Publications by authors named "Olle Kampe"

104 Publications

Severe COVID-19 in an APS1 patient with interferon autoantibodies treated with plasmapheresis.

J Allergy Clin Immunol 2021 Apr 16. Epub 2021 Apr 16.

Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2021.03.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051851PMC
April 2021

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

Nat Commun 2021 02 11;12(1):959. Epub 2021 Feb 11.

Department of Clinical Science, University of Bergen, Bergen, Norway.

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). 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) 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 (h).
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http://dx.doi.org/10.1038/s41467-021-21015-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878795PMC
February 2021

Potential Transcriptional Biomarkers to Guide Glucocorticoid Replacement in Autoimmune Addison's Disease.

J Endocr Soc 2021 Mar 4;5(3):bvaa202. Epub 2021 Jan 4.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Background: No reliable biomarkers exist to guide glucocorticoid (GC) replacement treatment in autoimmune Addison's disease (AAD), leading to overtreatment with alarming and persistent side effects or undertreatment, which could be fatal.

Objective: To explore changes in gene expression following different GC replacement doses as a means of identifying candidate transcriptional biomarkers to guide GC replacement in AAD.

Methods: Step 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. In 3 of the most highly upregulated genes, we performed real-time PCR (rt-PCR) to compare gene expression levels before and 3, 4, and 6 hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD.

Results: Step 1: Two hours after infusion of 100 mg HC, there was a marked increase in and expression levels. and expression levels correlated with serum cortisol. Step 2: Expression levels of , and were increased and levels of and decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with , and expression.

Conclusions: We introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of and are particularly promising candidate biomarkers of GC replacement, followed by , and .
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http://dx.doi.org/10.1210/jendso/bvaa202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853175PMC
March 2021

Adrenal insufficiency.

Lancet 2021 Feb 20;397(10274):613-629. Epub 2021 Jan 20.

Department of Clinical Science and KG Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen, Norway; Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Center of Molecular Medicine, and Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.

Adrenal insufficiency can arise from a primary adrenal disorder, secondary to adrenocorticotropic hormone deficiency, or by suppression of adrenocorticotropic hormone by exogenous glucocorticoid or opioid medications. Hallmark clinical features are unintentional weight loss, anorexia, postural hypotension, profound fatigue, muscle and abdominal pain, and hyponatraemia. Additionally, patients with primary adrenal insufficiency usually develop skin hyperpigmentation and crave salt. Diagnosis of adrenal insufficiency is usually delayed because the initial presentation is often non-specific; physician awareness must be improved to avoid adrenal crisis. Despite state-of-the-art steroid replacement therapy, reduced quality of life and work capacity, and increased mortality is reported in patients with primary or secondary adrenal insufficiency. Active and repeated patient education on managing adrenal insufficiency, including advice on how to increase medication during intercurrent illness, medical or dental procedures, and profound stress, is required to prevent adrenal crisis, which occurs in about 50% of patients with adrenal insufficiency after diagnosis. It is good practice for physicians to provide patients with a steroid card, parenteral hydrocortisone, and training for parenteral hydrocortisone administration, in case of vomiting or severe illness. New modes of glucocorticoid delivery could improve the quality of life in some patients with adrenal insufficiency, and further advances in oral and parenteral therapy will probably emerge in the next few years.
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http://dx.doi.org/10.1016/S0140-6736(21)00136-7DOI Listing
February 2021

Limited Genetic Overlap Between Overt Hashimoto's Thyroiditis and Graves' Disease in Twins: A Population-based Study.

J Clin Endocrinol Metab 2021 Mar;106(4):1101-1110

Department of Medical Epidemiology and Biostatistics Karolinska Institutet, Stockholm, Sweden.

Context: Hashimoto's thyroiditis (HT) and Graves' disease (GD) are known to coaggregate in families, but the magnitude and nature of a shared etiology is unknown.

Objectives: To estimate the shared genetic influence on overt HT and GD and to examine if the heritability differs between men and women.

Design, Setting, And Patients: We used national health registries to identify cases of HT and GD in a cohort of 110 814 Swedish twins. By comparing intra-class and cross-twin cross-trait correlations in dizygotic and monozygotic twins, we calculated heritability and the proportions thereof shared between the diseases. Univariate estimates of heritability were calculated by sex.

