HLA-G Molecules Research Articles

Expression of Soluble HLA-G Identifies Favorable Outcomes in Liver Transplant Recipients

Human leukocyte antigen (HLA)-G displays immunotolerogenic properties toward the main effector cells involved in graft rejection through inhibition of natural killer cell- and cytotoxic T-lymphocyte-mediated cytolysis, and CD4 T-cell alloproliferation. An increase in serum and graft levels of HLA-G has been noted in transplant patients with improved allograft survival. However, the clinical relevance of soluble serum HLA-G molecules in tolerant pediatric and young adult liver transplant patients remains to be studied. We examined the serum HLA-G levels in 42 pediatric and young adult liver transplant patients with a mean age of 15 years; 13 patients had operational tolerance (TOL), with complete immunosuppression withdrawal for 2.3 to 13.2 years. Median HLA-G level in patients with acute rejection (AR) was similar to the level in pediatric healthy volunteers (9.9 vs. 4.2 U/mL, P=0.13). HLA-G was higher in patients with stable liver function on immunosuppression (54.6 U/mL) than in patients with AR (P=0.01) and healthy volunteers (P=0.003), but almost 6-fold lower than in TOL patients (325.4 U/mL). HLA-G did not correlate with clinical confounders or a history of posttransplant lymphoproliferative disease or Epstein-Barr virus; although levels in the TOL group were negatively correlated with time after immunosuppression withdrawal (r=-0.75, P=0.003). In rejectors, HLA-G levels trended to negatively correlate with a higher number (r=-0.58) and greater severity of AR episodes (r=-0.56) after 1 year posttransplantation. Increased serum HLA-G levels track with operational tolerance of liver grafts and support favorable outcomes in pediatric and young adult recipients.

Biology of HLA-G in cancer: a candidate molecule for therapeutic intervention?

Although the expression of the non-classical HLA class I molecule HLA-G was first reported to be restricted to the fetal-maternal interface on the extravillous cytotrophoblasts, the distribution of HLA-G in normal tissues appears broader than originally described. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic lineage. More interestingly, under pathophysiological conditions HLA-G antigens may be expressed on various types of malignant cells suggesting that HLA-G antigen expression is one strategy used by tumor cells to escape immune surveillance. In this article, we will focus on HLA-G expression in cancers of distinct histology and its association with the clinical course of diseases, on the underlying molecular mechanisms of impaired HLA-G expression, on the immune tolerant function of HLA-G in tumors, and on the use of membrane-bound and soluble HLA-G as a diagnostic or prognostic biomarker to identify tumors and to monitor disease stage, as well as on the use of HLA-G as a novel therapeutic target in cancer.

The Antigenicity of Ex Vivo Cultivated Human Corneal Limbal Epithelial and Stromal Cells: Temporal Changes In Vitro

To investigate the effect of ex vivo culture on the expression of human leukocyte antigen (HLA) in human corneal limbal epithelial cells (LECs), and to evaluate the expression of HLA and costimulatory molecules on human corneal limbal stromal cells (LSCs). The expression of HLA-ABC and HLA-DR were evaluated using flow cytometry on cultured human LECs and LSCs after serial passage and compared with that on freshly isolated cells. Additionally, the expression of costimulatory molecules CD80, CD86, CD40, and immunoregulatory molecule HLA-G were investigated on LSCs with or without an addition of interferon (IFN) γ (250 U/mL, 4 days). HLA-ABC and HLA-DR were expressed in 99.12 ± 1.02% and 25.86 ± 4.34% of freshly isolated LECs, respectively. After culture, the HLA-DR-expressing cells significantly decreased with serial passage, whereas the percentage of HLA-ABC-expressing cells did not change. More than 90% of LSCs expressed HLA-ABC and HLA-G, whereas the expression of HLA-DR, CD80, CD86, and CD40 was negligible. This expression profile did not change after serial passage. However, the treatment with IFN-γ induced a significant increase in HLA-DR (0.17% vs. 17.68%) and CD40 (0.19% vs. 13.19%) expression on LSCs. The immunogenicity of LECs can be lowered after ex vivo cultivation, whereas LSCs can be immunogenic in the presence of IFN-γ.

