A novel cell-based assay for measuring neutralizing autoantibodies against type I interferons in patients with autoimmune polyendocrine syndrome type 1.

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

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A novel cell-based assay for measuring neutralizing autoantibodies against type I interferons in patients with autoimmune polyendocrine syndrome type 1

Clinical Immunology ◽

10.1016/j.clim.2014.04.013 ◽

2014 ◽

Vol 153 (1) ◽

pp. 220-227 ◽

Cited By ~ 4

Author(s):

Lars Breivik ◽

Bergithe E.V. Oftedal ◽

Anette S. Bøe Wolff ◽

Eirik Bratland ◽

Elizaveta M. Orlova ◽

...

Keyword(s):

Type I Interferons ◽

Type I ◽

Syndrome Type ◽

Autoimmune Polyendocrine Syndrome

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Autoantibodies against Type I Interferons as an Additional Diagnostic Criterion for Autoimmune Polyendocrine Syndrome Type I

Yearbook of Endocrinology ◽

10.1016/s0084-3741(09)79342-4 ◽

2009 ◽

Vol 2009 ◽

pp. 91-93

Author(s):

H.S. Willenberg

Keyword(s):

Type I Interferons ◽

Type I ◽

Syndrome Type ◽

Autoimmune Polyendocrine Syndrome ◽

Diagnostic Criterion

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Autoantibodies to 21-hydroxylase as a diagnostic marker of primary autoimmune adrenal insufficiency, including at its potential and latent stages

Almanac of Clinical Medicine ◽

10.18786/2072-0505-2020-48-023 ◽

2020 ◽

Vol 48 ◽

Author(s):

N. F. Nuralieva ◽

M. Yu. Yukina ◽

E. A. Troshina ◽

N. M. Malysheva ◽

L. V. Nikankina

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Immune Tolerance ◽

Type I ◽

Syndrome Type ◽

Type Ii ◽

Autoimmune Polyendocrine Syndrome ◽

Group 2

Rationale: In Russia, assessment of anti-P450c21 antibodies (AB) in the diagnosis of autoimmune adrenal insufficiency (AAI) has not been commonly used, and the disease screening has not been implemented.Aims: 1) To determine the sensitivity and specificity of anti-P450c21 AB determination in the AAI diagnosis; 2) To estimate the prevalence of anti-P450c21 AB carriage in patients without AAI.Materials and methods: Anti-P450c21 AB were assessed in 40 patients (group 1) with manifest AAI; 171 patients without established diagnosis of AAI, including 113 subjects with autoimmune thyroid disorders or type 1 diabetes mellitus (AID, group 2); 25 carriers of AB markers of thyroid AID and/or type 1 diabetes mellitus without any target organ dysfunctions (group 3); 33 patients with non-autoimmune endocrine disorders (group 4), and 25 healthy individuals (group 5).Results: Determination of anti-P450c21 AB for the diagnosis of AAI had 95% sensitivity, with specificity of 100%, predictive value of a positive result of 100%, and predictive value of a negative result 92.6%. Anti-P450c21 AB were inversely correlated with the duration of glucocorticoid replacement therapy (r = -0.222, p < 0.05). High levels of anti-P450c21 AB were found in 4 (3.5%) patients of group 2; based on the results of additional hormonal testing, 50% cases were diagnosed with the latent stage of the disease and 50% cases with the potential stage.Discussion: The sensitivity of the anti-P450c21 AB determination for AAI diagnosis in our study was higher, than in the works by other authors. We have confirmed a time-related reduction of anti-P450c21 AB levels, whereby the strength of the correlation was higher in the subgroups with autoimmune polyendocrine syndrome type II and, to a greater extent, autoimmune polyendocrine syndrome type I. This might be related to their different pathogenesis, with an abnormality of central immune tolerance in autoimmune polyendocrine syndrome type I and that of peripheral immune tolerance in autoimmune polyendocrine syndrome type II. According to our data, in 50% of cases, the development of AAI was preceded by the manifestation of other AIDs (in 15% of cases being multiple). Among all patients with no AAI diagnosis at the study entry, increased anti- P450c21 AB levels were found exactly in those with pre-existing AID. Thus, we have confirmed the feasibility of AAI screening primarily in a cohort of patients with other AID (especially multiple) belonging to the risk group.Conclusion: The determination of blood anti-P450c21 AB is a highly sensitive and highly specific method to diagnose AAI. The frequency of anti-P450c21 AB detection might depend on the duration of glucocorticoid treatment. Screening for early AAI stages is relevant primarily in the risk groups with multiple autoimmune disorders.