Results: The heritability for HT and GD was 65% (95% CI, 61-70) and 63% (95% CI, 55-72), respectively. The genetic correlation was 0.35 (95% CI, 0.20-0.50) and shared genetic effects accounted for 8% of the variance for both HT and GD. Univariate heritability was significantly higher in men than in women for HT (90% vs 60%, P < 0.001) but not for GD (79% vs 63%, P = 0.085).

Conclusions: From a genetic perspective, HT and GD appear to be only modestly related diseases. Hence, the term "autoimmune thyroid disease," used to cluster these disorders, may have limited validity in a genetic context. Moreover, the mechanisms contributing to HT are partly different for the sexes, with genetic components more important in men.
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http://dx.doi.org/10.1210/clinem/dgaa956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993582PMC
March 2021

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

Hepatology 2021 Mar;73(3):1088-1104

Translational, Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

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.
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http://dx.doi.org/10.1002/hep.31421DOI Listing
March 2021

Residual Corticosteroid Production in Autoimmune Addison Disease.

J Clin Endocrinol Metab 2020 07;105(7)

Department of Clinical Science, University of Bergen, Norway.

Context: Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis.

Objective: To determine frequencies and clinical features of residual corticosteroid production in patients with AAD.

Design: Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone after > 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography-tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test.

Results: Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (n = 33; P < 0.002) and in shorter disease duration (median 6 [0-44] vs 13 [0-53] years; P < 0.001). Residual MC production was found in 26 (13.5%) patients and associated with shorter disease duration (median 5.5 [0.5-26.0] vs 13 [0-53] years; P < 0.004), lower fludrocortisone replacement dosage (median 0.075 [0.050-0.120] vs 0.100 [0.028-0.300] mg; P < 0.005), and higher plasma renin concentration (median 179 [22-915] vs 47.5 [0.6-658.0] mU/L; P < 0.001). There was no significant association between residual production and frequency of adrenal crises or quality of life. None had a normal cosyntropin response, but peak cortisol strongly correlated with unstimulated cortisol (r = 0.989; P < 0.001) and plasma adrenocorticotropic hormone (ACTH; r = -0.487; P < 0.001).

Conclusion: In established AAD, one-third of the patients still produce GCs even decades after diagnosis. Residual production is more common in men and in patients with shorter disease duration but is not associated with adrenal crises or quality of life.
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http://dx.doi.org/10.1210/clinem/dgaa256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274491PMC
July 2020

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

BMC Genomics 2020 Apr 16;21(1):307. Epub 2020 Apr 16.

Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.

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), 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.
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http://dx.doi.org/10.1186/s12864-020-6700-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160888PMC
April 2020

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

Clin Epidemiol 2020 24;12:327-331. Epub 2020 Mar 24.

Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, 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.
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http://dx.doi.org/10.2147/CLEP.S242528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102876PMC
March 2020

Co-aggregation and heritability of organ-specific autoimmunity: a population-based twin study.

Eur J Endocrinol 2020 May;182(5):473-480

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Objective: Co-aggregation of autoimmune diseases is common, suggesting partly shared etiologies. Genetic factors are believed to be important, but objective measures of environmental vs heritable influences on co-aggregation are absent. With a novel approach to twin studies, we aimed at estimating heritability and genetic overlap in seven organ-specific autoimmune diseases.

Design: Prospective twin cohort study.

Methods: We used a cohort of 110 814 twins to examine co-aggregation and heritability of Hashimoto's thyroiditis, atrophic gastritis, celiac disease, Graves' disease, type 1 diabetes, vitiligo and Addison's disease. Hazard ratios (HR) were calculated for twins developing the same or different disease as compared to their co-twin. The differences between monozygotic and dizygotic twin pairs were used to estimate the genetic influence on co-aggregation. Heritability for individual disorders was calculated using structural equational modeling adjusting for censoring and truncation of data.

