in clinical trials.