Autoimmune Mechanism Causing Vitiligo
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Autoimmune Mechanism Causing Vitiligo
Vitiligo is an Acquired Skin Depigmenting disorder characterized by the loss of Melanocytes, Exocrine cells, from basal layer of the Epidermal and the matrix portion of the hair bulb. Vitiligo is defined clinically by expanding areas of well-circumscribed, milky white, cutaneous macules on the skin surface due to the destruction or inactivation of epidermal Melanocytes. It affects all races and occurs in 0.3-1.0% of the world population, and in 50% of cases the condition begins before the age of 20 years. More women than men are referred with Vitiligo, although the incidence of the disorder is not believed to be sex-linked. Vitiligo is not a physically debilitating disease; other than an increased sensitivity to UV radiation, most of the disease’s effects are social and psychological, especially for dark-skinned races (Ref.1).

There are two commonly recognized forms of Vitiligo: Nonsegmental and Segmental, and classification relies on the distribution of hypopigmented lesions. In segmental Vitiligo the areas of depigmentation are random and often occur on just one location on the body. Segmental Vitiligo is also sometimes marked with the loss of Melanocytes from the hair follicles and a loss of hair pigment. Segmental Vitiligo is less likely to repigment than non-segmental Vitiligo; however it is also less likely to spread to other areas of the body. Non-segmental Vitiligo is characterized by depigmented macules involving both sides of the body in a remarkably symmetrical pattern. It often does not affect the hair follicles in the areas of depigmentation. Non-segmental Vitiligo often gets progressively worse, spreading to more areas of the body over time (Ref.2).

The exact etiology of Vitiligo is unknown, but four main theories exist to explain it: the Autoimmune hypothesis, the Neural hypothesis, the Self-destruct hypothesis, and the Growth Factor Defect hypothesis. None of these mechanisms are conclusively proven. It is believed that Vitiligo is a polygenic trait and that a Convergence theory, combining elements of different theories across a spectrum of expression is the most accurate etiology. In a number of recent studies, strong evidence in favor of the Autoimmune hypothesis has been obtained. The Autoimmune model proposes that Melanocytes death occurs through inappropriate immune system destruction of pigment cells. Both Cellular and Humoral immunity co-operate in the destruction of Melanocytes. The association of Vitiligo with other known Autoimmune disorders such as Addison’s Disease, Hashimoto’s Thyroiditis, Pernicious Anemia and Alopecia Areata also supports the Autoimmune theory of disease (Ref.3).

Antigens produced by Melanocytes (including those released from damaged Melanocytes) can be recognized by Antigen-specific immune effector cells including Cytotoxic T-cells, T-Helper cells and B-cells. Recognition of Melanocyte Antigens might also arise through cross-reaction from immune responses to other cell types or infectious agents. The presence of Lymphocytes as well as Autoantibodies significantly decreases the number of living Melanocytes, illustrating the role of cellular immunity by Antibody-dependent cellular cytotoxic reaction. A simultaneous increase of LMIF (Leukocyte Migration Inhibition Factor) by activated T-cells and circulating Igs (Immunoglobulins) and immune complexes occur as a result of T-Cell mediated B-cell activation during Vitiligo. The principle antigen recognized by these Autoantibodies is Tyrosinase. Other Melanocyte differentiation Antigens that are recognized are Gp100/Pmel17, and TRP1 (Tyrosinase-Related Proteins-1) and TRP2 (Tyrosinase-Related Proteins-2). These antigens localize primarily to the Melanosomes, whereas it is a well-established fact that Antibody-mediated killing requires membrane expression of the target antigens. If the immune system raises Antibodies or Cytotoxic T-Cells to damage Melanocytes, the mode of action the cells take against the Melanocytes can be a direct induction of apoptosis against Melanocytes or Ig induced Complement (Ref.4).

In Cell-mediated immunity, after processing of Antigens by APC (Antigen-Presenting Cells), Antigenic peptides are presented to the TCR (T-Cell Receptors) of CTLs (Cytotoxic T-Lymphocytes) in the context of MHC-I (Major Histocompatibility Complex Class I) molecules. Majority of these T-cells also expressed the cytotoxic effector molecules Perforin and Granzyme. CD8+ CTL plays an important role in immune-mediated destruction of autologous Melanocytes. However, cellular cytotoxicity against Melanocyte differentiation antigens may not be solely dependent on MHC Class-I restricted T cells. The in vivo activation of such CD4+ CTL may occur when professional APC, after endocytosis of dying Melanocytes, migrate to skin-draining lymph nodes to present peptides derived from Melanosomal Antigens. However, actual killing of Melanocytes by MHC Class-II restricted CTL also requires that target cells present endogenous Melanosomal proteins in the context of MHC Class-II molecules. Cognate help (via Cytokine production) by Antigen-specific T-Helper cells, in the context of Antigenic peptides presented on MHC Class-II molecules, is required for a long-lasting Cytotoxic T-cell response against Melanocytes that can lead to their destruction. The major cytokines involved in coagnate help include IL-2R (Interleukin-2 Receptor) , IL-6 (Interleukin-6) and IL-8 (Interleukin-8). IL-6 can induce the expression of ICAM1 (Intercellular Adhesion Molecule-1) on Melanocytes, which facilitates Leukocyte-Melanocyte interaction, leading to immunological damage of the pigment cells. IL-8 may attract Neutrophils to Vitiligo lesions, which could lead to the amplification of inflammatory reactions and the destruction of Melanocytes (Ref.5).

The Humoral immune reaction has been implicated through the detection of circulating antibodies. The Antigen-specific membrane Igs of B-Cells captures antigens. The production and secretion of Antigen-specific Antibodies by B-Cells are also dependent on cognate help (via Cytokine production) by antigen-specific T-helper cells. Anti-Melanocyte antibodies can destroy pigment cells by either antibody-dependent Complement-mediated damage or ADCC (Antibody-Dependent Cell-mediated Cytotoxicity) (Ref.6). Autoimmune hypothesis of Melanocyte destruction is further appreciated by the current clinical practice of Vitiligo management; all of the nonsurgical Vitiligo treatments with proven efficacy are based on immunosuppression. Thus, future investigations in Vitiligo etiology would focus on finding the exact conditions that trigger and sustain this Melanocyte-specific Autoimmune response. Establishing the triggers that awaken this latent mechanism in Vitiligo will not only benefit patients with this Autoimmune disease, but may also be of considerable importance for Melanoma therapy, where an effective immune response against Melanocyte differentiation Antigens is lacking (Ref.7).