The impaired distribution of adenosine deaminase isoenzymes in multiple sclerosis plasma and cerebrospinal fluid

Cellular stress or apoptosis triggers the release of ATP, ADP and other nucleotides into the extracellular space. Extracellular nucleotides function as autocrine and paracrine signalling molecules by activating cell-surface P2 purinergic receptors that elicit pro-inflammatory immune responses. Over time, extracellular nucleotides are metabolized to adenosine, leading to reduced P2 signalling and increased signalling through anti-inflammatory adenosine (P1 purinergic) receptors. Here, we review how local purinergic signalling changes over time during tissue responses to injury or disease, and we discuss the potential of targeting purinergic signalling pathways for the immunotherapeutic treatment of ischaemia, organ transplantation, autoimmunity or cancer.

Adenosine is a modulator that has a pervasive and generally inhibitory effect on neuronal activity. Tonic activation of adenosine receptors by adenosine that is normally present in the extracellular space in brain tissue leads to inhibitory effects that appear to be mediated by both adenosine A1 and A2A receptors. Relief from this tonic inhibition by receptor antagonists such as caffeine accounts for the excitatory actions of these agents. Characterization of the effects of adenosine receptor agonists and antagonists has led to numerous hypotheses concerning the role of this nucleoside. Previous work has established a role for adenosine in a diverse array of neural phenomena, which include regulation of sleep and the level of arousal, neuroprotection, regulation of seizure susceptibility, locomotor effects, analgesia, mediation of the effects of ethanol, and chronic drug use.

Understanding of autoimmune diseases, including multiple sclerosis, has expanded considerably in recent years. New insights have been provided by not only animal models but also studies of patients, often in conjunction with experimental therapies. It is accepted that autoimmune T cells mediate the early steps of new multiple sclerosis lesions, and although uncertainties remain about the specific targets of autoreactive T cells, several studies indicate myelin antigens. Recent findings obtained with both animal models and patients with multiple sclerosis indicate involvement of a T helper cell with a T(H)-17 phenotype, in contrast to previous data indicating that T helper type 1 cells are critical. Evidence has also been presented for CD8(+) and regulatory T cell populations, although their involvement remains to be established. Despite evidence supporting the idea that autoreactive T cells are involved in disease induction, cells of myeloid lineage, antibodies and complement as well as processes intrinsic to the central nervous system seem to determine the effector stages of tissue damage. Careful analysis of the alterations in immune processes should further advance knowledge of the relationship between the inflammatory component of this disease and the more diffuse degeneration of progressive multiple sclerosis.