TNF Receptor Superfamily 1A Research Articles

Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy

Engineered regulatory T cell (Treg cell) therapy is a promising strategy to treat patients suffering from inflammatory diseases, autoimmunity, and transplant rejection. However, in many cases, disease-related antigens that can be targeted by Treg cells are not available. In this study, we introduce a class of synthetic biosensors, named artificial immune receptors (AIRs), for murine and human Treg cells. AIRs consist of three domains: (a) extracellular binding domain of a tumor necrosis factor (TNF)-receptor superfamily member, (b) intracellular costimulatory signaling domain of CD28, and (c) T cell receptor signaling domain of CD3-ζ chain. These AIR receptors equip Treg cells with an inflammation-sensing machinery and translate this environmental information into a CD3-ζ chain-dependent TCR-activation program. Different AIRs were generated, recognizing the inflammatory ligands of the TNF-receptor superfamily, including LIGHT, TNFα, and TNF-like ligand 1A (TL1A), leading to activation, differentiation, and proliferation of AIR-Treg cells. In a graft-versus-host disease model, Treg cells expressing lymphotoxin β receptor-AIR, which can be activated by the ligand LIGHT, protect significantly better than control Treg cells. Expression and signaling of the corresponding human AIR in human Treg cells prove that this concept can be translated. Engineering Treg cells that target inflammatory ligands leading to TCR signaling and activation might be used as a Treg cell-based therapy approach for a broad range of inflammation-driven diseases.

Tumour necrosis factor receptor-1 associated periodic syndrome (TRAPS)-related AA amyloidosis: a national case series and systematic review.

TNF receptor-1-associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder associated with mutations in the TNF receptor super family 1 A (TNFRSF1A) gene. AA amyloidosis (AA) is the most severe complication of TRAPS. To study the occurrence and prognosis of AA in TRAPS, we conducted a retrospective study of all French cases and a systematic literature review. This case series includes TRAPS patients followed by our centre from 2000 to 2020 presenting with histologically confirmed AA. We conducted a systematic literature review on the PubMed and EMBASE databases for articles published up to February 2021 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and using the keywords: amyloidoisis, amyloid, TNF receptor-associated periodic syndrome, TNF receptor-associated periodic syndrome, tumor necrosis factor receptor-associated periodic syndrome, TRAPS, TNFRSF1A, familial hibernian fever and hibernian familial fever. A total of 41 TRAPS with AA were studied: three new patients and 38 cases from the literature. AA diagnosis preceded that of TRAPS in 96% of cases, and 17/36 (47%) required renal replacement therapy. Death occurred in 5/36 (14%) with a median follow-up of 23 months. Effect of biologics on AA were available for 21 regimens in 19 patients: 10 improved renal function, seven stabilized and four worsened. Four patients (36% of transplanted patients) relapse AA on kidney graft (only one under etanercept). TRAPS is revealed by AA in most cases. Therefore, clinical features of TRAPS should be screened for in AA patients. IL-1 antagonist can help to normalize inflammation and to preserve renal function.

Regulation of the expression of tumor necrosis factor‑related genes by abnormal histone H3K27 acetylation: Implications for neural tube defects.

The association between apoptosis and neural tube defects (NTDs) is recognized as important, however, the precise link remains to be elucidated. Epigenetic modifications in human NTDs have been detected previously. In the present study, the occurrence of epigenetic modifications in apoptosis-related genes was investigated in a retinoic acid (RA)-induced mouse NTD model. Among 84 key genes involved in programmed cell death, 13 genes, including tumor necrosis factor (Tnf), annexin A5, apoptosis inhibitor 5, Bcl2-associated athanogene 3, baculoviral IAP repeat-containing 3, caspase (Casp)12, Casp4, Casp8, lymphotoxin β receptor, NLR family, apoptosis inhibitory protein 2, TNF receptor superfamily (Tnfrsf)1a, TNF superfamily (Tnfs)f10 and Tnfsf12, were downregulated, whereas nucleolar protein 3 was upregulated in the RA-induced NTD mice. Chromatin immunoprecipitation assays revealed that the regulatory regions of these differentially expressed TNF-related genes showed reduced histone H3K27 acetylation in NTDs, compared with control mice without NTDs. Reverse transcription-quantitative polymerase chain reaction revealed that H3K27ac-binding to the differentially regulated genes was markedly decreased in the NTD mice, whereas binding to the unchanged genes Casp3 and Nfkb1 was unaffected. In conclusion, certain TNF-related genes appeared to be downregulated in NTDs, possibly as a result of abnormal histone H3K27 acetylation. These results shed new light on the epigenetic dysregulation of apoptosis-related genes in NTDs.

