Altered biomarkers for cardiovascular disease and inflammation in autoimmune Addison's disease - a cross-sectional study.

OBJECTIVE: Increased prevalence of cardiovascular disease has been reported in autoimmune Addison's disease (AAD), but pathomechanisms are poorly understood. DESIGN: Cross-sectional study. METHODS: We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250 µg tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH. RESULTS: Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = -0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60 min after injection of ACTH in AAD without RAF (-0.15 normalized protein expression [NPX], P = .0001, and -0.25 NPX, P = .0003, respectively). CONCLUSIONS: We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small.

A gene-centric approach to biomarker discovery identifies transglutaminase 1 as an epidermal autoantigen.

Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases.

GWAS for autoimmune Addison's disease identifies multiple risk loci and highlights AIRE in disease susceptibility.

Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10-8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10-25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h2).

APECED-Associated Hepatitis: Clinical, Biochemical, Histological and Treatment Data From a Large, Predominantly American Cohort.

BACKGROUND AND AIMS: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by autoimmune regulator (AIRE) mutations, manifests with chronic mucocutaneous candidiasis (CMC) and multisystem autoimmunity, most often hypoparathyroidism (HP) and adrenal insufficiency (AI). European cohorts previously reported a ~10% prevalence of APECED-associated hepatitis (APAH) with presentations ranging from asymptomatic laboratory derangements to fatal fulminant hepatic failure. Herein, we characterized APAH in a large APECED cohort from the Americas. APPROACH AND RESULTS: Forty-five consecutive patients with APECED were evaluated (2013-2015) at the National Institutes of Health (NIH; NCT01386437). Hepatology consultation assessed hepatic and autoimmune biomarkers and liver ultrasound in all patients. Liver biopsies evaluated autoimmune features and fibrosis. The 16S ribosomal RNA (rRNA) sequencing was performed in 35 patients' stools (12 with and 23 without APAH). Among 43 evaluable patients, 18 (42%) had APAH; in 33.3% of those with APAH, APAH occurred before developing classic APECED diagnostic criteria. At APAH diagnosis, the median age was 7.8 years, and patients manifested with aminotransferase elevation and/or hyperbilirubinemia. All patients with APAH were in clinical remission during their NIH evaluation while receiving immunomodulatory treatment. We found no difference in age, sex, or prevalence of CMC, AI, or HP between patients with or without APAH. Autoantibody positivity against aromatic L-amino acid decarboxylase, cytochrome P450 family 1 subfamily A member 2, histidine decarboxylase (HDC), bactericidal/permeability-increasing fold-containing B1, tryptophan hydroxlase, and 21-hydroxylase (21-OH), and the homozygous c.967_979del13 AIRE mutation were associated with APAH development. Classical serological biomarkers of autoimmune hepatitis (AIH) were only sporadically positive. AIH-like lymphoplasmacytic inflammation with mild fibrosis was the predominant histological feature. Stool microbiome analysis found Slackia and Acidaminococcus in greater abundance in patients with APAH. CONCLUSIONS: APAH is more common than previously described, may present early before classic APECED manifestations, and most often manifests with milder, treatment-responsive disease. Several APECED-associated autoantibodies, but not standard AIH-associated biomarkers, correlate with APAH.

Whole-genome genotyping and resequencing reveal the association of a deletion in the complex interferon alpha gene cluster with hypothyroidism in dogs.

BACKGROUND: Hypothyroidism is a common complex endocrinopathy that typically has an autoimmune etiology, and it affects both humans and dogs. Genetic and environmental factors are both known to play important roles in the disease development. In this study, we sought to identify the genetic risk factors potentially involved in the susceptibility to the disease in the high-risk Giant Schnauzer dog breed. RESULTS: By employing genome-wide association followed by fine-mapping (top variant p-value = 5.7 × 10- 6), integrated with whole-genome resequencing and copy number variation analysis, we detected a ~ 8.9 kbp deletion strongly associated (p-value = 0.0001) with protection against development of hypothyroidism. The deletion is located between two predicted Interferon alpha (IFNA) genes and it may eliminate functional elements potentially involved in the transcriptional regulation of these genes. Remarkably, type I IFNs have been extensively associated to human autoimmune hypothyroidism and general autoimmunity. Nonetheless, the extreme genomic complexity of the associated region on CFA11 warrants further long-read sequencing and annotation efforts in order to ascribe functions to the identified deletion and to characterize the canine IFNA gene cluster in more detail. CONCLUSIONS: Our results expand the current knowledge on genetic determinants of canine hypothyroidism by revealing a significant link with the human counterpart disease, potentially translating into better diagnostic tools across species, and may contribute to improved canine breeding strategies.

