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Annales d’Endocrinologie 79 (2018) 157–163

Klotz Communications 2018: Cortisol and all its disorders

Autoimmune Addison’s disease – An update on pathogenesis

La maladie d’Addison auto-immune – une mise à jour sur la pathogenèse
Alexander Hellesen a,b , Eirik Bratland a,b , Eystein S. Husebye a,b,c,d,∗
a Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
b K.G. Jebsen Senter for Autoimmune Sykdommer, University of Bergen, 5021 Bergen, Norway
c Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway
d Department of Medicine (Solna), Karolinska Institutet, 17176 Stockholm, Sweden

Abstract
Autoimmunity against the adrenal cortex is the leading cause of Addison’s disease in industrialized countries, with prevalence estimates ranging
from 93–220 per million in Europe. The immune-mediated attack on adrenocortical cells cripples their ability to synthesize vital steroid hormones
and necessitates life-long hormone replacement therapy. The autoimmune disease etiology is multifactorial involving variants in immune genes
and environmental factors. Recently, we have come to appreciate that the adrenocortical cell itself is an active player in the autoimmune process.
Here we summarize the complex interplay between the immune system and the adrenal cortex and highlight unanswered questions and gaps in our
current understanding of the disease.
© 2018 Elsevier Masson SAS. All rights reserved.

Keywords: Addison’s disease; Autoimmunity; Pathogenesis; Adrenalitis

Résumé
L’auto-immunité contre le cortex surrénalien est la principale cause de la maladie d’Addison dans les pays industrialisés, avec des estimations
de prévalence allant de 93 à 220 cas par million d’habitants en Europe. L’attaque immunitaire des cellules corticosurrénales affaiblit leur capacité
à synthétiser des hormones stéroïdes vitales et nécessite un traitement hormonal substitutif définitif. L’étiologie de la maladie auto-immune est
multifactorielle impliquant des polymorphismes dans les gènes immunitaires et des facteurs environnementaux. Récemment, nous avons appris
que la cellule corticosurrénale elle-même joue un rôle actif dans le processus auto-immun. Nous résumons ici l’interaction complexe entre le
système immunitaire et le cortex surrénalien et soulignons les questions et les lacunes sans réponse dans notre compréhension actuelle de la
maladie d’Addison.
© 2018 Elsevier Masson SAS. Tous droits réservés.

Mots clés : Maladie d’Addison ; Glande surrénale ; Auto-immunité

1. Introduction
Addison’s disease (AAD), or primary adrenocortical insuf-
ficiency, is characterized by inability of the adrenal cortex to
produce sufficient amounts of glucocorticoids and mineralo-
corticoids. The disease often manifests itself between the 2nd
and 4th decade of life and affects women more often than
∗ Corresponding author. Department of Clinical Science and University of
Bergen, 5021 Bergen, Norway.
E-mail address: Eystein.Husebye@uib.no (E.S. Husebye).
https://doi.org/10.1016/j.ando.2018.03.008
0003-4266/© 2018 Elsevier Masson SAS. All rights reserved.
men [1–3]. Patients may present with several diffuse symp-
toms such as fatigue, nausea, dizziness and weight loss, but can
often be identified by specific signs like salt-craving and, espe-
cially, hyperpigmentation of the skin and mucosal surfaces [1,4].
The latter is caused by increased stimulation of melanocortin
receptors in the skin by ACTH and pro-opiomelanocortin (the
precursor for ACTH), that builds up in patients due to lack of
cortisol-mediated feedback inhibition of the HPA-axis [5]. Con-
sequently, elevated plasma ACTH as well as low serum cortisol
levels serves as diagnostic criteria for AAD.
The current recommended treatment regimen consists of
hormone replacement therapy in the form of hydrocortisone
158 A. Hellesen et al. / Annales d’Endocrinologie 79 (2018) 157–163