Results: Co-aggregation was more pronounced in monozygotic twins (median HR: 3.2, range: 2.2-9.2) than in dizygotic twins (median HR: 2.4, range: 1.1-10.0). Heritability was moderate for atrophic gastritis (0.38, 95% CI: 0.23-0.53) but high for all other diseases, ranging from 0.60 (95% CI: 0.49-0.71) for Graves' disease to 0.97 (95% CI: 0.91-1.00) for Addison's disease.

Conclusions: Overall, co-aggregation was more pronounced in monozygotic than in dizygotic twins, suggesting that disease overlap is largely attributable to genetic factors. Co-aggregation was common, and twins faced up to a ten-fold risk of developing diseases not present in their co-twin. Our results validate and refine previous heritability estimates based on smaller twin cohorts.
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http://dx.doi.org/10.1530/EJE-20-0049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182094PMC
May 2020

Screening for autoantibody targets in post-vaccination narcolepsy using proteome arrays.

Scand J Immunol 2020 Apr 13;91(4):e12864. Epub 2020 Feb 13.

Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a specific loss of hypocretin-producing neurons. The incidence of NT1 increased in Sweden, Finland and Norway following Pandemrix®-vaccination, initiated to prevent the 2009 influenza pandemic. The pathogenesis of NT1 is poorly understood, and causal links to vaccination are yet to be clarified. The strong association with Human leukocyte antigen (HLA) DQB1*06:02 suggests an autoimmune pathogenesis, but proposed autoantigens remain controversial. We used a two-step approach to identify autoantigens in patients that acquired NT1 after Pandemrix®-vaccination. Using arrays of more than 9000 full-length human proteins, we screened the sera of 10 patients and 24 healthy subjects for autoantibodies. Identified candidate antigens were expressed in vitro to enable validation studies with radiobinding assays (RBA). The validation cohort included NT1 patients (n = 39), their first-degree relatives (FDR) (n = 66), population controls (n = 188), and disease controls representing multiple sclerosis (n = 100) and FDR to type 1 diabetes patients (n = 41). Reactivity towards previously suggested NT1 autoantigen candidates including Tribbles homolog 2, Prostaglandin D2 receptor, Hypocretin receptor 2 and α-MSH/proopiomelanocortin was not replicated in the protein array screen. By comparing case to control signals, three novel candidate autoantigens were identified in the protein array screen; LOC401464, PARP3 and FAM63B. However, the RBA did not confirm elevated reactivity towards either of these proteins. In summary, three putative autoantigens in NT1 were identified by protein array screening. Autoantibodies against these candidates could not be verified with independent methods. Further studies are warranted to identify hypothetical autoantigens related to the pathogenesis of Pandemrix®-induced NT1.
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http://dx.doi.org/10.1111/sji.12864DOI Listing
April 2020

Comment on 'AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies'.

Elife 2019 06 27;8. Epub 2019 Jun 27.

Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.

The gene plays a key role in the development of central immune tolerance by promoting thymic presentation of tissue-specific molecules. Patients with -deficiency develop multiple autoimmune manifestations and display autoantibodies against the affected tissues. In 2016 it was reported that: i) the spectrum of autoantibodies in patients with -deficiency is much broader than previously appreciated; ii) neutralizing autoantibodies to type I interferons (IFNs) could provide protection against type 1 diabetes in these patients (Meyer et al., 2016). We attempted to replicate these new findings using a similar experimental approach in an independent patient cohort, and found no evidence for either conclusion.
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http://dx.doi.org/10.7554/eLife.43578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597240PMC
June 2019

The autoimmune targets in IPEX are dominated by gut epithelial proteins.

J Allergy Clin Immunol 2019 07 23;144(1):327-330.e8. Epub 2019 Apr 23.

Center for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

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http://dx.doi.org/10.1016/j.jaci.2019.02.031DOI Listing
July 2019

Sex-Specific Risk of Cardiovascular Disease in Autoimmune Addison Disease-A Population-Based Cohort Study.

J Clin Endocrinol Metab 2019 06;104(6):2031-2040

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Context: Little is known of cardiovascular disease (CVD) in autoimmune Addison disease (AAD). Inadequate glucocorticoid replacement might potentially increase CVD risk.

Objective: To examine CVD in AAD in subgroups of ischemic heart disease (IHD) and cerebrovascular disease (CeVD) and investigate the effects of glucocorticoid and mineralocorticoid dosing.

