Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity.

Prithvi Raj,Bo Zhang,Kasthuribai Viswanathan,Ran Song,Igor Dozmorov,Chris Cotsapas,Shaheen Khan,Chandrashekhar Pasare,Ferdicia Carr-Johnson,Quan Zhen Li,Ekta Rai,Carlos Arana,Chaim O Jacob ,Christine Kim Garcia ,Carol A Wise ,Bernard Lauwerys ,Betty P Tsao ,John B Harley ,Benjamin Wakeland ,David R Karp ,Jennifer A Kelly ,Patrick M Gaffney ,Graham B Wiley ,Swapan K Nath ,Judith A James ,Nancy J Olsen ,Mitja Mitrovič ,Chao Liang ,Edward K Wakeland

doi:10.7554/elife.12089

Abstract

Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.

Highlights

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease resulting from a profound loss of immune tolerance to self-antigens (Olsen and Karp, 2014; Theofilopoulos, 1995a; 1995b; Fairhurst et al, 2006)
The specific technologies, bioinformatics algorithms, and quality assessments used to generate these data are discussed in Materials and Methods and relevant data are provided in Supplementary file 1B and Figures 1A–H
The surface expression of HLA-DQ on monocytederived dendritic cell cultures (MDDC) from a risk/protective heterozygote is greater than the expression levels of those from a homozygote for a protective haplotype (Figure 7C.1–C.2). This increased surface expression of HLA-DQ is maintained on dendritic cells following activation with the TLR7/8 ligand R848 in a time course over 18 hours, indicating that HLA-D risk haplotypes drive higher levels of HLA class II molecule surface expression during TLR activation and dendritic cell maturation (Figure 7C.3–C.8). These findings indicate that variations in the XL9 regulatory region modify chromatin structure and transcription factor binding, leading to a significant increase in the surface expression of HLA class II in the dendritic cell lineage of individuals expressing SLE risk alleles of HLA-D

Summary

Introduction

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease resulting from a profound loss of immune tolerance to self-antigens (Olsen and Karp, 2014; Theofilopoulos, 1995a; 1995b; Fairhurst et al, 2006). Patients with SLE can present with combinations of symptoms, including skin rashes, oral ulcers, glomerulonephritis, neurologic disorders, severe vasculitis, and a distinct form of arthritis (Tsokos, 2011). This extensive heterogeneity in clinical presentation presumably reflects variations in the sites of immune complex deposition and induced inflammation among patients, and suggests that SLE may be a collection of related diseases, rather than a single pathogenic process. A generalized loss in immune tolerance by the humoral immune system and the aberrant activation of inflammatory effector mechanisms at the sites of immune complex deposition, are consistent features of SLE

Methods

Results

Conclusion