(glucocorticoid replacement) and fludrocortisone (mineralocor- Table 1

ticoid replacement) [6]. If left untreated, a stressful event (e.g. Genes outside the MHC complex associated with autoimmune Addison’s
disease.
watching a high profile premier league football match [7]) may
eventually precipitate acute adrenal insufficiency (adrenal cri- Gene Function References
sis) – a potentially life-threatening condition caused by critical CTLA-4 Inhibits T cell activation [32,96]
hormone-deficiency [8]. PD-L1 Inhibits T cell activation [97]
Although tuberculosis was the predominant cause of AAD PTPN22 Regulates T cell responses to [34,98]
earlier [9], autoimmunity is now responsible for most of the weak peptide agonists; promotes
TLR-induced type I IFN
cases in developed countries [1,4]. The identification of steroid production in myeloid cells
cytochrome P450 21-hydroxylase (21OH) of the adrenal cor- NALP1 Inflammasome activation [99,100]
tex as a major autoantigen has led to routine use of 21OH STAT4 Involved in TH1 and TH17 [101]
autoantibody assays in determining the disease aetiology [6,10]. differentiation
Among Norwegian patients, 86% was found positive for such CIITA Regulator of MHC class II [102,103]
transcription
autoantibodies [1], and similar numbers have been reported in BACH2 Regulates B and T cell [23,37]
other populations [2,4,11]. Autoantibodies against the adrenal differentiation
cortex are often detectable prior to the development of overt FCRL3 Regulates signalling pathways in [104]
disease [12] and in as much as 95% of patients at the time lymphocytes
of diagnosis [13]. Less than 0.5% of the general population GPR174 Involved in suppression of IL2 [105]
production in T cells
harbor anti-21OH antibodies [14] and these “antibody biomark- GATA3 Transcription factor that acts on T [101]
ers” are therefore highly specific for autoimmune AAD. In a cell differentiation
prospective study, the cumulative risk of developing AAD in NFATC1 Involved in gene transcription in [106]
antibody-positive individuals was estimated to about 30% [12]. activated T cells and a major
Although AAD may occur in isolation, more than half of the target of cyclosporine
CLEC16A Modulates autophagy and T cell [103]
patients suffer from additional autoimmune diseases. Autoim- selection in the thymus
mune thyroid disease (AITD; hypo- or hyperthyroidism) is the CYP27B1 Enzyme involved in vitamin D [107–109]
most frequent comorbidity, followed by diseases like type 1 dia- metabolism
betes (T1D), chronic atrophic gastritis and vitiligo [2,11,15,16]. VDR Vitamin D receptor [110]
The coexistence of at least two out of the three diseases AAD,
AITD and T1D is commonly referred to as autoimmune polyen- (MICA) [29], which encodes a ligand for the activating NK and
docrine syndrome type 2 (APS-2) [17]. AAD is also a major T cell receptor NKG2D. Homozygosity for the MICA5.1 allelic
disease component of the monogenic syndrome APS-1 [18,19], variant was associated with increased frequency of progression
in which the presence of two out of the following three manifes- to AAD in 21OH autoantibody-positive individuals bearing the
tations is diagnostic: AAD, chronic mucocutaneous candidiasis high-risk genotype (DR3/DQ2-DR4/DQ8) [30].
and hypoparathyroidisim. While the two syndromes share sev- Several studies have reported SNPs in immune-related genes
eral features such as the presence of serum 21OH autoantibodies that confer increased risk for AAD. Most of these genes encode
[4] and immune infiltration of the adrenal cortex (when AAD is proteins that are active in regulating T and B cell activation
involved) [20,21], the genetic background of APS-1 differs from and differentiation (Table 1, see also [31] for a review of the
APS-2 as the former is caused by mutations in the autoimmune subject), underlining the importance of these cell types in the
regulator (AIRE) gene while APS-2 (including isolated AAD) pathobiology of AAD. A recent meta-analysis of European AAD
is a polygenic disorder. Also, APS-1 is more rare than APS-2, cohorts strengthened the link to CTLA-4 [32], hypothesizing
with an estimated prevalence of 1:90,000 in Norway [22]. that the associated genetic variants may impair CTLA-4 func-
tion and thereby lower the threshold for T cell activation as
2. Genetic susceptibility suggested in AITD [33]. Another interesting association is the
1858T-allele of PTPN22 [34] as recent publications implicate
In agreement with most other organ-specific autoim- PTPN22 in distinct processes that may be of particular impor-
mune disorders, the strongest genetic associations to AAD tance to autoimmunity; regulation of T cell responses to weak
are found within certain HLA class II alleles. Sig- self-peptide agonists [35] and promotion of type I IFN produc-
nificant risk has been confirmed in the presence of tion in myeloid cells following TLR stimulation [36]. Recently,
HLA DR3/DQ2 (DRB1*0301-DQA1*0501-DQB1*0201) and a comprehensive exome sequencing effort of patients from the
DR4/DQ8 (DRB1*0404-DQA1*0301-DQB1*0302) haplo- Swedish Addison Registry revealed BACH2 as a major risk locus
types, and especially the compound heterozygote combination for AAD [23], corroborating another recent finding that a SNP
(odds ratio = 32) [1,23,24]. Also, in a study of families with mul- in BACH2 is associated with increased risk of developing AAD
tiple affected individuals, increased risk for AAD was found to in the UK and in Norway [37]. BACH2 is a transcription factor
be associated with the HLA DR3-B8 haplotype [25]. The impor- that is essential for T and B cell development and variants in the
tance of these alleles has been further reinforced by studies on T BACH2 gene has been associated with increased risk of develop-
cell responses in AAD [25–28]. Within the HLA locus, a connec- ing a wide range of autoimmune diseases, including T1D, AITD
tion has also been made to the MHC-class I chain-related gene A and celiac disease [38–40].
 A. Hellesen et al. / Annales d’Endocrinologie 79 (2018) 157–163 159

