IL-13 Genetic Susceptibility to Bullous Pemphigoid: A Potential Target for Treatment and a Prognostic Marker

Abstract

Background: Bullous pemphigoid (BP) is a senile chronic autoimmune bullous skin disease with a high relapse rate, which significantly impairs patients' quality of life and contributes to disease mortality. This observational case-control study explores the gene polymorphisms of cytokines and their clinical significance in Chinese patients with BP.

Methods: IL-1α (rs1800587), IL-1β (rs16944, rs1143627, rs1143634), IL-4 (rs2243250), IL-6 (rs1800795), IL-10 (rs1800896, rs1800871, rs1800872), IL-13 (rs1800925, rs20541), TNF-α (rs1799964, rs1800630, rs1799724, rs361525), IFN-γ (rs1799964, rs1800630, rs361525, rs1800629, rs4248160, rs1800750), and TGF-β1 (rs2317130, rs1800469, rs4803457) genes were genotyped in the healthy controls and BP patients, respectively. Expression of these cytokines in serum was measured. Medical profiles of patients, including baseline characteristics and prognosis, were statistically analyzed.

Results: We found that IL-1 β and IL-13 concentrations were higher in the BP patients' sera compared to those in the controls. For IL-13, significant differences were found in the nucleotide ratio/genotype/haploid frequency/haplotype, respectively. IL-13 (rs20541, rs1800925) is related to gender, and the IL-13 genotype was significantly associated with recurrence.

Conclusions: BP is associated with IL-13 gene polymorphism and IL-13 concentration is elevated in blood circulation in patients with BP. Our results support that IL-13 is relevant in the pathogenesis of BP, suggesting that IL-13 could potentially represent a promising target for BP therapy and a prognostic marker.

Keywords: IL-13; SNP; bullous pemphigod; cytokine; gender; recurrence.

Figure 1

Comparison of serum cytokine levels between bullous pemphigoid patients and control groups. The protein concentrations were measured in the BP patients and healthy control subjects using the commercially available ELISA kits. Statistical analysis revealed a significant difference in the concentrations of IL-1β (P=0.048) and IL-13 (P=0.044) between the patient and control groups, respectively.

Figure 2

Immunological roles of IL-13 in BP pathogenesis. IL-13 secreted from Th2 cells, or mast cells activates eosinophils that produce more IL-13 molecules in a “positive feedback” pattern. IL-13 also mediates the transition of Th0 to Th2 cells, the primary cells expressing IL-13. Moreover, IL-13 promotes activated B cell maturation to plasma cells expressing BP IgE autoantibodies and enhances BP immunoglobulins (Igs) class switching. IL-13 also enhances VCAM-1 expression that promotes transmigration of eosinophils and basophils to the dermis. In BP, IL-13 also promotes B cell maturation and directly stimulates plasma cells to secrete BP autoantibodies that play a central role in the BP disease pathomechanism. Secretion of proteolytic enzymes including NE and Metalloproteinase-9 from eosinophils or neutrophils causes degradation of BP180 molecules, contributing to the BP disease pathology.