Abstract
Bullous pemphigoid (BP) is a rare autoimmune skin blistering disease, characterized by the presence of autoantibodies against hemidesmosomal autoantigens. Cytokine expression is altered in BP patients, and several of these differently expressed cytokines, including IL-1α, IL-1β, IL-8, and TNF-α, contribute to disease pathogenesis. Since genetic polymorphisms in the genes of these cytokines might be implicated in susceptibility to BP disease, we aimed at testing this implication in susceptibility to BP in an Iranian cohort. Blood samples were collected from the subjects and genomic DNA was extracted. To detect the single nucleotide polymorphisms (SNPs), IL-1α (rs1800587), IL-1β (rs1143627, rs16944, rs1143634), IL-8 (rs4073), and TNF-α (rs1799964, rs1800630, rs1799724, and rs361525) genes were genotyped in BP patients and healthy controls as well as IL-8 (rs4073) in pemphigus vulgaris (PV) patients. Quantitative gene expression was evaluated by RT-PCR analysis. A significant difference was observed in the distribution of genotypes or alleles of IL-8 SNP between the BP patients and controls. The A-allele of IL-8 SNP is significantly more prevalent in the control individuals compared to the BP patient. To further validate this observation, we included PV patients as an additional control. Again, the A-allele of IL-8 SNP is significantly more prevalent in the PV compared to the BP patients. While we observed a trend toward significant differences regarding alleles of TNF-α rs1799724 as well as alleles of TNF-α rs1799964, this difference was, however, not evident after correction for multiple analysis. There was no significant difference in all other studied SNPs. In contrast to IL-1α, IL-1β, and TNF-α, IL-8 gene expression levels were significantly higher in the patients than that of controls. The minor allele in IL-8 SNP might play a protective role in susceptibility to BP in Iranian patients. Although higher expression levels of IL-8 gene was found in the patients compared with healthy controls, these levels, however, suggest no association with the examined polymorphism. Moreover, further investigation revealed an elevation in gene expression between wild and polymorphic genotypes of IL-1α rs1800587 and TNF-α rs361525 in the patient group and these SNPs are therefore associated with altering the levels of gene expression.
Highlights
Bullous pemphigoid (BP) is a rare and difficult-totreat autoimmune skin blistering disease characterized by the presence of an autoimmune response against type XVII collagen (COL17, BP180) and BP230, and presents with blisters and erythema, and/or urticarial plaques, where itch is clinically a leading symptom [1–4]
Since altered expression of cytokines could affect the pathogenesis of BP, functional polymorphisms in cytokine genes may alter cytokine production and its biological balance which in terms results in higher susceptibility or severity of BP disease
Lack of sufficient data about any possible effect of gene variations on susceptibility to BP disease in different ethnicity indicates a necessity for further investigations
Summary
Bullous pemphigoid (BP) is a rare and difficult-totreat autoimmune skin blistering disease characterized by the presence of an autoimmune response against type XVII collagen (COL17, BP180) and BP230, and presents with blisters and erythema, and/or urticarial plaques, where itch is clinically a leading symptom [1–4]. Binding of autoantibodies to their antigens attenuate skin integrity and initiate a cascade of the inflammatory response [5]. This response is mainly mediated by infiltration of inflammatory cells, deposition of complement, and activation of proteases and reactive oxygen species which result in blister formation [5]. As regulators of inflammatory and immune reactions in the skin, contribute to inflammatory blister induction by recruitment of inflammatory cells as well as activation of resident cells [6]. Tumor necrosis factor- α (TNF- α) is another proinflammatory cytokine and acts as a central and multifunctional mediator of diverse cellular events [12]. IL-8 is a chemoattractant cytokine produced by a variety of cell types which contribute to a variety of proinflammatory activities [14]
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