Concordance Between ICD-10 Codes and Clinical Diagnosis of Hypoparathyroidism in Sweden.

INTRODUCTION: Chronic hypoparathyroidism is a rare disorder. The disease is characterized by low serum calcium, high serum phosphate, and deficient production of parathyroid hormone. The most common etiology is unintentional damage and intentional removal to the parathyroid glands during anterior neck surgery. Other causes include genetic disorders and autoimmune diseases. Knowledge about the epidemiology of chronic hypoparathyroidism is sparse and the prevalence in Sweden is unknown. It is of importance to know the validity of the registers used to study the epidemiology of hypoparathyroidism in Sweden. The purpose of this study was to validate the International Classification of Diseases - 10th revision (ICD-10) diagnosis of hypoparathyroidism in the Swedish National Patient Register. METHODS: We included patients with the ICD-10 diagnosis of hypoparathyroidism that were found in the Swedish National Patient Register during 2004 to 2016. Through the unique national registration number assigned to all Swedish inhabitants, we could link this information to the Swedish Prescribed Drug Register. We included patients with an ICD-10 diagnosis for hypoparathyroidism and on concurrent conventional treatment for the disease. The validation of the diagnosis was assessed through review of medical records of 120 patients. RESULTS: A total of 958 patients, 70% women (n=671) and 30% men (n=287) met the inclusion criteria. In total, 120 randomly chosen medical records were reviewed and 109 cases were confirmed. This corresponds to an overall positive predictive value of 91%. CONCLUSION: The validity of the ICD-10 diagnosis of hypoparathyroidism in the Swedish National Patient Register is high and the register is a reliable source for further research. There is a risk of miscoding when assigning an ICD-code to the medical records. We urge clinicians to be aware of this risk, especially the risk of mix-ups with the more common diagnosis of hyperparathyroidism.

Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1.

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1. Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease. Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE. Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure. Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.

Expanding the Phenotypic and Genotypic Landscape of Autoimmune Polyendocrine Syndrome Type 1.

Context: Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene and characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency. Comprehensive characterizations of large patient cohorts are rare. Objective: To perform an extensive clinical, immunological, and genetic characterization of a large nationwide Russian APS-1 cohort. Subjects and Methods: Clinical components were mapped by systematic investigations, sera were screened for autoantibodies associated with APS-1, and AIRE mutations were characterized by Sanger sequencing. Results: We identified 112 patients with APS-1, which is, to the best of our knowledge, the largest cohort described to date. Careful phenotyping revealed several additional and uncommon phenotypes such as cerebellar ataxia with pseudotumor, ptosis, and retinitis pigmentosa. Neutralizing autoantibodies to interferon-ω were found in all patients except for one. The major Finnish mutation c.769C>T (p.R257*) was the most frequent and was present in 72% of the alleles. Altogether, 19 different mutations were found, of which 9 were unknown: c.38T>C (p.L13P), c.173C>T (p.A58V), c.280C>T (p.Q94*), c.554C>G (p.S185*), c.661A>T (p.K221*), c.821del (p.Gly274Afs*104), c.1195G>C (p.A399P), c.1302C>A (p.C434*), and c.1497del (p.A500Pfs*21). Conclusions: The spectrum of phenotypes and AIRE mutation in APS-1 has been expanded. The Finnish major mutation is the most common mutation in Russia and is almost as common as in Finland. Assay of interferon antibodies is a robust screening tool for APS-1.

Prevalence of Celiac Disease in Patients with Autoimmune Thyroid Disease: A Meta-Analysis.

BACKGROUND: Several screening studies have indicated an increased prevalence of celiac disease (CD) among individuals with autoimmune thyroid disease (ATD), but estimates have varied substantially. OBJECTIVE: The aim of this study was to examine the prevalence of CD in patients with ATD. METHOD: A systematic review was conducted of articles published in PubMed Medline or EMBASE until September 2015. Non-English papers with English-language abstracts were also included, as were research abstracts without full text available when relevant data were included in the abstract. Search terms included "celiac disease" combined with "hypothyroidism" or "hyperthyroidism" or "thyroid disease." Fixed-effects inverse variance-weighted models were used. Meta-regression was used to examine heterogeneity in subgroups. RESULTS: A pooled analysis, based on 6024 ATD patients, found a prevalence of biopsy-confirmed CD of 1.6% [confidence interval (CI) 1.3-1.9%]. Heterogeneity was large (I(2) = 70.7%). The prevalence was higher in children with ATD (6.2% [CI 4.0-8.4%]) than it was in adults (2.7%) or in studies examining both adults and children (1.0%). CD was also more prevalent in hyperthyroidism (2.6% [CI 0.7-4.4%]) than it was in hypothyroidism (1.4% [CI 1.0-1.9%]). CONCLUSIONS: About 1/62 patients with ATD have biopsy-verified CD. It is argued that patients with ATD should be screened for CD, given this increased prevalence.

