HLA Class II Functional Motifs Associated with Severe Systemic Sclerosis (SSc) and Sclerotic Graft Versus Host Disease (sclGVHD): The Shared Epitopes of Fibrosis - ACR Meeting Abstracts

Abstract Number: 805

HLA Class II Functional Motifs Associated with Severe Systemic Sclerosis (SSc) and Sclerotic Graft Versus Host Disease (sclGVHD): The Shared Epitopes of Fibrosis

Jelena Blagojevic^1,2, David Venzon³, Lorenzo Beretta⁴, Edward W Cowen⁵, Laurin M Curtis⁶, Marco Matucci-Cerinic⁷, Steven Z Pavletic⁸ and Francesco Del Galdo⁹, ¹Department of Clinical and Experimental Medicine, Division of Rheumatology, University of Florence, Florence, Italy, ²Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom, ³Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA, Bethesda, MD, ⁴Scleroderma Unit, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy, ⁵Dermatology Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD, ⁶Experimental Transplantation and Immunology Branch, National Cancer institute (NCI), National Institutes of Health (NIH), Bethesda,, Bethesda, MD, ⁷Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy, ⁸Experimental Transplantation and Immunology Branch, National Cancer institute (NCI), National Institutes of Health (NIH), Bethesda, Bethesda, MD, ⁹Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: fibrosis and systemic sclerosis

Session Information

Date: Sunday, November 13, 2016

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's – Pathogenesis, Animal Models and Genetics - Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Single Nucleotide polymorphisms within the HLA region have been strongly associated with the occurrence of SSc and sclGVHD. However, specific studies on the amino acidic sequences of the HLA antigen presenting regions are scanty. Such approach has been very informative in predicting severity of rheumatoid arthritis (Shared Epitope). The aim of our study was to explore the presence of HLA class II functional motifs associated with severe skin fibrosis in SSc and sclGVHD (shared epitopes of fibrosis). The study was designed with a discovery cohort analysed by 4-digit HLA class II typing and a validation cohort of imputated HLA typing from GWAS data of 1000 SSc patients and controls. Here we present the results of the discovery cohort.

Methods: The discovery cohort comprised 70 SSc patients (15 with diffuse (dSSc) and 55 with limited (lSSc) subset) fulfilling 2013 ACR classification criteria and 43 sclGVHD patients with severe skin fibrosis involving >50 % of body surface area recruited from the observational clinical trial on chronic GVHD (04-C-0281). Four-digit HLA class II typing and β chain hypervariable region amino acidic sequence alignment was performed for HLA-DP and HLA-DR alleles in all patients. The obtained sequences were compared between sclGVHD patients and SSc patients with severe skin fibrosis characterized by maximum modified Rodnan skin score ≥ 25 (fibrotic phenotype group) and lSSc controls (non-fibrotic phenotype group). For the qualitative analysis amino acids were classified according the polarity, charge and hydrophobicity.

Results: Prevalence of hydrophobic and non-polar side chains was higher in patients with fibrotic phenotype compared to patients with non-fibrotic phenotype at position 26 of HLA–DQ β chain (p = 0.047) and lower at position 11 of HLA- DP β chain (p = 0.026). Comparison between two groups showed a lower prevalence of the following amino acidic motifs in patients with fibrotic phenotype compared with those with non-fibrotic phenotype: VVDE at positions 8,36,55 and 56 of HLA-DP β chain and FD at positions 67 and 70 of HLA-DR β chain (p = 0.013 and 0.0007, respectively). They were defined as non-permissive for fibrosis. More importantly “non-permissive” amino acids F and D at positions 67 and 70 of HLA-DR β chain were present in at least one copy in 75% of patients with non-fibrotic phenotype vs 40% of the patients with fibrotic phenotype (p=0.0004). Similarly, a second non permissive sequence VVDE at positions 8,36,55 and 56 of HLA-DP β chain was present in 53% of patients in the non-fibrotic group vs only 29% of the fibrotic group (p=0.018).

Conclusion: This is the first study which describes common sequences (shared epitopes), codified by three of the most important genes associated with SSc that seem to display a protective effect against severe fibrotic involvement in SSc and sclGVHD. We identified two non-permissive motifs within the hypervariable regions of β chains of HLA – DP, HLA – DQ and HLA – DR molecules that warrant validation in the large imputation cohort. Validation of these findings will be crucial to stratify patients diagnosed with SSc or candidate to bone marrow transplant for their risk of severe fibrosis.

Disclosure: J. Blagojevic, None; D. Venzon, None; L. Beretta, None; E. W. Cowen, None; L. M. Curtis, None; M. Matucci-Cerinic, None; S. Z. Pavletic, None; F. Del Galdo, None.

To cite this abstract in AMA style:

Blagojevic J, Venzon D, Beretta L, Cowen EW, Curtis LM, Matucci-Cerinic M, Pavletic SZ, Del Galdo F. HLA Class II Functional Motifs Associated with Severe Systemic Sclerosis (SSc) and Sclerotic Graft Versus Host Disease (sclGVHD): The Shared Epitopes of Fibrosis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/hla-class-ii-functional-motifs-associated-with-severe-systemic-sclerosis-ssc-and-sclerotic-graft-versus-host-disease-sclgvhd-the-shared-epitopes-of-fibrosis/. Accessed .

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