Sparking Fire Under the Skin? Answers From the Association of Complement Genes With Pemphigus Foliaceus

Bumiller-Bini, Valéria; Cipolla, Gabriel Adelman; Almeida, Rodrigo Coutinho de; Petzl-Erler, María Luiza; Augusto, Danillo G.; Boldt, Angelica Beate Winter

doi:10.3389/fimmu.2018.00695

Cited by 14 publications

(22 citation statements)

References 108 publications

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“…After excluding SNPs with minor allele frequency they found some gene expression (<1%), out of a Hardy‐Weinberg equilibrium in controls or in strong linkage disequilibrium ( r 2 ≥ 0.8); 201 SNPs remained for logistic regression. The authors also reported increased serum levels of complement C3, and C5‐b9 deposition in lesions observed more frequently in the PF and EPF patients in comparison with the normal controls …”

Section: Discussionsupporting

confidence: 88%

“…The authors also reported increased serum levels of complement C3, and C5-b9 deposition in lesions observed more frequently in the PF and EPF patients in comparison with the normal controls. 23 Of interest is the correlation we found between positivity of other autoimmune blistering and skin diseases such lupus, BP, DH, and PV and the positivity of the staining for complement C5-b9 that perfectly matched what we had reported on IHC staining with other immunoglobulins and complement. 24 Indeed, our findings suggest that in these other autoimmune skin diseases, the immune response may also be more complex than the classically described and currently accepted mechanisms.…”

Section: Discussionsupporting

confidence: 86%

“…22 Recently, patients affected by PF including EPF, were evaluated for 992 single-nucleotide polymorphisms (SNPs) of 44 CS genes, genotyped through microarray hybridization in 229 PF patients, and 194 controls. 23 After excluding SNPs with minor allele frequency they found some gene expression (<1%), out of a Hardy-Weinberg equilibrium in controls or in strong linkage disequilibrium (r 2 ≥ 0.8); 201 SNPs remained for logistic regression. The authors also reported increased serum levels of complement C3, and C5-b9 deposition in lesions observed more frequently in the PF and EPF patients in comparison with the normal controls.…”

Section: Discussionmentioning

confidence: 99%

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Membrane attack complex (C5b‐9 complex or Mac), is strongly present in lesional skin from patients with endemic pemphigus foliaceus in El Bagre, Colombia

et al. 2019

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Background El Bagre endemic pemphigus foliaceus (El Bagre‐EPF) is a new variant of endemic pemphigus foliaceus present in the El Bagre area of Colombia, South America. Here, we investigate the presence of complement/C5‐b9 in lesional skin of patients and matched controls from the endemic area. We also aim to compare the patient's autoantibody levels using indirect immunofluorescent titers (IIF) and correlate with the lesional presence of complement/C5b‐9. Methods A case‐control study was carried out by testing for the presence of complement/C5b‐9 in lesional skin in 43 patients affected by El Bagre‐EPF, as well as 43 matched, healthy controls from the endemic area. Skin biopsies were obtained and evaluated via hematoxylin and eosin staining, and immunohistochemistry. Results The presence of complement/C5b‐9 was observed in all cases of the patients affected by El Bagre‐EPF and was not observed in the controls from the endemic area (P < 0.001). The patients' autoantibody titers utilizing IIF for IgG and IgM showed correlation between higher autoantibody titers and stronger intensity of staining with complement/C5‐b9 staining (P < 0.001). Conclusion Patients affected by El Bagre‐EPF have lesional deposition of complement/C5b, which correlates with disease severity and previously established serologies.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Membrane attack complex (C5b‐9 complex or Mac), is strongly present in lesional skin from patients with endemic pemphigus foliaceus in El Bagre, Colombia

et al. 2019

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“…Even so, this regulatory intergenic SNP was not associated with PF and PV in the Tunisian population (Mejri et al, 2009). In line with this result, C5 polymorphisms were also not associated with FS (Bumiller-Bini et al, 2018).…”

Section: Genetics Sheds Light On the Controversial Relevance Of The Csupporting

confidence: 59%

Beyond the HLA polymorphism: A complex pattern of genetic susceptibility to pemphigus

Petzl-Erler

2020

Genet. Mol. Biol.

