Genetic and immunologic findings in children with recurrent aphthous stomatitis with systemic inflammation (original) (raw)
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Proceedings of the National Academy of Sciences, 2020
Significance In this report we identify genetic susceptibility variants for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, the most common periodic fever syndrome in children. PFAPA shares risk loci at IL12A , STAT4, IL10 , and CCR1-CCR3 with Behçet’s disease and recurrent aphthous stomatitis, defining a family of Behçet’s spectrum disorders. Differential HLA associations along this spectrum may determine where individual phenotypes fall among the Behçet’s spectrum disorders.
Archives of Oral Biology, 2007
Recurrent aphthous stomatitis (RAS) is characterized by recurrent episodes of oral ulceration in an otherwise healthy individual. Some reports in the literature indicate that RAS may have immunological, psychological, genetic and microbiological bases. The purpose of the present study was to investigate, using binary logistic regression analyses, a possible association between the functional IL-1beta +3954 (C/T), IL-6 -174 (G/C), IL-10 -1082 (G/A) and TNF-alpha -308 (G/A) genetic polymorphism and RAS in a sample of Brazilian patients, using a multivariate statistical analysis. Sixty-four consecutive subjects affected by minor and major forms of RAS and 64 healthy volunteers were genotyped. To investigate the association between the single nucleotide polymorphisms and risk of RAS, binary logistic regression models were fitted. The associations were expressed by odd ratios (ORs) and adjusted for age and gender, with the corresponding 95% CIs. P-values less than 0.05 were considered significant. A significant increase in the IL-1beta and TNF-alpha heterozygous genotypes were associated with an increased risk of RAS development (OR 2.40 and 3.07, respectively), in the multivariate model. Our findings demonstrate that polymorphisms of high IL-1beta and TNF-alpha production were associated with an increased risk of RAS development. Our findings also give additional support to a genetic basis for RAS pathogenesis.
Immunobiology, 2018
The etiology of recurrent aphthous stomatitis (RAS) remains unknown. RAS can be presented as primary, idiopathic condition and as a secondary RAS, which is associated with a systemic disease. The aim of our study was to evaluate the presence and concentrations of antibodies specific for celiac disease (CeD) and antibodies related to inflammatory bowel diseases (IBD) in patients with RAS without gastrointestinal symptoms. Antibodies against tissue transglutaminase (anti-tTG), deaminated gliadin peptides (DGP), deaminated gliadinanalogous fragments (anti-GAF-3X) and Saccharomyces cerevisiae (ASCA) were determined by ELISA and antineutrophil cytoplasmic antibodies (ANCA) by indirect immunoflurescence (IIF) in 57 patients with RAS and 60 control subjects. The prevalence of CeD specific antibodies did not differ between RAS patients and controls. However, the concentrations of IgA anti-tTG, IgA anti-GAF-3X antibodies in patients with RAS were significantly higher compared to controls (p = 0.002 and p = 0.04 respectively). Histological changes consistent with CeD were confirmed by duodenal biopsy in one RAS patient with highly positive IgA anti-tTG, anti-GAF-3X and anti-DGP antibodies. Higher prevalence along with higher concentrations of IgG ASCA were found in RAS patients compared to controls (p < 0.01). Patients with positive IgG ASCA in the absence of clinical symptoms decided not to pursue any further testing. Dysfunction of oral mucosa and the exposure to various antigens might be a reason for the loss of tolerance resulting in increased production of autoantibodies. It seems likely that antibodies are markers of aberrant immune response, rather than key effectors involved in the pathogenesis of the disease.
Arthritis Research & Therapy, 2020
Background Systemic lupus erythematosus (SLE) is a complex multi-system disease, characterized by both autoimmune and autoinflammatory clinical and laboratory features. The role of type I interferon (IFN) in SLE has been demonstrated from the 2000s, by gene expression analyses showing significant over-expression of genes related to type I IFN signalling pathway (IFN signature). However, several studies questioned the role of measuring the intensity of IFN signature (IFN score) to chase SLE activity. We would assess if the IFN signature can help the clinical and therapeutic stratification of patients with pediatric SLE. Methods We measured the IFN score in peripheral whole blood from a series of subjects with childhood-onset SLE and correlated the results with clinical and laboratory parameters. Results Thirty-one subjects were included in the study, among which the 87% displayed a positive IFN score. The only significant relation was found for high IFN score in subjects with normoco...
Background: Pediatric Inflammatory Bowel Disease (PIBD) is a chronic condition seen in genetically-predisposed individuals. GWAS have implicated >160 genomic loci in IBD with many genes coding for proteins in key immune pathways. This study looks at autoimmune disease burden in patients diagnosed with PIBD and interrogates exome data of a subset of patients. Methods: Patients were recruited from the Southampton Genetics of PIBD cohort. Clinical diagnosis of autoimmune disease in these individuals was ascertained from medical records. For a subset of patients with PIBD and concurrent asthma, exome data was interrogated to ascertain the burden of pathogenic variants within genes implicated in asthma. Association testing was conducted between cases and population controls using the SKAT-O test. Results: Forty-nine (28.3%) PIBD children (18.49%CD, 8.6% UC and 2 1.15% IBDU patients) had a concurrent clinical diagnosis of at least one other autoimmune disorder; asthma was the most prevalent, affecting 16.2% of the PIBD cohort. Rare and common variant association testing revealed six significant genes (p< 0.05) prior to Bonferroni adjustment. Three of these genes were previously implicated in both asthma and IBD (ZPBP2 IL1R1 and IL18R1) and three in asthma only (PYHIN1, IL2RB and GSTP1). Conclusions: One third of our cohort had a concurrent autoimmune condition. We observed higher incidence of asthma compared to the overall pediatric prevalence. Despite a small sample size, SKAT-O evaluated a significant burden of rare and common mutations in 6 genes. Variant burden suggests a systemic immune dysregulation rather than organ specific could underpin immune dysfunction for a subset of patients.
