THU0407 Evaluation of soluble and membrane hla-g in patients with systemic sclerosis and role of these molecules in the pathogenesis of the disease
Authors: G. Murdaca, P. contini, S. Negrini, M. Borro, F. Puppo
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Systemic sclerosis (SSc) is a complex disease characterised by immune abnormalities, vascular damage and fibrosis. Human leukocyte antigen-G (HLA-G) is a non-classic class I major histocompatibility complex (MHC) molecule expressed on different cell lineages in both physiological and pathological conditions and detectable in soluble forms (sHLA-G1 and HLA-G5 shed and secreted isoform, respectively). Several immunomodulatory functions have been attributed to both membrane-bound and soluble HLA-G molecules. HLA-G is expressed on extravillous cytotrofoblast, in placenta but also in a few normal tissues, solid tumours, transplanted organs and virally infected cells. Soluble form (sHLA-G) derives from shedding of cleaved surface isoforms (sHLA-G1) or secretion of soluble isoforms (HLA-G5). Immunosuppressive functions have been attributed to both membrane HLA-G (mHLA-G) and sHLA-G. <h3>Objectives</h3> The aims of the present study were: 1) to determine the serum levels of sHLA-G molecules in a cohort of SSc patients with the limited or diffuse form of the disease; 2) to correlate sHLA-G levels with TGF-β; 3) to evaluate the expression of HLA-G in peripheral blood mononuclear cells (PBMC). <h3>Methods</h3> Thirtyfive patients (28 females/7 males, age 40–89 years) with diffuse SSc (dSSc, n. 12) or limited SSc (lSSc, n. 23) and 40 healthy sex and age matched controls were enrolled. Plasma sHLA-G, sHLA-G1 and HLA-G5 levels were determined by immunoenzymatic assays. mHLA-G expression in peripheral blood mononuclear cells (PBMC) was evaluated by flow cytometry. <h3>Results</h3> The plasma levels of sHLA-G were higher in SSc patients (444.27±304.84 U/ml) compared to controls (16.74±20.58 U/ml) (p&lt;0.0001). The plasma levels of TGF-β were higher in SSc patients (18937±15217 pg/ml) compared to controls (11099±6081 pg/ml; p=0.003) and a significant correlation was found between TGFβ and the plasma levels of total sHLA-G (r: 0.65; p&lt;0.01), sHLA-G1 (r: 0.60; p=0.003) and HLA-G5 (r: 0.47; p=0.02). The percentage of HLA-G-positive monocytes (0.98±1.72), CD4+ (0.37±0.68), CD8+ (2.05±3.74) and CD4 +CD8+double positive cells (14.53±16.88) was higher in SSc patients than in controls (0.11±0.08, 0.01±0.01, 0.01±0.01 and 0.39±0.40, respectively) (p&lt;0.0001). A high percentage of HLA-G +cells (30.47±26.75) was detectable on CD4<sup>dull</sup>CD8<sup>high</sup> cells from SSc patients only. <h3>Conclusions</h3> These data indicate that in SSc secretion and/or shedding of sHLA-G and mHLA-G are clearly elevated and involved in immune dysregulation. <h3>References</h3> [1] Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med2009;360:1989–2003. [2] Negrini S, Fenoglio D, Parodi A, Kalli F, Battaglia F, Nasi G, et al. Phenotypic Alterations Involved in CD8+ Treg Impairment in Systemic Sclerosis. Front Immunol2017;8:18. [3] Parel Y, Aurrand-Lions M, Scheja A, Dayer JM, Roosnek E, Chizzolini C. Presence of CD4+CD8+ double-positive T cells with very high interleukin-4 production potential in lesional skin of patients with systemic sclerosis. Arthritis Rheum2007;56:3459–67. <h3>Acknowledgements</h3> This work was supported by "Gruppo Italiano Lotta alla Sclerodermia" (GILS). The sponsor had no role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication. <h3>Disclosure of Interest</h3> None declared