Novel Dual-Action Targeted Nanomedicine in Mice With Metastatic Thyroid Cancer and Pancreatic Neuroendocrine Tumors.

The advantages of nanomedicines include preferential delivery of the payload directly to tumor tissues. CYT-21625 is the novel, first-in-class gold nanomedicine designed to target tumor vasculature and cancer cells by specifically delivering recombinant human tumor necrosis factor alpha (rhTNF) and a paclitaxel prodrug. We analyzed TNF receptor expression in publicly available gene expression profiling data and in thyroid tissue samples. Mice with metastatic FTC-133 and 8505C xenografts and the MEN1 conditional knock-out mice were treated weekly with CYT-21625 and gold nanoparticles with rhTNF only (CYT-6091); controls included mice treated with either paclitaxel or saline. In vivo luciferase activity was used to assess the effects on tumor growth. Computed tomography, magnetic resonance imaging, and 18F-Fludeoxyglucose positron emission tomography were used to study tumor selectivity in mice with insulin-secreting pancreatic neuroendocrine tumors (PNETs). All statistical tests were two-sided. Anaplastic thyroid cancer (ATC) expressed statistically significantly higher levels of TNF receptor superfamily 1A and 1B messenger RNA (n = 11) and protein (n = 6) than control samples (n = 45 and 13, respectively). Mice (n = 5-7 per group) with metastatic ATC (P < .009) and FTC-133 xenografts (P = .03 at week 3, but not statistically significant in week 4 owing to reduced sample size from death in non-CYT-21625 groups) treated with CYT-21625 had a statistically significantly lower tumor burden. Treatment with CYT-21625 resulted in loss of CD34 expression in intratumoral vasculature, decreased proliferating cell nuclear antigen, and increased cleaved caspase-3. Intratumoral vascular leakage occurred only in mice with PNET and ATC treated with CYT-6091 and CYT-21625. CYT-6091 and CYT-21625 preferentially deposited in PNETs and statistically significantly decreased serum insulin levels (n = 3 per group, P < .001). There were no toxicities observed in mice treated with CYT-21625. CYT-21625 is effective in mice with PNETs and metastatic human thyroid cancer with no toxicities. Thus, CYT-21625 should be studied in patients with advanced PNETs and thyroid cancer.

Recurrent fever and arthralgia as the presentation of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a Chinese girl: a case report and review of the literature

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is characterized by recurrent episodes of inflammation with fever, abdominal pain, chest pain, rash, myalgia, arthralgia, conjunctivitis, and periorbital edema. This condition is a rare autosomal dominant disease that is strongly associated with heterozygous mutations in the tumor necrosis factor (TNF) receptor super family 1A (TNFRSF1A) gene. This condition is believed to be more common in Western countries than in Asian countries, and the AA amyloidosis rate for European countries is estimated to be 10%. Herein, we report the case of a 14-year-old girl with recurrent fever and arthralgia with inflammatory marker elevation for 10years. After extensive investigation of the infectious etiology with negative results and similar phenomenon observed within her family, the diagnosis of TRAPS was made based on next-generation sequencing, which revealed a T50M mutation; she was also sensitive to corticosteroids. Although none of our TRAPS patients developed AA amyloidosis, we suggest the continual monitoring of urinalysis results and serum amyloid A concentrations during long-term follow-up. Moreover, we also reviewed the related literature and found no Asian patients who had developed AA amyloidosis.

