Autoimmune adrenal insufficiency (AAI) is a classic organ-specific autoimmune disease caused by immune-mediated destruction of steroidogenic cells in the adrenal cortex. Autoreactive T cells and autoantibodies targeting the steroidogenic cytochrome P450 enzyme 21-hydroxylase (21OH) are present in the majority of patients. AAI can appear isolated or as part of two forms of autoimmune polyendocrine syndromes, the rare monogeneic autoimmune polyendocrine syndrome type 1 (APS-1) and the common autoimmune polyendocrine syndrome type 2 (APS-2), the latter affecting more than half of the AAI population. A study of the Swedish twin registry has revealed that the probandwise concordance for monozygotic twins was 0.71 (95% CI 0.40-0.90) and the heritability 0.97 (95% CI 0.88-99), which is at least as high as for celiac disease. Several genes are implicated in disease risk, first and foremost the major histocompatibility complex (MHC). Other associated genes include BACH2 (BTB and CNC Homology 1, Basic Leucine Zipper Transcription factor 2) and AIRE (autoimmune regulator). Disease risk is associated with an accumulated number of risk variants in the individual patient. Lymphocytic infiltrations of the adrenal cortex of deceased AAI patients have been described. We now demonstrate the presence of both T- and B cells during active autoimmune adrenalitis. The majority of the T cells are CD8+ cytotoxic T cells, although CD4+T and CD20+B cells as well, particularly in distinct foci of dense lymphocytic infiltrations. T cells with reactivity towards distinct and conserved portions the 21OH protein have been reported in peripheral blood and is probably present in abundance in these foci. Autoimmune adrenalitis is a slowly evolving process in most cases, leading to clinical symptoms and biochemical aberrations only in the latter stages of the disease. Although the majority are thought to loose all adrenocortical function, a subset of patients seem to retain both glucocorticoid and mineralocorticoid function even decades after being diagnosed with AAI. This indicates that there is an opportunity for immunomodulary and regenerative therapy in AAI.
18 - 21 May 2019
European Society of Endocrinology