Inherited anomalies of innate immune receptors in pediatric-onset inflammatory diseases
Autoimmunity Reviews, 2015
Pattern-recognition receptors (PRRs) can detect various pathogen-associated molecular patterns such as carbo-27 hydrates, nucleic acids or bacterial peptides and play a major role in both innate and adaptive immunity. In phys-28 iological conditions, the engagement of PRRs triggers the production of proinflammatory cytokines and promotes 29 pathogen destruction. Inappropriate stimulation or defective regulation of PRR has been recently evidenced in 30 several inherited inflammatory disorders. This new field of childhood-onset inflammatory diseases encompass 31 the so-called type-I interferon-related diseases and autoinflammatory diseases. 32
Archives of rheumatology :/Archives of rheumatology, 2023
The periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease named according to its characteristic fever flares associated with pharyngitis, adenitis, or aphthous stomatitis in the absence of any infection and is the most common cause of periodic fever among children population. It is a self-limited condition of early childhood (below 5 years of age) that can be managed most effectively by corticosteroids and tonsillectomy and generally fades away before adulthood. 1 While the syndrome was initially thought to be a monogenic autoinflammatory disease, exome sequencing results revealed no common mutation shared by the PFAPA patients. 2 Nevertheless, the higher prevalence of the syndrome among family members with PFAPA implies the inheritance of genetic predisposition to the disorder. 3,4 Previously demonstrated risk mutations for PFAPA included those associated with inflammasome and immune dysregulation, such as NLRP3, CARD8, IL-12A, STAT4, IL10, and CCR1-CCR3. 5-12 HLA (human leukocyte antigen) alleles were also suggested as risk factors for PFAPA, 11 which further implies a possible role played by microbial organisms. This was further supported by studies showing altered tonsillar microbial population between PFAPA and control subjects. 13,14 Nevertheless, today there is no microorganism or external/internal factor identified as the cause of the syndrome. PFAPA was also associated with variants of the MEFV (Mediterranean fever) gene, the causative mutation for familial Mediterranean fever (FMF). The gene encodes a pyrin protein with regulatory roles in inflammasome activity, which leads to ABSTRACT Objectives: This study aimed to extend the literature by analyzing immunoglobulin (Ig) A, IgE, IgG, IgG2, IgG3, and IgM antibody levels in periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) patients. Patients and methods: This study retrospectively analyzed the antibody test results of 20 pediatric patients (10 males, 10 females; mean age: 2.5±1.5 years; range, 0.5 to 5.4 years) with and without flare who were initially evaluated for a number of underlying diseases due to periodic fever/infectious symptoms but then diagnosed with PFAPA between January 2015 and December 2020. Antibody levels were determined by chemiluminescence microparticle immunoassay. The results were retrospectively compared with a group of healthy children after the PFAPA diagnosis was confirmed. Results: The chemiluminescence microparticle immunoassay revealed 35%, 65%, 20%, 86.6%, and 55% of PFAPA cases with low serum levels of IgA, IgG, IgG2, IgG3, and IgM respectively, while 56.2% had high IgE levels. Moreover, low serum levels of at least two antibody classes or subclasses were reported in 80% of the PFAPA children. While cases with low IgG serum levels were with the highest incidence rates among the low IgG3 PFAPA patient population, both high IgE and low IgM cases were common in the rest of the patients. Conclusion: Our results suggest an association between PFAPA and low serum antibody levels, particularly of IgG3. Future studies are needed to confirm our conclusion.
Effects of interleukin (IL)-6 gene polymorphisms on recurrent aphthous stomatitis
Archives of Dermatological Research, 2014
Recurrent aphthous stomatitis (RAS) is a common disease with oral ulceration in which cytokines are thought to play an important role. High levels of interleukin (IL)-6, a pro-inflammatory cytokine have been detected in the circulation of ulcer tissue. The purpose of the present study was to investigate if the IL-6 gene polymorphisms are associated with RAS or clinical characteristics of RAS in a cohort of Turkish population. 184 RAS patients and 150 healthy controls were included in the study. The genotypes of IL-6 gene -572G[C and -174G[C polymorphisms were determined using polymerase chain reaction based restriction fragment length polymorphism analysis. The genotype frequencies of -572G[C polymorphism showed statistically significant differences between RAS patients and controls (p = 0.01). Frequencies of GG ? GC genotypes and G allele of -572G[C polymorphism were found higher in RAS patients (p = 0.0001, OR 10.8, 95 % CI 2.79-70.5; p = 0.0008, OR 2.06, 95 % CI 1.35-3.17, respectively). The genotype frequencies of -174G[C polymorphism also showed statistically significant differences between RAS patients and controls (p \ 0.0001). Frequencies of GG genotype and G allele of -174G[C polymorphism were found higher in RAS patients (p \ 0.0001, OR 4.87, 95 % CI 3.06-7.85; p \ 0.0001, OR 3.82, 95 % CI 2.64-5.59, respectively). GG-GG combined genotype and G-G haplotype of -174G[C to -572G[C loci were also significantly higher in RAS patients (p \ 0.0001 and p = 1.5 9 10 -8 , respectively). After stratifying clinical and demographical characteristics of RAS patients according to IL-6 gene polymorphisms, an association was observed between family history of RAS and -174G[C polymorphism (p = 0.011). Susceptibility effects of both IL-6 gene -572G[C and -174G[C polymorphisms for RAS were observed. Further studies are necessary to prove the association of IL-6 gene polymorphisms with RAS.