Myron Gordon Award paper: Microbes, T‐cell diversity and pigmentation

Abstract

Melanocytes are static, minimally proliferative cells. This leaves them vulnerable in vitiligo. Yet upon malignant transformation, they form vicious tumors. This profound switch in physiology is accompanied by genetic change and is driven by environmental factors. If UV exposure in younger years supports malignant transformation and melanoma formation, it can likewise impart mutations on melanocytes that reduce their viability, to initiate vitiligo. A wide variety of microbes can influence these diametrically opposed outcomes before either disease takes hold. These microbes are vehicles of change that we are only beginning to study. Once a genetic modification occurs, there is a wide variety of immune cells ready to respond. Though it does not act alone, the T cell is among the most decisive responders in this process. The same biochemical process that offered the skin protection by producing melanin can become an Achilles heel for the cell when the T cells target melanosomal enzymes or, on occasion, neoantigens. T cells are precise, determined, and consequential when they strike. Here, we probe the relationship between the microbiome and its metabolites, epithelial integrity, and the activation of T cells that target benign and malignant melanocytes in vitiligo and melanoma.

Understanding of Pathomechanisms and Clinical Practice for Vitiligo

“…Although the pathophysiology has not been completely elucidated, recent studies have clarified it in both mouse and human settings. Mainly in non-segmental vitiligo, based on the genetic background including genes alteration, i.e., single nucleotide polymorphisms, related to melanocyte fate and HLAs haplotype 10 in addition to environmental factors like dysbiosis and a high fat/salt diet triggering proinflammatory conditions 9 , the following compound steps are involved in the vitiligo pathogenesis: 1) damage to melanocytes due to oxidative stress, such as reactive oxygen generated in the process of melanin synthesis; 2) decreased function of melanocytes or melanocyte stem cells; 3) cytotoxic autoimmune responses to melanocytes; and 4) melanocytes in vitiligo patients being inherently vulnerable to oxidative stress. In association with these processes, melanocytes and/or melanocyte stem cells eventually disappear as a complication of these processes and vitiligo lesions are expanded or maintained without repigmentation.…”

“…Interestingly, recent reports indicate that the age of onset of vitiligo has increased between 1970 and 2004, with a biphasic onset peak in adult vitiligo 7 . It has been noted that spouses of patients with vitiligo have a 1.89- to 1.96-fold higher risk of developing vitiligo 8 ; therefore, in addition to genetic background factors, the influence of living environment factors may be involved in the development of modern vitiligo 9 .…”

Benign tumors in TSC are amenable to treatment by GD3 CAR T cells in mice

“…We observed overexpression of GD3 in LAM, wherein mutations in TSC1 or TSC2 are responsible for tumor development ( 16 ). In LAM, however, multiple options for antigen-specific immune targeting exist as pulmonary lesions express melanogenic enzymes that are immunogenic in vitiligo and melanoma ( 17 , 18 ). In TSC, the additional challenge remains to identify a target molecule expressed by lesions in every location, while engaging a therapeutic with the potential to overcome immune privilege ( 19 ).…”