The potential role for infections in the pathogenesis of autoimmune Addison’s disease

Abstract

Autoimmune Addison's disease (AAD), or primary adrenocortical insufficiency, is a classical organ-specific autoimmune disease with 160 years of history. AAD is remarkably homogeneous with one major dominant self-antigen, the cytochrome P450 21-hydroxylase enzyme, which is targeted by both autoantibodies and autoreactive T cells. Like most autoimmune diseases, AAD is thought to be caused by an unfortunate combination of genetic and environmental factors. While the number of genetic associations with AAD is increasing, almost nothing is known about environmental factors. A major environmental factor commonly proposed for autoimmune diseases, based partly on experimental and clinical data and partly on shared pathways between anti-viral immunity and autoimmunity, is viral infections. However, there are few reports associating viral infections to AAD, and it has proved difficult to establish which immunological processes that could link any viral infection with the initiation or progression of AAD. In this review, we will summarize the current knowledge on the underlying mechanisms of AAD and take a closer look on the potential involvement of viruses.

Primary Adrenal Insufficiency After COVID-19 Infection

“…Addison’s disease is a primary adrenocortical deficiency resulting from damage to the adrenal cortex ( 7 , 8 ), which does not become clinically apparent until 80 to 90% of both adrenal cortices are destroyed ( 9 ). Causes of Addison’s disease include infections, infiltration, and hemorrhage, and most commonly in Western countries, autoimmunity ( 7 ).…”

“…Like with AAI, the pathogenesis of many autoimmune conditions remain unclear but an interplay between genetic predisposition and environmental factors, such as viral and bacterial infection, are thought to play a major role ( 9 , 11 , 12 ). Certain viruses could partake in development of AAI either by infecting steroid hormone-producing cells of the adrenal cortex or by affecting the balance of the immune system ( 9 ). Autoimmunity can be induced by infectious agents via varying mechanisms, such as epitope spreading, standard activation, and autoinflammatory activation of innate immunity, to name a few ( 12 ).…”

Identification and characterization of rare toll-like receptor 3 variants in patients with autoimmune Addison's disease

“…On the other hand, even though the genotype does not correlate with the phenotype, we could speculate that it may predict the etiology of the disease. In that case, patients with damaging variants in innate immune genes may share the same triggers, such as viral infections, initiating or perpetuating the immunological attack of adrenal tissue [70] .…”

COVID-19 and the Endocrine System: A Comprehensive Review on the Theme

“…On the other hand, it is also known that acute infectious diseases may induce bilateral adrenal bleeding or adrenal venous thrombosis, leading to acute adrenal insufficiency and mortality excess in fatal sepsis [207]. In addition, adrenal insufficiency may result from a direct or immune-mediated adrenal injury after different acute infectious diseases, mostly with viral etiology [208]. For instance, autoptic studies in SARS deceased patients had shown degeneration and necrosis of adrenal cortical cells, and SARS-CoV was identified in the adrenal glands, possibly confirming a direct cytopathic effect [209].…”