Toward a better understanding of type I interferonopathies: a brief summary, update and beyond.

BACKGROUNDS: Type I interferonopathy is a group of autoinflammatory disorders associated with prominent enhanced type I interferon signaling. The mechanisms are complex, and the clinical phenotypes are diverse. This review briefly summarized the recent progresses of type I interferonopathy focusing on the clinical and molecular features, pathogeneses, diagnoses and potential therapies. DATA SOURCES: Original research articles and literature reviews published in PubMed-indexed journals. RESULTS: Type I interferonopathies include Aicardi-Goutières syndrome, spondyloenchondro-dysplasia with immune dysregulation, stimulator of interferon genes-associated vasculopathy with onset in infancy, X-linked reticulate pigmentary disorder, ubiquitin-specific peptidase 18 deficiency, chronic atypical neutrophilic dermatitis with lipodystrophy, and Singleton-Merten syndrome originally. Other disorders including interferon-stimulated gene 15 deficiency and DNAse II deficiency are believed to be interferonopathies as well. Intracranial calcification, skin vasculopathy, interstitial lung disease, failure to thrive, skeletal development problems and autoimmune features are common. Abnormal responses to nucleic acid stimuli and defective regulation of protein degradation are main mechanisms in disease pathogenesis. First generation Janus kinase inhibitors including baricitinib, tofacitinib and ruxolitinib are useful for disease control. Reverse transcriptase inhibitors seem to be another option for Aicardi-Goutières syndrome. CONCLUSIONS: Tremendous progress has been made for the discovery of type I interferonopathies and responsible genes. Janus kinase inhibitors and other agents have potential therapeutic roles. Future basic, translational and clinical studies towards disease monitoring and powerful therapies are warranted.

MDA5-Associated Neuroinflammation and the Singleton-Merten Syndrome: Two Faces of the Same Type I Interferonopathy Spectrum.

In 1973, Singleton and Merten described a new syndrome in 2 female probands with aortic and cardiac valve calcifications, early loss of secondary dentition, and widened medullary cavities of the phalanges. In 1984, Aicardi and Goutières defined a phenotype resembling congenital viral infection with basal ganglia calcification and increased protein content in the cerebrospinal fluid. Between 2006 and 2012, mutations in 6 different genes were described to be associated with Aicardi-Goutières syndrome, specifically-TREX1, RNASEH2A, RNASEH2B, RNASEH2C, ADAR, and SAMHD1. More recently, mutations in IFIH1 were reported in a variety of neuroimmunological phenotypes, including Aicardi-Goutières syndrome, while a specific Arg822Gln mutation in IFIH1 was described in 3 discrete families with Singleton-Merten syndrome (SMS). IFIH1 encodes for melanoma differentiation-associated gene 5 (MDA5), and all mutations identified to date have been associated with an enhanced interferon response in affected individuals. In this study, we present a male child demonstrating recurrent febrile episodes, spasticity, and basal ganglia calcification suggestive of Aicardi-Goutières syndrome, who carries the same Arg822Gln mutation in IFIH1 previously associated with SMS. We conclude that both diseases are part of the interferonopathy grouping and that the Arg822Gln mutation in IFIH1 can cause a spectrum of disease, including neurological involvement.

Generation R birth cohort study shows that specific enamel defects were not associated with elevated serum transglutaminase type 2 antibodies.

AIM: Coeliac disease can induce specific enamel defects (SED), but little is known about the consequences of antitissue transglutaminase (TG2A) autoimmunity. We investigated whether TG2A positivity in children and their mothers was associated with SED in the primary dentition. METHODS: Maternal and child serum immunoglobulin A-TG2A levels were measured as part of the Generation R prospective cohort study. Clinical oral photographs of the primary dentition were taken, and SED and caries were recorded. We performed logistic regression analysis. RESULTS: We analysed data on 4775 mothers and 4233 children (median age of 6.2 ± 0.5 years). SED and caries were not associated with maternal TG2A levels. The 59 TG2A-positive children tended to have more SED, particularly the 31 in the strongly positive subgroup, with odds ratio of 1.72 and 2.29, respectively. A positive linear trend was observed between higher TG2A levels and paediatric SED (p = 0.04), but this became nonsignificant after adjusting for ethnic and socio-economic background. No difference in caries was found between the groups. CONCLUSION: TG2A did not play an independent role on SED in the primary dentition during pregnancy and childhood, and the relationship may be explained by ethnic and socio-economic background.

Type I interferonopathies in pediatric rheumatology.