Design, Setting, And Patients: In this cohort-control study, we used Swedish health registries from 1964 to 2013 to identify 1500 subjects with AAD and 13,758 matched controls. Incident CVD was analyzed from 2006 to 2013. Adjusted hazard ratios (aHRs) were calculated using Cox proportional hazard models. Glucocorticoid and mineralocorticoid doses were stratified to examine dose-related risks.

Results: During 8807 person-years (PY), 94 events of first CVD (10.7/1000 PY) in patients with AAD occurred compared with 563 events during 80,163 PY (7.0/1000 PY) in controls. IHD was significantly more common in women (aHR, 2.15; 95% CI, 1.49 to 3.10) but not men (aHR, 1.16; 95% CI, 0.75 to 1.78) with AAD compared with controls. No increase in CeVD risk was detected (aHR, 0.88; 95% CI, 0.56 to 1.37, women; aHR, 0.88; 95% CI 0.53 to 1.50, men). CVD was associated with greater glucocorticoid and mineralocorticoid replacement doses in women but not men.

Conclusion: The risk of IHD but not CeVD is increased in AAD, especially in women. The risk of CVD independently correlated with greater glucocorticoid and mineralocorticoid replacement doses in women. Our data suggest that close monitoring and early treatment of risk factors for CVD, among women in particular, might be warranted.
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http://dx.doi.org/10.1210/jc.2018-02298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469226PMC
June 2019

Autoimmune Polyendocrine Syndromes.

N Engl J Med 2018 06;378(26):2543-2544

Karolinska Institutet, Stockholm, Sweden

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http://dx.doi.org/10.1056/NEJMc1805308DOI Listing
June 2018

Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden.

Sci Rep 2018 05 30;8(1):8395. Epub 2018 May 30.

Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.
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http://dx.doi.org/10.1038/s41598-018-26842-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976627PMC
May 2018

Autoimmune Polyendocrine Syndromes.

N Engl J Med 2018 Mar;378(12):1132-1141

From the Department of Clinical Science and K.G. Jebsen Center for Autoimmune Disorders, University of Bergen (E.S.H., O.K.), and the Department of Medicine, Haukeland University Hospital (E.S.H.), Bergen, Norway; the Department of Medicine (Solna), Karolinska Institutet, Stockholm (E.S.H., O.K.); and the Diabetes Center and the Department of Medicine, University of California, San Francisco, San Francisco (M.S.A.).

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http://dx.doi.org/10.1056/NEJMra1713301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007870PMC
March 2018

ILF2 and ILF3 are autoantigens in canine systemic autoimmune disease.

Sci Rep 2018 03 19;8(1):4852. Epub 2018 Mar 19.

Department of Clinical Sciences, Swedish University of Agricultural Sciences, SE-750 07, Uppsala, Sweden.

Dogs can spontaneously develop complex systemic autoimmune disorders, with similarities to human autoimmune disease. Autoantibodies directed at self-antigens are a key feature of these autoimmune diseases. Here we report the identification of interleukin enhancer-binding factors 2 and 3 (ILF2 and ILF3) as autoantigens in canine immune-mediated rheumatic disease. The ILF2 autoantibodies were discovered in a small, selected canine cohort through the use of human protein arrays; a method not previously described in dogs. Subsequently, ILF3 autoantibodies were also identified in the same cohort. The results were validated with an independent method in a larger cohort of dogs. ILF2 and ILF3 autoantibodies were found exclusively, and at a high frequency, in dogs that showed a speckled pattern of antinuclear antibodies on immunofluorescence. ILF2 and ILF3 autoantibodies were also found at low frequency in human patients with SLE and Sjögren's syndrome. These autoantibodies have the potential to be used as diagnostic biomarkers for canine, and possibly also human, autoimmune disease.
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http://dx.doi.org/10.1038/s41598-018-23034-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859008PMC
March 2018

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

J Clin Endocrinol Metab 2018 01;103(1):179-186

Center for Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1210/jc.2017-01957DOI Listing
January 2018

Heritability of Addison's disease and prevalence of associated autoimmunity in a cohort of 112,100 Swedish twins.