Expression of nonclassical molecule human leukocyte antigen–G in oral lesions

IntroductionHuman leukocyte antigen (HLA)–G is a nonclassic class I molecule that acts as a modulator of immune responses, and the expression of these molecules in virus-infected cells has been associated with subversion of the immune response. ObjectiveIn this study, we performed a cross-sectional study, systematically comparing the expression of the HLA-G in benign, premalignant, and malignant oral lesions and correlating it with the presence of high-risk and low-risk human papillomavirus (HPV) types. Specimens and MethodsOral biopsies were collected from 51 patients and analyzed by immunohistochemistry using anti–HLA-G antibody. Human papillomavirus detection and typing from oral biopsies were obtained by polymerase chain reaction using GP5+/GP6+ and specific primers. ResultsThe 51 biopsies were stratified into 3 groups according to lesion grade: oral benign lesions (oral hyperplasia and papilloma, n = 16), oral premalignant lesions (oral leukoplakia with dysplasia and lichen planus, n = 17), and malignant lesions (oral squamous cell carcinoma, n = 18). Human leukocyte antigen–G overexpression was mainly observed in benign and premalignant oral lesions but was not related to HPV infection (P > .05). On the other hand, HPV DNA was detected in 24 (47%) oral lesions, mainly in benign and premalignant lesions, with the most frequent type detected being high-risk HPV type. ConclusionThe HLA-G molecule was expressed in a significant number of benign oral lesions and was not correlated with HPV infection or oral cancer.

Non‐classical transcriptional regulation of HLA‐G: an update

There are corrections concerning two entries in the References section of [1]. These are presented below. 52. Menier C, Rabreau M, Challier JC, et al. Erythroblasts secrete the nonclassical HLA-G molecule from primitive to definitive hematopoiesis. Blood. 2004; 104: 3153–60. 53. Rouas-Freiss N, Moreau P, Ferrone S, Carosella ED. HLA-G proteins in cancer: do they provide tumor cells with an escape mechanism?Cancer Res. 2005; 65: 10139–44. We apologise for these errors.

HLA-G 14 bp Deletion/Insertion Polymorphism in Celiac Disease

Nonclassical major histocompatibility class I HLA-G antigen is a tolerogenic molecule that inhibits lytic activity of natural killer (NK) cells and cytotoxic T lymphocytes. Because of its immunomodulatory and tolerogenic properties, HLA-G molecules may have a role in celiac disease (CD). We analyzed the HLA-G 14 bp deletion/insertion polymorphism, known to have a functional effect on mRNA stability, in a group of 522 CD patients, stratified for the presence of HLA-DQ2 genotype, and 400 healthy individuals to evaluate the possible effect of the polymorphism on the risk to develop the disease. HLA-G 14 bp deletion/insertion polymorphism (rs1704) was detected by polymerase chain reaction and double-checked by direct sequencing. The 14 bp inserted (I) allele and the homozygous I/I genotype were significantly more frequent in CD patients than in healthy controls. The presence of I allele was associated with an increased risk of CD (OR 1.35) and the effect of I allele was consistent with a recessive genetic model (P<0.001). Our results also indicate that the effect of the HLA-G D/I polymorphism is restricted for HLA-DQ2, and not simply due to the presence of linkage disequilibrium with the major known risk factor; moreover we found that the presence of the I allele confers an increased risk of CD in addition to the risk conferred by HLA-DQ2 alone and that subjects that carry both DQ2 and HLA-G I alleles have an increased risk of CD than subjects that carry DQ2 but not the I allele.

Soluble HLA-G Inhibits Myeloid Dendritic Cell Function in HIV-1 Infection by Interacting with Leukocyte Immunoglobulin-Like Receptor B2

Dendritic cells represent a specialized class of professional antigen-presenting cells that are responsible for priming and maintaining antigen-specific effector cell responses and regulating immune activation by cytokine secretion. In HIV-1 infection, myeloid dendritic cells are highly dysfunctional, but mechanisms contributing to their functional alterations are not well defined. Here, we show that soluble molecules of the nonclassical major histocompatibility complex class Ib (MHC-Ib) antigen HLA-G are highly upregulated in the plasma during progressive HIV-1 infection, while levels of membrane-bound HLA-G surface expression on dendritic cells, monocytes, and T cells only slightly differ among HIV-1 progressors, HIV-1 elite controllers, and HIV-1-negative persons. These elevated levels of soluble HLA-G in progressive HIV-1 infection likely result from increased secretion of intracellularly stored HLA-G molecules in monocytes and dendritic cells and contribute to a functional disarray of dendritic cells by inhibiting their antigen-presenting properties, while simultaneously enhancing their secretion of proinflammatory cytokines. Interestingly, we observed that these immunoregulatory effects of soluble HLA-G were mainly mediated by interactions with the myelomonocytic HLA class I receptor leukocyte immunoglobulin-like receptor B2 (LILRB2; ILT4), while binding of soluble HLA-G to its alternative high-affinity receptor, LILRB1 (ILT2), appeared to be less relevant for its immunomodulatory functions on dendritic cells. Overall, these results demonstrate a critical role for soluble HLA-G in modulating the functional characteristics of professional antigen-presenting cells in progressive HIV-1 infection and suggest that soluble HLA-G might represent a possible target for immunotherapeutic interventions in HIV-1-infected persons.

