In vivo analysis of helper T cell responses in patients with autoimmune polyendocrinopathy – candidiasis – ectodermal dystrophy provides evidence in support of an IL-22 defect

Abstract

Autoimmune polyendocrinopathy - candidiasis - ectodermal dystrophy (APECED) is caused by mutations in the Autoimmune regulator (AIRE) gene and is associated with neutralizing anti-cytokine autoantibodies. We have used an in vivo challenge model to analyze antigen-specific CD4(+) T cell responses. Bacille Calmette-Guérin (BCG)-vaccinated patients and controls were injected tuberculin intradermally, skin blisters were induced by suction on the indurations and on unexposed skin, and the infiltrating cells harvested. The patients had a quantitatively normal CD4(+) T cell response and no significant abnormalities in the expression of T helper type (Th) 1- or Th2-related genes. The expression of interleukin (IL)-22, in contrast, was lower in the patients. Two patients, both with a pre-existing ocular keratopathy, experienced a relapse of keratoconjunctivitis, suggesting a possible immunological basis for this APECED component. Our in vivo data are compatible with a selective IL-22 defect in the activated CD4(+) T cells of APECED patients, affecting also unexposed skin in steady-state conditions.

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy

“…In contrast to several other syndromes associated with CMC [78,79], the circulating lymphocytes of APECED patients produce normal or even increased amounts of IL-17A [80,81], but are deficient in IL-22 and IL-17F secretion [69,80,81]. Moreover, the production of IL-22 is severely impaired by the skin-populating T cells of APECED patients [82]. APECED patients also develop high titer neutralizing autoantibodies against IL-22, IL-17F and IL-17A [29,69].…”

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

“…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]. 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].…”

Interleukin-22: Immunobiology and Pathology

“…Although recipient-derived IL-22 was shown to be protective for gut tissue after allogeneic BMT, the potential benefit of IL-22 was limited during GVHD due to the elimination of recipient-derived IL-22+ ILCs by alloreactive donor T cells (137). This pathophysiology of IL-22 deficiency in GVHD may have a natural parallel in autoimmune polyendocrinopathy - candidiasis - ectodermal dystrophy (APECED) patients who have neutralizing antibodies to cytokines including IL-22, contributing to their susceptibility to candidal infections (372, 373). Furthermore, colon biopsy samples from patients with IBD have also demonstrated a deficiency of IL-22 + cells, and impaired T cell and innate cell IL-22 production has been reported in a primate model of celiac disease, indicating that intestinal pathology due to loss of IL-22-producing cells is not limited to GVHD pathogenesis and the transplant setting (374, 375).…”