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].