Role and mechanism of human Kupffer cells in liver allo-geneic transplantation

Objective To explore the possible role and mechanism of the Kupffer cells (KCs) in liver allo-geneic transplantation at the early stage. Methods In vitro cell contact coculture system was established. Culture supernatants were collected respectively on the 1st, 2nd, 4th, 6th d after cocul-ture and the KCs and PBMCs were harvested on the 6th day after culture. The expression of HLA-G on the membrane of the KCs and PBMCs was detected with immunochemistry. Nitrate reduction test was used to determine the concentration of nitric oxide. IFN-γ, IL-10, TGF-β1 cytokine levels in the supernatants were also measured with ELISA. The proliferation of lymphocytes was evaluated with MTT. Results six days later, no HLA-G molecules were detected on the membrane of the KCs and PBMCs. In the experimental group containing KCs, the levels of NO, IL-10 and TGF-β1 was signifi-cantly increased(P<0. 05), while the levels of IFN-γ was relatively lower(P<0. 05) as compared to the experimental group without KCs. No IL-10 and IFN-γ were detected in the control group, and on-ly few NO and TGF-β1 was found in the control group with KCs. MTT test showed that the value of optical density was lower in the experimental group with KCs than that in any other group(P<0. 05).Conclusion No HLA-G is expressed on the membrane of KCs and PBMCs after contact coculture.KCs may participate in regulating production of NO and Th2/Th3-like cytokines and suppressing the proliferation of lymphocytes, through which KCs probably take part in inducing immunotolerance of liver transplantation in early stage. Key words: Liver transplantation; Kupffer cell; Mixed lymphocyte culture; Immunotoler-ance; Nitric oxide; Cytokine

The role of Qa-2, the functional homolog of HLA-G, in a Behcet's disease-like mouse model induced by the herpes virus simplex

BackgroundIt has been suggested that the HLA-G molecule is a genetic risk factor for Behcet's disease (BD). In this study, we evaluated the level of Qa-2, a murine nonclassical class I MHC molecule and possible functional homolog of HLA-G, to determine if it was associated with various symptoms of BD-like mice. In addition, we investigated siRNA (small interfering RNA) treatment to determine if it inhibited Qa-2 expression, thereby changing the symptoms of mice.MethodsRNA interference (RNAi) and vector transfection were employed to manipulate gene expression in vivo in mice. siRNA (small interfering RNA) or Qa-2 expression vector was applied to inhibit or up-regulate Qa-2 expression, respectively.ResultsThe Qa-2 levels in granulocytes were lower in BD-like mice than in normal controls. The silencing of Qa-2 by intravenous injection of siRNA (500 nmol/mouse, 4 times at 3-day intervals) specifically reduced the Qa-2 levels and worsened the BD-like symptoms.ConclusionsSilencing Qa-2 by injecting siRNA into mice resulted in deterioration of symptoms in BD-like mice.

Expression of human leucocyte antigen-G primarily targets affected skin of patients with psoriasis

The nonclassical human leucocyte antigen (HLA)-G molecule has been well recognized as a tolerogenic molecule and few studies have evaluated the role of the molecule in inflammatory cutaneous autoimmune diseases. To evaluate the expression of HLA-G in skin specimens of patients with psoriasis and to analyse its correlation with epidemiological and clinical variables. Thirty untreated patients with psoriasis and 32 healthy individuals were enrolled. Immunohistochemistry was applied to identify HLA-G expression in formalin-fixed paraffin-embedded cutaneous skin biopsies. Soluble and membrane-bound HLA-G expression was detected in 30 (90%) of the skin specimens from patients presenting clinical and histopathological features of psoriasis. Although infiltrating lymphomononuclear cells of the dermis exhibited HLA-G expression, the epidermis was primarily targeted. HLA-G expression was also observed in 27% (three of 11) of the specimens that exhibited no clinical and histopathological features of psoriasis (nonaffected areas). In contrast, skin specimens obtained from healthy individuals exhibited no HLA-G expression (P < 0·0001). The intensity of HLA-G expression was not associated with type I/II psoriasis, Psoriasis Area and Severity Index score or clinical forms. As the HLA-G molecule was consistently expressed in affected and, to a lesser extent, in nonaffected areas of untreated patients with psoriasis, irrespective of the severity of the clinical variants, one may hypothesize that the presence of HLA-G may be responsible, at least in part, for the regulation of autoimmune effector cells.

