Humoral Immunity in Vitiligo
Besides cellular immunity, humoral (antibody-mediated) immunity adds supportive evidence for a pathological role of autoimmunity in vitiligo.
Different antibodies to melanocytes have been identified at significantly elevated levels in the sera of vitiligo patients as opposed to healthy controls [108-111], and their levels are directly associated with the extent and activity of vitiligo [109, 112, 113], being present in 93% of patients with wider depigmentation (5-10% of skin area involved) and in only 50% of patients with minimal pigment loss (<2% of skin area involved) [114].
These anti-melanocyte antibodies belong to the immunoglobulin G (IgG) class [111], including subclasses IgG1, IgG2 and IgG3 [115], though IgA anti-melanocyte antibodies have also been detected [116].
Immunoprecipitation studies using melanocyte protein extracts have shown that antibodies in vitiligo patients are most frequently directed to antigens with molecular weights of 35, 40 to 45, 75, 90 and 150-kDa, these being found on the cell surface [117]. Some of these proteins, including those of 40-45, 75, and 150-kDa, appear to be common tissue antigens, whereas the 35 and 90- kDa proteins are preferentially expressed on melanocytes [118]. Additionally, other reports have identified vitiligo antibody targets of 45, 65, 70, 88, and 110-kDa, which are specifically expressed in melanocytes [119]. Various melanocyte-associated autoantigens have been reported. Antibodies against tyrosinase, a melanocyte-specific protein, have been extensively detected [120-122], as have antibodies against other proteins of the melanogenic pathway such as L-dopachrome tautomerase, TYRP1, PMEL, albeit at a low prevalence [123-125]. Considering this autoantibody response, rituximab, a monoclonal directed against CD20 protein expressed on the B cell surface, has shown promise in a small clinical trial in vitiligo patients [126]. A variety of circulating organ-specific antibodies against gastric parietal cells, pancreatic islet cells, thyroid and adrenal glands, are common in vitiligo patients’ sera, though these are not recognised as major melanocyte antigens [127]. Phage display technology has identified other targets such as melanin-concentrating hormone receptor 1, tyrosine hydroxylase, heat-shock protein 90, osteopontin, ubiquitin-conjugating enzyme, translation-initiation factor 2, GTP-binding protein Rab38, γ-enolase, α-enolase and lamin A [128-130], as well as four novel autoantigens glycoprotein non-metastatic melanoma protein b, melanocortin 1 receptor, OCA2-encoded P protein and GTP-binding protein Rab27A (unpublished data). Vitiligo-associated antibodies are capable of melanocytotoxicity in vitro and in vivo by complement-mediated cytotoxicity and by antibody-dependent cellular cytotoxicity [131, 132]. Melanin-concentrating hormone receptor 1 block the function of the receptor, though it is not known if this affects melanocyte function [133]. Melanocyte expressed of HLA-DR and intercellular adhesion molecule-1 (ICAM-1) induced by anti-melanocyte antibodies may make them a target for cytotoxic T cells [134]. Presently, it unclear whether melanocytes are a primary or secondary target of the humoral immunity in vitiligo. Autoantibodies might arise from a genetic susceptibility to immune dysregulation at the T or B lymphocyte level, with lack of tolerance to pigment cell antigens, or from an immune response against melanocytes damaged by other mechanisms, such as T cell destruction [135]. Repigmentation observed in vitiligo patients receiving immunosuppressive treatments supports the notion of an immune-mediated process in vitiligo [13]. Tacrolimus, a reagent that suppresses T cells by blocking cytokine gene-activating cofactor calcineurin works in vitiligo [136, 137], as do topical corticosteroids, which suppress T lymphocyte activity and B cell antibody responses [138]. Phototherapy, reduces the number of Langerhans cell in the skin and down regulates expression of vitiligo-associated melanocyte antigens [139].