Canakinumab for the treatment of TNF-receptor associated periodic syndrome

ABSTRACTIntroduction: TNF-receptor-associated periodic syndrome is an autoinflammatory disorder caused by mutations in TNF receptor superfamily 1A gene. The molecular pathogenesis of TRAPS remains unclear; it is known that a key role is played by mutations in TNFRSF1A that induce the hypersecretion of pro-inflammatory cytokines as well as IL-1β, resulting in uncontrolled inflammatory reactions. Furthermore, TNFRSF1A gene mutations result in intracellular stress ultimately leading to increased production of interleukin-1β, but the exact mechanism referred to in the connection between TNFRSF1A mutation and increased release of IL-1β, is still under study. This explains why IL-1 inhibition treatment can be effective in treating TRAPS patients. The purpose of this review is to discuss the safety and efficacy of canakinumab, a high-affinity human monoclonal anti IL-1β antibody.Areas covered: The data obtained from case reports, case series, Phase II study and a phase III randomized, double-blind, placebo controlled trial have been analyzed. Efficacy and safety profiles of canakinumab are discussed.Expert commentary: Was discussed an overview of treatment options in TRAPS patients. The understanding of pathogenesis of TNF-receptor-associated periodic syndrome led to realize why TRAPS patients respond to IL-1 inhibition. Canakinumab became approved for the treatment in TRAPS patients very recently.

The Regulation of Uterine Proinflammatory Gene Expression during Pregnancy in the Live-Bearing Lizard, Pseudemoia entrecasteauxii.

The evolutionary transition from egg-laying to live-bearing in amniote vertebrates (reptiles and mammals) requires the development of a closer association between the maternal and embryonic tissue to facilitate gas and nutrient exchange with the embryo. Because the embryo is an allograft to the father and mother, it could be considered foreign by the maternal immune system and thus be immunologically rejected during pregnancy. In eutherian ("placental") mammals, the proinflammatory genes interleukin 1B (IL1B), tumor necrosis factor (TNF) and tumor necrosis factor receptor superfamily 1A (TNFRSF1A) are tightly regulated in the pregnant uterus to prevent embryonic rejection. We tested whether inflammation is similarly regulated in pregnant viviparous reptiles by comparing the expression of IL1B, TNF, and TNFRSF1A in the pregnant and nonpregnant uterus of the viviparous lizard, Pseudemoia entrecasteauxii. We found statistically significant support for the downregulation of pregnant uterine TNF mRNA expression in P. entrecasteauxii, but no statistically significant changes in mRNA expression of TNFRSF1A or IL1B between pregnant and nonpregnant uteri. Although these genes are apparently not regulated at the transcriptional level, our immunofluorescence microscopy analyses nonetheless demonstrate that the IL1B proteins are stored intracellularly during pregnancy, possibly resulting in inhibition of inflammatory response. We therefore conclude that processes of both transcriptional (TNF) and posttranslational (IL1B) gene regulation may reduce inflammation in the pregnant uterus of this viviparous reptile. Our study is important because it demonstrates that regulating the maternal immune system to prevent embryonic rejection may be important in reptilian pregnancy as it is in mammalian pregnancy.

In search of human proteins and infectious triggers involved in periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome

Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome is the most prevalent pediatric autoinflammatory syndrome. For unexplained reasons tonsillectomy induces remission. The etiology of PFAPA is unknown; however, mutations of TNF receptor superfamily 1A (TNFRSF1A) and elevated circulating TNF-a have been described in some patients.

Tumour necrosis factor receptor I blockade shows that TNF-dependent and TNF-independent mechanisms synergise in TNF receptor associated periodic syndrome.

