Autoimmune disease researchers find immune cells escape treatment due to ‘exhausted’ state

In autoimmune diseases, the immune system mistakenly attacks the body’s own structures. A team of researchers from Kiel, Lübeck and Berlin has succeeded in analyzing certain pathogenic immune cells more precisely using a method they developed.

They discovered that these cells can sometimes go into a dormant (“exhausted”) state for years, making them inaccessible to existing therapeutic approaches. If the cells then return to an active state, they trigger other immune cells that attack the body’s own structures and thus restart the disease.

The interdisciplinary research team, which included many members of the “Precision Medicine in Chronic Inflammation” (PMI) cluster of excellence, recently published its results in Immunity.

Dormant autoreactive immune cells

The researchers analyzed blood samples from patients with one of three autoimmune diseases for which the structures against which the immune system is directed are known. Using a method they developed (antigen-reactive T-cell enrichment, ARTE), they were able to selectively enrich and analyze the rare autoreactive immune cells among the many different immune cells present in the blood. These are cells that react incorrectly to the body’s own structures, trigger inflammation and cause other immune cells to attack the body’s own structures.

“Until now, it was assumed that these cells were chronically activated in autoimmune diseases and thus caused inflammation,” explains first author Dr. Carina Saggau from the Institute of Immunology at Kiel University and the University Medical Center Schleswig-Holstein (UKSH), Kiel campus.

“But we have now been able to show that, surprisingly, some of them are in a dormant state, scientifically called ‘exhausted’, and in some cases circulate in the blood in this state for years.” This dormant state is known from tumor research: in tumors, the immune cells that should fight the tumor are in this state and thus allow the tumor to grow unhindered.

“In the autoimmune diseases we study, we believe that chronic activation by the body’s own structure leads to a kind of ’emergency shutdown’ after a certain period of time. The body needs a mechanism to switch off cells that are permanently activated,” explains Professor Alexander Scheffold, Director of the Institute of Immunology and member of the PMI Cluster of Excellence “Precision Medicine in Chronic Inflammation”.

The immunologist led the interdisciplinary research work in collaboration with neuroimmunologist PD Frank Leypoldt from the Institute of Clinical Chemistry at UKSH, Kiel campus, and Professor Friedemann Paul from the Experimental and Clinical Research Center at Charité, Berlin.

Reactivation of dormant cells leads to new disease flare-ups

In autoimmune diseases, the dormant state also means that these cells escape the usual therapies aimed at suppressing the over-reactive immune system. This means that the therapy often works and suppresses the symptoms of the autoimmune reaction, but some of the pathogenic T cells survive the dormant state. If some of the dormant cells are reactivated, probably by infections or environmental factors, they can reactivate the entire disease process. Those affected then experience a new flare-up of the disease.

“This observation explains why current therapies do not offer lasting protection against relapses,” says Dr. Frank Leypoldt, also a member of the PMI Cluster of Excellence. “At the same time, they open up new avenues for more targeted therapies. For example, we could try to selectively attack dormant cells with therapies specifically designed for them and thus treat the disease more effectively, sustainably and precisely. Alternatively, based on existing approaches in tumor medicine, the cells could be reactivated in order to better target them therapeutically.”

The observations are also important for better understanding the underlying mechanisms of the disease, Scheffold emphasizes. “We have now demonstrated the connections in three model diseases for the first time. We would then like to investigate in which other inflammatory diseases we find this pathology in order to better understand what is behind the different diseases. This is the only way to enable specific treatment of the respective causes of the disease in the sense of true precision medicine,” Scheffold explains.

About the ARTE method

In a blood sample, only one in a hundred thousand T cells reacts against the specific autoantigen (i.e. the body’s own molecule against which the immune system is directed in autoimmune diseases). Professors Petra Bacher and Alexander Scheffold from the PMI Cluster of Excellence have developed the so-called “antigen-reactive T cell enrichment” (ARTE) in order to be able to study these rare cells.

The method involves briefly exposing blood cells to the antigen in a test tube. The antigen-specific T cells are thus activated and can be labeled with magnetic particles using “activation markers”. Using magnetic separation columns, these rare T cells are then filtered from a larger quantity of blood and analyzed.

Provided by Exzellenzcluster Präzisionsmedizin für chronicle Entzündungserkrankungen