AUCTORES
Globalize your Research
Research Article | DOI: https://doi.org/10.31579/2578-8949/009
Department of Dermatology, Jiujiang Road, Huangpu District, Shanghai, China.
*Corresponding Author: Chaounge An, Department of Dermatology, Jiujiang Road, Huangpu District, Shanghai, China.
Citation: Chaounge An. Despite genetic and proteomic arguments, the three common variants of NOD2/ CARD15 genes : Pemphigus Foliaceus. J .Dermatology and Dermatitis. Doi: 10.31579/2578-8949/009
Copyright: © 2017 Chaounge An. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 20 June 2017 | Accepted: 22 July 2017 | Published: 27 July 2017
Keywords: NOD2; CARD15; single nucleotide polymorphism; restriction fragment length polymorphism; pemphigus; tunisia
Background: Knowledge about the pathogenesis of Pemphigus Foliaceus (PF), an autoimmune disorder of the skin natural barrier, is still modest. Genetic susceptibility factors have been widely studied, while environmental factors remain still ambiguous. NOD2/CARD15 gene encodes an intracytoplasmic receptor involved in recognition of microbial components and NF-κB inflammatory signaling pathway. Three common CD-associated variations (R702W, G908R and 1007fs) cause a "loss of function" of the molecule and lead to a chronic inflammation in the intestinal epithelial barrier. The aim of this study is to analyze NOD2/CARD15 gene polymorphisms in Tunisian endemic PF.
Methods and Results:A case-control study including 79 PF patients and 160 controls was conducted using PCR-RFLP and direct sequencing. Our results showed that the three SNPs are not polymorphic in both patients and controls (allelic frequencies were 0.63% vs 1.25%, 0.63% vs 1.87% and 0% vs 0.62%, respectively). There was no association of mutant alleles with the disease.
Conclusions: Our results suggest that the three common variants of NOD2/CARD15 gene are not involved in susceptibility to Tunisian PF. The alteration of the molecule's functionality caused by these mutations seems to not interfere with the development of the disease.
"Pattern Recognition Receptors" (PRRs) are innate immunity receptors involved in antiinfectious defense of the organism [1]. There are several classes of PRRs: the "Toll-Like-Receptors" (TLRs), the "Retinoic acid inducible gene-I-Like Receptors" (RLRs), the "Nod-Like Receptors" (NLRs) and the "C-type Lectin-Receptors" (CLRs) [2]. NOD2/CARD15 (nucleotide binding oligomerisation domain 2/ caspase-recruitment domain containing protein 15) is an intracytoplasmic receptor from the NLRs family. It is composed of three parts: two N-terminal domains of recruitment and activation of caspases (CARD), a Nucleotide-Binding Domain (NBD) in the middle and a C-terminal domain composed of Leucin-Rich-Repeats (LRRs). This receptor is expressed mainly in monocytes/macrophages, dendritic and epithelial cells and is upregulated by pro-inflammatory stimuli [3] NOD2 receptor is involved in the recognition of bacterial components through its LRRs, leading to NF-κB inflammatory signaling pathway [3,4]. The NOD2/CARD15 gene is located in the peri-centromeric region of chromosome 16 (16q12) and belongs to the super-family of Ced4 apoptosis regulators [5-7]. Three main mutations, within or near the LRRs domain of the receptor, are commonly associated with Crohn’s Disease (CD), an inflammatory disorder of the intestinal epithelium: two "missense mutations" (R702W, G908R) and a "frameshift" mutation generating a stop codon and leading to a truncated protein (L1007fsinsC) [3]. Te impaired function of the receptor caused by these mutated variants in intestinal phagocytic and epithelial cells results in abnormal function of the intestinal barrier leading to increased bacterial invasion and inflammation of the intestine. It has been also demonstrated that Nod2 wild-type (unlike mutated variants) could induce a more efficient bacterial clearance and adaptive immune response by mediating autophagy. Furthermore, it could activate antiviral innate immune response after viral ssRNA recognition [3]. Indeed, the human microbiome, which behavior is affected by host susceptibility factors, seems to play a major role in the pathogenesis of inflammatory disorders located in epithelial surfaces like the gut (CD) and the skin [2]. Pemphigus Foliaceus (PF), an endemic disease in rural Tunisian regions, is an autoimmune blistering disorder of the skin epithelial barrier [7,8]. Pathogenesis of PF involves a complex interaction of multiple factors (genetic, immunological, environmental, and infectious factors) [7- 9]. The possible implication of various infectious agents ("black fly", Onchocerciasis, Leishmaniasis, Staphylococcus aureus toxin, Herpes virus....) in the etiopathogenesis of pemphigus has been reported in different studies [10-12]. PRRs (including NODs) are described to play an important role in the infectious defense in the skin natural barrier [2,13]. In this study, we analyzed the role of the 3 common CD-associated NOD2 variants (R702W, G908R and L1007fsinsC), which encode a receptor for microbial components with impaired function, in the susceptibility to Tunisian endemic PF.
We conducted a case-control study which included 79 SouthTunisian unrelated patients with PF (department of Dermatology, Hedi Chaker University Hospital of Sfax, Tunisia) and 160 healthy controls not suffering from any autoimmune nor inflammatory disease). All patients had clinical, histological and immunological criteria of PF. The sex ratio was 9/1; the average age was 33.5 years. Controls were matched to patients in age (± 5 years), sex and geographical origin. All patients and healthy controls gave informed consent to participate in the study. We chose to analyze 3 tagSNPs (rs2066844 (R702W), rs2066845 (G908R), rs2066847 (1007fs)) of the NOD2/CARD15 gene located in the peri-centromeric region of chromosome 16 (16q12) (Table1). The 3 mutations are located inside or close to the C-terminal domain of NOD2 protein: «LRR domain», which is involved in recognition of bacterial wall component (muramyl dipeptide).
