• #2-1. The Etiology of Vitiligo: Autoimmune Theory and Neurohumoral Theory


    ▶ Previous Artlcle : #1-2. Vitiligo Treatment


    Following the previous article, let’s have a look at the etiology of vitiligo.

    2) Autoimmune theory. It is well known that the immune system plays a major role in melanocyte destruction. The prognosis of hypochromatism better in patients with malignant melanoma signifies that the induction of hypochromatism and a combat with the malignancy occur by common immune reaction against melanocyte. Vitiligo that appears after bone marrow transplantation or lymphocyte injection for the treatment of leukemia is also the evidence demonstrating the involvement of the immune system.


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    ① Humoral immunity. Serum antibodies in patients with vitiligo are classified into cell surface antigens and intracellular antigens of melanocytes, and antigens not related to melanocytes. Cell surface antigens have molecular weights of 35, 40, 75, 90 and 150 kDa, of which 40, 75 and 90 kDa are observed more frequently and 30 and 150 kDa less frequently. In particular, antigens with molecular weights of 40, 75 and 90 kDa are positive in 93% of patients with vitiligo, which is significantly different from 7% positivity in controls. Antigens with molecular weight of 90 kDa are observed solely on the surface of melanocytes, unlike 40 and 75 kDa antigens present also in ordinary cells. However, since melanocytes are more vulnerable to damages by toxic materials or immune response compared to keratinocytes or fibroblasts, melanocytes can be fatally damaged while surrounding cells are intact.

    Tyrosinase and tyrosinase-related proteins 1 and 2 (TRP-1, TRP-2) present in melanosome play a vital role in melanin synthesis. As the proportion of vitiligo patients who have antibodies to these proteins widely varies across studies, the role of these antibodies in disease development is still unclear. Antibodies to SOX9 and SOX10, the transcription factors related to the differentiation of cells derived from the neural crest, have recently been found in patients with autoimmune polyendocrinopathy syndrome type 1 and vitiligo patients without comorbidity, which are thought to play an important role in the pathogenesis of vitiligo.

    There is also a direct correlation between disease activity and antibody. When the serum from patients with vitiligo was added to melanocytes, melanocytes were found to be damaged by both complement activation and antibody-dependent cellular immunity.

    ② Cellular immunity. Cellular immunity change is also observed in vitiligo and is thought to work in combination with humoral immunity reaction. Even the normal-appearing skin around lesions involve degenerative changes of melanocytes, including vesicular degeneration of the basal cell layer, lymphocyte infiltration and melanophages in the dermal layer. These changes are prominent in the areas in which the lesions are more diffusible. The CD8/CD4 ratio is increased in the skin around lesions and a large number of T cells expressing recurrent cutaneous lymphocyte antigen (CLA) infiltrate the perimeter of damaged melanocytes in the epidermis. These T cells express CD25 and major histocompatibility complex II, particularly HLA-DR, and release interferon gamma to induce additional migration of T cells to the skin. Melan-A-specific CLA+ and CD8+ T cells are observed in the blood of patients with vitiligo, and their numbers correspond to the disease intensity.

    3) Neurohumoral theory. Local or systemic nervous system dysfunction may be the cause of melanocyte damage in vitiligo. Melanocytes and nerve cells are originated from the neural crest. Segmental vitiligo develops along the innervation and accompanies the change in the control of perspiration. Immunochemical staining showed increased neuropeptide Y in vitiligo lesions and the perimeter. Increased norepinephrine and reduced activity of acetylcholine esterase in the sympathetic nerve have been observed in vitiligo lesions. These increased neurotransmitters induce cytotoxicity directly or indirectly through hypoxia from local vasoconstriction and resultantly produced H₂O₂. In addition to these local changes, there are evidences that nervous system dysfunction occurs systematically and vitiligo develops in such circumstances. Epinephrine and norepinephrine changes occur in the serum. Patients with progressive lesions have elevated metabolites, omovanillic acid and vanillmandelic acid, in their 24-hour urine. Since these neurotransmitters can be synthesized and released from both nerve endings and keratinocytes, it is still uncertain where those are exactly released from. High concentration of catecholamines increases the activity of catechol-o-methyltransferase in the lesion, which neutralizes neurotransmitters and produces harmful byproducts, causing cytotoxicity.


    -To be continued-


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