Endocrine 2017 Dec 16;58(3):521-527. Epub 2017 Oct 16.

Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176, Stockholm, Sweden.

Purpose: The pathophysiology behind autoimmune Addison's disease (AAD) is poorly understood, and the relative influence of genetic and environmental factors remains unclear. In this study, we examined the heritability of AAD and explored disease-associated autoimmune comorbidity among Swedish twins.

Methods: A population-based longitudinal cohort of 112,100 Swedish twins was used to calculate the heritability of AAD, and to explore co-occurrence of 10 organ-specific autoimmune disorders in twin pairs with AAD. Diagnoses were collected 1964-2012 through linkage to the Swedish National Patient Register. The Swedish Prescribed Drug Register was used for additional diagnostic precision. When available, biobank serum samples were used to ascertain the AAD diagnosis through identification of 21-hydroxylase autoantibodies.

Results: We identified 29 twins with AAD. Five out of nine (5/9) monozygotic pairs and zero out of fifteen (0/15) dizygotic pairs were concordant for AAD. The probandwise concordance for monozygotic twins was 0.71 (95% CI 0.40-0.90) and the heritability 0.97 (95% CI 0.88-99). Autoimmune disease patterns of monozygotic twin pairs affected by AAD displayed a higher degree of similarity than those of dizygotic twins, with an incidence rate ratio of 15 (95% CI 1.8-116) on the number of shared autoimmune diagnoses within pairs.

Conclusions: The heritability of AAD appears to be very high, emphasizing the need for further research on the genetic etiology of the disease. Monozygotic twin concordance for multiple autoimmune manifestations suggests strong genetic influence on disease specificity in organ-specific autoimmunity.
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http://dx.doi.org/10.1007/s12020-017-1441-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693969PMC
December 2017

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

J Clin Endocrinol Metab 2017 09;102(9):3546-3556

Department of Clinical Science, University of Bergen, Bergen 5020, Norway.

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.
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http://dx.doi.org/10.1210/jc.2017-00139DOI Listing
September 2017

Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1.

Autoimmunity 2017 Jun 30;50(4):223-231. Epub 2017 May 30.

a Department of Medical Sciences , Uppsala University , Uppsala , Sweden.

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in up to 7% of all APS1 patients, with immunoreactivity to pituitary tissue frequently reported. We aimed to isolate and identify specific pituitary autoantigens in patients with APS1. Immunoscreening of a pituitary cDNA expression library identified endothelin-converting enzyme (ECE)-2 as a potential candidate autoantigen. Immunoreactivity against ECE-2 was detected in 46% APS1 patient sera, with no immunoreactivity detectable in patients with other autoimmune disorders or healthy controls. Quantitative-PCR showed ECE-2 mRNA to be most abundantly expressed in the pancreas with high levels also in the pituitary and brain. In the pancreas ECE-2 was co-expressed with insulin or somatostatin, but not glucagon and was widely expressed in GH producing cells in the guinea pig pituitary. The correlation between immunoreactivity against ECE-2 and the major recognized clinical phenotypes of APS1 including hypopituitarism was not apparent. Our results identify ECE-2 as a specific autoantigen in APS1 with a restricted neuroendocrine distribution.
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http://dx.doi.org/10.1080/08916934.2017.1332183DOI Listing
June 2017

Autoimmune polyendocrine syndrome type 1 in an Indian cohort: a longitudinal study.

Endocr Connect 2017 Jul 26;6(5):289-296. Epub 2017 Apr 26.

Departments of EndocrinologySanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

Objective: Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator () gene mutations in a cohort of Indian APS1 patients.

Design: Twenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2-19) years.

Methods: Clinical features, mortality, organ-specific autoantibodies and gene mutations were studied.

Results: Patients varied widely in their age of presentation [3.5 (0.1-17) years] and number of clinical manifestations [5 (2-11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3-23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-α and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians.

Conclusions: Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.
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http://dx.doi.org/10.1530/EC-17-0022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510449PMC
July 2017

Clinical and Immunological Characteristics of Autoimmune Addison Disease: A Nationwide Swedish Multicenter Study.

J Clin Endocrinol Metab 2017 02;102(2):379-389

Centre for Molecular Medicine, Department of Medicine (Solna).

