Publications by authors named "Asa Hallgren"

17 Publications

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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

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

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

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

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

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

Autoantibodies Targeting a Collecting Duct-Specific Water Channel in Tubulointerstitial Nephritis.

J Am Soc Nephrol 2016 Oct 16;27(10):3220-3228. Epub 2016 Mar 16.

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

Tubulointerstitial nephritis is a common cause of kidney failure and may have diverse etiologies. This form of nephritis is sometimes associated with autoimmune disease, but the role of autoimmune mechanisms in disease development is not well understood. Here, we present the cases of three patients with autoimmune polyendocrine syndrome type 1 who developed tubulointerstitial nephritis and ESRD in association with autoantibodies against kidney collecting duct cells. One of the patients developed autoantibodies targeting the collecting duct-specific water channel aquaporin 2, whereas autoantibodies of the two other patients reacted against the HOXB7 or NFAT5 transcription factors, which regulate the aquaporin 2 promoter. Our findings suggest that tubulointerstitial nephritis developed in these patients as a result of an autoimmune insult on the kidney collecting duct cells.
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http://dx.doi.org/10.1681/ASN.2015101126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042672PMC
October 2016

Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 in Cancer-Associated Retinopathy.

Ophthalmology 2016 06 4;123(6):1401-4. Epub 2016 Feb 4.

Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institute, 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.ophtha.2015.12.031DOI Listing
June 2016

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

Sci Rep 2016 Feb 1;6:20104. Epub 2016 Feb 1.

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

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.
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http://dx.doi.org/10.1038/srep20104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735587PMC
February 2016

Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies.

J Clin Invest 2015 Dec 9;125(12):4612-24. Epub 2015 Nov 9.

Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.
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http://dx.doi.org/10.1172/JCI81031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665781PMC
December 2015

Transglutaminase 4 as a prostate autoantigen in male subfertility.

Sci Transl Med 2015 Jun;7(292):292ra101

Department of Medicine (Solna), Karolinska University Hospital, Karolinska Institutet, Stockholm SE 171 76, Sweden. Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala SE 751 85, Sweden.

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.
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http://dx.doi.org/10.1126/scitranslmed.aaa9186DOI Listing
June 2015

Autoantibody response against NALP5/MATER in primary ovarian insufficiency and in autoimmune Addison's disease.

J Clin Endocrinol Metab 2015 May 3;100(5):1941-8. Epub 2015 Mar 3.

Department of Internal Medicine (A.B., S.M., V.M., A.F.), University of Perugia, 06126 Perugia, Italy; Department of Medical Sciences (M.A., O.K.), Science for Life Laboratory, Uppsala University, 750 03 Uppsala, Sweden; Centre of Molecular Medicine (M.A., A.H., O.K.), Department of Medicine (Solna), Karolinska Institutet, 171 76 Stockholm, Sweden; Division of Endocrinology, Diabetology, and Metabolism (R.G.), Department of Medical Sciences, University of Turin, 10126 Turin, Italy; Department of Cardio-Thoracic and Respiratory Science (A.D.B.), Endocrinology Unit, Second University of Naples, 80132 Naples, Italy; and Department of Pediatrics-Neonatal Intensive Care (R.P.), V. Fazzi Regional Hospital, 73100 Lecce, Italy.

Context: NACHT leucine-rich-repeat protein 5 (NALP5)/maternal antigen that embryo requires (MATER) is an autoantigen in hypoparathyroidism associated with autoimmune polyendocrine syndrome type 1 (APS1) but is also expressed in the ovary. Mater is an autoantigen in experimental autoimmune oophoritis.

Objectives: The objectives of the study were to determine the frequency of NALP5/MATER autoantibodies (NALP5/MATER-Ab) in women with premature ovarian insufficiency (POI) and in patients with autoimmune Addison's disease (AAD) and to evaluate whether inhibin chains are a target for autoantibodies in POI.

Methods: Autoantibodies against NALP5/MATER and inhibin chains-α and -βA were determined by radiobinding assays in 172 patients with AAD without clinical signs of gonadal insufficiency, 41 women with both AAD and autoimmune POI [steroidogenic cell autoimmune POI (SCA-POI)], 119 women with idiopathic POI, 19 patients with APS1, and 211 healthy control subjects.

Results: NALP5/MATER-Ab were detected in 11 of 19 (58%) sera from APS1 patients, 12 of 172 (7%) AAD sera, 5 of 41 (12%) SCA-POI sera, 0 of 119 idiopathic POI sera and 1 of 211 healthy control sera (P < .001). None of 160 POI sera, including 41 sera from women with SCA-POI and 119 women with idiopathic POI, and none of 211 healthy control sera were positive for inhibin chain-α/βA autoantibodies.

Conclusions: NALP5/MATER-Ab are associated with hypoparathyroidism in APS1 but are present also in patients with AAD and in women with SCA-POI without hypoparathyroidism. Inhibin chains do not appear to be likely candidate targets of autoantibodies in human POI.
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http://dx.doi.org/10.1210/jc.2014-3571DOI Listing
May 2015

Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model.

Eur J Immunol 2011 Jan 3;41(1):235-45. Epub 2010 Dec 3.

