Flow Cytometry Study of Blood Cell Subtypes Reflects Autoimmune and Inflammatory Processes in Autoimmune Polyendocrine Syndrome Type I

Abstract

Autoimmune polyendocrine syndrome type I (APS I) is a recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. AIRE is expressed in medullary epithelial cells where it activates transcription of organ‐specific proteins in thymus, thereby regulating autoimmunity. Patients with APS I have, in addition to autoimmune manifestations in endocrine organs, also often ectodermal dystrophies and chronic mucocutaneous candidiasis. The aim of this study was to characterize immune cell subpopulations in patients with APS I and their close relatives. Extensive blood mononuclear cell immunophenotyping was carried out on 19 patients with APS I, 18 first grade relatives and corresponding sex‐ and age‐matched healthy controls using flow cytometry. We found a significant relative reduction in T helper cells coexpressing CCR6 and CXCR3 in patients with APS I compared to controls (mean = 4.10% versus 5.94% respectively, P = 0.035). The pools of CD16+ monocytes and regulatory T cells (Tregs) were also lower in patients compared with healthy individuals (mean = 15.75% versus 26.78%, P = 0.028 and mean = 4.12% versus 6.73%, P = 0.029, respectively). This is the first report describing reduced numbers of CCR6+CXCR3+ T helper cells and CD16+ monocytes in patients with APS I We further confirm previous findings of reduced numbers of Tregs in these patients.

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

“…Recently, we have studied Th17 responses in APECED patients in vivo and found a predominant defect in IL-22 production both in antigenchallenged skin and unexposed skin [18]. Similarly, the composition of the CD4 + population has been reported to be either normal or skewed, and the full pattern of functional Th differentiation has not been studied [17,19,20]. Here, we report the characteristics of the circulating Th cell population in Finnish APECED patients.…”

“…IL-17A production after stimulation was reported either normal or increased, while IL-17F response was reduced [13,15]. One study of five patients reported increased frequency of Th17 cells after stimulation with Candida [16], while another suggested a normal frequency of circulating cells co-expressing CXCR3 and CCR6, surrogate markers for IL-17A-producing cells [17]. Recently, we have studied Th17 responses in APECED patients in vivo and found a predominant defect in IL-22 production both in antigenchallenged skin and unexposed skin [18].…”

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy

“…The deficient number, impaired function and diminished FOXP3 expression of T regulatory cells has been reported by several studies [148][149][150][151]. However, whether the defects in APECED regulatory T cells are the result of changes occurring in the thymic environment or in the periphery remains unknown [152].…”

Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy Patients

“…Regulatory T cells are essential to intestinal tolerance, but in APECED patients they are dysfunctional (8) and express significantly decreased levels of FOXP3 (8,10,11). Only 8 of the 12 patients were available for isolation of live cells and functional suppressive testing.…”

“…Several studies have reported defects in the number or function of regulatory T cells (Treg) (8)(9)(10)(11), and dendritic cells have been shown to be abnormal (12,13). Practically all patients have neutralizing Abs against type I IFNs (14), which are often the earliest manifestation of the disease, and autoantibodies targeting other cytokines are also found, of which anti-IL-17 and -IL-22 Abs have been linked to impaired defense against Candida (2,15,16).…”