RESUMO
In vitiligo, cutaneous depigmentation is accompanied by increased T cell cytolytic activity targeting melanocytes, indicating that autoimmune tolerance is disrupted. The inhibited amount and function of Tregs have been indicated to be involved in the autoimmune intolerance in vitiligo, however, with the conclusion still controversial and the involved mechanism unknown. In this study, we explored the molecular and cellular alterations accounting for the impaired Treg response in vitiligo. Our results showed that the amount of Tregs was drastically reduced in peripheral blood of active vitiligo patients. Furthermore, the immunoregulatory function of Tregs was attenuated, with lower expression of CTLA4, IL-10 and TGF-ß. Moreover, the expression of HO-1, a functional modulator of Tregs, was decreased in vitiligo Tregs, and the concentrations of HO-1 metabolites, including bilirubin, CoHb and iron, were correspondingly decreased in serum of vitiligo patients. In addition, we treated the Tregs from vitiligo patients with Hemin, an agonist of HO-1, and found that enhanced HO-1 expression restored the function of Tregs by up-regulating IL-10 expression. Our study demonstrates the essential role of HO-1 in the impaired Treg response in vitiligo and indicates the potential of HO-1 as a therapeutic target in vitiligo management.
Assuntos
Antígeno CTLA-4/genética , Heme Oxigenase-1/genética , Interleucina-10/genética , Melanócitos/imunologia , Linfócitos T Reguladores/imunologia , Vitiligo/genética , Adolescente , Adulto , Idoso , Bilirrubina/sangue , Bilirrubina/imunologia , Antígeno CTLA-4/imunologia , Carboxihemoglobina/imunologia , Carboxihemoglobina/metabolismo , Progressão da Doença , Feminino , Regulação da Expressão Gênica , Heme Oxigenase-1/imunologia , Hemina/farmacologia , Humanos , Tolerância Imunológica , Interleucina-10/imunologia , Ferro/sangue , Ferro/imunologia , Contagem de Linfócitos , Masculino , Melanócitos/patologia , Pessoa de Meia-Idade , Cultura Primária de Células , Índice de Gravidade de Doença , Transdução de Sinais , Pele/imunologia , Pele/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia , Vitiligo/imunologia , Vitiligo/patologiaRESUMO
An anti-hemoglobin antiserum obtained from a sheep immunized with human carboxyhemoglobin A0 demonstrated little difference in its reactivity with deoxy- or carboxyhemoglobin A0. However, a subpopulation of this antiserum isolated by synthetic peptide affinity chromatography clearly distinguished between these two hemoglobin species. This subpopulation, designated alpha(129-141) anti-hemoglobin antibodies, represents less than 1% of the total anti-hemoglobin antibodies. They are nonprecipitating by Ouchterlony analysis, and fluorescence-quenching studies demonstrate the interaction of a single antibody binding site per hemoglobin dimer. These antibodies bind preferentially to carboxyhemoglobin with a median affinity constant of 5 X 10(8) M-1 compared to binding to deoxyhemoglobin with a binding affinity of less than 1 X 10(8) M-1. Furthermore, the presence of these antibodies in stoichiometric amounts increases the oxygen affinity of hemoglobin, and thus antibody and oxygen binding to hemoglobin can be considered as a linked function.
