Adaptive Immunity

Adaptive Immunity: Adaptive immunity describes immune responses that involve T and/or B cells, and target very specific proteins. Adaptive responses are slow to develop, but are highly potent, like a bloodhound catching the scent of a fugitive, and not giving up until he or she is found. A role for adaptive immunity in vitiligo is well-established. First, vitiligo associates with other autoimmune diseases in which adaptive immunity seems to play a role, like type 1 diabetes, autoimmune thyroiditis, alopecia areata, and pernicious anemia. Second, T cells, and in particular CD8+ “cytotoxic” T cells, infiltrate the epidermis and are found next to dying melanocytes in vitiligo. Third, melanocyte-specific CD8+ T cells are found at a higher frequency in the blood and skin of patients with vitiligo compared to healthy controls, and are capable of killing melanocytes directly. One group found that CD8+ T cells isolated from affected skin from vitiligo patients crawled into unaffected skin from that patient and killed melanocytes. Finally, genetic studies have found a number of genes that affect the risk of getting vitiligo, and a large number of these genes play major roles in adaptive immunity. These observations strongly implicate the adaptive immune system in vitiligo. 

Our own studies have focused on identifying cytokine pathways involved in promoting vitiligo, and how these pathways affect the migration of CD8+ T cells and their ability to target melanocytes for destruction. Using a mouse model of vitiligo that we developed, we found that the cytokine IFN-g is important for vitiligo to develop.

Cytokine IFN-g in Vitiligo Development Cytokine IFN-g in Vitiligo Development

In addition, we found that many of the other genes that are active in vitiligo skin are turned on by IFN-g. This suggests that IFN-g is an essential “master switch” that is turned on in the skin in vitiligo. Therefore, we hypothesized that turning off the IFN-g master switch would reverse the disease process and provide new treatments for vitiligo. However, consistent with the theme of IFN-g as a master switch, IFN-g in turn activates many additional switches that serve different purposes. One important purpose is control of infection, and mice and humans can die from certain infections if IFN-g is missing. We hypothesize that turning off the smaller switches downstream of IFN-g that are specifically responsible for vitiligo, while leaving on other switches important for infection control, is a better and safer strategy to develop new treatments.

We recently discovered that the IFN-g-induced chemokine CXCL10 is highly expressed in vitiligo patient skin and blood, and its receptor CXCR3 is found on melanocyte-specific CD8+ T cells, which cause vitiligo. Our mouse model revealed a similar pattern of expression, and in this model we found that we could both prevent and reverse vitiligo by treating the mice with an antibody that blocks CXCL10 signaling.  

Function of CXCL10 in Vitiligo Function of CXCL10 in Vitiligo

There are a number of pharmaceutical companies that have drugs that target the IFN-g-CXCL10-CXCR3 pathway, and we are hopeful that our studies will translate into a safe and effective new treatment for vitiligo soon.

We continue to explore this pathway to develop new and improved treatments for vitiligo.