Context: Studies of the clinical and immunological features of autoimmune Addison disease (AAD) are needed to understand the disease burden and increased mortality.

Objective: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles, and cardiovascular risk factors.

Design, Setting, And Participants: A cross-sectional, population-based study that included 660 AAD patients from the Swedish Addison Registry (2008-2014). When analyzing the cardiovascular risk factors, 3594 individuals from the population-based survey in Northern Sweden, MONICA (monitoring of trends and determinants of cardiovascular disease), served as controls.

Main Outcome Measures: The endpoints were the prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.

Results: The proportion of 21-hydroxylase autoantibody-positive patients was 83%, and 62% of patients had ≥1 associated autoimmune diseases, more frequently coexisting in females (P < 0.0001). AAD patients had a lower body mass index (P < 0.0001) and prevalence of hypertension (P = 0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of the patients, with a mean dose of 28.1 ± 8.5 mg/d. The mean hydrocortisone equivalent dose normalized to the body surface was 14.8 ± 4.4 mg/m2/d. A greater hydrocortisone equivalent dose was associated with a greater incidence of hypertension (P = 0.046).

Conclusions: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients did not have an increased prevalence of overweight, hypertension, type 2 diabetes mellitus, or hyperlipidemia. However, high glucocorticoid replacement doses could be a risk factor for hypertension.
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http://dx.doi.org/10.1210/jc.2016-2522DOI Listing
February 2017

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

Thyroid 2016 07;26(7):880-90

1 Celiac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons , New York, New York.

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.
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http://dx.doi.org/10.1089/thy.2016.0108DOI Listing
July 2016

A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1.

J Clin Endocrinol Metab 2016 08 2;101(8):2975-83. Epub 2016 Jun 2.

Department of Clinical Science (Ø.B., B.E.O., E.B., B.G.N., L.B., P.M.K., K.Lo., A.B.W., E.S.H.), University of Bergen, 5021 Bergen, Norway; Department of Medicine (Solna) (N.L., O.K.), Karolinska Institutet, 171 76 Stockholm, Sweden; Science for Life Laboratory (N.L.), Department of Medical Sciences, University of Uppsala, 751 05 Uppsala, Sweden; Department of Medicine (M.M.E., K.Lo., E.S.H.), Haukeland University Hospital, 5021 Bergen, Norway; Department of Medicine (K.Li.,), Akershus University Hospital, 1474 Nordbyhagen, Norway; Department of Endocrinology (K.Li., A.P.J.), Oslo University Hospital, 0372 Oslo, Norway; Department of Pediatrics (A.G.M.), Oslo University Hospital, 0424 Oslo, Norway; Division of Internal Medicine (J.S.), University Hospital of North Norway, 9019 Tromsø, Norway; Institute of Clinical Medicine (J.S.), University of Tromsø, The Artic University of Norway, 9019 Tromsø, Norway; Department of Endocrinology (K.J.F.), St. Olavs Hospital, 7006 Trondheim, Norway; Department of Medicine (Å.B.), Stavanger University Hospital, 4011 Stavanger, Norway; Department of Medicine (B.G.N.), Haugesund Hospital, 5504 Haugesund, Norway; Department of Medicine (B.M.), Østfold Hospital, 1603 Fredrikstad, Norway; Department of Immunology (M.K.V.), Oslo University Hospital, 0372 Oslo, Norway; University of Oslo (M.K.V.), 0372 Oslo, Norway; Center for Medical Genetics and Molecular Medicine (P.M.K.), Haukeland University Hospital, 5021 Bergen, Norway; Department of Clinical Dentistry (M.C.M.), Faculty of Medicine and Dentistry, University of Bergen, 5021 Bergen, Norway; and Oral Health Centre of Expertise in Western Norway (M.C.M.), 5021 Bergen, Norway.

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse.

Objective: To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996-2016).

Patients: All known Norwegian patients with APS1.

Results: Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceased siblings with a high probability of undisclosed APS1. All except three had interferon-ω) autoantibodies, and all had organ-specific autoantibodies. The most common AIRE mutation was c.967_979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes.

