RESUMEN
BACKGROUND AIMS: The beneficial activity of mesenchymal stromal cells (MSC) in allogeneic hematopietic stem cell transplantation requires correct use in terms of cell dose and timing of infusion and the identification of biomarkers for selection. The immunosuppressive bone marrow (BM)-derived MSC (BM-MSC) functions have been associated with the production of soluble HLA-G molecules (sHLA-G) via interleukin (IL)-10. We have established a reliable method for evaluating BM-MSC HLA-G expression without the influence of peripheral blood mononuclear cells (PBMC). METHODS: Thirteen BM-MSC from donors were activated with recombinant IL-10 or co-cultured with 10 different phytohemagglutinin (PHA)-treated PBMC (PHA-PBMC). Membrane-bound and sHLA-G expression was evaluated by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively; lymphoproliferation was measured by (methyl-(3)H)thymidine. RESULTS: The results demonstrated the ability of IL-10 to stimulate both membrane-bound and sHLA-G production by BM-MSC. The levels of HLA-G expression induced by IL-10 in BM-MSC were associated with the inhibition of PHA-PBMC proliferation (sHLA-G, P = 0.0008, r = 0.9308; membrane HLA-G, P = 0.0005, r = 0.9502). CONCLUSIONS: We propose the evaluation of sHLA-G production in IL-10-treated BM-MSC cultures as a possible marker of immunoregulatory function.
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Células de la Médula Ósea/inmunología , Separación Celular/métodos , Antígenos HLA/análisis , Antígenos de Histocompatibilidad Clase I/análisis , Tolerancia Inmunológica , Terapia de Inmunosupresión , Células Madre Mesenquimatosas/inmunología , Adulto , Células de la Médula Ósea/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Antígenos HLA/biosíntesis , Antígenos HLA-G , Antígenos de Histocompatibilidad Clase I/biosíntesis , Humanos , Interleucina-10/farmacología , Leucocitos Mononucleares/inmunología , Activación de Linfocitos , Células Madre Mesenquimatosas/efectos de los fármacos , Persona de Mediana Edad , Fitohemaglutininas/farmacología , Células del Estroma/efectos de los fármacos , Células del Estroma/inmunologíaRESUMEN
Bacterial LPS induces the release of ATP from immune cells. Accruing evidence suggests that extracellular ATP participates in the inflammatory response as a proinflammatory mediator by activating the inflammasome complex, inducing secretion of cytokines (IL-1, IL-18) and cell damaging agents such as oxygen radicals, cationic proteins, and metalloproteases. It is not known whether ATP can also act as a proinflammatory mediator by inhibiting production of molecules down-modulating the immune response. Here, we show that extracellular ATP impairs in an IL-10-dependent fashion the expression of the tolerogenic soluble and membrane-bound HLA-G Ag in human monocytes. The effect of ATP was mimicked by BzATP (3'-O-(4-benzoyl)benzoyl-ATP) and greatly reduced by pretreatment with oATP (periodate-oxidized ATP), KN-62 (1-[N,O-bis(5-isoquinoline-sulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine), and an anti-P2X(7) mAb, thus pointing to a specific role of the P2X(7) receptor. The effect of ATP was time- and dose-dependent and was not due to a decrease in expression of IL-10 receptor. Inhibition by ATP was reverted by supplementation of culture medium with exogenous IL-10. Due to the well-known immunosuppressive activity of IL-10 and soluble HLA-G, this novel effect of ATP might be relevant for the pathophysiology and therapy of inflammatory disorders.
