ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Ann Endocrinol (Paris). 2018; 79(3): 157–163.

This review summarizes the current knowledge regarding the genetic susceptibility to autoimmune Addison’s disease (AAD) and the genes outside the MHC complex associated with AAD. Fourteen genes (CTLA-4, PD-L1, PTPN22, NALP1, STAT4, CIITA, BACH2, FCRL3, GPR174, GATA3, NFATC1, CLEC16A, CYP27B1, and VDR) have been reported to be associated with AAD and the majority are involved in the function of the T cell.

The theories regarding the pathophysiology of AAD are also discussed, as well as the plausible involvement of the 21-hydroxylase antibodies in the process of adrenal destruction, as a major T cell autoantigen. Two epitopes targeted by CD8+T cells have been described, the 21OH342-361 and 21OH431-438 regions, and one epitope (21OH342-350) has been described as a HLA-A2-restricted epitope. Clones of the latter produced IFNγ upon stimulation with the cognate peptide and were able to lyse target cells expressing 21OH through production of granzyme B. A central question to the pathogenesis of AAD is what drives the infiltration of mononuclear cells into the adrenal cortex. Patients with AAD have increased serum levels of interferon induced chemokines CXCL9 and CXCL10, which potentially could recruit self-reactive lymphocytes to the adrenal cortex.

The authors further discuss the role of viruses in promoting adrenal autoimmunity, as well as the importance of type I interferons and checkpoint inhibitors (antibodies) targeting CTLA-4 and PD-1. Patients treated for malignancies with these types of drugs have developed AAD and other endocrinopathies. Finally, the potential role of immunomodulatory (rituximab) and regenerative therapies in AAD are discussed.