Interleukin-2: A Possible Trigger for Autoimmunity

Abstract

High doses of recombinant interleukin-2 (IL-2) may induce autoimmune lesions in patients receiving experimental cancer treatment. In most cases, the manifestation of autoaggression is transient and organ-specific, predominantly affecting the thyroid gland. Only a fraction of the patients are concerned; most individuals (around 90%) do not develop any signs of autoimmunity. Apparently, endogenously hyperproduced IL-2 may also be implicated in the pathogenesis of autoaggression, since active phases of such disparate autoimmune diseases, like multiple sclerosis and systemic lupus erythematosus, are accompanied by elevated IL-2 serum levels. Taking into account that immunological self-tolerance is maintained by several distinct mechanisms, we investigated whether IL-2 would interfere with clonal deletion or clonal anergy in vivo. In several experimental systems, IL-2 failed to abolish clonal deletion in the murine thymus or in the peripheral T-cell compartment. IL-2 did not affect the clonal deletion of self-reactive B cells in the bone marrow either. In contrast, IL-2 was found to be effective in abrogating clonal anergy of non-deleted self-specific T cells. Only in the presence of high frequencies of self-specific, potentially autoreactive T cells, IL-2 induces autoimmune lesions. Thus, IL-2 interferes with a mechanism of self-tolerance that guarantees the inactivation of T cells that for some reason have ‘escaped’ clonal deletion. If these data, obtained in the murine system, are extrapolated to man, then it may be stated that the T-cell repertoire of most individuals has been completely purged from self-reactive cells. Only in the presence of a non-deleted, anergic, potentially autoreactive T-cell population, could organ-specific disease be induced by IL-2.

Imbalance in T-cell and cytokine profiles in patients with relapsing-remitting multiple sclerosis

“…Expression of IL-17 generates a highly pro-inflammatory environment and induces severe pathological conditions [23]. IL-2 operates as an activator of antigen-specific lymphocytes and is involved in an autoimmune onset [24]. Other inflammatory cytokines such as IL-6, IL-8 and IL-12 are often connected with the development of autoimmunity and ultimately in immune-mediated injury via subsequent activation of macrophages and other reactive cells [4,25,26].…”

Drugs Recently Associated With Lupus Syndromes

“…In humans, endogenous hypersecretion of IL-2 is associated with a number of autoimmune phenomena including rapid disease progression in rheumatoid arthritis and active disease in SLE (reviewed in ref. 9). In other studies, the administration of monoclonal antibodies to the IL-2 receptor resulted in suppression or postponement of autoimmune diseases' 0…”

IL-2, IL-3, and IFN-gamma differently affect in vivo frequencies of circulating precursors of cytotoxic T lymphocytes (CTL-p)

“…Exogenous IL-2 and IFN-gamma are able to induce autoantibody production [24,31], which may presumedly be enhanced by B-cell stimulatory properties of IL-3 [38,48]. IL-2 has additionally been discussed as reverting the energy of potentially autoreactive T cells [17]. However, in our system, we did not find induction of detectable autoreactive CTL-p clones by any of the cytokines tested.…”