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Regulación hacia Abajo/inmunología , Espacio Extracelular/inmunología , Antígenos HLA/inmunología , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Mediadores de Inflamación/fisiología , Monocitos/inmunología , Monocitos/metabolismo , Receptores Purinérgicos P2/metabolismo , Línea Celular Tumoral , Membrana Celular/inmunología , Membrana Celular/metabolismo , Células Cultivadas , Espacio Extracelular/metabolismo , Antígenos HLA/biosíntesis , Antígenos HLA-G , Antígenos de Histocompatibilidad Clase I/biosíntesis , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-10/antagonistas & inhibidores , Interleucina-10/biosíntesis , Interleucina-10/metabolismo , Lipopolisacáridos/sangre , Receptores Purinérgicos P2/fisiología , Receptores Purinérgicos P2X7RESUMEN
Taxanes represent a group of anticancer drugs with a wide range of activity against breast cancer. Therapy side effects include haematologic toxicity (neutropenia, leucopenia), peripheral neuropathy and hypersensitivity, and demonstrate inter-individual variations. Since it is known that three genes are implicated in taxane turnover, namely ABCB1 in the transport, CYP2C8 in the metabolism and CYP1B1 in the activity, we explored the association among polymorphisms (single nucleotide polymorphisms, SNPs) in these three genes and the occurrence of taxane-induced toxicity. We studied 95 patients affected by breast cancer and under treatment with taxanes as adjuvant, metastatic or neo-adjuvant therapy. We genotyped them for SNPs in the CYP2C8 (alleles *1, *2, *3 and *4), CYP1B1 (alleles *1 and *3) and ABCB1 (1236 C>T; 2677 G>T/A; 3435 C>T) genes by real-time PCR assay. We observed a significant association between the CYP1B1*3 allele and a lower occurrence of hypersensitivity reactions to taxane treatment. We speculate that the highest production of 4-hydroxyestradiol (4-OHE2) metabolite by CYP1B1*3 allele could increase the formation of the 4-OHE2-taxane adduct and possibly inhibit taxane toxicity. We suggest that CYP1B1 might affect taxane hypersensitivity therefore representing, if confirmed in a large cohort of patients, an exploratory hypersensitivity predictive biomarker.
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Antineoplásicos Fitogénicos/efectos adversos , Neoplasias de la Mama Masculina/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Sistema Enzimático del Citocromo P-450/genética , Hipersensibilidad a las Drogas/genética , Paclitaxel/efectos adversos , Polimorfismo de Nucleótido Simple , Taxoides/efectos adversos , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Anciano , Antineoplásicos Fitogénicos/farmacocinética , Hidrocarburo de Aril Hidroxilasas/genética , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Neoplasias de la Mama Masculina/enzimología , Neoplasias de la Mama Masculina/genética , Quimioterapia Adyuvante , Distribución de Chi-Cuadrado , Citocromo P-450 CYP1B1 , Citocromo P-450 CYP2C8 , Sistema Enzimático del Citocromo P-450/metabolismo , Docetaxel , Hipersensibilidad a las Drogas/enzimología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Italia , Modelos Logísticos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Oportunidad Relativa , Paclitaxel/farmacocinética , Fenotipo , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Taxoides/farmacocinética , Resultado del TratamientoRESUMEN
HLA-G antigens are non-classical HLA-class I anti-inflammatory molecules. Since styrene exposure has been suggested to induce immune alteration, we analyzed plasma levels and "in vitro" peripheral blood mononuclear cell (PBMC) production of soluble HLA-G (sHLA-G) and interleukin-10 (IL-10) molecules after lipopolysaccharide (LPS) stimulation, in styrene exposed workers and healthy subjects. Exposed workers showed reduced plasma levels of sHLA-G and IL-10 in comparison to healthy controls. Similarly, lower levels of sHLA-G and IL-10 molecules were observed in PBMC culture supernatants after LPS activation. These data propose styrene exposure as a mediator of impaired sHLA-G production.
RESUMEN
BACKGROUND: HLA-G antigens are nonclassical major histocompatibility complex (MHC) class I molecules characterized by tolerogenic and antiinflammatory properties. Recently, a different expression of HLA-G antigens has been observed between intestinal biopsies of ulcerative colitis (UC) and Crohn's disease (CD) patients. These data suggested a functional role for HLA-G molecules in the diseases and proposed the HLA-G modulation as a marker for the diagnosis of UC and CD. The soluble HLA-G antigens (sHLA-G) are circulating molecules mainly produced by activated peripheral blood CD14+ monocytes. METHODS: We tested, by specific enzyme-linked immunosorbent assay (ELISA), the sHLA-G molecule levels in the supernatants of unstimulated and bacterial lipopolysaccharide (LPS)-stimulated cultures of peripheral blood mononuclear cells (PBMC) from 30 healthy subjects, 10 CD, and 18 UC patients. The data were not influenced by treatment or disease activity. RESULTS: The results confirmed a different sHLA-G expression between the diseases, with a spontaneous secretion of sHLA-G in CD patients but not in UC and healthy subjects. Moreover, a lack of sHLA-G antigens has been reported in UC patient cultures after LPS activation but not in healthy subjects and CD patients. The defective sHLA-G production was related to an impaired IL-10 secretion in UC but not in CD. CONCLUSIONS: Overall, these results confirm the presence of a different biological characteristic between CD and UC patients and suggest sHLA-G production by PBMC as a noninvasive diagnostic tool in the early phases of the diseases.