Another important aspect is that the heritability of AAD

appears to be very high [41], strongly indicating the existence
of highly penetrant AAD susceptibility alleles [31]. The genetic
risk factors described so far can only account for a small part
of the total heritability observed, which justifies large scale
genetic studies on AAD such as genome-wide association stud-
ies (GWAS) or whole genome sequencing.

3. Pathophysiology

The histopathological picture in AAD is characterized by

lymphocytic infiltration of the adrenal cortex and extensive atro-
phy of the parenchyma, while the adrenal medulla remains intact
[20,21,42]. Over the course of the disease, the integrity of the
cortex is gradually lost as the three layers of cells are progres-
sively destroyed and replaced by fibrous tissue [4,43]. Despite
continuous loss of adrenocortical cells, AAD may remain sub-
clinical for long periods before overt disease develops. In fact,
adrenocortical failure may not manifest itself until 90% of the
cells are destroyed [44]. In end-stage disease, the adrenals are
often very small on CT scans and can be difficult to identify on
autopsies [4]. Unfortunately, histochemical studies have been
restricted to post-mortem analyses due to practical and ethical
reasons, and have in general been few and far between. There-
fore, a detailed analysis of the mononuclear infiltrate in AAD
is lacking. Rather, most work related to the immunopathogen-
esis of the disease has been performed on peripheral blood and
serum.
Specific immunological responses towards adrenal antigens
in patients with AAD were first observed several decades ago.
Autoantibodies against adrenal extracts was demonstrated as
early as in 1957 [45], and was subsequently shown to be specif-
ically directed against the adrenal cortex [46]. The major target
of these adrenal cortex autoantibodies (ACAs) was later iden-
tified as 21OH [10], an enzyme involved in the biosynthesis of
steroid hormones in the adrenal cortex. Although 21OH autoan-
tibodies correlate with the degree of adrenal dysfunction in the
preclinical phase of AAD [47], they do not seem to inhibit 21OH
activity in vivo [48]. This is not all that surprising given that
21OH is an intracellular protein anchored to the smooth endo-
plasmic reticulum membrane [49]. Evidence for a role for these
antibodies in the disease pathogenesis is in fact very sparse. The
only publication of note that has suggested a functional signif-
icance role of 21OH autoantibodies was Bratland et al., who
observed a reduced response of patient PBMC to 21OH pro-
tein in stimulation cultures with autologous plasma (containing
21OH autoantibodies) when anti-CD32 (Fc␥RII, receptor for
IgG) blocking antibodies were added [26].
Only in recent years has 21OH been established as a major T
cell autoantigen in AAD. Following immunization of BALB/c
and SJL mice with recombinant 21OH or 21OH-derived pep-
tide, Husebye et al. reported proliferation of lymph node cells
to an immunodominant peptide (21OH342-361) [50]. A few
years later, T cell responses to 21OH whole protein and the pep-
tide 21OH342-361 were demonstrated in patients with AAD,
providing the first evidence of 21OH as a T cell autoantigen
in the disease, and clearly demonstrating that 21OH-specific T
Fig. 1. T cell responses against 21OH protein in patients with AAD. Peripheral
blood mononuclear cells (PBMC) from patients with AAD and healthy controls
(HC) were isolated and stimulated with recombinant purified 21OH or medium
only as the negative control. A. Lymphocyte proliferation assay: 2 × 105 PBMC
were cultured in the presence or absence of 21OH for 7 days in triplicates. [3H]-
thymidine was added for the last 16 hours and antigen specific proliferation
was estimated based on genomic uptake of radioactive thymidine. Data are
reported as (mean counts per minute (cpm) in the presence of 21OH–mean cpm
in the presence of medium only). The positive cut-off value at 1000 cpm is
displayed as a dotted horizontal line. B. IFN␥ Elispot assay: 1 × 106 PBMC
were prestimulated with 21OH or medium only for 24 hours, before performing
the Elispot assay. Cells were then assayed in triplicates or quadruplicates for 24
additional hours in the Elispot filter wells. Spots were counted in a dissecting
microscope and are reported as (mean spot forming units (SFU) per 1 × 106
PBMC in the presence of 21OH–mean SFU per 1 × 106 PBMC in the presence
of medium only). The positive cut-off value at 20 SFU per 1 × 106 PBMC is
displayed as a dotted horizontal line.
cells are detectable in the peripheral blood of AAD patients
(Fig. 1) [26]. Since then, epitope mapping has revealed two
specific 21OH sequences targeted by CD8+ T cells. Rottem-
