Recent evidence suggests that oxidative stress, auto-immunity and melanocyte apoptosis are involved vitiligo. R

Essentially what happens in vitiligo is hyperactive T cells decide to target and kill melanocytes: R

Melanocytes have abnormally high levels of cellular stress, which can be caused by inherited factors, genetic factors, or both. Stressed melanocytes produce signals that activate innate immune cells to initiate inflammation that leads to autoimmunity. Innate immune signals recruit adaptive immune cells (primarily CD8+ T Cells) into the skin, which then find melanocytes and kill them, resulting in white spots, or depigmentation.

Innate Immunity

The innate immunity is the first line of "defense" against pathogens and immune problems. R

It can identify infectious agents through pattern recognition receptors (PRRs). R

PRRs responde to tissue injury by recognizing damage associated molecular patterns (DAMPs). R

Abnormal melanocytes release DAMPs that activate the innate immunity. R

Adaptive Immunity

The adaptive immunity involves T and/or B cells. R

They target specific proteins. R

In vitiligo, CD8+ T cells infiltrate the epidermis and kill melanocytes. R

IP-10 (The Master Switch)

IFN-g (Interferon gamma) is a cytokine that is important for the development of vitiligo. R

Many genes are turned on by IFN-g, so IFN-g may be a master switch for vitiligo. R

We need IFN-g for survival or we will die, since it helps with infection. R

IFN-g induces IP-10 (CXCL10). R

CXCL10 binds with CXCR3, which is found on melanocyte-specific CD8+ T cells, which cause vitiligo. R

IL-8

TH1 cells increase the expression of VEGF, by TH1 cells and mast cells. R

Mast cells then release inflammatory cytokines IL-6 and TNF-a.

NLP1 can also activate IL-1b. R

IL-1, IL-6 and TNF-a can stimulate IL-8 release. R

IL-8 is produced by monocytes, mast cells, fibroblasts, endothelial cells, dendritic cells and keratinocytes. It is chemotactic to neutrophils, T-cells, basophils and keratinocytes. R

IL-8 induces oxidative stress in the skin. R

IL-1 and TNF-a, released from mast cells, can also increase vitiligo lesions. R R

Things like phenols can induce the production of IL-8 (and IL-6), making vitiligo worse. R

Oxidative Stress

Melanocytes in vitiligo patients are abnormal. R

They get damaged by reactive oxygen species (ROS) and activate of the unfolded protein response. R

HSP70, a heat shock protein, and exosomes, secretes cell-derived nanoparticles, as potentially important signals that promote inflammation in vitiligo. R

Systemic oxidative stress in vitiligo patients may develop due to an imbalance in enzymatic and non-enzymatic antioxidant systems. R

This problem may be caused by low glutathione peroxidase and reduced glutathione, which may prolong hydrogen peroxide exposure. R

Also, in vitiligo patients, there has been shown decreased recycling levels of tetrahydrobiopterns. R

ROS can trigger the loss of dendrites of melanocytes, thus affecting melanosome transfer to surrounding keratinocytes. R

Oxidative stress can induce apoptosis in melanocytes by releasing caspase-activating cytochrome c from mitochondria. R

Neurotransmitters

Neurochemical mediators that are secreted by cutaneous axon terminals, such as norepinephrine (NE) and acetylcholine (Ach) are toxic to melanocytes. R

Melanocytes seem to have less acetylcholine esterase, the enzyme to break down acetylcholine. R

NE has direct melanocytotoxic effects by interfering with cellular sulfhydryl groups, impairing mitochondrial calcium uptake and inhibiting melanogenesis. R

Elevated levels of the NE degrading enzyme monoamine oxidase (MAO) in both melanocytes and keratinocytes can kill melanocytes. R

CD49a

Vitiligo is characterised by the accumulation of a subgroup of T cells called CD49a+, which recognise and are ready to kill pigment cells. R



In psoriasis, another kind of T cell, CD49a- accumulates in the afflicted skin and produces the inflammation-causing protein IL-17. R

In healthy skin, CD49a+ and CD49a cells are dormant, but quickly respond with inflammatory and cytotoxic effects when stimulated by IL-15, a protein secreted from skin cells as a rapid-response defence against microbial attack. R

More Inflammatory Pathways

Haptens can cause sensitization of skin cells, priming the immune system to react to chemicals.

Histamine can cause itching and stimulated the proliferation and migration of melanocytes and the vitiliginous keratinocyte survival. R R

IL-33 augments substance P (SP)-induced VEGF release from human mast cells. R

SP can stimulate TNF secretion from mast cells and a good correlation has been recently reported between serum TNF and the extent of vitiligo. R

Corticotropin releasing hormone (CRH) secreted under stress, can activate local mast cells to release pro-inflammatory mediators. R

This could potentially trigger the release of melanin degrading and pro-apoptotic molecules, rendering the stressed skin vulnerable to hypopigmentation. R

Melanocytes have been reported to express corticotropin releasing hormone receptor-1. R

CRH in the skin upregulates the synthesis and secretion of proopiomelanocortin (POMe) and its peptides, with POMC being an important regulator ofmelanogenesis. R

mRNA expression of POMC and its receptors, melanocortin receptor-1 (MC1R) and -4 (MC4R), is significantly decreased in lesional vitiligo skin, but increased in non-lesional vitiligo skin compared to healthy controls. R