TNF receptor associated periodic syndrome (TRAPS) is an autoinflammatory disease involving recurrent episodes of fever and inflammation. It is associated with autosomal dominant mutations in TNF receptor superfamily 1A gene localised to exons encoding the ectodomain of the p55 TNF receptor, TNF receptor-1 (TNFR1). The aim of this study was to investigate the role of cell surface TNFR1 in TRAPS, and the contribution of TNF-dependent and TNF-independent mechanisms to the production of cytokines. HEK-293 and SK-HEP-1 cell lines were stably transfected with WT or TRAPS-associated variants of human TNF receptor superfamily 1A gene. An anti-TNFR1 single domain antibody (dAb), and an anti-TNFR1 mAb, bound to cell surface WT and variant TNFR1s. In HEK-293 cells transfected with death domain-inactivated (R347A) TNFR1, and in SK-HEP-1 cells transfected with normal (full-length) TNFR1, cytokine production stimulated in the absence of exogenous TNF by the presence of certain TNFR1 variants was not inhibited by the anti-TNFR1 dAb. In SK-Hep-1 cells, specific TRAPS mutations increased the level of cytokine response to TNF, compared to WT, and this augmented cytokine production was suppressed by the anti-TNFR1 dAb. Thus, TRAPS-associated variants of TNFR1 enhance cytokine production by a TNF-independent mechanism and by sensitising cells to a TNF-dependent stimulation. The TNF-dependent mechanism requires cell surface expression of TNFR1, as this is blocked by TNFR1-specific dAb.

P02-011 - TRAPS syndrome debuted as systemic JIA

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is characterized by periodic fever, cutaneous rash, conjunctivitis, lymphadenopathy, abdominal pain, myalgia, and arthralgia. It is a rare autosomal dominant disease and strongly associated with heterozygous mutations in the tumor necrosis factor (TNF) receptor super family 1A (TNFRSF1A) gene. The great diversity of manifestations and the difficulties in genetic analyses make the diagnosing of this disease a challenge. Our aim was to report on case of autoinflammatory syndromes that is considered to be rare entity.

Role of TNFRSF1B polymorphisms in the response of Crohn’s disease patients to infliximab

Infliximab (IFX) is a valid treatment for Crohn’s disease (CD), but a relevant percentage of patients do not benefit from this therapy. In the Japanese population, the response to IFX was associated with markers in the TNF receptor superfamily 1A (TNFRSF1A) and 1B (TNFRSF1B) genes. We aimed to replicate the association previously described in the Japanese population and to ascertain the role of TNF receptors as modulators of the response to IFX. We studied 297 white Spanish CD patients with a known response to IFX: 238 responders and 59 primary nonresponders. Four single nucleotide polymorphisms (SNPs) were analyzed: rs767455 in TNFRSF1A and rs1061622, rs1061624, and rs3397 in TNFRSF1B. Comparisons between groups were performed with chi-square tests or the Fisher’s exact test. Different features (sex, age, disease duration, smoking among others) were evaluated as possible confounding factors. No significant association was found between the studied TNFRSF1A polymorphisms and response to IFX. In the TNFRSF1B gene, the haplotype rs1061624_A-rs3397_T was significantly increased in nonresponders: p=0.015, OR=1.78, 95% CI 1.09–2.90; and an increased frequency of rs1061622_G carriers was observed in patients with remission: p=0.033 vs nonresponders and p=0.023 vs patients with a partial response. Our results support a role of TNFRSF1B gene variants in the response to IFX in CD patients.