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Pemphigus is a group of autoimmune bullous skin diseases that result in significant morbidity. As for other multifactorial autoimmune disorders, environmental factors may trigger the disease in genetically susceptible individuals. The goals of this review are to summarize the state of knowledge about the genetic variation that may affect the susceptibility and pathogenesis of pemphigus vulgaris and pemphigus foliaceus-both the endemic and the sporadic forms-, to compare and discuss the possible meaning of the associations reported, and to propose recommendations for new research initiatives. Understanding how genetic variants translate into pathogenic mechanisms and phenotypes remains a mystery for most of the polymorphisms that contribute to disease susceptibility. However, genetic studies provide a strong foundation for further developments in this field by generating testable hypotheses. Currently, results still have limited influence on disease prevention and prognosis, drug development, and clinical practice, although the perspectives for future applications for the benefit of patients are encouraging. Recommendations for the continued advancement of our understanding as to the impact of genetic variation on pemphigus include these partially overlapping goals: (1) Querying the functional effect of genetic variants on the regulation of gene expression through their impact on the nucleotide sequence of cis regulatory DNA elements such as promoters and enhancers, the splicing of RNA, the structure of regulatory RNAs and proteins, binding of these regulatory molecules to regulatory DNA elements, and alteration of epigenetic marks; (2) identifying key cell types and cell states that are implicated in pemphigus pathogenesis and explore their functional genomes; (3) integrating structural and functional genomics data; (4) performing disease-progression longitudinal studies to disclose the causal relationships between genetic and epigenetic variation and intermediate disease phenotypes; (5) understanding the influence of genetic and epigenetic variation in the response to treatment and the severity of the disease; (6) exploring gene-gene and genotype-environment interactions; (7) developing improved pemphigus-prone and non-prone animal models that are appropriate for research about the mechanisms that link genotypes to pemphigus. Achieving these goals will demand larger samples of patients and controls and multisite collaborations.

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“…The first genetic associations reported were variants within the human leucocyte antigen ( HLA ) genes, with strong associations with alleles of HLA‐DRB1 and HLA‐DQB1 . Furthermore, our group has demonstrated several other associations of PF with genes involved in immune responses …”

Section: Introductionmentioning

confidence: 91%

Screening the full leucocyte receptor complex genomic region revealed associations with pemphigus that might be explained by gene regulation

et al. 2018

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Pemphigus foliaceus (PF) is a blistering autoimmune skin disease rare in most of the world but endemic in certain regions of Brazil. PF is characterized by the detachment of epidermal cells and the presence of autoantibodies against desmoglein 1. In previous studies, we have shown that genetic polymorphisms and variable expression levels of certain leucocyte receptor complex (LRC) genes were associated with PF. However, the role of the LRC on PF susceptibility remained to be investigated. Here, we analysed 527 tag single nucleotide polymorphisms (SNPs) distributed within the 1·5 Mb LRC. After quality control, a total of 176 SNPs were analysed in 229 patients with PF and 194 controls. Three SNPs were associated with differential susceptibility to PF. The intergenic variant rs465169 [odds ratio (OR) = 1·50; P = 0·004] is located in a region that might regulate several immune-related genes, including VSTM1, LILRB1/2, LAIR1/2, LILRA3/4 and LENG8. The rs35336528 (OR = 3·44; P = 0·009) and rs1865097 (OR = 0·57; P = 0·005) SNPs in LENG8 and FCAR genes, respectively, were also associated with PF. Moreover, we found four haplotypes with SNPs within the KIR3DL2/3, LAIR2 and LILRB1 genes associated with PF (P < 0·05), which corroborate previously reported associations. Thus, our results confirm the importance of the LRC for differential susceptibility to PF and reveal new markers that might influence expression levels of several LRC genes, as well as candidates for further functional studies.

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Sparking Fire Under the Skin? Answers From the Association of Complement Genes With Pemphigus Foliaceus

Cited by 14 publications

References 108 publications

Membrane attack complex (C5b‐9 complex or Mac), is strongly present in lesional skin from patients with endemic pemphigus foliaceus in El Bagre, Colombia

Membrane attack complex (C5b‐9 complex or Mac), is strongly present in lesional skin from patients with endemic pemphigus foliaceus in El Bagre, Colombia

Beyond the HLA polymorphism: A complex pattern of genetic susceptibility to pemphigus

Screening the full leucocyte receptor complex genomic region revealed associations with pemphigus that might be explained by gene regulation

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