Prognostic relevance of soluble human leukocyte antigen–G and total human leukocyte antigen class I molecules in lung cancer patients

The aim of this study was to determine the prognostic significance of soluble human leukocyte antigen (HLA) class I (sHLA-I) and HLA-G molecules in lung cancer patients. A total of 23 small-cell lung cancer (SCLC) and 114 non–small-cell lung cancer (NSCLC) patients, including 55 adenocarcinoma, 46 squamous cell carcinoma (SCC), and 13 patients with undifferentiated carcinoma, were prospectively enrolled. Levels of sHLA-G and sHLA-I were analyzed by specific enzyme-linked immunosorbent assay. Median levels of sHLA-G and sHLA-I were significantly increased in patients compared with controls (34 ng/ml [3.6–160] vs 14 ng/ml [0–98], p < 0.0001; 2580 ng/ml [749–5770] vs 1370 ng/ml [274–2670], p < 0.0001, respectively). Regarding the different subgroups, patients with NSCLC or SCLC showed increased sHLA-I levels, whereas sHLA-G was exclusively elevated in NSCLC, especially in patients with SCC. Patients with sHLA-I<2800 ng/ml ( p = 0.008) or sHLA-G<40 ng/ml ( p = 0.073) showed prolonged overall survival (OS). Using these cut-offs in patients with SCC, a pronounced prognostic significance for sHLA-G ( p = 0.003) and sHLA-I ( p = 0.004) was observed for the prediction of OS. Here, multivariate analysis confirmed sHLA-G and sHLA-I in addition to disease stage as independent prognostic factors. The prognostic power was further enhanced by combining the two factors and comparing the OS of patients with low sHLA-I and low sHLA-G against the remaining ones. In conclusion, plasma levels of sHLA-G and sHLA-I are potent predictors for OS in lung cancer patients.

Production of immune-modulatory nonclassical molecules HLA-G and HLA-E by tumor infiltrating ameboid microglia/macrophages in glioblastomas: A role in innate immunity?

The possible role of immune-modulatory nonclassical molecules HLA-G and HLA-E in an anti-tumoral response and development of glioblastoma is not well characterized. In this study, we evaluated an expression of HLA-G and HLA-E by activated tumor infiltrating microglia/macrophages. We found production of HLA-G and HLA-E by tumor infiltrating activated microglia/macrophages in a majority of glioblastomas. We speculate that the expression of these molecules by activated microglia/CNS macrophages plays a role in the anti-tumoral immunity in the development of glioblastoma. Mechanisms of microglia–glioblastoma cell interactions with respect to the expression of these molecules deserves further study.

Human leukocyte antigen-G molecules are constitutively expressed by synovial fibroblasts and upmodulated in osteoarthritis

Human leukocyte antigen (HLA)-G molecules are nonclassical HLA class I antigens expressed as membrane bound and soluble isoforms (sHLA-G) with a restricted tissue distribution and anti-inflammatory functions. Because inflammation is involved in the pathogenesis of osteoarthritis (OA), we have analyzed the expression and production of HLA-G molecules in in vitro cultured synovial fibroblasts (SFs) from OA patients and control subjects. We have analyzed the levels of sHLA-G1 and HLA-G5 isoforms by immunoenzymatic assay (enzyme-linked immunosorbent assay) in the SF culture supernatants from six OA patients and six control subjects in 70-day in vitro cultures and after the addition of lipopolysaccharide or recombinant interleukin (IL)-10 (rIL-10). We have confirmed HLA-G modulation by cytofluorimetry and immunofluorescence. The results have demonstrated the spontaneous production of sHLA-G1 molecules by both OA and control SFs. The expression was confirmed by cytofluorimetry and immunofluorescence. OA SFs produce both sHLA-G1 and HLA-G5 molecules during the first 23 days of culture and higher levels of sHLA-G1 during the first 40 days of in vitro culture and after lipopolysaccharide or rIL-10 activation compared with control SFs. The production of HLA-G1 molecules, constitutively expressed by control and OA SFs, is significantly increased in OA, suggesting a possible mechanism to counteract the inflammation of the synovial joints.