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Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/inmunología , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/inmunología , Antígenos HLA/biosíntesis , Antígenos de Histocompatibilidad Clase I/biosíntesis , Leucocitos Mononucleares/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Análisis Químico de la Sangre , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Antígenos HLA-G , Humanos , Interleucina-10/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
Human leukocyte antigen-G (HLA-G) is thought to play a key role in implantation by controlling trophoblast invasion and maintaining a local immunosuppressive state. The secretion of soluble HLA-G antigens (sHLA-G) by early embryos seems necessary for a successful implantation and could be a marker of increased pregnancy rate following in vitro fertilization. We have reviewed the results obtained during the last years (from 1987 to 2005). They overall confirmed the predictive role of sHLA-G production in pregnancy outcome. Furthermore, we have examined the technical procedures utilized, with a particular attention to the monoclonal antibodies used in the enzyme-linked immunosorbent assay (ELISA) techniques. New functional roles for HLA-G molecules in pregnancy could be suggested by the relationship observed between the presence of sHLA-G antigens in follicular fluids and sHLA-G expression in the corresponding fertilized oocyte. Furthermore, since maternal mRNA is fundamental for protein production in early embryos, the biologic role of the HLA-G 14 base pair polymorphism could be explored.
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Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase I/genética , Embarazo/inmunología , Femenino , Antígenos HLA/biosíntesis , Antígenos HLA-G , Antígenos de Histocompatibilidad Clase I/biosíntesis , HumanosRESUMEN
The nonclassical human leukocyte antigen (HLA) class Ib gene HLA-G may be important for the induction and maintenance of immune tolerance between the mother and the semi-allogeneic fetus during pregnancy. Expression of HLA-G can influence cytokine and cytotoxic T-lymphocyte responses. Different HLA-G mRNA isoform expression patterns have been associated with HLA-G polymorphism, especially with a 14-bp insertion deletion polymorphism in the 3' untranslated region (3'UTR) of the HLA-G gene. A significantly high level of interleukin-10 (IL-10) secretion is observed in homozygous +14/+14-bp HLA-G peripheral blood mononuclear cells after lipopolysaccharide (LPS) stimulation. This study finds that polymorphism in the 5' upstream regulatory region (5'URR) of the HLA-G gene may also be implicated in differences in IL-10 secretion. However, this may also be due to linkage disequilibrium with the 14-bp polymorphism. A single-nucleotide polymorphism located -477 bp from the start site of exon 1 had a significant association with IL-10 concentrations but not after correction (p=0.011; pc=0.154). This polymorphism is located next to a heat shock element. Eighteen 5'-URR/3'-UTR HLA-G haplotypes were defined; one common homozygous genotype based on these haplotypes was significantly associated with a high IL-10 level after LPS stimulation compared to certain other genotypes. This study indicates that polymorphism in the 5'-URR of the HLA-G gene may have functional significance, although a new line of investigations is needed to elucidate these findings.
