HMS Researchers Discover Key Protein in Activating Autoimmune Responses

Harvard Medical School scientists have identified a key protein in the human immune system that drives inflammatory and autoimmune conditions when it turns against the body.

The protein, Granzyme K, can cause the body’s protective system to attack its own tissues, which leads to severe tissue damage and inflammation once it’s expressed. A new study published in Nature last month dentified the protein’s unique immune activation strategy, opening up new therapeutic targets for autoimmune diseases.

Carlos A. Donado — lead study author and instructor at HMS — said that recent experiments show that Granzyme K has the ability to both recognize invaders and initiate cleavage of invading proteins, which becomes a problem when it recognizes molecules present in the cells and tissues it is supposed to be protecting.

“Granzyme K, we find, actually recognizes these sugar molecules that are present on our own cells, on our own tissues,” Donado said. “When it binds those, it actually by itself starts cleaving the components, cutting those proteins that are involved in the complement system, and generating the same mediators that will usually generate in response to detection of the microbes.”

Donado and his team first became interested in the role of this protein after noticing that Granzyme K is produced in patients with a chronic inflammatory disease — such as rheumatoid arthritis synovium — a major focus of the Brenner Laboratory at Brigham and Women’s Hospital where Donado works. Donado then compared the structure of Granzyme K to other proteins in the body to hypothesize its function.

“I compared the structure, the protein structure Granzyme K, to the structure of all the proteins that we have structures for in humans,” Donaldo said. “It turned out that the proteins that Granzyme K was most closely related to are proteins that activate what we call the complement system.”

Researchers pulled cells from synovial fluid to understand the enzyme’s function. They found that it cleaves C2 and C4 — two important proteins in the complement system — into fragments that bind together to form an essential component in eventual pathogen destruction.

Prior to this discovery, there were only three known major ways that the complement system could be activated. According to Donado, this is the fourth.

“That’s the significance of this discovery. This complement system has been known for about 125 years now, and over those years — over a century now — we’ve known there are three ways of activating,” Donaldo said. “Now, we’ve discovered a fourth one.”

Researchers then used mice to show Granzyme K’s impact in two inflammatory diseases — rheumatoid arthritis and psoriasiform dermatitis — where mice without Granzyme K experienced fewer symptoms of the diseases.

“There’s much less inflammation, much less disease severity, but also much less complement activation, and so we think that this pathway is actually active in the mouse as well as the human but also acts across multiple diseases,” Erin M. Theisen, co-author of the study and HMS instructor, said.

Theisen said that this discovery provides new pathways for autoimmune treatments that target Granzyme K.

“There are plenty of inhibitors and treatments targeting the complement cascade,” Theisen said. “But they have significant side effects — and in particular, infectious side effects — because you're blocking one of the main roles of the complement system, which is preventing infections,” Theisen said.

“We think that if we target Granzyme K specifically, the rest of the complement pathway should remain functional,” she said.