Elevated Levels of SOX10 in Serum from Vitiligo and Melanoma Patients, Analyzed by Proximity Ligation Assay.

BACKGROUND: The diagnosis of malignant melanoma currently relies on clinical inspection of the skin surface and on the histopathological status of the excised tumor. The serum marker S100B is used for prognostic estimates at later stages of the disease, but analyses are marred by false positives and inadequate sensitivity in predicting relapsing disorder. OBJECTIVES: To investigate SOX10 as a potential biomarker for melanoma and vitiligo. METHODS: In this study we have applied proximity ligation assay (PLA) to detect the transcription factor SOX10 as a possible serum marker for melanoma. We studied a cohort of 110 melanoma patients. We further investigated a second cohort of 85 patients with vitiligo, which is a disease that also affects melanocytes. RESULTS: The specificity of the SOX10 assay in serum was high, with only 1% of healthy blood donors being positive. In contrast, elevated serum SOX10 was found with high frequency among vitiligo and melanoma patients. In patients with metastases, lack of SOX10 detection was associated with treatment benefit. In two responding patients, a change from SOX10 positivity to undetectable levels was seen before the response was evident clinically. CONCLUSIONS: We show for the first time that SOX10 represents a promising new serum melanoma marker for detection of early stage disease, complementing the established S100B marker. Our findings imply that SOX10 can be used to monitor responses to treatment and to assess if the treatment is of benefit at stages earlier than what is possible radiologically.

Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 1.

Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features multiple autoimmune disease manifestations. It is caused by mutations in the Autoimmune regulator (AIRE) gene, which promote thymic display of thousands of peripheral tissue antigens in a process critical for establishing central immune tolerance. We here used proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Interrogation of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of more than 9000 proteins we further identified MAGEB2 and PDILT as novel major autoantigens in APS1. Our proteome-wide assessment revealed a marked enrichment for tissue-specific immune targets, mirroring AIRE's selectiveness for this category of genes. Our findings also suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1, which contrasts the broad defect of thymic presentation associated with AIRE-deficiency and raises novel questions what other factors are needed for break of tolerance.

Mammalian CSAD and GADL1 have distinct biochemical properties and patterns of brain expression.

Variants in the gene encoding the enzyme glutamic acid decarboxylase like 1 (GADL1) have been associated with response to lithium therapy. Both GADL1 and the related enzyme cysteine sulfinic acid decarboxylase (CSAD) have been proposed to be involved in the pyridoxal-5'-phosphate (PLP)-dependent biosynthesis of taurine. In the present study, we compared the catalytic properties, inhibitor sensitivity and expression profiles of GADL1 and CSAD in brain tissue. In mouse and human brain we observed distinct patterns of expression of the PLP-dependent decarboxylases CSAD, GADL1 and glutamic acid decarboxylase 67 (GAD67). CSAD levels were highest during prenatal and early postnatal development; GADL1 peaked early in prenatal development, while GAD67 increased rapidly after birth. Both CSAD and GADL1 are being expressed in neurons, whereas only CSAD mRNA was detected in astrocytes. Cysteine sulfinic acid was the preferred substrate for both mouse CSAD and GADL1, although both enzymes also decarboxylated cysteic acid and aspartate. In silico screening and molecular docking using the crystal structure of CSAD and in vitro assays led to the discovery of eight new enzyme inhibitors with partial selectivity for either CSAD or GADL1. Lithium had minimal effect on their enzyme activities. In conclusion, taurine biosynthesis in vertebrates involves two structurally related PLP-dependent decarboxylases (CSAD and GADL1) that have partially overlapping catalytic properties but different tissue distribution, indicating divergent physiological roles. Development of selective enzyme inhibitors targeting these enzymes is important to further dissect their (patho)physiological roles.

Transglutaminase 4 as a prostate autoantigen in male subfertility.