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Regiones no Traducidas 3'/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase I/genética , Interleucina-10/metabolismo , Polimorfismo Genético , Elementos Reguladores de la Transcripción/genética , Secuencia de Bases , Expresión Génica , Antígenos HLA-G , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Desequilibrio de Ligamiento , Lipopolisacáridos/farmacología , Datos de Secuencia MolecularRESUMEN
OBJECTIVE: We have investigated expression and function of the P2X7 receptor in fibroblasts from healthy subjects and patients with type 2 diabetes. METHODS AND RESULTS: Fibroblasts were isolated from skin biopsies. P2X7 receptor expression in both cell populations was measured by functional assays, RT-PCR, fluorescence-activated cell sorter, and immunoblotting. We found that fibroblasts from diabetic subjects are characterized by enhanced P2X7-mediated responses as indicated by increased shape changes, microvesiculation, enhanced fibronectin and interleukin 6 secretion, and accelerated apoptosis. These responses were blocked by preincubation with the P2X blockers KN-62, oxidized ATP, or pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid). Furthermore, we also found a higher level of spontaneous fibronectin secretion and of apoptosis in fibroblasts from diabetic compared with healthy subjects. Both higher basal level of fibronectin secretion and spontaneous rate of apoptosis were likely attributable to the increased pericellular concentration of ATP because fibroblasts from diabetic subjects released 3x as much ATP into the supernatants compared with fibroblasts from healthy subjects. CONCLUSIONS: We conclude that fibroblasts from type 2 diabetes patients are characterized by a hyperactive purinergic loop based either on a higher level of ATP release or on increased P2X7 reactivity.
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1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Adenosina Trifosfato/análogos & derivados , Diabetes Mellitus Tipo 2/patología , Angiopatías Diabéticas/etiología , Fibroblastos/patología , Fosfato de Piridoxal/análogos & derivados , Receptores Purinérgicos P2/fisiología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Adenosina Difosfato/farmacología , Adenosina Trifosfato/metabolismo , Adenosina Trifosfato/farmacología , Apoptosis/efectos de los fármacos , Apirasa/farmacología , Comunicación Autocrina , Forma de la Célula/efectos de los fármacos , Citidina Trifosfato/farmacología , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Regulación de la Expresión Génica , Humanos , Interleucina-6/metabolismo , Potenciales de la Membrana/efectos de los fármacos , Comunicación Paracrina , Fosfato de Piridoxal/farmacología , Receptores Purinérgicos P2/biosíntesis , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2X7 , Uridina Difosfato/farmacología , Uridina Trifosfato/farmacologíaRESUMEN
Human leucocyte antigen-G (HLA-G) is a non-classical HLA class I molecule with an important role at the fetus-maternal interface, preventing fetus recognition and abortion. The role of HLA-G as an immune-modulatory and anti-inflammatory molecule has led to investigate its role in pathological conditions. In these years, HLA-G has been shown to have an important implication in inflammatory pathologies. The focus of this review is to up-date the scientific knowledge on the expression of HLA-G molecules in inflammatory conditions.
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Feto/inmunología , Antígenos HLA-G/inmunología , Inflamación/inmunología , Femenino , Humanos , Inflamación/patología , EmbarazoRESUMEN
Human umbilical cord blood units (UCBs) are an alternative source in allogeneic-stem-cell transplantation. Human leukocyte antigen (HLA)-G is a tolerogenic molecule with a possible implication in UCB immunoregulatory effect. HLA-G expression was observed in UCB myeloid and plasmacytoid dendritic cells; in contrast, CD34(+) cells did not produce this molecule. CD34(+) cells are primitive hematopoietic progenitor cells that are present in UCB and are necessary for long-term engraftment via production of immunoregulatory molecules and a hematopoietic progeny that supports cellular recovery. The role of these cells in UCB transplantation needs further evaluation of HLA-G expression in CD34(+) cells and their hematopoietic progeny. We confirmed the absence of HLA-G expression in CD34(+) cells, whereas CD34(+)-derived progeny secreted HLA-G molecules and expressed HLA-G mRNA in in vitro cultures. Furthermore, soluble HLA (sHLA)-G molecules purified from the culture supernatants of CD34(+)-derived progeny were able to suppress lymphoproliferative response in an HLA-G dose-dependent manner. Overall these results identify CD34(+)-derived hematopoietic progeny as producers of HLA-G molecules and support a role of this antigen as an immuno-modulatory factor in UCB.