Inhibitory NK Receptor Recognition of HLA-G: Regulation by Contact Residues and by Cell Specific Expression at the Fetal-Maternal Interface

The non-classical HLA-G protein is distinguished from the classical MHC class I molecules by its expression pattern, low polymorphism and its ability to form complexes on the cell surface. The special role of HLA-G in the maternal-fetal interface has been attributed to its ability to interact with specific receptors found on maternal immune cells. However this interaction is restricted to a limited number of receptors. In this study we elucidate the reason for this phenomenon by comparing the specific contact residues responsible for MHC-KIR interactions. This alignment revealed a marked difference between the HLA-G molecule and other MHC class I molecules. By mutating these residues to the equivalent classical MHC residues, the HLA-G molecule regained an ability of interacting with KIR inhibitory receptors found on NK cells derived either from peripheral blood or from the decidua. Functional NK killing assays further substantiated the binding results. Furthermore, double immunofluorescent staining of placental sections revealed that while the conformed form of HLA-G was expressed in all extravillous trophoblasts, the free heavy chain form of HLA-G was expressed in more distal cells of the column, the invasion front. Overall we suggest that HLA-G protein evolved to interact with only some of the NK inhibitory receptors thus allowing a control of inhibition, while permitting appropriate NK cell cytokine and growth factor production necessary for a viable maternal fetal interface.

Different functional outcomes of intercellular membrane transfers to monocytes and T cells.

Trogocytosis is the uptake of membranes from one cell by another. Trogocytosis has been demonstrated for monocytes, B cells, T cells, and NK cells. The acquisition of the tolerogenic molecule HLA-G by T cells and NK cells makes them behave as regulatory cells. We investigated here whether HLA-G, which is expressed by tumor cells in vivo, could be acquired by monocytes and if this transfer could have functional consequences. We demonstrate that resting, and even more so, activated monocytes efficiently acquire membrane-bound HLA-G from HLA-G tumor cells by trogocytosis. However, we demonstrate that HLA-G quickly disappears from the surface of the monocytes in contrast to the HLA-G acquired by T cells. Consequently, HLA-G(acq+) monocytes do not reliably inhibit the on-going proliferation of autologous activated T cells and do not inhibit their cytokine production. Thus, we show that the acquirer cell may control the functional outcome of trogocytosis.

HLA-G molecules are costitutively expressed by human synovial fibroblasts and up-modulated in osteoarthritis

Objective HLA-G molecules are non classical HLA class I antigens expressed as membrane bound and soluble isoforms (sHLA-G) with a restricted tissue distribution and anti-inflammatory functions [1]. Osteoarthritis (OA) is a complex degenerative disease that affects articular cartilage components and causes damage to the entire joint structure including synovium [2]. Since inflammation is involved in the pathogenesis of OA, we have analyzed the expression and the production of HLA-G molecules in “in vitro” cultured synovial fibroblasts (SFs) from OA patients and control subjects. Design We have analyzed the levels of sHLA-G1 and HLA-G5 isoforms by immunoenzymatic assay (ELISA) in the SFs culture supernatants from six OA patients and six control subjects during a 70 day “in vitro” cultures in the presence and in the absence of lipopolysaccharide (LPS) or recombinant IL-10 (rIL-10). We have confirmed HLA-G modulation by cytofluorimetry and immunofluorescence. Results Data in ELISA have demonstrated the spontaneous production of sHLA-G molecules by both OA and control SFs. The expression has been confirmed by cytofluorimetry and immunofluorescence. OA SFs produce higher levels of sHLA-G1 and HLA-G5 molecules during the first 23 days of culture in comparison to control SFs. The sHLA-G1 levels further increase over the next 20 days of “in vitro” culture. Atfer LPS and rIL-10 treatments, sHLA-G secretion increases in a similar manner in both OA and control SFs. Conclusions The production of sHLA-G1 molecules, constitutively expressed by control and OA SFs, is significantly higher in OA than in control SFs, suggesting that these molecules represent a possible molecular target to counteract the synovial joints inflammation.