bourg et al. showed IFN␥ production in response to a C-terminal
peptide of 21OH and mapped the response to an octameric
sequence (21OH431-438, amino acid sequence: EPLARLEL)
[28]. The epitope was found to be HLA-B8 restricted, and stain-
ing of PBMCs with HLA-B8*21OH431-438 tetramers showed
higher frequencies of circulating 21OH431-438-specific CD8+
T cells in two patients with AAD compared to a HLA-B8-
positive control. More recently, an HLA-A2-restricted epitope
(21OH342-350, amino acid sequence: LLNATIAEV) was iden-
tified [27]. 21OH342-350-specific clones produced IFN␥ upon
stimulation with the cognate peptide and were able to lyse tar-
get cells expressing 21OH through the production of granzyme
B (and possibly other mediators). These reports offer solid evi-
dence for the presence of 21OH-specific autoreactive T cells
in AAD and pave way for more functional analyses of these
disease-specific cells.
160 A. Hellesen et al. / Annales d’Endocrinologie 79 (2018) 157–163
4. Intrinsic factors of the adrenal cortex
The adrenocortical cells themselves are probably active col-
laborators in the pathogenesis of AAD as they communicate
with the immune system in several ways. Adrenocortical cells
respond to inflammation by producing a number of immunolog-
ical mediators [51], including IL-1␤ [52–54], IL-6 [53], IL-8
[55], IL-18 [56], TNF␣ [57] and CXCL10 [58]. Moreover,
they regularly interact with tissue-resident or patrolling den-
dritic cells and macrophages [52,59]. Several toll-like receptors
(TLR)s, recognizing conserved molecular microbial patterns,
are expressed within the adrenal cortex and has been shown to
induce pro-inflammatory cytokines upon stimulation [55], indi-
cating an ability to promote local anti-microbial responses and
inflammation.
A central question to the pathogenesis of AAD is what drives
the infiltration of mononuclear cells into the adrenal cortex. Sim-
ilar to related autoimmune endocrine disorders, we and others
have shown that patients with AAD have increased serum lev-
els of the interferon induced chemokines CXCL9 and CXCL10
compared to healthy controls [58,60,61]. Furthermore, cultured
primary adrenocortical zona fasciculata cells as well as adreno-
cortical carcinoma cells have the ability to produce CXCL10
upon stimulation with pro-inflammatory cytokines [58,60], sug-
gesting that these cells may contribute to the elevated serum
levels of CXCL10 in patients and potentially to the recruitment
of self-reactive lymphocytes to the adrenal cortex.
5. Environmental triggering events
Better insight into the interplay between adrenocortical cells,
environmental factors and the immune system should offer
valuable cues to the pathogenic mechanisms of AAD (Fig. 2).
Very little is currently known about the initial stages of disease
development, that is, the establishment of inflammation and an
immune response against the adrenal cortex. It is widely appreci-
ated that in order for autoimmunity to develop, there is the need
for genetic susceptibility and a precipitating event to convert
inherent disease susceptibility [62]. Local infections of the tar-
get organ and viral infections in particular, are commonly viewed
as potentially triggering factors. Under infections, parenchymal
cells are exposed to various microbial products and cytokines
that alter their status and their steady-state dialogue with the
immune system [63]. These changes are most likely instrumental
to the development and progression of autoimmune disease.
Certain herpesviruses like herpes simplex virus 1 (HSV-1)
[64–67] and cytomegalovirus (CMV) [68–70], as well as the
adenovirus [71], have a tropism for adrenocortical cells. In
some cases, a connection between herpes virus infection and
adrenocortical insufficiency has indeed been suggested [72–75]
although the exact disease aetiology in these cases was uncertain.
Recently, two studies showing seasonal variation in the onset of
AAD provide indirect evidence for a role of a seasonal microbial
agent such as a virus in the pathogenesis of AAD [76,77].
A link between type I interferons (IFNs) and adrenal
autoimmunity also seems to exist. The development of 21OH
autoantibodies has been reported in patients receiving IFN␣
Fig. 2. Simplified model of the pathogenesis of autoimmune Addison’s dis-
ease. Similar to most autoimmune diseases, autoimmune Addison’s disease
(AAD) is believed to be caused by a combination of several unfortunate genetic
variants and environmental factors. Although variants in several genes encod-
ing immunological proteins have been shown to be associated with AAD, the
majority of the genetic component in AAD pathogenesis remains undefined.
Knowledge of possible environmental factors is sparse, although certain viruses
