Evaluation of membrane-bound and soluble forms of human leucocyte antigen-G in systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a complex disease characterized by immune dysregulation, extensive vascular damage and widespread fibrosis. Human leucocyte antigen-G (HLA-G) is a non-classic class I major histocompatibility complex (MHC) molecule characterized by complex immunomodulating properties. HLA-G is expressed on the membrane of different cell lineages in both physiological and pathological conditions. HLA-G is also detectable in soluble form (sHLA-G) deriving from the shedding of surface isoforms (sHLA-G1) or the secretion of soluble isoforms (HLA-G5). Several immunosuppressive functions have been attributed to both membrane-bound and soluble HLA-G molecules. 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 < 0·0001). The plasma levels of transforming growth factor (TGF)-β were higher in SSc patients (18 937 ± 15 217 pg/ml) compared to controls (11 099 ± 6081 pg/ml; P = 0·003), and a significant correlation was found between TGF-β and the plasma levels of total sHLA-G (r = 0·65; P < 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 < 0·0001). These data indicate that in SSc the secretion and/or shedding of soluble HLA-G molecules and the membrane expression of HLA-G by peripheral blood mononuclear cells (PBMC) is clearly elevated, suggesting an involvement of HLA-G molecules in the immune dysregulation of SSc.

Soluble HLA-G Expression Inversely Correlates With Fetal Microchimerism Levels in Peripheral Blood From Women With Scleroderma

“…To our knowledge, only two studies have recently evaluated sHLA-G in sera/plasma samples from patients with SSc ( 52 , 53 ). The first one showed a tendency for lower levels in patients but failed to find statistical difference.…”

“…Contradictory results could come from the relatively small number of patients [ N = 35 in Ref. ( 53 )] and/or of healthy controls tested in both studies [ N = 32 and 40, respectively ( 52 , 53 )].…”

HLA-G Expressing Immune Cells in Immune Mediated Diseases

“…Our research group analyzed the role of both membrane HLA-G and sHLA-G in SSc patients. In particular, we recently reported that the percentage of HLA-G-positive monocytes, CD4+ T cells, CD8+ T cells and DP cells are significantly higher in SSc patients as compared to healthy subjects ( 34 ). Among DP cells a subpopulation of CD4 dull CD8 high lymphocytes highly expressing HLA-G was detected.…”

“…Notably, plasma levels of sHLA-G1 and sHLA-G5 isoforms were comparable and no significant differences were detected in total sHLA-G, sHLA-G1 and sHLA-G5 levels between limited and diffuse SSc forms. The total sHLA-G plasma levels correlated with the elevated TGF-β levels circulating in SSc patients ( 34 ). This finding is in agreement with in vitro data demonstrating that the production of TGF-β by myelomonocytic cells is strongly increased after incubation with recombinant sHLA-G ( 99 ).…”

“…This finding is in agreement with in vitro data demonstrating that the production of TGF-β by myelomonocytic cells is strongly increased after incubation with recombinant sHLA-G ( 99 ). In summary, it may be proposed that there is a possible involvement of HLA−G in SSc pathogenesis, as the elevated HLA−G membrane expression by PBMC and the increased sHLA−G plasma levels may reflect an attempt to control the immune derangement occurring in this disease and concur, through TGF-β up-regulation, with fibroblast activation and fibrosis development ( 34 ).…”