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

Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal failure are hallmarks of the disease. The critical mechanisms causing chronic mucocutaneous candidiasis in APS-1 patients have not been identified although autoantibodies to cytokines are implicated in the pathogenesis. To investigate whether the Th reactivity to Candida albicans (C. albicans) and other stimuli was altered, we isolated PBMC from APS-1 patients and matched healthy controls. The Th17 pathway was upregulated in response to C. albicans in APS-1 patients, whereas the IL-22 secretion was reduced. Autoantibodies against IL-22, IL-17A and IL-17F were detected in sera from APS-1 patients by immunoprecipitation. In addition, Aire-deficient (Aire(0/0) ) mice were much more susceptible than Aire(+/+) mice to mucosal candidiasis and C. albicans-induced Th17- and Th1-cell responses were increased in Aire(0/0) mice. Thus an excessive IL-17A reactivity towards C. albicans was observed in APS-1 patients and Aire(0/0) mice.
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http://dx.doi.org/10.1002/eji.200939883DOI Listing
January 2011

Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen.

Proc Natl Acad Sci U S A 2009 Mar 26;106(11):4396-401. Epub 2009 Feb 26.

Department of Medical Sciences, University Hospital, Uppsala University, 751 85 Uppsala, Sweden.

Patients with autoimmune polyendocrine syndrome type 1 (APS-1) suffer from multiple organ-specific autoimmunity with autoantibodies against target tissue-specific autoantigens. Endocrine and nonendocrine organs such as skin, hair follicles, and liver are targeted by the immune system. Despite sporadic observations of pulmonary symptoms among APS-1 patients, an autoimmune mechanism for pulmonary involvement has not been elucidated. We report here on a subset of APS-1 patients with respiratory symptoms. Eight patients with pulmonary involvement were identified. Severe airway obstruction was found in 4 patients, leading to death in 2. Immunoscreening of a cDNA library using serum samples from a patient with APS-1 and obstructive respiratory symptoms identified a putative potassium channel regulator (KCNRG) as a pulmonary autoantigen. Reactivity to recombinant KCNRG was assessed in 110 APS-1 patients by using immunoprecipitation. Autoantibodies to KCNRG were present in 7 of the 8 patients with respiratory symptoms, but in only 1 of 102 APS-1 patients without respiratory symptoms. Expression of KCNRG messenger RNA and protein was found to be predominantly restricted to the epithelial cells of terminal bronchioles. Autoantibodies to KCNRG, a protein mainly expressed in bronchial epithelium, are strongly associated with pulmonary involvement in APS-1. These findings may facilitate the recognition, diagnosis, characterization, and understanding of the pulmonary manifestations of APS-1.
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http://dx.doi.org/10.1073/pnas.0809986106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2648890PMC
March 2009

Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen.

N Engl J Med 2008 Mar;358(10):1018-28

University Hospital, Uppsala University, Uppsala, Sweden.

Background: Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune regulator gene. Though recent studies concerning AIRE deficiency have begun to elucidate the molecular pathogenesis of organ-specific autoimmunity in patients with APS-1, the autoantigen responsible for hypoparathyroidism, a hallmark of APS-1 and its most common autoimmune endocrinopathy, has not yet been identified.

Methods: We performed immunoscreening of a human parathyroid complementary DNA library, using serum samples from patients with APS-1 and hypoparathyroidism, to identify patients with reactivity to the NACHT leucine-rich-repeat protein 5 (NALP5). Subsequently, serum samples from 87 patients with APS-1 and 293 controls, including patients with other autoimmune disorders, were used to determine the frequency and specificity of autoantibodies against NALP5. In addition, the expression of NALP5 was investigated in various tissues.

Results: NALP5-specific autoantibodies were detected in 49% of the patients with APS-1 and hypoparathyroidism but were absent in all patients with APS-1 but without hypoparathyroidism, in all patients with other autoimmune endocrine disorders, and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of parathyroid chief cells.

Conclusions: NALP5 appears to be a tissue-specific autoantigen involved in hypoparathyroidism in patients with APS-1. Autoantibodies against NALP5 appear to be highly specific and may be diagnostic for this prominent component of APS-1.
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http://dx.doi.org/10.1056/NEJMoa0706487DOI Listing
March 2008

Autoantibodies linked to autoimmune polyendocrine syndrome type I are prevalent in Down syndrome.

Acta Paediatr 2006 Dec;95(12):1657-60

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

Background: Patients with Down syndrome are prone to autoimmune diseases which also occur in the recessive disease autoimmune polyendocrine syndrome type I (APS I). Since this disease is caused by mutations in the gene AIRE on chromosome 21, one might speculate that altered expression of AIRE contributes to autoimmune disease in Down syndrome.

Aim: To study the prevalence of 11 well-defined autoantibodies, five of which are specific for APS I, associated with various manifestations of APS I in patients with Down syndrome.

Methods: Sera from 48 patients with Down syndrome were analysed. Autoantibodies against 21-hydroxylase, 17alpha-hydroxylase, side-chain cleavage enzyme, aromatic L-amino acid decarboxylase, cytochrome P4501A2, tyrosine hydroxylase, tryptophan hydroxylase, glutamic acid decarboxylase 65, tyrosine phosphatase IA-2 and transglutaminase were analysed using an immunoprecipitation assay, and thyroid peroxidase autoantibodies were measured using a haemagglutination assay.

Results: Seven of 48 patients had elevated titres of autoantibodies: one against 21-hydroxylase, three against aromatic L-amino acid decarboxylase, one against cytochrome P4501A2, one against glutamic acid decarboxylase 65 and one against tyrosine phosphatase IA-2. None of the patients had clinical or laboratory signs of disease coupled to the respective autoantibody.

Conclusion: Four patients with Down syndrome had autoantibodies hitherto regarded as unique for APS I, which may suggest a dysregulation of AIRE.
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http://dx.doi.org/10.1080/08035250600771466DOI Listing
December 2006