are suggested candidates. The recent advent of checkpoint inhibitors in cancer
treatment has revealed that antibodies against PD-1 and maybe also CTLA4
can induce AAD. AAD is characterized by a highly targeted immune response
against steroidogenic enzymes in the adrenal cortex, 21OH in particular. Anti-
bodies against 21OH are present in the majority of patients and constitute a great
biomarker for autoimmunity as the underlying cause of adrenal insufficiency.
However, it is thought that 21OH-specific cytotoxic T cells are responsible for
the actual destruction of adrenocortical tissue. These T cells are also detectable
in the peripheral blood of the patients. The 21OH-specific T cells are proba-
bly recruited into the adrenal cortex by chemokines released by adrenocortical
cells themselves (intrinsic factors) as a result of inflammatory or stressful
events. Finally, AAD like many autoimmune diseases are probably permis-
sive to immunotherapy aiming to inhibit the underlying immunopathological
mechanisms. For AAD this has been demonstrated with the use of rituximab
(anti-CD20 antibodies). Images are adapted from Servier Medical Art by Servier
(http://www.servier.com/Powerpoint-image-bank) and modified by the authors
under the following terms: CREATIVE COMMONS Attribution 3.0 Unported
(CC BY 3.0).
treatment for chronic hepatitis C virus (HCV) infection [78].
In one instance, a woman carrying the HLA high-risk genotype
for AAD developed transient AAD over a 2-year period of IFN␣
treatment [79]. Also, IFN␣ therapy has been reported to exacer-
bate clinical or subclinical adrenocortical insufficiency, leading
to an increased need for hormone supplement [80–82]. Collec-
tively, these findings could indicate a role for viruses and/or type
I interferons in promoting adrenal autoimmunity. The mech-
anisms operative under such a scenario would likely involve
a number of effects on the adrenal cortex, as these cells seem
responsive to both TLR stimuli and various cytokines, including
type I IFNs [60,83–85].
The recent introduction of so-called checkpoint inhibitors
targeting CTLA-4, programmed cell death protein 1 (PD-
1), and PD-1 ligand (PD-L1), in the treatment of malignant
diseases such as malignant melanoma and lung cancer have
brought about significant immunological side-effects [86],
including endocrinopathies like autoimmune hypophysitis, thy-
roiditis and type 1 diabetes. A few cases of AAD have also
been observed. One patient developed thyrotoxicosis and later
 A. Hellesen et al. / Annales d’Endocrinologie 79 (2018) 157–163
AAD with 21OH autoantibodies after treatment with pem-
brolizumab (anti-PD-1) for metastatic melanoma [87]. A similar
case has also been reported with nivolumab (also anti-PD-1)
[88]. Furthermore, using immunodeficient mice reconstituted
with human stem cells it was demonstrated that treatment
with anti-CTLA4 antibodies induced a number of presumably
autoimmune pathologies including hepatitis, sialitis, and most
importantly, adrenalitis [89].
6. Preventive and regenerative treatment for
autoimmune adrenal insufficiency
It is commonly assumed that primary adrenal insufficiency
is complete, but we and others have found that a subgroup of
patients retain a certain degree of cortisol production even after
several years of disease [90–92]. Thus, there are still function-
ing cells that might regenerate and proliferate if the autoimmune
attack is contained. Pearce and co-workers have explored the
capacity for regeneration of adrenal function by either stim-
ulation with long-acting cosyntropin or immunomodulation by
rituximab [93,94]. In both cases, a few patients regained function
of the adrenals. Recently it was reported that steroid-producing
cells could be regenerated by lentiviral transformation of stem
cells harvested from blood and urine with different transcription
factors [95]. Use of such cells in combination with immunomod-
ulatory therapy could constitute a future therapeutic approach in
AAD.
Still, a deeper understanding of the pathogenesis, including
the underlying genetic background, the interplay of the adrenal
cortex and the immune system with environmental factors, and
the immunological mechanisms destroying the steroidogenic tis-
sue, is needed to bring new immunomodulatory and regenerative
therapy to the table that can restore adrenal function in the not
too distant future.
Disclosure of interest
The authors declare that they have no competing interest.
Acknowledgements
The study was supported by Grants from The Regional Health
authorities of Western Norway, The Research Council of Nor-
way and The Novo Nordisk Foundation.
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