Recent advances on the non-classical major histocompatibility complex class I HLA-G molecule

The human leukocyte antigen (HLA)-G non-classical major histocompatibility complex (MHC) class I molecule was originally described in first-trimester trophoblasts at the fetal-maternal interface in 1990. Eight years later, the First International Conference on this molecule was inaugurated by Prof Jean Dausset, recipient of the Nobel Prize in Medicine. The Fifth International Conference on HLA-G, held in Paris on July 2009, began with a tribute to Prof Jean Dausset who left us recently. This conference was co-chaired by Dr Edgardo D. Carosella and Prof Hans Grosse-Wilde, included 57 oral presentations and was attended by approximately 140 delegates from 16 countries. We summarize here the major advances on the HLA-G molecule that were reported, including findings on its biological activity and characterization of new mechanisms of action, notably through mesenchymal stem cells and regulatory cells, and the previously unexplored role of HLA-G on immune cells such as gammadelta T-cells and B lymphocytes. Furthermore, the role of HLA-G during pregnancy was revisited and its impact in pathologies such as cancer, autoimmune disorders and transplantation was further extended.

In vitro fertilized embryos do not secrete detectable HLA-G on day two.

Pregnancy is a successful transplantation. The factors evading rejection of the fetus are poorly understood. Recently an interest has grown, in HLA-G molecules as one of these factors. Since these antigens are mainly expressed on the surface of cytotrophoblasts that are in direct contact with maternal tissues, it has been suggested that these molecules may have a role in induction of immune tolerance in mothers. to find the association of soluble HLA-G (sHLA-G) and the success of pregnancy with intracytoplasmic sperm injection (ICSI) procedure. In this study, the supernatant of 287 individually cultured embryos corresponding to 96 women under ICSI procedure were assayed for soluble HLA-G1 and G5 by a sandwich ELISA. Clinical pregnancy successfully occurred in 30 of candidates. No differences in clinical parameters (age, infertility duration, stimulation regimen) were observed between pregnant and nonpregnant women under ICSI procedure. None of the embryo supernatants in either group showed any detectable sHLA-G molecules. Our results showed that detectable level of sHLA-G is not produced by day 2 embryos and such a measurement may not provide reliable information for embryo selection and estimation of pregnancy success.

CD8+HLA-G+ Regulatory T Cells Are Expanded in HIV-1-Infected Patients

It has been recently reported that CD8(+) T cells from healthy human peripheral blood express the tolerogenic HLA-G molecule originally described in trophoblasts. The majority of these CD8(+)HLA-G(+) cells exhibit a naïve phenotype and are FoxP3 negative, and they have been classified as a novel subset of regulatory T cells based on their potent suppressive function. We have investigated if this new cell population is expanded during HIV-1 infection. The results presented here show an increase in the percentage of CD8(+)HLA-G(+) cells within the total CD8 T-cell population in HIV-1(+) patients. As in healthy controls, these CD8(+)HLA-G(+) are mostly naïve T cells. However, we have also observed that only in HIV-1-infected patients are there effector and effector memory cells that express HLA-G.

HLA‐G polymorphism influences the susceptibility to HCV infection in sickle cell disease patients

Despite its well known monogenic etiopathogenesis, sickle cell disease (SCD) is characterized by a striking variability of clinical presentation. There is growing evidence that genetic factors may be involved in this variability. Human leukocyte antigen (HLA)-G is a non-classical HLA molecule which was shown to be expressed at sites of inflammation and in inflammatory diseases. Besides its large and highly polymorphic promoter region, the 3' UTR region seems also to play an important role on regulating HLA-G expression. We investigated the influence of the 14 pb (rs1704) and the +3142 (rs1063320) HLA-G polymorphisms in 93 SCD patients in order to evaluate its potential role on clinical parameters. Twenty-one patients presented an HCV infection. Among all SCD patients 16 (22.2%) were homozygous for the +3142C genotype, none of them hepatitis C (HCV) positive. Controlling for blood transfusions in the last year, the C allele represented a dose dependent protection effect for HCV infection (PR = 0.41; 95% CI: 0.24-0.71). The +3142C allele was also underrepresented among patients with history of respiratory-tract infections. Our results support a role of the +3142 polymorphism in the susceptibility to infections, in particular to HCV infection, and suggest a possible interference of the HLA-G molecule in the response to infections, among SCD patients.