Symptoms Related to Tumor Necrosis Factor Receptor 1-associated Periodic Syndrome, Multiple Sclerosis, and Severe Rheumatoid Arthritis in Patients Carrying the TNF Receptor Superfamily 1A D12E/p.Asp41Glu Mutation

Tumor necrosis factor (TNF) receptor 1-associated periodic syndrome (TRAPS) is an autoinflammatory disorder caused by autosomal dominantly inherited mutations in the TNF receptor superfamily 1A (TNFRSF1A) gene. The D12E substitution has been described only once to date, in a 4-year-old boy with fever. For DNA sequence analysis of the TNFRSF1A gene, genomic DNA was isolated, amplified by PCR, purified, and sequenced. We describe 3 families (8 subjects) with the TNFRSF1A D12E substitution and TRAPS-related symptoms, in 4 cases associated with the autoimmune diseases multiple sclerosis and rheumatoid arthritis. The clinical phenotype might be associated with the TNFRSF1A D12E mutation. There is a close pathophysiological relationship between TNF signaling and autoimmune disorders.

Recurrent abdominal pain as the presentation of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in an Asian girl: A case report and review of the literature

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is characterized by periodic fever, cutaneous rash, conjunctivitis, lymphadenopathy, abdominal pain, myalgia, and arthralgia. It is a rare autosomal dominant disease and strongly associated with heterozygous mutations in the tumor necrosis factor (TNF) receptor super family 1A (TNFRSF1A) gene. It is believed to be more common in Western countries than in Asian countries. Here, we present the case of a 14-year-old girl with periodic fever and abdominal pain with elevation of inflammatory markers for 2 years. After extensive work-up of infectious etiology with negative results, the diagnosis of TRAPS was made although no gene mutations were identified in the TNFRSF1A gene, MVK gene, and NALP3/CIAS1 gene. She had partial clinical response to corticosteroids and immunomodulatory agents. However, the treatment response to TNF-α inhibitor etanercept was dramatic. She has remained symptom free under regular weekly to biweekly etanercept treatment for 2 years. We also reviewed the related literature and summarized the data of 10 Asian cases of TRAPS.

Genetic polymorphisms of tumour necrosis factor receptor superfamily 1b and fas ligand are associated with clinical efficacy and/or acute severe infusion reactions to infliximab in Crohn's disease

Single nucleotide polymorphisms (SNPs) in TNF receptor superfamily (TNFRSF) 1A and 1B, and Fas ligand (FASLG) genes, have been associated with responsiveness to infliximab (IFX) in Crohn's disease. To investigate if SNPs in TNFRSF1A and 1B, and FAS (TNFRSF6) and FASLG (TNFSF6), associated with short- or long-term clinical and biological efficacy and with acute severe infusion reactions. Observational, retrospective and explorative cohort study of IFX-treated Caucasian patients with Crohn's disease classified as primary nonresponders (n = 21), response failures on maintenance therapy (n = 37), maintained remission (n = 47) and occurrence of acute severe infusion reactions (n = 20). During IFX maintenance therapy, minor allele carriage of TNFRSF1B, rs976881 is associated with loss of response [OR 3.3 (1.2-9.1), P = 0.014]. Minor allele homozygosity increased the risk substantially (OR estimated 19, P = 0.006), and furthermore associated with a mean CRP increase of 17 mg/L as compared to a mean decrease of 17 mg/L in all others (P = 0.036). In contrast, minor allele carriage of TNFRSF1B, rs1061622 is associated with beneficial response to IFX induction [OR 4.2 (1.2-18.2), P = 0.014], and with persistence of remission during maintenance therapy [OR 5.5 (1.5-25.5), P = 0.007]. Carriage of the minor allele of FASLG, rs76110 increased risk of severe infusion reactions [OR 4.0 (1.1-22.4), P = 0.041]; minor allele carriage of TNFRSF1B, rs652625 decreased the risk (OR estimated 0.2, P = 0.043 ). The TNFRSF1B polymorphisms may contribute to predict efficacy of infliximab. Moreover, FASLG and TNFRSF1B polymorphisms may confer genetic susceptibility to severe infusion reactions. These findings could potentially aid clinical decisions if confirmed in larger studies.