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Antígenos CD34/inmunología , Sangre Fetal/citología , Sangre Fetal/inmunología , Antígenos HLA-G/inmunología , Adulto , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Electroforesis en Gel de Poliacrilamida , Ensayo de Inmunoadsorción Enzimática , Femenino , Regulación de la Expresión Génica , Antígenos HLA-G/aislamiento & purificación , Antígenos HLA-G/farmacología , Humanos , Factores Inmunológicos/farmacología , EmbarazoRESUMEN
HLA-G is believed to act as an anti-inflammatory molecule in Multiple Sclerosis (MS). The 3' untranslated region of the HLA-G gene is characterized by two polymorphisms, DEL/INS14bp and +3142C>G, which control soluble HLA-G (sHLA-G) production. The influence of these two HLA-G variants on sHLA-G serum and cerebrospinal fluid (CSF) levels was investigated in 69 Relapsing-Remitting MS patients grouped in magnetic resonance imaging (MRI) inactive and active disease. Serum and CSF sHLA-G levels were more elevated in high than in low DEL/INS 14bp and +3142C>G sHLA-G producers and were different among the various combined HLA-G genotypes in both MRI inactive and active diseases. The highest and the lowest sHLA-G values were identified in MS patients with C/C,DEL/DEL and G/G,INS/INS genotypes, respectively. Our preliminary findings suggest that serum and CSF sHLA-G levels in MS could be influenced by HLA-G polymorphisms irrespective of the inflammatory microenvironment.
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Antígenos HLA-G/genética , Esclerosis Múltiple Recurrente-Remitente/genética , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Mutagénesis Insercional , Polimorfismo de Nucleótido Simple , Eliminación de Secuencia , Adulto , Alelos , Femenino , Frecuencia de los Genes , Genotipo , Antígenos HLA-G/sangre , Antígenos HLA-G/líquido cefalorraquídeo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/diagnósticoRESUMEN
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.
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Fibroblastos/metabolismo , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Osteoartritis/inmunología , Membrana Sinovial/patología , Anciano , Anciano de 80 o más Años , Separación Celular , Células Cultivadas , Femenino , Fibroblastos/inmunología , Fibroblastos/patología , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Regulación de la Expresión Génica/inmunología , Antígenos HLA/genética , Antígenos HLA/inmunología , Antígenos HLA-G , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Interleucina-10/inmunología , Interleucina-10/metabolismo , Lipopolisacáridos/inmunología , Lipopolisacáridos/metabolismo , Masculino , Persona de Mediana Edad , Osteoartritis/genética , Osteoartritis/metabolismo , Osteoartritis/patologíaRESUMEN
Human leucocyte antigen-G (HLA-G) is a nonclassical HLA class I molecule observed for the first time in human cytotrophoblast. Several investigations have demonstrated the presence of soluble HLA-G in oocyte/embryo secretome. A focus on the possible role of HLA-G in oocyte/embryo context will be developed in this review. In addition, the possible use of HLA-G in assisted reproductive technology will be treated.
