Clinical and Serologic Parallels to APS-I in Patients with Thymomas and Autoantigen Transcripts in Their Tumors

Abstract

Patients with the autoimmune polyendocrine syndrome type I (APS-I), caused by mutations in the autoimmune regulator (AIRE) gene, and myasthenia gravis (MG) with thymoma, show intriguing but unexplained parallels. They include uncommon manifestations like autoimmune adrenal insufficiency (AI), hypoparathyroidism (HP), and chronic mucocutaneous candidiasis (CMC) plus autoantibodies neutralizing IL-17, IL-22 and type I interferons. Thymopoiesis in the absence of AIRE is implicated in both syndromes. To test whether these parallels extend further, we screened 247 patients with MG and/or thymoma for clinical features and organ-specific autoantibodies characteristic of APS-I patients, and assayed 26 thymoma samples for transcripts for AIRE and 16 peripheral tissue-specific autoantigens (TSAgs) by quantitative PCR. We found APS-I-typical autoantibodies and clinical manifestations, including CMC, AI and asplenia, respectively in 49/121 (40%) and 10/121 (8%) thymoma patients, but clinical features seldom co-occurred with the corresponding autoantibodies. Both were rare in other MG subgroups (N=126). In 38 APS-I patients, by contrast, we observed neither autoantibodies against muscle antigens nor any neuromuscular disorders. Whereas relative transcript levels for AIRE and 7 of 16 TSAgs showed the expected under-expression in thymomas, levels were increased for 4 of the 5 TSAgs most frequently targeted by these patients’ autoAbs. Hence the clinical and serologic parallels to APS-I in patients with thymomas are not explained purely by deficient TSAg transcription in these aberrant AIRE-deficient tumors. We therefore propose additional explanations for the unusual autoimmune biases they provoke. Thymoma patients should be monitored for potentially life-threatening APS-I manifestations such as AI and HP.

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy

“…However, the expression of APECED-specific autoantigens (CYP21A2, CYP17A1, CYP11A1 and TPH) that are often targeted by autoantibodies in thymoma patients did not correlate with AIRE expression in thymoma samples, suggesting that they are not AIRE-dependent genes. Furthermore, as often observed in APECED patients, the presence of these autoantibodies in thymoma patients is not associated with the autoimmune damage of the corresponding target organ [145]. Although we cannot rule out the possibility that these autoantibodies develop in the course of epitope spreading following autoimmunity towards still unidentified AIRE-dependent TSA it is intriguing that the earliest autoantibody targets in APECED are expressed in thymus by other cell types than mTECs.…”

“…However, the mechanisms that lead to early autoimmunization to these cytokines are yet to be discovered. Thymoma patients also share the organ-specific autoantibodies found in APECED patients, some of which are regarded to be APECED-specific [145]. Importantly, most thymomas are AIRE-deficient but still support T-cell development [146].…”

Thymoma related myasthenia gravis in humans and potential animal models

“…In contrast to EOMG, there is no major gender bias and no strong HLA association in TAMG (Table 1). TAMG is more commonly than EOMG accompanied by additional autoimmune diseases: the spectrum of them is broader but partially overlapping with the spectrum in EOMG [3,39,40]. Immunodeficiency states are also quite frequent [41,42].…”

“…The decline of autoantibody titers in such tumors after tumor removal suggests that there is intratumorous autoantigen presentation, which in turn triggers the autoimmune response [47]. The failure of peripheral tolerance mechanisms in such tumor patients is by all likelihood also a facet of the tolerance breakdown observed in thymomas [39]. However, the unusually high frequency (>50%) of thymoma-associated autoimmune phenomena compared to their low frequency (<5%) in other tumor types suggests that additional mechanism are likely operative in TAMG [3,42].…”

Expanded CD4+ Effector/Memory T Cell Subset in APECED Produces Predominantly Interferon Gamma

“…periphery [3,4]. However, autoimmunity can also be directed against antigens not regulated by AIRE (e.g., α-fodrin, 21-hydroxylase, and SOX9), and conversely, only a fraction of AIRE-regulated tissue-specific antigens are targeted [5,6]. Because these phenomena are difficult to explain by failed negative selection alone, alternative pathogenetic models including disrupted thymic microenvironment have been proposed [7,8].…”