Autoimmune Endocrine Diseases Research Articles

Aspects of Humoral Immunity in a Group of Children With Type 1 Diabetes and Thyroid Disorders

Patients with diabetes have a high prevalence of thyroid disease compared with non-diabetic population. In the case of type 1 diabetes, it is often associated with autoimmune endocrine and systemic diseases as: Graves-Basedow disease, autoimmune chonic thyroiditis (ACT), Addison's disease, celiac disease, pernicious anemia, myasthenia gravis, vitiligo, etc.. The purpose of this study is to determine the main aspects of humoral immunity in a group of children with type 1 diabetes and thyroid disorders. The studied group was represented by 83 cases (71 girls and 12 boys), aged between 7-17 years. They were used clinical, imaging, biochemical, hormonal and immunological parameters. Results: Prevalence of positive anthyroid antibodies (ACAT) in the study group was: Basedow – Graves disease – 100% (both), ACT - 85.18% antiTPO and 83.33% antiTg, euthyroid difusse goiter – 0% (both). In the case of children and adolescents with type 1 diabetes and ACT with positive antiTPO AB we notice that they had a younger onset age of diabetes (4.86 ± 3.94 vs. 8.62 ± 0.51 years), a longer duration of diabetes (9.23 ± 4.05 vs. 8.12 ± 0.64 years), elevated HbA1c values (8.91 ± 2.03 vs.7, 55 ± 1.96%) and lower TSH values (12.00 ± 23.7 vs. 14.77 ± 17.03 mIU/ml) than those negative. Conclusions: It is recommended determination of antithyroid antibodies, particularly those antiTPO in children and adolescents with type 1 diabetes at onset of diabetes, or before puberty and, if they are positive should be tested the thyroid function annually to minimize the risk of undiagnosed hypothyroidism.

Atypical Manifestation of LPS-Responsive Beige-Like Anchor Deficiency Syndrome as an Autoimmune Endocrine Disorder without Enteropathy and Immunodeficiency

Monogenic primary immunodeficiency syndromes can affect one or more endocrine organs by autoimmunity during childhood. Clinical manifestations include type 1 diabetes mellitus, hypothyroidism, adrenal insufficiency, and vitiligo. Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA) deficiency was described in 2012 as a novel primary immunodeficiency, predominantly causing immune dysregulation and early onset enteropathy. We describe the heterogeneous clinical course of LRBA deficiency in two siblings, mimicking an autoimmune polyendocrine disorder in one of them in presence of the same underlying genetic mutation. The third child of consanguineous Egyptian parents (Patient 1) presented at 6 months of age with intractable enteropathy and failure to thrive. Later on, he developed symptoms of adrenal insufficiency, autoimmune hemolytic anemia, thrombocytopenia, and infectious complications due to immunosuppressive treatment. The severe enteropathy was non-responsive to the standard treatment and led to death at the age of 22 years. His younger sister (Patient 2) presented at the age of 12 to the endocrinology department with decompensated hypothyroidism, perioral vitiligo, delayed pubertal development, and growth failure without enteropathy and immunodeficiency. Using whole exome sequencing, we identified a homozygous frameshift mutation (c.6862delT, p.Y2288MfsX29) in the LRBA gene in both siblings. To our knowledge, our patient (Patient 2) is the first case of LRBA deficiency described with predominant endocrine phenotype without immunodeficiency and enteropathy. LRBA deficiency should be considered as underlying disease in pediatric patients presenting with autoimmune endocrine symptoms. The same genetic mutation can manifest with a broad phenotypic spectrum without genotype–phenotype correlation. The awareness for disease symptoms among non-immunologists might be a key to early diagnosis. Further functional studies in LRBA deficiency are necessary to provide detailed information on the origin of autoimmunity in order to develop reliable predictive biomarkers for affected patients.

