Approach targets autoimmunity

NIH | AUGUST 9, 2016

In people with pemphigus, the cells in the top layer of the skin and the mucous membranes come under immune attack. The immune system mistakenly produces antibodies against proteins known as desmogleins. These proteins help keep skin cells attached and the skin and mucous membranes intact. When desmogleins are attacked, the cells separate from each other and fluid collects in the spaces, forming blisters.

A colorized scanning electron micrograph of a T cell. Image credits: NIH's National Institute of Allergy and Infectious Diseases (NIAID)

The most common type of pemphigus is pemphigus vulgaris. It arises when B cells make antibodies to desmoglein-3 (Dsg3, also known as keratinocyte adhesion protein).

Pemphigus can be treated with drugs that suppress the immune system or that specifically deplete B cells. However, these approaches can leave the body vulnerable to deadly infections.

A team of researchers at the University of Pennsylvania aimed to develop a more selective technique by adapting an emerging approach used to fight cancer. In that approach, immune system T cells are collected from patients and genetically engineered to produce special receptors on their surfaces that recognize a specific protein on tumor cells and attack the cancer.

In pemphigus vulgaris, B cells make specialized receptors that recognize and target the Dsg3 protein. The researchers reasoned they could genetically engineer T cells to express portions of Dsg3, and thus specifically destroy the miscreant B cells without affecting the rest of the immune system.

The team showed in laboratory experiments that human T cells engineered to express portions of Dsg3 killed anti-Dsg3 B cells derived from people with pemphigus vulgaris. The team tested the engineered T cells in a mouse model of pemphigus vulgaris. The engineered cells eliminated anti-Dsg3 B cells from the animals and prevented blisters from forming without any detectable side effects.

With further development, this approach could potentially be used for any autoimmune disease caused by misdirected antibodies.

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