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Embrión de Mamíferos/metabolismo , Líquido Folicular/metabolismo , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Oocitos/metabolismo , Receptores Inmunológicos/metabolismo , Embrión de Mamíferos/inmunología , Femenino , Líquido Folicular/inmunología , Antígenos HLA/inmunología , Antígenos HLA-G , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Relaciones Materno-Fetales , Oocitos/inmunología , Receptores Inmunológicos/inmunología , Receptores KIR2DL5RESUMEN
PROBLEM: Human Leukocyte Antigen (HLA)-G is a class Ib gene located in the human major histocompatibility complex (MHC). Several lines of investigation indicate that the HLA-G molecule is involved in the maternal acceptance of the semi-allogenic fetus during pregnancy and in the development of tolerance. Expression of soluble HLA-G (sHLA-G) is positively correlated with successful in vitro fertilization (IVF) treatments, and aberrant expression of HLA-G in certain complications of pregnancy, such as pre-eclampsia and spontaneous abortion, has been reported. The main purpose of this study was to investigate the levels of different soluble HLA-G isoforms in maternal plasma in early and late pregnancy. METHOD OF STUDY: Soluble HLA-G (sHLA-G) can be detected in maternal blood, and in this study, two different isoforms of sHLA-G, namely sHLA-G1 generated by shedding of membrane-bound HLA-G1 and HLA-G generated by specific HLA-G transcripts, have been investigated early [median of 16.4 weeks of gestation (GW)] and late (median: 38.9 GW) in pregnancy in an original cohort of 580 pregnant Caucasian women. RESULTS: Lower concentrations of sHLA-G1 were found late in pregnancy (>32 GW) in a group of women with severe pre-eclampsia compared with controls with uncomplicated pregnancies (P = 0.029, P(C) = 0.09; Mann-Whitney; Logistic regression analysis: P = 0.024, OR = 0.920, 95% CI: 0.855-0.989). However, this was not the case with HLA-G5, and significantly more of the cases with severe pre-eclampsia had detectable plasma HLA-G5 compared with that of the control group (P = 0.013, P(C) = 0.04; Mann-Whitney). Similar findings were not observed in women with gestational hypertension or existing hypertension continuing into pregnancy. Furthermore, there was a trend toward lower maternal plasma sHLA-G1 in a group of women with premature birth (<37 GW) compared with that of the control group (P = 0.028, P(C) = 0.17; Mann-Whitney). On the contrary, HLA-G5 was lower in the control group compared with that in the premature group (P = 0.004, P(C) = 0.02; Mann-Whitney). CONCLUSION: This study shows in line with other published studies that a high, detectable soluble HLA-G concentration in maternal plasma or serum is not mandatory for a successful pregnancy. However, complications during pregnancy, such as (severe) pre-eclampsia, spontaneous abortion, IUGR, and premature birth, are associated with a low or undetectable level of soluble HLA-G in the maternal blood circulation. Also, this study indicates that sHLA-G1 is the interesting soluble HLA-G isoform in pre-eclampsia, and that low or undetectable levels of HLA-G5 at the end of pregnancy seem to be associated with an uncomplicated normal pregnancy, whereas in severe pre-eclampsia and possibly other pregnancy complications, such as preterm birth and IUGR, the level of HLA-G5 is higher.
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Antígenos HLA/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Hipertensión/inmunología , Preeclampsia/inmunología , Complicaciones Cardiovasculares del Embarazo/inmunología , Nacimiento Prematuro/inmunología , Adulto , Estudios de Cohortes , Femenino , Regulación de la Expresión Génica , Edad Gestacional , Antígenos HLA/genética , Antígenos HLA/inmunología , Antígenos HLA-G , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Hipertensión/sangre , Hipertensión/fisiopatología , Tolerancia Inmunológica , Preeclampsia/sangre , Preeclampsia/fisiopatología , Embarazo , Complicaciones Cardiovasculares del Embarazo/sangre , Complicaciones Cardiovasculares del Embarazo/fisiopatología , Nacimiento Prematuro/sangre , Nacimiento Prematuro/fisiopatología , Factores de TiempoRESUMEN
Biologic and clinical interest in human mesenchymal stromal cells (hMSC) has risen over the last years, mainly due to their immunosuppressive properties. In this study, we investigated the basis of immunomodulant possible variability using hMSC from different sources (amniotic membrane, chorion, and bone marrow from either healthy subjects or patients with hematological malignancies, HM) and having discordant positivity for several immunological markers. The CD90+ hMSC reduced lymphoproliferative response in phytohemagglutinin (PHA) activated peripheral blood mononuclear cells (PBMC) via sHLA-G and IL-10 up-modulation. On the contrary, hMSC showing a significantly lower expression for CD90 antigen, elicited a lymphoproliferative allogeneic response in PHA/PBMCs without any increase in soluble HLA-G and IL-10 levels. These data seems to suggest that CD90 molecule may be considered a novel predictive marker for hMSC inhibitory ability, and might cooperate with HLA-G molecule in regulating suppressive versus stimulatory properties of hMSC. These results may have clinical implication in either transplantation or in regenerative medicine fields.
