Interférons et maladies auto-immunes

Imputability of thymic disorders caused by IFNα during the chronic Hepatitis C treatment – hepatitis C and depression – The infection by the hepatitis C virus (HCV) is a major public health concern since it affects 1.2 % in the French population. Eighty percent of those contaminated by HCV keep bearing the virus chronically although they remain asymptomatic during many years. HCV infection is associated with psychiatric symptoms like depression. Together with other factors (eg the severity of hepatic condition), depression may induce significant impairment in quality of life. Conversely, some psychiatric conditions may increase the risk of HCV infection. In drug-addicted subjects using intravenous route, HCV contamination rate ranges from 74 to 100 %. Compared with general population, a higher HCV contamination rate has also been noticed in some other subgroups of subjects (patients with alcohol abuse or dependence, with alcohol-induced hepatic disease and psychiatric inpatients). However, no valid explanation to this phenomenon has been established. Interferon α and depression – Interferons are a variety of cytokines naturally produced by human tissues and have also been synthesized for therapeutic purposes (treatment of a variety of cancers and viral infections). Many psychobehavioural symptoms are observed under IFNα treatment. Among them, mood disorders are known to occur early after entry into treatment and to be within the reach of preventive measures. The reported frequency of depression during IFNα treatment ranges from 0 to 37 %. This variation reflects either methodological biases (eg differences in psychiatric assessment) or the heterogeneity of the population of patients accepted in therapeutic protocols. Note that the adjunction of ribavirine to IFNα in therapeutic protocols has not brought any changes in the depression frequency. The causal relationship between IFNα administration and the occurrence of mood disorders has been tackled by various recent research works focusing on the importance of the immune system in the pathophysiology of depression. Miscellaneous pathophysiological hypotheses – nature of the psychobehavioural symptomatology – In addition to depressive symptoms, IFNα treatment also induces various cognitive impairments and disruptions in EEG patterns. These symptoms are consistent with a mild subcortical dementia. Data resulting from pharmacological trials in humans and in animals are controversial (eg IFNα-induced symptoms being alleviated by both immune and antidepressant therapies). However, the debate about the nature of the psychobehavioural disorders observed under IFNα treatment might be no longer relevant in the light of recent theories which regard depression as a maladaptive response to a particular form of stress, namely a deep and diffuse feeling of sickness (« malaise »). These theoretical views ascribe the production of depressive symptoms to a disruption in the immune function, mediated by the variety of cytokines. The therapeutic effects of anti-depressive drugs are thus attributed to their analgesic properties, reducing the « malaise » feeling underlying depressive symptoms. Necessity of a second messinger – Accordingly to current pathophysiological theories, depression results from disorders of various CNS functions, mainly limbic, monaminergic and neuroendocrinal systems. Though, exogenous IFNα does not cross the blood-brain barrier when unscathed and an intermediary mechanism is necessary. First to be addressed is the cytokines system itself since it is composed of numerous different molecules interacting in an infinite number of possible combinations. Some of these cytokines (eg some interleukins) both are activated by IFNα and can reach CNS ; they are good candidates for the role of second messenger mediating the induction of psychobehavioural disorders. Second, keeping in mind that serotonin is a monoaminergic neurotransmitter classically involved in depression pathophysiology, other works have demonstrated that IFNα modulates the peripheral activity of indolamine dioxygenase - a regulating enzyme of serotonin metabolism – possibly through lymphocyte T CD4 activation. Third, other authors have postulated an immune-induced vagal mechanism to explain depression caused by IFNα. Action of IFNα on the neuroendocrine and on neuromodulating functions : monoaminergic hypothesis – Cytokines could have an influence on the mood through their modulating role on the serotoninergic system. IFNα treatment is reported to produce : 1) a decrease in trytophan availability for serotonin synthesis, 2) a decrease in the 5-HIAA level in the LCR, and 3) a modification of the central serotoninergic receptors. Moreover, selective inhibitors of serotonin transporters are effective to treat or prevent depression caused by IFNα. Many studies support the serotonin-transporter hypothesis : in vitro, both IFNα and interleukine 4 (IL-4) increases the expression of serotonin transporter gene, IFNα increases in the production of IL-4 by mononucleus cells (not found in vivo). Serotoninergic system can also be altered by a peripheral action of IFNα on trytophan catabolism by activating a concurrent pathway (known as « kynurenine pathway») to serotonin synthesis. Finally, serotonin-mediated vulnerability to the psycho-behavioural effects of IFNα could be underlain by a polymorphism of serotonin transporter gene. Concerning the other monoaminergic systems, IFNα seems to have an amphetamine-like effect at its first administration, followed by a decrease in dopaminergic tone with chronic administration. Dopaminergic depletion, subsequent to psychostimulant abuse for instance, results in severe depressive syndromes. Interactions between IFNα and noradrenergic system have also been reported. Neuroendocrinian hypothesis – When administered through central or peripheral way, IFNα simulates/inhibits the corticotrope axis and alters endorphin system as shown by the induction of analgesia, catatonia and behavioural slowdown that can be suppressed by opioid antagonists. IFNα neurotoxic effects are successfully treated by naltrexone. Lastly, IFNα is known to cause disorders in thyroid function that are likely to contribute to the production or aggravation of mood disorders. Conclusion – A better understanding of pathophysiologic mechanisms underlying psychiatric side effects of IFNα is essential to extend access to treatment to some categories of patients that remain excluded from the protocols. A better management of those psychiatric side effects should help the clinician not to draw aside patients at risk, ie patients with depression, drug and alcohol addiction. Treating them in a pragmatic and careful way is a major issue, since this population represents a high percentage of the potential candidates for interferon therapy.