Candidate Genes in Patients with Autoinflammatory Syndrome Resembling Tumor Necrosis Factor Receptor-associated Periodic Syndrome Without Mutations in the TNFRSF1A Gene

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant multisystemic autoinflammatory condition. Patients display different mutations of the TNF receptor superfamily 1A gene (TNFRSF1A), coding for a nearly ubiquitous TNF receptor (TNFR1). No TNFRSF1A mutation has been identified in a proportion of patients with TRAPS-like phenotype. We investigated mechanisms downregulating the TNF-induced inflammatory response such as (1) receptor shedding, producing a secreted form acting as a TNF inhibitor; (2) receptor internalization with subsequent induction of apoptosis; and (3) negative regulation of nuclear factor-κB (NF-κB) transcription. We analyzed the sequence of genes known to play a pivotal role in these pathways, in 5 patients with TRAPS symptoms and showing shedding and/or apoptosis defects, but without mutations of the TNFRSF1A gene. Sequence analysis of 3 genes involved in TNFR1 shedding (ERAP1, NUCB2, RBMX) and 3 genes involved in negative regulation of NF-κB signaling (TNFAIP3, CARP-2) or NF-κB transcription (ZFP36) revealed only a few unreported variants, apparently neutral. Our study rules out any involvement in the pathogenesis of TRAPS of some of the genes known to regulate TNFR1 shedding and TNF-induced NF-κB signaling and transcription. Gene(s) responsible for TRAPS-like syndrome remain to be investigated among currently unidentified genes likely involved in these pathways, or by applying the genome-wide function-free sequencing approach.

The Effect of Very-Low-Calorie Diet on mRNA Expression of Inflammation-Related Genes in Subcutaneous Adipose Tissue and Peripheral Monocytes of Obese Patients with Type 2 Diabetes Mellitus

Low-grade inflammation links obesity, type 2 diabetes mellitus (T2DM), and cardiovascular diseases. To explore the expression profile of genes involved in inflammatory pathways in adipose tissue and peripheral monocytes (PM) of obese patients with and without T2DM at baseline and after dietary intervention. Two-week intervention study with very-low-calorie diet (VLCD). University hospital. Twelve obese females with T2DM, 8 obese nondiabetic females (OB) and 15 healthy age-matched females. Two weeks of VLCD (2500 kJ/d). Metabolic parameters, circulating cytokines, hormones, and mRNA expression of 39 genes in sc adipose tissue (SCAT) and PM. Both T2DM and OB group had significantly increased serum concentrations of circulating proinflammatory factors (C-reactive protein, TNFα, IL-6, IL-8), mRNA expression of macrophage antigen CD68 and proinflammatory chemokines (CCL-2, -3, -7, -8, -17, -22) in SCAT and complementary chemokine receptors (CCR-1, -2, -3, -5) and other proinflammatory receptors (toll-like receptor 2 and 4, TNF receptor superfamily 1A and 1B, IL-6R) in PM, with OB group showing less pronounced chemoattracting and proinflammatory profile compared to T2DM group. In T2DM patients VLCD decreased body weight, improved metabolic profile, and decreased mRNA expression of up-regulated CCRs in PM and chemokines [CCL 8, chemokine (C-X-C motif) ligand 10] in SCAT. VLCD markedly increased mRNA expression of T-lymphocyte attracting chemokine CCL-17 in SCAT. Obese patients with and without T2DM have increased mRNA expression of chemotactic and proinflammatory factors in SCAT and expression of corresponding receptors in PM. Two weeks of VLCD significantly improved this profile in T2DM patients.

Missense mutation V20A in the tumor necrosis factor receptor superfamily 1A (TNFRSF1A) gene is associated with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) presenting with periodic gastrointestinal symptoms

Missense mutation V20A in the tumor necrosis factor receptor superfamily 1A (TNFRSF1A) gene is associated with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) presenting with periodic gastrointestinal symptoms

Combined Mutation And Rearrangement Screening by Quantitative PCR High-Resolution Melting: Is It Relevant for Hereditary Recurrent Fever Genes?

