Anti-cytokine autoantibodies: Epiphenomenon or critical modulators of cytokine action

Abstract

Low amounts of high-affinity autoantibodies to various cytokines have been detected in sera from healthy donors. Their levels, although highly variable, are increased in the circulation of patients subjected to cytokine therapy or suffering from a variety of immunoinflammatory diseases. It has been suggested that these autoantibodies play a regulatory role in the intensity and duration of an immune response. The antibodies may prevent the binding of a cytokine to its specific cell surface receptor thereby neutralizing its biological activity in vivo. They may also act as carrier proteins preventing the rapid elimination of a cytokine from the circulation and thus increase its bioactivity. Additionally or alternatively, autoantibodies may modulate cytokine-induced intracellular signal transduction pathways or trigger complement-mediated cytotoxicity towards cells carrying membrane-bound cytokines. The autoantibodies may exert their regulatory role in compliance with the other factors that control cytokine activity, including soluble cytokine receptors, cell surface decoy receptors, and receptor antagonists. Although not favored by many investigators, a less sophisticated role for naturally occurring anti-cytokine autoantibodies should be considered as well. Recent evidence has shown that autoantibodies are generated at a high frequency as part of a response to foreign antigens. These antibodies are produced by B cells arising from the process of somatic mutation. Thus anti-cytokine autoantibodies may be the result of a "leaky" B cell response triggered by immunoinflammatory processes. High-titered autoantibodies induced by cytokine therapy are of clinical concern since their occurrence is often associated with the loss of response to treatment. Moreover, they may also neutralize endogenously produced cytokines with possible pathological consequences. In this paper we have reviewed the available information on the biological and clinical significance of both naturally occurring and therapeutically induced anti-cytokine autoantibodies in animals and man with the emphasis on antibodies directed to interferons.

Antibodies to Commercially Available Interferon–Beta Molecules in Multiple Sclerosis Patients Treated with Natural Interferon–Beta

“…A total of 150 sera (an average of 15 sera per patient) were analyzed, determining the binding and NAB activity to IFN–β. In addition, we also studied the specific antibodies to IFN–β in two control groups and we were able to observe that antibodies to IFN–β can be present in patients treated with IFN–β, in MS patients without treatment and in healthy controls, similar data have been reported by others [4]. …”

Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus

“…Cytokine-targeted autoantibodies have been described in healthy human subjects (45,46); however, the implications of this reactivity remain unclear. Small but detectable populations of circulating autoreactive lymphocytes appear in healthy humans, which indicates that immune homeostasis may involve a controlled level of self-recognition…”

Feline Leukemia Virus DNA Vaccine Efficacy Is Enhanced by Coadministration with Interleukin-12 (IL-12) and IL-18 Expression Vectors

“…Alternatively, anti-DNA or anti-cytokine antibodies, produced as a result of immunization with plasmid DNA or in vivo expression of cytokine adjuvant DNA constructs (48,71), may have interfered with the humoral immune response against the antigenic components of the DNA vaccine (36). If such inhibition did occur, it was not a permanent effect, since after challenge high levels of virus-neutralizing antibodies appeared in all but two of the cats that did not develop a persistent infection.…”