Conclusions: Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-ω) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center.
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http://dx.doi.org/10.1210/jc.2016-1821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971337PMC
August 2016

Identification of autoimmune polyendocrine syndrome type 1 in patients with isolated hypoparathyroidism.

Clin Endocrinol (Oxf) 2016 Oct 28;85(4):544-50. Epub 2016 Jun 28.

Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

Objective: The prevalence of autoimmune polyendocrine syndrome type 1 (APS1) among isolated hypoparathyroidism (HP) or primary adrenal insufficiency (PAI) is not well established. We studied the frequency of APS1 in patients with HP or PAI by measuring interferon-α (IFN-α) antibody levels, a highly sensitive and specific marker for APS1.

Design, Patients And Measurements: In a single-centre cross-sectional study, 37 Indian patients with isolated HP and 40 patients with PAI were tested for IFN-α antibody using an indirect ELISA. In patients with elevated IFN-α antibody, the autoimmune regulator (AIRE) gene was bidirectionally sequenced.

Results: Three (8·1%) patients with isolated HP had elevated IFN-α antibody levels (range: 367-17382 units; positive titre >56 units). Homozygous or compound heterozygous AIRE mutations were detected in all three patients, including a novel mutation (p.T68P). All three APS1 patients had atypical features. The first patient, diagnosed at 7 years of age, died suddenly 5 months later. The second patient had late-onset HP (at the age of 34 years) and a solitary episode of transient mucocutaneous candidiasis 5 years later. The final patient developed HP at the age of 14 years and premature ovarian insufficiency 14 years later. Interleukin-22 antibodies, as well as most other organ-specific antibodies, were absent in the 3 APS1 patients. All patients with PAI were negative for IFN-α antibody.

Conclusion: Eight percentage of patients with isolated HP had elevated IFN-α antibody levels and AIRE mutation-positive APS1. All APS1 patients had atypical clinical features. Testing for IFN-α antibody should be considered in patients with idiopathic HP.
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http://dx.doi.org/10.1111/cen.13111DOI Listing
October 2016

Is low molecular weight hyaluronan an early indicator of disease in avian systemic sclerosis?

Connect Tissue Res 2016 09 2;57(5):337-46. Epub 2016 May 2.

f Department of Medical Sciences , Uppsala University , Uppsala , Sweden.

Aim Of The Study: To further elucidate the pathogenesis of systemic sclerosis (SSc) an experimental avian model was used. The University of California at Davis line 200 (UCD-200) chickens spontaneously develop a SSc-like disease that has most features of human SSc with vascular effects, inflammation, autoimmunity, and fibrosis. The first signs of disease in UCD-200 chickens are swelling and ischemic lesions of the comb and the presence of a tissue containing high amounts of glycosaminoglycan hyaluronan (HA). The aim of this study was to evaluate inflammatory and fibrotic processes of the disease with regard to the molecular weight of HA.

Material And Methods: Comb biopsies from UCD-200 and healthy White Leghorn (WL) chickens, as controls, at different ages were studied with the histochemical localization of HA, hyaluronidase-1 (Hyal-1), cluster of differentiation 3, immunoglobulin Y, and collagen I and III. The molecular weight distribution of HA was estimated with gas-phase electrophoretic analysis.

Results: At 2 days of age, HA was visualized in UCD-200 chickens at the dermal part of the comb with no simultaneous staining of Hyal-1. In adult UCD-200 chickens, the comb skin was almost totally devoid of HA compared to WL chickens of the same age. An increase of low molecular weight (LMW) HA was detected in comb tissue from UCD-200 at the age of 1 day, 1 week, 2 weeks, and 4 weeks, in contrast to adult animals.

Conclusions: An early inflammatory process involving LMW HA was confirmed as a possible profibrotic process. This indicates that HA might be an important participant in the early inflammatory events of SSc in UCD-200 chickens and that the disappearance of HA in skin predisposes to fibrosis.
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http://dx.doi.org/10.1080/03008207.2016.1182997DOI Listing
September 2016

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

PLoS One 2016 25;11(4):e0154214. Epub 2016 Apr 25.

Dept. of Medical Sciences, Uppsala University, SE-751 08 Uppsala, Sweden.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154214PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844164PMC
March 2017