Autoimmune polyendocrine syndrome type 1 (APS1), a monogenic disorder caused by AIRE gene mutations, features multiple autoimmune disease components. Infertility is common in both males and females with APS1. Although female infertility can be explained by autoimmune ovarian failure, the mechanisms underlying male infertility have remained poorly understood. We performed a proteome-wide autoantibody screen in APS1 patient sera to assess the autoimmune response against the male reproductive organs. By screening human protein arrays with male and female patient sera and by selecting for gender-imbalanced autoantibody signals, we identified transglutaminase 4 (TGM4) as a male-specific autoantigen. Notably, TGM4 is a prostatic secretory molecule with critical role in male reproduction. TGM4 autoantibodies were detected in most of the adult male APS1 patients but were absent in all the young males. Consecutive serum samples further revealed that TGM4 autoantibodies first presented during pubertal age and subsequent to prostate maturation. We assessed the animal model for APS1, the Aire-deficient mouse, and found spontaneous development of TGM4 autoantibodies specifically in males. Aire-deficient mice failed to present TGM4 in the thymus, consistent with a defect in central tolerance for TGM4. In the mouse, we further link TGM4 immunity with a destructive prostatitis and compromised secretion of TGM4. Collectively, our findings in APS1 patients and Aire-deficient mice reveal prostate autoimmunity as a major manifestation of APS1 with potential role in male subfertility.

Clinical and serologic parallels to APS-I in patients with thymomas and autoantigen transcripts in their tumors.

Patients with the autoimmune polyendocrine syndrome type I (APS-I), caused by mutations in the autoimmune regulator (AIRE) gene, and myasthenia gravis (MG) with thymoma, show intriguing but unexplained parallels. They include uncommon manifestations like autoimmune adrenal insufficiency (AI), hypoparathyroidism, and chronic mucocutaneous candidiasis plus autoantibodies neutralizing IL-17, IL-22, and type I IFNs. Thymopoiesis in the absence of AIRE is implicated in both syndromes. To test whether these parallels extend further, we screened 247 patients with MG, thymoma, or both for clinical features and organ-specific autoantibodies characteristic of APS-I patients, and we assayed 26 thymoma samples for transcripts for AIRE and 16 peripheral tissue-specific autoantigens (TSAgs) by quantitative PCR. We found APS-I-typical autoantibodies and clinical manifestations, including chronic mucocutaneous candidiasis, AI, and asplenia, respectively, in 49 of 121 (40%) and 10 of 121 (8%) thymoma patients, but clinical features seldom occurred together with the corresponding autoantibodies. Both were rare in other MG subgroups (n = 126). In 38 patients with APS-I, by contrast, we observed neither autoantibodies against muscle Ags nor any neuromuscular disorders. Whereas relative transcript levels for AIRE and 7 of 16 TSAgs showed the expected underexpression in thymomas, levels were increased for four of the five TSAgs most frequently targeted by these patients' autoantibodies. Therefore, the clinical and serologic parallels to APS-I in patients with thymomas are not explained purely by deficient TSAg transcription in these aberrant AIRE-deficient tumors. We therefore propose additional explanations for the unusual autoimmune biases they provoke. Thymoma patients should be monitored for potentially life-threatening APS-I manifestations such as AI and hypoparathyroidism.

Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus.

AIMS/HYPOTHESIS: Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported. METHODS: Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide. RESULTS: None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted. CONCLUSIONS/INTERPRETATIONS: Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.

High frequency of cytolytic 21-hydroxylase-specific CD8+ T cells in autoimmune Addison's disease patients.

The mechanisms behind destruction of the adrenal glands in autoimmune Addison's disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme of the adrenal cortex, are found in >90% of patients, but these autoantibodies are not thought to mediate the disease. In this article, we demonstrate highly frequent 21-hydroxylase-specific T cells detectable in 20 patients with Addison's disease. Using overlapping 18-aa peptides spanning the full length of 21-hydroxylase, we identified immunodominant CD8(+) and CD4(+) T cell responses in a large proportion of Addison's patients both ex vivo and after in vitro culture of PBLs ≤20 y after diagnosis. In a large proportion of patients, CD8(+) and CD4(+) 21-hydroxylase-specific T cells were very abundant and detectable in ex vivo assays. HLA class I tetramer-guided isolation of 21-hydroxylase-specific CD8(+) T cells showed their ability to lyse 21-hydroxylase-positive target cells, consistent with a potential mechanism for disease pathogenesis. These data indicate that strong CTL responses to 21-hydroxylase often occur in vivo, and that reactive CTLs have substantial proliferative and cytolytic potential. These results have implications for earlier diagnosis of adrenal failure and ultimately a potential target for therapeutic intervention and induction of immunity against adrenal cortex cancer.

Altered expression of autoimmune regulator in infant down syndrome thymus, a possible contributor to an autoimmune phenotype.