The recent identification of genes implicated in hereditary recurrent fevers has allowed their specific diagnosis. So far however, only punctual mutations have been identified and a significant number of patients remain with no genetic confirmation of their disease after routine molecular approaches such as sequencing. The possible involvement of sequence rearrangements in these patients has only been examined in familial Mediterranean fever and was found to be unlikely. To assess the existence of larger genetic alterations in 3 other concerned genes, MVK (Mevalonate kinase), NLRP3 (Nod like receptor family, pyrin domain containing 3) and TNFRSF1A (TNF receptor superfamily 1A), we adapted the qPCR-HRM method to study possible intragenic deletions and duplications. This single-tube approach, combining both qualitative (mutations) and quantitative (rearrangement) screening, has proven effective in Lynch syndrome diagnosis. Using this approach, we studied 113 unselected (prospective group) and 88 selected (retrospective group) patients and identified no intragenic rearrangements in the 3 genes. Only qualitative alterations were found with a sensitivity similar to that obtained using classical molecular techniques for screening punctual mutations. Our results support that deleterious copy number alterations in MVK, NLRP3 and TNFRSF1A are rare or absent from the mutational spectrum of hereditary recurrent fevers, and demonstrate that a routine combined method such as qPCR-HRM provides no further help in genetic diagnosis. However, quantitative approaches such as qPCR or SQF-PCR did prove to be quick and effective and could still be useful after non contributory punctual mutation screening in the presence of clinically evocative signs.

A novel missense mutation in tumour necrosis factor receptor superfamily 1A (TNFRSF1A) gene found in tumour necrosis factor receptor-associated periodic syndrome (TRAPS) with high serum interleukin (IL)-22

Auteur(s) : Motonobu Nakamura, Yoshiki Tokura Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan Tumour necrosis factor receptor (TNFR)-associated periodic syndrome (TRAPS) is a rare autosomal dominant disorder characterized by recurrent episodes of fever, myalgia, abdominal pain, conjunctivitis and skin eruptions [1]. The most common cutaneous manifestation is a centrifugal migratory, erythematous patch [...]

Association of resistance to avian coccidiosis with single nucleotide polymorphisms in the zyxin gene

Our previous genetic studies demonstrated that resistance to avian coccidiosis is linked with microsatellite markers LEI0071 and LEI0101 on chromosome 1. In this study, the associations between parameters of resistance to coccidiosis and single nucleotide polymorphisms (SNP) in 3 candidate genes located between LEI0071 and LEI0101 [zyxin, CD4, and tumor necrosis factor receptor super family 1A (TNFRSF1A)] were determined. The SNP were genotyped in 24 F1 generation and 290 F2 generation animals. No SNP were identified in the TNFRSF1A gene, whereas 10 were located in the zyxin gene and 4 in the CD4 gene. At various times following experimental infection of the F2 generation with Eimeria maxima, BW, fecal oocyst shedding, and plasma levels of carotenoid, nitrite plus nitrate (NO2− + NO3−), and interferon-γ (IFN-γ) were measured as parameters of resistance. Single marker and haplotype-based tests were applied to determine the associations between the 14 SNP and the parameters of coccidiosis resistance. None of the CD4 SNP were correlated with disease resistance. However, by single marker association, several of the zyxin SNP were significantly associated with carotenoid or NO2− + NO3− concentrations. These were the SNP at nucleotide 149 associated with carotenoid at d 3 postinfection (PI), nucleotide 187 with carotenoid at d 6 and 9 PI, and nucleotide 159 with carotenoid between d 3 and 9 PI. In addition, the zyxin SNP at nucleotide 191 was significantly associated with increased levels of NO2− + NO3− at d 3 PI. By haplotype association, the zyxin SNP also were found to be highly associated with NO2− + NO3− at d 3 PI and increased IFN-γ at d 6 PI. These results suggest that zyxin is a candidate gene potentially associated with increased resistance to experimental avian coccidiosis.