Autoimmune Adrenal Insufficiency in Celiac Disease

Celiac disease is an immune-mediated intestinal disorder that may be associated with other immune-mediated extra-intestinal disorders, including immune-mediated endocrine diseases, such as autoimmune thyroiditis, most often with hypothyroidism. Other monoglandular autoimmune endocrine disorders may also occur, including autoimmune adrenal insufficiency (Addison’s disease). In celiac disease, clinical features of adrenal failure may be limited, difficult to differentiate from symptoms that might be attributed to celiac disease, or even life-threatening. In others with celiac disease, a polyglandular autoimmune syndrome has also been reported. Recent screening studies from multiple countries, particularly in , have indicated that patients with autoimmune adrenal failure or Addison’s disease should be carefully screened for occult or silent celiac disease. Up to 10% of Addisonian patients may be serologically positive and histopathological features of untreated celiac disease may be detected, even with clinically occult intestinal disease. Celiac disease patients with a monoglandular autoimmune disorder should also be followed carefully for the later appearance of other autoimmune endocrine disorders as these may not all appear at the time of diagnosis of celiac disease, but sporadically during the life-long clinical course of celiac disease.

Investigation of vitamin D deficiency in autoimmune endocrine disease in terms of frequency and causal or consequential relationship

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The frequency of tissue transglutaminase antibodies in the monoglandular and polyglandular autoimmune endocrine disorders

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

What affects functional ovarian reserve, thyroid function or thyroid autoimmunity?

BackgroundThyroid dysfunction is the most common autoimmune endocrine disorder in women of reproductive age, and is associated with menstrual irregularities, anovulation and infertility. Whether it is thyroid function or thyroid autoimmunity that affects functional ovarian reserve (FOR, i.e., the small growing ovarian follicle pool) reflected in anti-Müllerian hormone (AMH) has, however, remained under dispute.MethodsWe investigated in 225 infertile women whether thyroid function, after adjustment for thyroid autoimmunity, affects FOR within what is considered normal thyroid function (TSH, 0.4–4.5μIU/mL) by assessing AMH levels in reference to TSH levels, stratified for TSH < or ≥3.0μIU/mL. Thyroid autoimmunity was defined by presence of anti-thyroid peroxidase, −thyroglobulin and/or -thyroid receptor antibodies.ResultsMean age of studied women was 38.4 ± 5.0 years; their mean AMH was 1.3 ± 2.0 ng/mL and mean TSH 1.8 ± 0.9 μIU/mL. Thyroid autoimmunity was present in 11.1 % of patients. Women with TSH <3.0μIU/mL presented with significantly higher AMH compared to those with TSH ≥3.0μIU/Ml (P = 0.03). This difference remained significant after adjustment for thyroid autoimmunity as well as age (P = 0.02).ConclusionsEven after adjustment for thyroid autoimmunity and age, TSH <3.0μIU/mL in euthyroid infertility patients is associated with significantly better FOR (higher AMH) than TSH ≥3.0μIU/mL. This observation suggests a direct beneficial effect of lower TSH levels on follicular recruitment, and warrants investigations of thyroxin supplementation in infertile women with TSH levels ≥3.0μIU/mL in attempts to improve FOR.

Endocrine autoimmunity in patients with Latent Autoimmune Diabetes in Adults (LADA) — association with HLA genotype.

Latent autoimmune diabetes in adults (LADA) is a slow-developing form of autoimmune diabetes, characterised by the presence of type 1 diabetes-associated autoantibody and presentation at diagnosis similar to patients with type 2 diabetes. The aim of this study was to determine the prevalence of auto-antibodies related to endocrine autoimmune diseases in patients with LADA and to assess their association with HLA genotype. We evaluated the presence of anti-thyroglobulin (ATG), anti-thyroid peroxidase (ATPO), anti-tissue transglutaminase IgA (ATTA), and anti 21 hydroxylase (A21H) in 70 patients with LADA, 69 with Type 2 diabetes, and in 50 healthy controls HLA genotype was assed in subpopulation of sluclied subjects. The presence of ATPO (28.6 vs. 10%); ATG (28.6 vs. 14%) was higher in patients with LADA in comparison to healthy controls and ATPO in comparison to patients with type 2 diabetes (38.6 vs. 17.4 %). In patients with LADA the presence of autoimmune thyroid autoantibodies was associated with newly diagnosed subclinical hypothyroidism; almost 7% of patients presented with high TSH. The presence of A21H (2.86 vs. 5.8 vs. 6.1%) and ATTA (2.86 vs. 4.3 vs. 6.0%) was not different between groups. Patients with high TSH level were positive for DQA1*0301 and DRB1*04 HLA genotype: DQB1*0201 and DQB1*02 were higher in patients positive for ATTA. Patients with LADA have higher prevalence of thyroid autoimmune diseases. In patients with LADA similarly to type 1 genotype DQA1*0301 seems to CONFER susceptibility to thyroid autoimmunity, and DQB1*0201 to celiac disease.