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Tolerancia Inmunológica/inmunología , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/metabolismo , Antígenos Thy-1/análisis , Antígenos Thy-1/metabolismo , Adulto , Células Cultivadas , Técnicas de Cocultivo , Femenino , Citometría de Flujo , Antígenos HLA/inmunología , Antígenos HLA-G , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Masculino , Persona de Mediana Edad , Antígenos Thy-1/inmunologíaRESUMEN
HLA-G antigens are non classical HLA-class I molecules characterized by a low allelic polymorphism, a limited tissue distribution and the presence of membrane bound and soluble isoforms. The HLA-G antigens were firstly detected in cytotrophoblast cells at the feto-maternal interface where they maintain a tolerogenic status between the mother and the semiallogenic fetus. Recently a variable expression of HLA-G molecules has been documented in several autoimmune diseases, viral infections, cancer diseases and transplantation. Overall the presence of HLA-G molecules in both membranes bound and soluble isoforms was associated with tolerogenic functions against innate and adaptative cellular responses. HLA-G antigens are able to affect the cytotoxicity of natural killer and CD8+ T cells, CD4+ T lymphocyte functions and dendritic cell maturation. In addition to the allelic polymorphism the HLA-G gene shows a deletion/insertion polymorphism of a 14 base pairs sequence (14bp) in the exon 8 at the 3' untranslated region. Several reports have associated the presence of the 14bp insertion allele (+14bp) to an unstable mRNA and a lower sHLA-G protein production, suggesting a different ability to counteract inflammation between genotypes. We reviewed the literature on the expression of HLA-G antigens in autoimmune and allergic diseases and the possible functional role of these molecules in counteracting inflammation.
Asunto(s)
Antígenos HLA/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Tolerancia Inmunológica/inmunología , Inflamación/inmunología , Subgrupos Linfocitarios/inmunología , Trofoblastos/inmunología , Alelos , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Asma/inmunología , Asma/metabolismo , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Exones , Enfermedades Gastrointestinales/inmunología , Enfermedades Gastrointestinales/metabolismo , Antígenos HLA/sangre , Antígenos HLA/genética , Antígenos HLA/metabolismo , Antígenos HLA-G , Antígenos de Histocompatibilidad Clase I/sangre , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Inflamación/metabolismo , Subgrupos Linfocitarios/metabolismo , Isoformas de Proteínas/inmunología , Isoformas de Proteínas/metabolismo , ARN Mensajero/inmunología , ARN Mensajero/metabolismo , Piel/inmunología , Piel/metabolismo , Trofoblastos/metabolismoRESUMEN
OBJECTIVE: Methotrexate (MTX) represents the antirheumatic drug mainly used in rheumatoid arthritis (RA). HLA-G antigens are inducible nonclassical major histocompatibility complex class Ib molecules important for maintaining anti-inflammatory conditions. The HLA-G gene is characterized by a deletion/insertion polymorphism of 14 bp that controls specific mRNA stability and protein levels. It has been reported that MTX therapy mediates an increase of interleukin-10-producing cells. This cytokine up-regulates HLA-G expression. For this, we tested the hypothesis of an MTX-mediated HLA-G production and the possible relationship with the HLA-G 14-bp polymorphism. METHODS: Peripheral blood mononuclear cells from healthy individuals and non-MTX-treated RA patients were activated with different MTX concentrations, and soluble HLA-G (sHLA-G) and interleukin-10 production was investigated by specific immunoenzymatic assay. HLA-G 14-bp polymorphism genotyping was performed in healthy individuals and RA patients, defined as 'responders' and 'nonresponders' to the MTX therapy. RESULTS: MTX activation induces the production of sHLA-G molecules. A significant association was observed between the highest sHLA-G1 concentrations and the -14/-14 bp genotype. The analysis of the HLA-G 14-bp polymorphism in MTX-treated RA patients has confirmed an increase of the -14/-14 bp genotype in the responder group (chi=6.12, P=0.02; chi test) (odds ratio=2.46 (95% confidence interval, 1.26-4.84) P=0.009; logistic regression model). CONCLUSION: Our results propose that the MTX induces the production of the anti-inflammatory sHLA-G molecules that concur with the therapy response. Furthermore, the association between -14/-14 bp genotype and MTX clinical outcome proposes this polymorphism as a therapy marker in the early phases of the disease.