Abstract
BackgroundAutoimmune Addison’s disease (AAD) is caused by multiple genetic and environmental factors. Variants of genes encoding immunologically important proteins such as the HLA molecules are strongly associated with AAD, but any environmental risk factors have yet to be defined. We hypothesized that primary or reactivating infections with cytomegalovirus (CMV) could represent an environmental risk factor in AAD, and that CMV specific CD8+ T cell responses may be dysregulated, possibly leading to a suboptimal control of CMV. In particular, the objective was to assess the HLA-B8 restricted CD8+ T cell response to CMV since this HLA class I variant is a genetic risk factor for AAD.MethodsTo examine the CD8+ T cell response in detail, we analyzed the HLA-A2 and HLA-B8 restricted responses in AAD patients and healthy controls seropositive for CMV antibodies using HLA multimer technology, IFN-γ ELISpot and a CD107a based degranulation assay.ResultsNo differences between patients and controls were found in functions or frequencies of CMV-specific T cells, regardless if the analyses were performed ex vivo or after in vitro stimulation and expansion. However, individual patients showed signs of reactivating CMV infection correlating with poor CD8+ T cell responses to the virus, and a concomitant upregulation of interferon regulated genes in peripheral blood cells. Several recently diagnosed AAD patients also showed serological signs of ongoing primary CMV infection.ConclusionsCMV infection does not appear to be a major environmental risk factor in AAD, but may represent a precipitating factor in individual patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0822-z) contains supplementary material, which is available to authorized users.
Highlights
Autoimmune Addison’s disease (AAD) is caused by multiple genetic and environmental factors
After a primary infection, which can be asymptomatic or cause a clinical picture resembling mononucleosis with fever, hepatitis, swollen lymph nodes and lymphopenia, the virus resides in latently infected monocytes and premonocytic cells with periodical reactivation driven by inflammation or immunosuppression (e.g. HIV/AIDS or transplantation) [11, 12]
Antibodies to cytomegalovirus in AAD patients and healthy controls We measured the frequencies and levels of IgG and IgM CMV antibodies in 95 AAD patients and 49 healthy controls. 71.6 % of the patients had CMV IgG antibodies, while for the healthy controls this number was lower at 61.2 % (Fig. 1a). 3.2 % of the patients had CMV IgM antibodies compared to 4.1 % for the healthy controls (Fig. 1b)
Summary
Autoimmune Addison’s disease (AAD) is caused by multiple genetic and environmental factors. We hypothesized that primary or reactivating infections with cytomegalovirus (CMV) could represent an environmental risk factor in AAD, and that CMV specific CD8+ T cell responses may be dysregulated, possibly leading to a suboptimal control of CMV. The pathological significance of these autoantibodies are uncertain it is Edvardsen et al J Transl Med (2016) 14:68 include herpes simplex 1 and 2, Epstein-Barr virus, adenovirus, hepatitis B and cytomegalovirus (CMV) [9]. Their possible involvement in the induction of autoimmune adrenalitis, and eventually overt AAD, is unclear. CMV is known to infect and cause cytopathic damage to the adrenal cortex, and may directly cause adrenal insufficiency in infants and in immunodeficient individuals [23,24,25,26]
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