Endocrine manifestations in celiac disease.

Celiac disease (CD) is an autoimmune small intestinal mucosal disorder that often presents with diarrhea, malabsorption and weight loss. Often, one or more associated endocrine disorders may be associated with CD. For this review, methods involved an extensive review of published English-language materials. In children and adolescents, prospective studies have demonstrated a significant relationship to insulin-dependent or type 1 diabetes, whereas in adults, autoimmune forms of thyroid disease, particularly hypothyroidism, may commonly co-exist. In some with CD, multiple glandular endocrinopathies may also occur and complicate the initial presentation of the intestinal disease. In others presenting with an apparent isolated endocrine disorder, serological screening for underlying subclinical CD may prove to be positive, particularly if type 1 diabetes, autoimmune thyroid or other autoimmune endocrine diseases, such as Addison’s disease are first detected. A number of reports have also recorded hypoparathyroidism or hypopituitarism or ovarian failure in CD and these may be improved with a strict gluten-free diet.

GUT-the Trojan Horse in Remote Organs’ Autoimmunity

Human beings assemble and maintain a diverse but host-specific gut microbial community along the longitudinal axis of the intestines. Helped by a functional tight junction, the default response to commensal microbes is tolerance, whereas the default response to pathogens is an intricately orchestrated immune response, resulting in pathogen clearance. Nutrients and industrial food additives were suggested to impact the intestinal ecosystem and to breach tight junction integrity. Taken together, certain nutritional components, increased intestinal permeability, disease specific dysbiotic pathobionts and their capacity of post translation modification of proteins, are luminal events that impact autoimmunogenesis. The present review expands on the multi gut originated axes and their relationship to remote organ autoimmune diseases. Brain, joint, bone, endocrine, liver, kidney, heart, lung and skin autoimmune diseases are connected to the intestinal luminal compartmental deregulated events to form the gut-systemic organs axes.

Prevalence of premature ovarian failure in patients with systemic lupus erythematosus.

To estimate the prevalence of premature ovarian failure (POF) and its associated factors in patients with systemic lupus erythematosus (SLE). Cross-sectional study including consecutive SLE women <60 years of age attending a rheumatology clinic. A face-to-face interview was undertaken to obtain demographic, gynaecological and lupus characteristics. Additional rheumatologic and endocrine data were retrieved from patients' medical records. POF prevalence was estimated in the study sample and in a subgroup of patients aged <40 years at interview. Associations between POF and selected variables were assessed by logistic regression analyses. A total of 961 patients were analysed. Prevalence of POF, secondary amenorrhea of known cause, menopause and hysterectomy were 5.4%, 0.8%, 7.8% and 4.4%, respectively. In 674 (70%) patients who had not been exposed to cyclophosphamide (CYC) the prevalence of POF was 0.6%. Disease activity over time (OR 1.4 (CI 95% 1.0-1.8, p < 0.05)) and CYC treatment (OR 5.9 (CI 95% 1.8-18.8, p < 0.01)) were associated with higher prevalence. Association between POF and endocrine autoimmune diseases was not found. In the absence of CYC treatment, the prevalence of POF in lupus patients is consistent with that reported in the general population. The existence of autoimmune processes at the ovary seems unlikely in most lupus patients.

A novel FOXL2 gene mutation and BMP15 variants in a woman with primary ovarian insufficiency and blepharophimosis–ptosis–epicanthus inversus syndrome

This study aims to search for mutations in relevant genes in a woman with primary ovarian insufficiency (POI) and blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). This study reports on the case of a woman with POI, BPES, and autoimmune endocrine disorder. Bidirectional sequencing of the coding regions and intron/exon boundaries of FOXL2 and BMP15 genes and hormonal assays for the measurement of follicle-stimulating hormone, luteinizing hormone, estradiol, testosterone, Δ4-androstenedione, and dehydroepiandrosterone sulfate were employed. A novel de novo heterozygous deletion (p.K150Rfs*121) in the FOXL2 gene was identified to coexist with two BMP15 gene variants located in the same allele (c.-9C>G; p.N103S). The novel, de novo FOXL2 gene mutation (p.K150Rfs*121) expands the spectrum of molecular defects identified in women with BPES. Coexisting gene variants in POI-related genes, such as BMP15, may act synergistically and explain the observed phenotypic variability in women with BPES (ie, BPES with or without POI). The concept of digenic inheritance suggested herein has been previously introduced for other nosologies such as hypogonadotrophic hypogonadism. Endocrine autoimmunity might also contribute to the POI phenotype.

