21-Hydroxylase epitopes are targeted by CD8 T cells in autoimmune Addison’s disease

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy

“…AD is thought to be mediated by autoreactive cytotoxic T-cells [89][90][91], but the adrenal hormone deficiencies do not manifest clinically until at least 90 % of the functional adrenocortical cells have been destroyed [92,93]. Autoantibodies specific for steroidogenic enzymes steroid 21-hydroxylase (CYP21A2 or 21-OH), steroid 17-α-hydroxylase (CYP17A1 or 17-OH) and side chain cleavage enzyme (CYP11A1 or SCC) are useful markers for the autoimmune destruction of the adrenal cortex; their detection may even predate clinical symptoms [71,[94][95][96][97][98][99].…”

Induction of CXCL10 chemokine in adrenocortical cells by stimulation through toll-like receptor 3

“…AAD is manageable only to a certain extent because of difficulties in restoring the physiological hormone levels and biorhythm . The dominant antigen targeted by autoantibodies and autoreactive T cells from AAD patients is steroid cytochrome P450 21-hydroxylase (21OH), an enzyme involved in the cortisol and aldosterone biosynthetic pathway and exclusively expressed in the adrenal cortex (Bratland et al, 2009b;Rottembourg et al, 2010;Winqvist et al, 1992). Genetic factors associated with the risk of developing AAD have been described, the majority of which encodes proteins involved in antigen presentation (e.g.…”

Interleukin-2 and subunit alpha of its soluble receptor in autoimmune Addison's disease – An association study and expression analysis

“…Moreover, we observed a considerable variation in magnitude of responses, with some AAD samples displaying a very high increase in cytokine synthesis, while others remaining near the baseline despite 21OH stimulation. Low responsiveness was not correlated with disease duration and might probably be attributed to low number of 21OH-specific lymphocytes in peripheral blood [40] and/or inferior antigen presentation in PBMC cultures. We noticed a negative correlation between the age of PBMCs donors and the intensity of the IL2 gene transcription in response to 21OH.…”

“…Nonetheless, these data could be further refined by the analysis of 21OH reactivity in separate immune cell subsets. Formerly described interferon-gamma response to 21OHderived peptides seemed restricted to CD8+ T cells; however, only CD4+ and CD8+ T lymphocytes were considered [40]. Lack of distinction between immune cell populations, which might confirm and possibly expand these findings, remains the main limitation of our study.…”

“…Serum 21OHAb are detectable in most AAD individuals even before the disease onset, but are generally not considered to take part in the destruction of the adrenal cortex [38]. Although the presence of adrenal-specific T cells was evidenced over 40 years ago [1], it is only recently that cellular reactivity to 21OH has been explored in more detail [39,40]. In the current analysis, PBMCs from the AAD patients displayed vigorous reaction to 21OH, with enhanced production of both IL2 and sIL2Ra, demonstrated at the mRNA and protein level.…”