Lupus research maps the path to personalized treatments

3D image of a T follicular helper (TFH) cell (yellow), interacting with a B cell (teal) in kidney tissue

3D image of a T follicular helper (TFH) cell (yellow), interacting with a B cell (teal) in kidney tissue

Lupus is a frustrating and bewildering disease, for both patients and doctors. A chronic autoimmune disorder, lupus can damage almost any part of the body, including the skin, joints and internal organs. It also presents itself in so many different ways that it often takes years for patients to be diagnosed properly and find effective treatments.

“What we call lupus is probably 50 different kinds of lupus, and they need to be treated in different ways,” said Marcus Clark, MD, Chief of the Section of Rheumatology at the University of Chicago. “How do you figure that out? You do it by understanding the pathogenic cellular and molecular mechanisms, or what’s causing the disease, in individual patients.”

Clark and his team at the Knapp Center for Lupus and Immunology Research have taken on the painstaking job of unraveling these mechanisms. They intend to narrowly classify the various types of lupus to provide more effective, personalized treatments.

Lupus, like other autoimmune disorders such as type 1 diabetes, celiac disease and rheumatoid arthritis, causes damage to the body when the immune system attacks and destroys healthy tissue instead of just fighting off invaders like viruses and bacteria.

Marcus Clark, MD

In lupus, this autoimmune response sometimes plays out to damage the kidneys. White blood cells dispatched by the immune system—both T cells, the warriors that attack directly, and B cells, the armament makers that hijack perceived “invaders” as they travel through the blood—congregate in the kidneys, where they can cause inflammation. These cells don’t act alone, though—they always interact in specific ways to cause inflammation. Other types of cells involved in the immune response can also cluster and interact, with similar patterns of damaging inflammation.

Clark and his colleagues are studying these patterns to pinpoint the source of inflammation. Using high definition 3D images of inflamed kidney tissue, they have been able to identify various subsets of cells prone to causing damage. Clark and his team have invented a novel mathematical approach—cell distance mapping—to measure how these different groups of cells are paired in the kidneys, in particular combinations and distances from each other. This new technique, documented in a paper in Science Translational Medicine last year, is already being cited in the work of other lupus investigators.

In the case of T cells and B cells, Clark and his team saw that the cells were always paired closely together in patients with more severe disease, interacting to cause inflammation. By applying this same approach to other cell populations, Clark intends to build a complete cell-to-cell network of immune responses in the kidney that cause the damaging effects of lupus.

“With a mathematical approach, we can assign numerically which interactions are more frequent, and which ones are more likely to be important,” Clark said. “Then we can compare inflammation in one patient to that of another, and come up with different subsets of patients.”

Within these subsets, Clark and other researchers can identify the biomarkers that identify the kind of lupus they have, and how it should be treated. For example, patients with one genetic marker might respond better to some medications than others, or may be at higher risk for certain complications.

“There are probably 30 or more genes that contribute to lupus, and there are a variety of mechanisms that lead to a disease state,” Clark said. “This method will allow us to dissect what pathogenic mechanisms play a role in individual patients, so we can personalize therapy and improve those patients’ lives.”

About Matt Wood (439 Articles)
Matt Wood is a senior science writer for the University of Chicago Medicine and editor of the Science Life blog.
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