Towards an Earlier and Timely Diagnosis of Type 1 Diabetes: Is it Time to Change Criteria to Define Disease Onset?

Type 1 diabetes (T1D) is the immune-mediated form of diabetes requiring insulin treatment and affecting both children and adults. The incidence of T1D is increasing dramatically and has doubled in the past 2 decades. In the recent years, significant knowledge on the disease natural history has been gained and, nowadays, diabetes-related autoantibodies make T1D a predictable disease. Despite this great advance in the field of T1D, we still use diagnostic criteria defined by the American Diabetes Association (ADA) in 1997. In other autoimmune endocrine disorders (e.g., Hashimoto's thyroiditis and Addison's disease), that share several features with T1D, diagnosis is made early in the presence of circulating autoantibodies together with subclinical thyroid/adrenal functional impairment and treatments are often provided in the absence of a frank clinical glandular insufficiency. With this review, we propose to anticipate diagnosis also in T1D at the stage in which subjects have circulating multiple islet autoantibodies, are dysglycemic but are still insulin independent. We believe that anticipating T1D diagnosis can lead to better disease management and prevention of secondary complications but can also provide the possibility to perform earlier and likely more effective interventions for a disease that to date has proven controllable but still incurable.

Polymorphisms of the Toll-Like Receptor-3 Gene in Autoimmune Adrenal Failure and Type 1 Diabetes in Polish Patients.

Infectious agents are plausible environmental triggers for autoimmunity in genetically susceptible individuals. Polymorphic variants of genes implicated in innate immunity may affect immune responses and hence promote auto-aggressive reactions. Genes such as Toll-like receptor-3 (TLR3), which participate in recognizing conserved foreign molecules and mounting the first line of defence against viral infections, are promising functional candidates in autoimmune conditions. We investigated the association of the TLR3 variants, rs13126816 and rs3775291, with the autoimmune endocrine disorders, Addison’s disease (AD) and type 1 diabetes (T1D) in the Polish population. The study comprised 168 AD patients, 524 individuals with T1D and 592 healthy controls. Genotyping was performed by real-time PCR. Distribution of the TLR3 genotypes and alleles did not reveal significant differences between patients and controls (p > 0.05). No effect on age at disease onset was found in affected cohorts. This analysis does not support an association between TLR3 variants and the risk for autoimmune destruction of the adrenal cortex and beta cells. However, innate immunity merits further studies in autoimmune endocrine conditions.

HLA Class II Differentiates Between Thyroid and Polyglandular Autoimmunity.

The HLA class II genes are susceptibility genes for autoimmune endocrine diseases; however, scarce data are available pertaining to the determinants of genetic susceptibility to polyglandular autoimmunity (PGA). A total of 300 consecutive and unselected patients with either PGA or monoglandular autoimmune thyroid disease (AITD) and 100 healthy control subjects were genotyped for the HLA class II DRB1, -DQA1, and -DQB1 alleles. Compared to patients with AITD and controls, the HLA-DRB1*03 (pc =0.001), *04 (pc<0.001), -DQA1*03 (pc<0.001), and -DQB1*02 (pc =0.001) alleles were increased in patients with PGA. When dividing patients with Hashimoto's thyroiditis (HT) into those with PGA (PGA-HT) vs. those with HT as monoglandular disease, significant differences for the DRB1*03 (pc=0.001) and DQA1*03 (pc=0.001) alleles were observed. In contrast, the DQB1*02 allele was more prevalent in PGA patients with Graves' disease (PGA-GD) vs. those with monoglandular GD (pc=0.002). The HLA-DRB1*15 (pc =0.001), -DQA1*01 (pc =0.001), -DQB1*05 (pc =0.002) and -DQB1*06 (pc =0.002) alleles were significantly less present in PGA compared to monoglandular AITD and controls, thus indicating protective alleles. The HLA class II alleles differentiate between mono- and polyglandular autoimmunity in patients with autoimmune thyroid disease.