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Clinical, Genetic and Immunological Characteristics of Paediatric Autoimmune Polyglandular Syndrome Type 1 Patients in Slovenia / Klinične, Genetske nn Imunološke Značilnosti Otrok In Mladostnikov Z Avtoimunskim Poliglandularnim Sindromom Tipa 1 V Sloveniji

Slovenian Journal of Public Health ◽

10.1515/sjph-2015-0017 ◽

2015 ◽

Vol 54 (2) ◽

pp. 112-118 ◽

Cited By ~ 2

Author(s):

Nina Bratanic ◽

Kai Kisand ◽

Magdalena Avbelj Stefanija ◽

Tadej Battelino ◽

Katarina Trebusak Podkrajsek

Keyword(s):

Growth Retardation ◽

Type I Interferons ◽

Chronic Mucocutaneous Candidiasis ◽

Type I ◽

Syndrome Type ◽

Clinical Genetic ◽

Autoimmune Polyglandular Syndrome ◽

Aire Gene ◽

Autoimmune Polyglandular Syndrome Type

Abstract Introduction. Autoimmune polyglandular syndrome type 1 (APS-1) is an autosomal recessive disorder, caused by mutations in the AIRE gene. The major components of APS-1 are chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP) and Addison’s disease (AD). Clinical, genetic and immunological characteristics of Slovenian paediatric APS-1 patients were investigated. Methods. Existing medical records of 15 APS-1 patients were rewieved, when necessary, additional clinical and laboratory investigations were issued. AIRE gene analysis was performed to identify causative mutations, and autoantibodies against type I interferons were measured by luminescence immunoprecipitation system. Results. Patients had one to eight different manifestations of the disease. CMC was present in all, HP in 12/15 (80 %) and AD in 8/15 (53 %) patients. Growth retardation, due to hyposomatotropism, growth hormone resistance, autoimmune thyroiditis, corticosteroid treatment, malabsorption or secretory failure of exocrine pancreas, was observed in altogether 7 (46 %) patients. Six different AIRE gene mutations were detected and p.R257X mutation was present in 63.3 % of pathological alleles. Antibodies against type I interferons were detected in all patients. Conclusion. APS-1 is a rare disorder with a broad spectrum of clinical manifestations, which, if unrecognized or inadequately treated may be fatal. AIRE gene mutational analysis and autoantibodies against type I interferons are important in early identification of the disease. The aetiology of growth retardation was shown to be extremely diverse, frequently caused by less characteristic manifestations. APS-1 may affect patients’ quality of life in numerous ways, and may cause great psychosocial burden leading to depression and suicidal thoughts even in paediatric patients.

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Mild COVID-19 despite autoantibodies to type I IFNs in Autoimmune-Polyendocrine-Syndrome Type 1 (APS-1)

Journal of Clinical Investigation ◽

10.1172/jci150867 ◽

2021 ◽

Author(s):

Christian Meisel ◽

Bengisu Akbil ◽

Tim Meyer ◽

Erwin Lankes ◽

Victor M. Corman ◽

...

Keyword(s):

Type I ◽

Syndrome Type ◽

Type I Ifns ◽

Autoimmune Polyendocrine Syndrome

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Autoantibodies against Type I Interferons as an Additional Diagnostic Criterion for Autoimmune Polyendocrine Syndrome Type I

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-0935 ◽

2008 ◽

Vol 93 (11) ◽

pp. 4389-4397 ◽

Cited By ~ 115

Author(s):

Antonella Meloni ◽

Maria Furcas ◽

Filomena Cetani ◽

Claudio Marcocci ◽

Alberto Falorni ◽

...

Keyword(s):

