Anti-cytokine autoantibodies in autoimmunity: preponderance of neutralizing autoantibodies against interferon-alpha, interferon-omega and interleukin-12 in patients with thymoma and/or myasthenia gravis

Abstract

SUMMARYWe have screened for spontaneous anticytokine autoantibodies in patients with infections, neoplasms and autoimmune diseases, because of their increasingly reported co-occurrence. We tested for both binding and neutralizing autoantibodies to a range of human cytokines, including interleukin-1alpha (IL-1 a ), IL-1 b , IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-18, interferon-alpha2 (IFN-a 2), IFN-w , IFN-b , IFN-g , tumour necrosis factor alpha (TNF-a ), transforming growth factor beta-1 (TGF-b 1) and granulocyte-macrophage colony stimulating factor (GM-CSF), in plasmas or sera. With two notable exceptions described below, we found only occasional, mostly low-titre, non-neutralizing antibodies, mainly to GM-CSF; also to IL-10 in pemphigoid. Strikingly, however, high-titre, mainly IgG, autoantibodies to IFN-a 2, IFN-w and IL-12 were common at diagnosis in patients with late-onset myasthenia gravis (LOMG + ), thymoma (T) but no MG (TMG -) and especially with both thymoma and MG together (TMG + ). The antibodies recognized other closely related type I IFN-a subtypes, but rarely the distantly related type I IFN-b , and never (detectably) the unrelated type II IFN-g . Antibodies to IL-12 showed a similar distribution to those against IFN-a 2, although prevalences were slightly lower; correlations between individual titres against each were so modest that they appear to be entirely different specificities. Neither showed any obvious correlations with clinical parameters including thymoma histology and HLA type, but they did increase sharply if the tumours recurred. These antibodies neutralized their respective cytokine in bioassays in vitro ; although they persisted for years severe infections were surprisingly uncommon, despite the immunosuppressive therapy also used in most cases. These findings must hold valuable clues to autoimmunizing mechanisms in paraneoplastic autoimmunity.

The new immunological methods for diagnostics of type 1 autoimmune polyendocrine syndrome (the first experience in Russia)

“…В нескольких крупных исследованиях доказано самостоятельное значение аутоантител к ИФН-ω и -α 2 в диагностике АПС 1, при этом эти антитела не выявлялись при других аутоиммунных заболевани-ях [6,9,12]. В нашем исследовании данные антитела также не выявляются у пациентов с очаговой алопе-цией без АПС 1.…”

“…В дальнейшем проводились многочисленные работы по изучению АТ к ИФН-α и -ω, и было до-казано, что они являются высокоспецифичными и высокочувствительными маркерами АПС 1 [9,[11][12][13][14].…”

Anti-IFN-γ Autoantibodies in Disseminated Nontuberculous Mycobacterial Infections

“…The Abs they reported did not affect the antiviral effects of IFN-␥, but did alter the immunomodulatory effects of IFN-␥ on MHC class II up-regulation in U937 cells. The majority of anti-cytokine Abs described to date have occurred in autoimmune diseases, such as multiple sclerosis (17,18), rheumatoid arthritis (19,20), idiopathic pulmonary alveolar proteinosis (21), and myasthenia gravis (22). Among patients with myasthenia gravis and thymoma, anti-IL-12 and anti-IFN-␣ autoantibodies, in addition to those developed against the acetylcholine receptor, are common.…”

The new immunological methods for diagnostics of type 1 autoimmune polyendocrine syndrome

“…АТ к различным цитокинам (ИФН-α, ИФН-ω и ряду интерлейкинов) впервые были описаны у па-циентов с тимомами и миастенией [10]. Для этого применялся метод нейтрализации противовирус-ных ИФН (AVINA -AntiViral Interferon Neutrolization Assay).…”

“…Эти АТ не относились к группе нейтрализующих АТ [7]. У пациентов с тимомами также обнаруживались АТ к ИФН-α и ИФН-ω, но в меньших титрах и в мень-шем проценте случаев (60%) [10].…”