Patients with systemic lupus erythematosus have higher prevalence of thyroid autoantibodies: a systematic review and meta-analysis.

BackgroundThyroid autoimmunity is considered the most common type of organ-specific autoimmune disorder and can be associated with other autoimmune endocrine disorders or non-endocrine diseases. Systemic lupus erythematosus is a prototypical autoimmune disorder with multifactorial etiology. The pathogenesis and development of the disease may result from a loss of immune tolerance and the resulting synthesis of autoantibodies against nuclear antigens. Autoimmune factors may be common features of both thyroid autoimmunity and systemic lupus erythematosus, making it likely that both conditions may coexist within some patients.Methods and FindingsA number of studies have investigated whether an association between thyroid autoimmunity and systemic lupus erythematosus exists. However, the results of these studies have been inconsistent. Furthermore, most of these studies have had relatively small sample sizes, which have rendered them insufficiently powerful to determine whether there is an association between systemic lupus erythematosus and thyroid autoimmunity. The main objective of this meta-analysis is to provide reliable estimates of the extent of any association between thyroid autoimmunity and systemic lupus erythematosus by combining the primary data from all relevant studies. Literature databases were searched, including the Medline, Embase, Web of Science, Chinese Wanfang and CBM databases, from January 1970 to May 2014. A total of 1076 systemic lupus erythematosus cases and 1661 healthy controls were included in this study. From these data, the odds ratio (OR) and the corresponding 95% confidence interval (95% CI) were calculated. The meta-analysis results showed that the prevalence of thyroid autoantibody positivity in patients with systemic lupus erythematosus was higher than in healthy controls (TgAb: OR = 2.99, 95% CI = 1.83–4.89; TPOAb: OR = 2.20, 95% CI = 1.27–3.82, respectively).ConclusionThe results of this meta-analysis suggest that thyroid autoimmunity is more prevalent in patients with systemic lupus erythematosus than in a control group.

Type 1 diabetes and polyglandular autoimmune syndrome: A review.

Type 1 diabetes (T1D) is an autoimmune disorder caused by inflammatory destruction of the pancreatic tissue. The etiopathogenesis and characteristics of the pathologic process of pancreatic destruction are well described. In addition, the putative susceptibility genes for T1D as a monoglandular disease and the relation to polyglandular autoimmune syndrome (PAS) have also been well explored. The incidence of T1D has steadily increased in most parts of the world, especially in industrialized nations. T1D is frequently associated with autoimmune endocrine and non-endocrine diseases and patients with T1D are at a higher risk for developing several glandular autoimmune diseases. Familial clustering is observed, which suggests that there is a genetic predisposition. Various hypotheses pertaining to viral- and bacterial-induced pancreatic autoimmunity have been proposed, however a definitive delineation of the autoimmune pathomechanism is still lacking. In patients with PAS, pancreatic and endocrine autoantigens either colocalize on one antigen-presenting cell or are expressed on two/various target cells sharing a common amino acid, which facilitates binding to and activation of T cells. The most prevalent PAS phenotype is the adult type 3 variant or PAS type III, which encompasses T1D and autoimmune thyroid disease. This review discusses the findings of recent studies showing noticeable differences in the genetic background and clinical phenotype of T1D either as an isolated autoimmune endocrinopathy or within the scope of polyglandular autoimmune syndrome.

Genetic variants of interleukin-4 gene in autoimmune thyroid diseases: An updated meta-analysis

Autoimmune thyroid diseases (AITDs) including Graves' disease (GD) and Hashimoto's thyroiditis (HT) are common autoimmune endocrine disorders. Interleukin-4 (IL-4), a cytokine secreted by T cells, plays a critical role in antigen-specific Th2 responses. The IL-4 gene is highly polymorphic and it has been reported that the polymorphism at –590 (T/C, rs2243250) in the promoter region of IL-4 may contribute to the development of AITDs. Recently, several case-control studies have examined the association of genetic variants of IL-4 with AITDs. However, the results of these studies remain conflicting. To systematically study the role of IL-4 in the pathogenesis of AITDs, we conducted a meta-analysis including 11 eligible studies (1847 cases and 2068 healthy controls). Fixed-effect or random-effect models were used to calculate pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Our results revealed a significant association between the IL-4 genetic variant (−590, T/C, rs2243250) and the risk of developing AITDs (TC + TT versus TT genotype: OR = 1.83, 95% CI = 1.083–3.091, p = 0.024). These findings demonstrate that the IL-4 rs2243250 genetic variant might play a key role in the development of AITDs.

