Recent Study Published in Journal of Experimental Medicine Finds Targeting Myd88 Could Treat Systemic Lupus Erythematosus

A paper published in the Journal of Experimental Medicine in December 2023 demonstrates that targeting Myd88 or its upstream activators may be a viable therapeutic option for systemic lupus erythematosus (SLE).

Co-authors of the paper titled “B cell-intrinsic Myd88 regulates disease progression in murine lupus” include Jeremy Tilstra, MD, PhD, and Rachael Gordon, MD, PhD, from the UPMC Division of Rheumatology and Clinical Immunology, as well as collaborators from the University of Pittsburgh School of Medicine Departments of Immunology and Pathology.

Dr. Tilstra’s research at the UPMC Lupus Center of Excellence focuses on understanding basic signaling mechanisms leading to lupus nephritis, a condition that occurs often in patients with SLE.

“The need for further basic understanding of lupus nephritis is exemplified by the fact that only three new medications have been approved for lupus in the last 50 years and only two are indicated for lupus nephritis. Therefore, my work focuses on both immune cells and tissue signaling to better define this complex disease state,” says Dr. Tilstra. One specific focus is to evaluate the Myd88 in B cells as a mediator of disease in murine lupus.

Study Overview and Findings

Toll-like receptors (TLRs) particularly TLR7 and TLR9 are essential for the development of autoantibodies and driving disease, particularly in murine models of lupus, but likely also in human disease.

“There have been recent groundbreaking publications looking at TLR7 gain-of-function mutations in humans as a driver of lupus,” he says. “Toll-like receptors signal through a shared signaling pathway, mediated by Myd88. In many mouse models, we knockout a receptor and ask, ‘does it impact disease development?’ It's much easier to cure disease before it starts.”

Through the study, the team wanted to answer the question: “If we blocked a signaling pathway after disease onset, could we ameliorate disease?”

“We chose Myd88 because it's downstream of these two very important toll-like receptors and then using a specific, genetic model where we could knock out this signaling pathway after disease onset, we showed that not only disease significantly improved, but it also stopped disease in its tracks,” says Dr. Tilstra.

He explains that the mice developed antibodies, which plateaued after signaling through this pathway was blocked.

“We found improvement in immune function, autoantibody production, as well as disease endpoints,” says Dr. Tilstra. “The outstanding question was, ‘Are B cells and this signaling pathway important to initiate disease with unrestricted T-cells and other immune activation? Or do you need continued fuel to drive the inflammatory fire? Our findings would suggest that you really need these B cells to continually fuel disease and by targeting them, even late in disease, you can probably have therapeutic benefits.”

The Impact of CAR T-Cell Therapies for Autoimmune Diseases

When the research team knocked out this pathway, it wasn’t throughout the entire animal or even in all immune cells. It was in a specific cell type – the B cells.

“This is important because of the growing impact of CAR T-cell therapies for autoimmune diseases,” adds Dr. Tilstra. “CAR T-cells are a genetically engineered T-cell, previously used in cancer, to target B cell malignancies.”

According to Dr. Tilstra, a research group out of Germany published an article a last year showing they could put patients in remission by having these T-cells destroy the B cells.

“More clinical trials on lupus have been started in the past two years based on that study, than any other drug target in recent history. In light of that study, we now show that this specific signaling pathway is quite important in B cells,” he says. “It's coming at a nice convergence point where we now have shown in humans that B cells are a very important cell type in treating disease. In mice, we've already shown that B cells are important in promoting disease, but now we can show that it's this specific pathway in B cells. They can potentially achieve a new targetable approach.”

Dr. Tilstra adds that his team’s study has direct therapeutic implications based on their work.

“We showed while all the B cells were targeted, a specific type of B cells, antigen-associated B cells called age-associated B cells were impacted in our study and we think they play a significant role in the disease development,” he says.

Read the study.