Defective regulation of type I interferon response is associated with severe inflammatory phenotypes and autoimmunity. Type I interferonopathies are a clinically heterogenic group of Mendelian diseases with a constitutive activation of this pathway that might present as atypical, severe, early onset rheumatic diseases. Skin vasculopathy with chilblains and livedo reticularis, interstitial lung disease, and panniculitis are common. Recent studies have implicated abnormal responses to nucleic acid stimuli or defective regulation of downstream effector molecules in disease pathogenesis. As observed for IL1-ß and autoinflammatory diseases, knowledge of the defects responsible for type I interferonopathies will likely promote the development of targeted therapy.

[Type I interferonopathies]. / Interféronopathies de type I.

Type I interferonopathies are a group of Mendelian disorders characterized by a common physiopathology: the up-regulation of type I interferons. To date, interferonopathies include Aicardi-Goutières syndrome, familial chilblain lupus, spondyenchondromatosis, PRoteasome-associated auto-inflammatory syndrome (PRAAS) and Singleton-Merten syndrome. These diseases present phenotypic overlap including cutaneous features like chilblain lupus, that can be inaugural or present within the first months of life. This novel set of inborn errors of immunity is evolving rapidly, with recognition of new diseases and genes. Recent and improved understanding of the physiopathology of overexpression of type I interferons has allowed the development of targeted therapies, currently being evaluated, like Janus-kinases or reverse transcriptase inhibitors.

Enamel defects associated with coeliac disease: putative role of antibodies against gliadin in pathogenesis.

Enamel defects in the permanent teeth of patients with coeliac disease (CD) are often reported as an atypical manifestation, sometimes being suggestive of an undiagnosed atypical disease. We proposed to explore the pathogenesis of these oral defects, which are poorly studied. Sequence analyses of proteins from gluten (gliadins) and of proline-rich enamel proteins (amelogenin and ameloblastin) suggested the presence of common antigenic motifs. Therefore, we analyzed, by ELISA and western blotting, the reactivity of sera from patients with CD against gliadin and enamel-derived peptides. Correlation analyses between the levels of specific antibodies against gliadin and enamel derived peptides and inhibition experiments confirmed the presence of cross-reactive antibodies. Immunoblot analysis revealed that the most prominent component in enamel matrix derivative (of approximately 18.6 kDa), identified by an amelogenin-specific antibody, is recognized by sera from patients with CD; in addition, several fractions of pure gliadin were recognized by amelogenin-specific antibody. In agreement, sera from mice immunized with enamel matrix-derived proteins generated antibodies that recognized a peptide (of approximately 21.2 kDa) derived from gliadin. In conclusion, antibodies against gliadin generated in patients with CD can react in vitro with a major enamel protein. The involvement of anti-gliadin serum in the pathogenesis of enamel defects in children with untreated CD can be hypothesized on the basis of these novel results.

Implications of gluten exposure period, CD clinical forms, and HLA typing in the association between celiac disease and dental enamel defects in children. A case-control study.

BACKGROUND: The association between coeliac disease (CD) and dental enamel defects (DED) is well known. AIM: The aim of this study was to investigate the prevalence of DED in children with CD and to specifically find the association of DED and gluten exposure period, CD clinical forms, HLA class II haplotype. DESIGN: This study was designed as a matched case-control study: 250 children were enrolled (125 coeliac children - 79 female and 46 male, 7.2 +/- 2.8 years and 125 healthy children). Data about age at CD diagnosis, CD clinical form, and HLA haplotype were recorded. RESULTS: Dental enamel defects were detected in 58 coeliac subjects (46.4%) against seven (5.6%) controls (P < 0.005). We found an association between DED and gluten exposure period, as among CD subjects the mean age at CD diagnosis was significantly (P = 0.0004) higher in the group with DED (3.41 +/- 1.27) than without DED (1.26 +/- 0.7). DED resulted more frequent (100%) in atypical and silent CD forms than in the typical one (30.93%). The presence of HLA DR 52-53 and DQ7antigens significantly increased the risk of DED (P = 0.0017) in coeliac children. CONCLUSIONS: Our results confirmed a possible correlation between HLA antigens and DED.

[Hypoplasia of enamel. A useful marker in the diagnosis of celiac disease in its subclinical form]. / Ipoplasia dello smalto. "Marker" utile nella diagnosi di malattia celiaca in forma subclinica.

Oral cavity alterations are often indicative sign of chronic gastrointestinal disorders, such as malabsorption and malnutrition syndromes. The relationship between oral pathology and intestinal diseases is rarely a chance association. This prompted odontostomatological research to focus on the study of alterations of the oral cavity, hypotetical markers of intestinal disorders if they can be measured in terms of frequency and incidence, as a tool for the early diagnosis of the intestinal disease itself. This paper should be seen against this background since it examines the possible connection between celiac disease and the presence of oral alterations as an index of disease.