High Titer ◽

Age At Onset ◽

Dominant Negative ◽

Type I Interferons ◽

Chronic Mucocutaneous Candidiasis ◽

Type I ◽

Syndrome Type ◽

Autoimmune Polyendocrine Syndrome ◽

Diagnostic Potential ◽

Interferon Α2

Context: In autoimmune polyendocrinopathy syndrome type I (APS-I), mutations in the autoimmune regulator gene (AIRE) impair thymic self-tolerance induction in developing T cells. The ensuing autoimmunity particularly targets ectodermal and endocrine tissues, but chronic candidiasis usually comes first. We recently reported apparently APS-I-specific high-titer neutralizing autoantibodies against type I interferons in 100% of Finnish and Norwegian patients, mainly with two prevalent AIRE truncations. Objectives: Because variability in clinical features and age at onset in APS-I frequently results in unusual presentations, we prospectively checked the diagnostic potential of anti-interferon antibodies in additional APS-I panels with other truncations or rare missense mutations and in disease controls with chronic mucocutaneous candidiasis (CMC) but without either common AIRE mutation. Design: The study was designed to detect autoantibodies against interferon-α2 and interferon-ω in antiviral neutralization assays. Setting and Patients: Patients included 14 British/Irish, 15 Sardinian, and 10 Southern Italian AIRE-mutant patients with APS-I; also 19 other patients with CMC, including four families with cosegregating thyroid autoimmunity. Outcome: The diagnostic value of anti-interferon autoantibodies was assessed. Results: We found antibodies against interferon-α2 and/or interferon-ω in all 39 APS-I patients vs. zero of 48 unaffected relatives and zero of 19 British/Irish CMC patients. Especially against interferon-ω, titers were nearly always high, regardless of the exact APS-I phenotype/duration or AIRE genotype, including 12 different AIRE length variants or 10 point substitutions overall (n = 174 total). Strikingly, in one family with few typical APS-I features, these antibodies cosegregated over three generations with autoimmune hypothyroidism plus a dominant-negative G228W AIRE substitution. Conclusions: Otherwise restricted to patients with thymoma and/or myasthenia gravis, these precocious persistent antibodies show 98% or higher sensitivity and APS-I specificity and are thus a simpler diagnostic option than detecting AIRE mutations.

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Characterization of the clinical and genetic spectrum of autoimmune polyendocrine syndrome type 1 in Chinese case series

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01933-y ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Ya-Bing Wang ◽

Ou Wang ◽

Min Nie ◽

Yan Jiang ◽

Mei Li ◽

...

Keyword(s):

Case Series ◽

Pure Red Cell Aplasia ◽

Hereditary Disease ◽

Chinese Patients ◽

Chronic Mucocutaneous Candidiasis ◽

Syndrome Type ◽

Myeloproliferative Disease ◽

College Hospital ◽

Autoimmune Polyendocrine Syndrome

Abstract Background Autoimmune polyendocrine syndrome type 1 (APS1) is a hereditary disease caused by mutations in the AIRE gene with both endocrine and non-endocrine organ involvement. The existing data from China are limited, and this study aims to describe the phenotypes and genetic characterization in Chinese APS1 patients. In this single-center, retrospective, observational study, comprehensive endocrine and extra-endocrine manifestations were collected, and genetic analysis in AIRE was conducted in patients with APS1 between the years of 1984 and 2018 at Peking Union Medical College Hospital. Results In total, 13 patients from 12 unrelated families were enrolled, seven of whom were female, with hypoparathyroidism, chronic mucocutaneous candidiasis, and Addison’s disease being the most frequently observed manifestations. Up to 84.7% presented with two or three of the above-mentioned manifestations, and nearly 4.9 ± 1.8 components presented in patients aged 21.2 ± 7.9 years old. Several less common phenotypes, such as myeloproliferative disease, pure red cell aplasia, renal tubular acidosis, asplenia, autoimmune hepatitis, and ankylosing spondylitis, were also observed in patients. Altogether, seven different AIRE mutations were found in six patients, four of which (K161fs, G208V, A246fs, and L308F) had not been previously reported in patients with APS1. Conclusion We have provided a comprehensive profile of Chinese patients with APS1, with less commonly observed features being observed in addition to more regularly seen manifestations. Additionally, different AIRE mutations that were observed have expanded the genetic spectrum, which will help with future understanding of the molecular pathogenesis of APS1.

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Acquired pure red cell aplasia and T cell large granular lymphocytic leukaemia in patients with autoimmune polyglandular syndrome type 1

BMC Medical Genomics ◽

10.1186/s12920-020-00866-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Jing Ruan ◽

Xuan Wang ◽

Xianyong Jiang ◽

Miao Chen

Keyword(s):

Lymphocytic Leukaemia ◽

Pure Red Cell Aplasia ◽

Chronic Diarrhoea ◽

Syndrome Type ◽

Red Cell ◽

Recurrent Pneumonia ◽

Red Cell Aplasia ◽

Autoimmune Polyendocrine Syndrome ◽

Immunological Mechanisms

Abstract Background Pure red cell aplasia (PRCA) and large granular lymphocytic leukaemia (LGLL) are very rare complications of autoimmune polyendocrine syndrome type 1 (APS1). Here, we report a case of APS1 with PRCA and LGLL. Previous cases were reviewed, and possible mechanisms are discussed. Case presentation A 31-year-old female presented with anaemia and was diagnosed with PRCA in our centre. She also had hypoparathyroidism for 24 years, premature ovarian failure for 10 years, osteoporosis for 5 years, recurrent pneumonia with bronchiectasis for 4 years and chronic diarrhoea for 1 year. Boosted whole-exome analysis showed AIRE heterozygous mutations, confirming the diagnosis as APS1. LGLL was diagnosed during follow-up. The PRCA responded well to glucocorticoid. treatment Conclusion AIRE is causally related to the development of LGLL and consequent PRCA, which may be due to some immunological mechanisms.

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