Blood samples were collected in EDTA-anticoagulated tubes and DNA was extracted using standard methods. All SNPs were genotyped by conventional polymerase chain reaction/restriction fragment length polymorphism analysis (PCR-RFLP) (Table 1). Primers were designed using primer3 software (http://primer3.ut.ee/) and restriction enzymes were selected using the NEBcutter software (http://nc2.neb.com/NEBcutter2/) (Table 2). Digestion products were electrophoresed through 3% agarose gel and scored following ethidium-bromide staining. The accuracy of the genotyping was confirmed by direct sequencing of each SNP.
The data were analysed with Hardy-Weinberg equilibrium tests. Statistical analysis was carried out using SHEsis program (http:// analysis.bio-x.cn) and SPSS 16.0 software. P values <0.05 >were considered statistically significant. Allele and genotype frequencies were calculated and associations with susceptibility to PF were tested by calculating Odds Ratios (OR) with asymptotic 95% Confidence Intervals (CIs).
The results of the allelic and genotypic frequencies distribution of the studied NOD2/ CARD15 SNPs (R702W, G908R and L1007fs) in patients and controls are summarized in Table 3. The distribution of R702W, G908R, and L1007fs genotypes were in accordance with the Hardy-Weinberg equilibrium test results (p >0.05). Minor of all the three polymorphisms was consistent with that reported in the HapMap database. In our control group, the heterozygous mutations were found in 4 controls (2.5%) for each of the R702W and G908R SNPs, and in 2 controls (1.25%) for the L1007fs SNP. The G908R homozygous mutation was found in only 1 individual (0.62%) of the 160 controls. No other homozygous mutations were found in this group.
The heterozygous mutation frequencies of R702W, G908R and L1007fs SNPs in PF patients were equal or lower than those found in the control group (1.26%, 1.26% and 0%, respectively). No homozygous genotypes were found in patients. No significant differences in genotypic and allelic frequencies of the 3 SNPs were detected among the two groups (p values >0.05). Despite the small number of heterozygote patients (1 patient with R702W-CT and 1 patient with G908R-GC), we performed stratified analyzes for rs2066844 (R702W) and rs2066845 (G908R) genotypes in PF patients according to gender, age, disease severity (based on involved surface body area and Activity Score) and need for immunosuppressive therapy or plasmapheresis. No statistical differences were observed between allelic/genotypic frequencies and patients' stratifications (data not shown). None of the individuals (patients/controls) presenting the NOD2/ CARD15 mutations had clinical features of an inflammatory bowel disorder.
In PF pathogenesis, genetic susceptibility factors have been widely studied, however involvement of environmental factors remains misunderstood. In this data, we studied the possible role of variation (tag SNPs) in a gene encoding an innate receptor (NOD2/ CARD15) involved in the recognition of microbial components in the development of endemic Tunisian PF. To the best of our knowledge, the possibility of NOD2/CARD15 gene involvement in PF pathogenesis has not been studied previously. Several arguments have led us to suspect that these gene variants could be involved in susceptibility to PF. (i) Environmental factors, including bacterial infections, have been implicated in the pathogenesis of PF [10]. (ii) Recently, we have demonstrated that the expression of some TLRs (TLR2, TLR3 and TLR4) is significantly up-regulated in the epidermis of Tunisian PF patients [14], (iii) Several functional studies showed that various skin cells (keratinocytes and Langerhans cell) express the NOD2 receptor and are involved via this receptor in the immune defense of the skin natural barrier [3,13,15]. (iv) Finally, genetic association of different SNPs of genes encoding NOD2 receptor or related molecules (especially the 3 common CD-associated NOD2 variants) with diseases involving skin lesions and/or diseases with auto-inflammatory or autoimmune pathogenesis (atopic dermatitis, psoriatic arthritis, BlauSyndrom /Early onset of sarcoidosis...) were largely described [8,16-18]. NOD2/CARD15 gene mutations could therefore lead to an inability of the immune system to control bacterial infection and to the development of chronic inflammation [2], which may cause various dysimmune disorders such as PF.
Our results showed that these 3 SNPs are not polymorphic in the general Tunisian population (minor allele frequency <5%). These findings are relatively consistent with those described in two previous Tunisian studies and in two other North African studies [19-24]. Thus, these polymorphisms constitute rare mutations in healthy Tunisian population.
The common association of NOD2 mutations with CD and Inflammatory Bowel Disease [19,20] has been widely, but not universally [21] replicated, especially in North African populations [9,22-26]. Despite the similarities in etio-pathogenesis between CD and PF (two disorders of natural epithelial barriers, role of the microbiome in the disease development, expression of PRRs, especially NODs by intestinal and skin cells and their role in infectious defense) [3], our analysis provides evidence of no genetic association between Tunisian endemic PF development and variation in NOD2 gene. The higher prevalences of the 3 CD-associated variations found in phenotypic healthy controls compared to PF patients could be explained by the need of complex interactions (gene–gene or gene– environment) for the development and the clinical expression of the disease.
In summary, our results suggest that, despite genetic and proteomic arguments, the three common variants of NOD2/ CARD15 genes are not involved in susceptibility to Tunisian PF. We conclude that the genetic variants analyzed do not alter the functionality of the molecules in a way that would interfere with the development of the disease. Genetic association studies of other pattern recognition receptors in PF are necessary to confirm the importance of environmental factors in the pathogenesis of this autoimmune disease.
Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.
Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.
Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.
Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.
We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.
The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.
Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.
Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.
Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.
Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.
Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.
This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.
Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.
As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.
Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.
International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.
Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.
Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.
I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!
"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
