IFN-γ–producing self-reactive CD4+ T cells induce autoimmune adrenalitis in a mouse model of Addison’s disease
Arina Andreyeva, Juraj Michalik, Veronika Niederlova, Veronika Cimermanova, Ales Drobek, Radislav Sedlacek, Jan Prochazka, Juraj Labaj, Olha Fedosieieva, Waldemar Kanczkowski, Peter Draber, André Sulen, Ondrej Stepanek, Aleš Neuwirth
Arina Andreyeva, Juraj Michalik, Veronika Niederlova, Veronika Cimermanova, Ales Drobek, Radislav Sedlacek, Jan Prochazka, Juraj Labaj, Olha Fedosieieva, Waldemar Kanczkowski, Peter Draber, André Sulen, Ondrej Stepanek, Aleš Neuwirth
View: Text | PDF
Research Article Clinical Research Endocrinology

IFN-γ–producing self-reactive CD4+ T cells induce autoimmune adrenalitis in a mouse model of Addison’s disease

Abstract

Autoimmune Addison’s disease (AD) is a rare but life-threatening disorder caused by immune-mediated destruction of the adrenal cortex, and progress in therapy has been limited by insufficient mechanistic insight. Here, we establish a model of experimental autoimmune adrenalitis that recapitulates key features of AD and reveals sex-dependent differences in disease manifestation within the model. Immunization with peptides derived from the adrenal self-antigen CYP11A1 induces corticosterone insufficiency. We show that autoimmune adrenalitis is driven by IFN-γ produced by self-reactive CD4+ T cells, promoting granulomatous inflammation in the adrenal cortex. Together, these findings identify IFN-γ as a central effector of autoimmune adrenalitis and suggest that targeting the IFN-γ pathway may represent a potential therapeutic strategy for AD.

Authors

Arina Andreyeva, Juraj Michalik, Veronika Niederlova, Veronika Cimermanova, Ales Drobek, Radislav Sedlacek, Jan Prochazka, Juraj Labaj, Olha Fedosieieva, Waldemar Kanczkowski, Peter Draber, André Sulen, Ondrej Stepanek, Aleš Neuwirth

×

Figure 4

Long-term adrenal pathology in EAA.

Options: View larger image (or click on image) Download as PowerPoint
Long-term adrenal pathology in EAA. (A) Representative H&E-stained a...
(A) Representative H&E-stained adrenal sections 3–5 months after immunization (p.i.) (n = 9 NT, 33–47 Ctr and EAA mice). Whole-organ sections (scale bar: 200 μm) and magnified views (scale bar: 100 μm). Adrenal borders, medulla, and multinucleated foamy cells are highlighted in yellow. (B) Representative Oil Red O staining of adrenal sections from EAA mice (1 experiment; n = 6). Scale bar: 100 μm. (C) Representative immunofluorescence of adrenal sections from EAA mice stained for DAPI (nuclei, blue) and CYP11A1 (red) (1 experiment; n = 6). Multinucleated foamy cells appear green due to lipid autofluorescence. Scale bar: 100 μm. (D) Representative F4/80 staining showing macrophage infiltration in adrenal sections from EAA mice; the right panel shows the no-primary-antibody control (1 experiment; n = 8). Middle and bottom panels show different fields of the same section. Scale bar: 100 μm. (E) Cortical granuloma frequency in B6 mice 3–4 months p.i. (4 independent experiments; n = 24–32 mice/group) and 5 months p.i. (3 independent experiments; n = 9–15 mice/group). (F) Serum corticosterone after ACTH stimulation in B6 mice 5 months p.i. (3 independent experiments; n = 16–20 mice/group). (G) Basal serum sodium and potassium in male B6 mice 5 months p.i. (2 independent experiments; n = 11–12 mice/group). (H and I) Cortical granuloma frequency and serum corticosterone after ACTH stimulation in Aire+/+, Aire−/−, and NT (Aire+/−) mice 5 months p.i. (2 independent experiments; n = 6–16 mice/group). (J) Cortical granuloma frequency in Tnfr1+/+, Tnfr1+/−, and Tnfr1−/− mice 5 months p.i. (5 independent experiments; n = 13–23 mice/group). (E–J) Statistical significance was determined using the 2-tailed Mann-Whitney U test; P values are indicated. Bars show mean ± SEM; symbols represent individual mice.