Behçet's disease risk-variant HLA-B51/ERAP1-Hap10 alters human CD8 T cell immunity

Abstract

ObjectivesThe endoplasmic reticulum aminopeptidase (ERAP1) haplotype Hap10 encodes for a variant allotype of the endoplasmic reticulum (ER)-resident peptide-trimming aminopeptidase ERAP1 with low enzymatic activity. This haplotype recessively confers the highest risk for Behçet’s diseases (BD) currently known, but only in carriers of HLA-B*51, the classical risk factor for the disease. The mechanistic implications and biological consequences of this epistatic relationship are unknown. Here, we aimed to determine its biological relevance and functional impact.MethodsWe genotyped and immune phenotyped a cohort of 26 untreated Turkish BD subjects and 22 healthy donors, generated CRISPR-Cas9 ERAP1 KOs from HLA-B*51+ LCL, analysed the HLA class I-bound peptidome for peptide length differences and assessed immunogenicity of genome-edited cells in CD8 T cell co-culture systems.ResultsAllele frequencies of ERAP1-Hap10 were similar to previous studies. There were frequency shifts between antigen-experienced and naïve CD8 T cell populations of carriers and non-carriers of ERAP1-Hap10 in an HLA-B*51 background. ERAP1 KO cells showed peptidomes with longer peptides above 9mer and significant differences in their ability to stimulate alloreactive CD8 T cells compared with wild-type control cells.ConclusionsWe demonstrate that hypoactive ERAP1 changes immunogenicity to CD8 T cells, mediated by an HLA class I peptidome with undertrimmed peptides. Naïve/effector CD8 T cell shifts in affected carriers provide evidence of the biological relevance of ERAP1-Hap10/HLA-B*51 at the cellular level and point to an HLA-B51-restricted process. Our findings suggest that variant ERAP1-Hap10 partakes in BD pathogenesis by generating HLA-B51-restricted peptides, causing a change in immunodominance of the ensuing CD8 T cell response.

EULAR study group on ‘MHC-I-opathy': identifying disease-overarching mechanisms across disciplines and borders

“…The fact that CD8+T cells are clonotypically expanded in patients with SpA, PsO and PsA supports this concept. [135][136][137][138] In BD, carriers of the disease-associated ERAP1 allotype 107 show enrichment for circulating antigen-experienced effector CD8+T cells and ERAP1 modulation influenced CD8+T cell responses. 107 The lack of identification of causative autoantigens or indeed alloantigens has resulted in discussion about whether CD8+T cells drive pathology in MHC-I-opathies.…”

“…[135][136][137][138] In BD, carriers of the disease-associated ERAP1 allotype 107 show enrichment for circulating antigen-experienced effector CD8+T cells and ERAP1 modulation influenced CD8+T cell responses. 107 The lack of identification of causative autoantigens or indeed alloantigens has resulted in discussion about whether CD8+T cells drive pathology in MHC-I-opathies. 17 Regardless, autoantigen-derived peptide recognition by CD8+T cells in patients has previously been reported, including an HLA-B51presented peptide derived from a stress-inducible autoantigen in BD, 139 HLA-C06:02 presented peptide from innate host defence protein LL-37 in PsO, 140 and HLA-B27-restricted epitope from a peptide hormone receptor and cartilage-derived peptides in SpA.…”

A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs

“… 3 , 4 , 5 Dysfunctional ERAP may alter the repertoires of peptides presented by MHC-I, potentially activating CD8 + T cells and causing adverse immune responses. 6 , 7 , 8 …”

Polymorphic positions 349 and 725 of the autoimmunity-protective allotype 10 of ER aminopeptidase 1 are key in determining its unique enzymatic properties

“…These ERAP1 allotypes present significant functional differences that may underlie their association with disease predisposition 14 . Of the ten most common ERAP1 allotypes, allotype 10 (often referred to as Hap10) is a strong functional outlier that is found in approximately 22% of humans and has been reported to be protective for some forms of autoimmunity such as Psoriasis and Behçet’s 15,16 . ERAP1 allotype 10 has been shown to have much lower enzymatic activity (up to 60-fold) when measured using some substrates 14 .…”