Down syndrome (DS), caused by trisomy of chromosome 21, is associated with immunological dysfunctions such as increased frequency of infections and autoimmune diseases. Patients with DS share clinical features, such as autoimmune manifestations and specific autoantibodies, with patients affected by autoimmune polyendocrine syndrome type 1. Autoimmune polyendocrine syndrome type 1 is caused by mutations in the autoimmune regulator (AIRE) gene, located on chromosome 21, which regulates the expression of tissue-restricted Ags (TRAs) in thymic epithelial cells. We investigated the expression of AIRE and TRAs in DS and control thymic tissue using quantitative PCR. AIRE mRNA levels were elevated in thymic tissue from DS patients, and trends toward increased expression of the AIRE-controlled genes INSULIN and CHRNA1 were found. Immunohistochemical stainings showed altered cell composition and architecture of the thymic medulla in DS individuals with increased frequencies of AIRE-positive medullary epithelial cells and CD11c-positive dendritic cells as well as enlarged Hassall's corpuscles. In addition, we evaluated the proteomic profile of thymic exosomes in DS individuals and controls. DS exosomes carried a broader protein pool and also a larger pool of unique TRAs compared with control exosomes. In conclusion, the increased AIRE gene dose in DS could contribute to an autoimmune phenotype through multiple AIRE-mediated effects on homeostasis and function of thymic epithelial cells that affect thymic selection processes.

Intermediate lobe immunoreactivity in a patient with suspected lymphocytic hypophysitis.

Lymphocytic hypophysitis is an organ-specific autoimmune disease characterised by destruction of pituitary hormone-secreting cells due to attack by self-reactive T lymphocytes. The spectrum of pituitary autoantibodies characterised by indirect immunofluorescence (IF) in these patients has not been substantially defined. The purpose of this study was to determine the spectrum of pituitary autoantibodies in 16 lymphocytic hypophysitis patients. Pituitary sections were prepared from guinea pigs and sera from 16 lymphocytic hypophysitis patients (13 biopsy proven and 3 suspected cases) and 13 healthy controls were evaluated for immunoreactivity to the pituitary tissue by immunofluorescence. A single patient was found to have high titre pituitary autoantibodies against guinea pig pituitary tissue. Immunoreactivity was directed against cells of the intermediate lobe. We present the case report of the patient who is a 24 year old woman that presented with headaches, polyuria and polydipsia. A uniformly enlarged pituitary mass was visible on MRI and a diagnosis of suspected lymphocytic hypophysitis was made. Based on our IF study, we postulate this patient has an autoimmune process directed towards the major cell type in the intermediate lobe, the melanotroph. Pre-adsorption with peptides representing adrenocorticotropic hormone, α-melanocyte stimulating hormone or ß-endorphin did not affect the IF signal suggesting our patient's pituitary autoantibodies may target some other product of Proopiomelanocortin (POMC) processing, such as corticotrophin-like intermediate peptide or γ-lipoprotein. Alternatively, the autoantibodies may target a peptide completely unrelated to POMC processing.

Drug prescription patterns in patients with Addison's disease: a Swedish population-based cohort study.

CONTEXT: There are no published data on drug prescription in patients with Addison's disease (AD). OBJECTIVE: Our objective was to describe the drug prescription patterns in Swedish AD patients before and after diagnosis compared with population controls. DESIGN AND SETTING: We conducted a population-based cohort study in Sweden. PATIENTS: Through the Swedish National Patient Register and the Swedish Prescribed Drug Register, we identified 1305 patients with both a diagnosis of AD and on combination treatment with hydrocortisone/cortisone acetate and fludrocortisone. Direct evidence of the AD diagnosis from patient charts was not available. We identified 11 996 matched controls by the Register of Population. MAIN OUTCOME MEASURE: We determined the ratio of observed to expected number of patients treated with prescribed drugs. RESULTS: Overall, Swedish AD patients received more prescribed drugs than controls, and 59.3% of the AD patients had medications indicating concomitant autoimmune disease. Interestingly, both before and after the diagnosis of AD, patients used more gastrointestinal medications, antianemic preparations, lipid-modifying agents, antibiotics for systemic use, hypnotics and sedatives, and drugs for obstructive airway disease (all P values < .05). Notably, an increased prescription of several antihypertensive drugs and high-ceiling diuretics was observed after the diagnosis of AD. CONCLUSION: Gastrointestinal symptoms and anemia, especially in conjunction with autoimmune disorders, should alert the physician about the possibility of AD. The higher use of drugs for cardiovascular disorders after diagnosis in patients with AD raises concerns about the replacement therapy.