Increased prevalence of autoimmune diseases in functional gastrointestinal disorders: case-control study of 23471 primary care patients.

There is increasing evidence that impaired mucosal defence mechanisms are implicated in the pathogenesis of the functional gastrointestinal disorders (FGIDs), allowing inappropriate immune activation. To test the hypothesis that an excess of autoimmune disorders among sufferers, using a large primary care database to examine this. Cases were diagnosed with FGIDs - irritable bowel syndrome (IBS), functional dyspepsia (FD), chronic idiopathic constipation (CIC), and multiple FGIDs. Controls were those without FGIDs. Prevalence of autoimmune disorders was compared between cases and controls using odds ratios (ORs) and 95% confidence intervals (CIs). We included 23,471 patients (mean age 51.4 years, 66.1% female). Prevalence of autoimmune disorders was greater among all FGIDs, compared with controls without. In those with FD (OR 1.35; 95% CI 1.12-1.63), CIC (OR 1.75; 95% CI 1.11-2.75), or multiple FGIDs (OR 1.49; 95% CI 1.25-1.77) this was statistically significant after controlling for age and gender. Rheumatological autoimmune disorders were significantly more frequent in those with FD (OR 1.44; 95% CI 1.15-1.80), CIC (OR 1.84; 95% CI 1.08-3.13), or multiple FGIDs (OR 1.53; 95% CI 1.24-1.88), after controlling for age and gender. However, endocrine autoimmune disorders were no more frequent in those with FGIDs, after controlling for age and gender. In a large sample of primary care patients, there was a significantly higher prevalence of autoimmune disorders among those with FD, CIC, or multiple FGIDs not explained by differences in age or gender. We were unable to control for concomitant drug use, which may partly explain this association.

Primary Hypoparathyroidism and Non-functioning Pituitary Adenoma: An Incidental Coexistence?

Primary hypoparathyroidism is caused by a group of heterogeneous conditions in which hypocalcemia and hyperphosphatemia occur as a result of deficient parathyroid hormone (PTH) secretion. The most common cause is surgical excision and damage to the parathyroid gland(s). Nonetheless, autoimmune endocrine disorder of primary hypothyroidism has been well-described in polyglandular autoimmune syndromes (PAS). 1 Its association with pituitary lesion may be autoimmune lymphocytic hypophysitis as the cause for pituitary disorder. In this report, we encountered a patient with primary hypoparathyroidism who had a non-functioning pituitary tumour. It was confirmed as pituitary adenoma rather than lymphocytic hypophysitis from the histopathological examination. To our knowledge, this is the first reported case of non-functioning pituitary macroadenoma and primary hypoparathyroidism.

The effect of types I and III interferons on adrenocortical cells and its possible implications for autoimmune Addison's disease

Autoimmune Addison's disease (AAD) is caused by selective destruction of the hormone-producing cells of the adrenal cortex. As yet, little is known about the potential role played by environmental factors in this process. Type I and/or type III interferons (IFNs) are signature responses to virus infections, and have also been implicated in the pathogenesis of autoimmune endocrine disorders such as type 1 diabetes and autoimmune thyroiditis. Transient development of AAD and exacerbation of established or subclinical disease, as well as the induction of autoantibodies associated with AAD, have been reported following therapeutic administration of type I IFNs. We therefore hypothesize that exposure to such IFNs could render the adrenal cortex susceptible to autoimmune attack in genetically predisposed individuals. In this study, we investigated possible immunopathological effects of type I and type III IFNs on adrenocortical cells in relation to AAD. Both types I and III IFNs exerted significant cytotoxicity on NCI-H295R adrenocortical carcinoma cells and potentiated IFN-γ- and polyinosine-polycytidylic acid [poly (I : C)]-induced chemokine secretion. Furthermore, we observed increased expression of human leucocyte antigen (HLA) class I molecules and up-regulation of 21-hydroxylase, the primary antigenic target in AAD. We propose that these combined effects could serve to initiate or aggravate an ongoing autoimmune response against the adrenal cortex in AAD.