Professor Recher, your research focuses on rare and unexplained disorders of the immune system. In a new publication, you report on a patient who spent years searching for an explanation for his symptoms. What was wrong with him?

The patient repeatedly suffered from peeling of the oral mucosa; similar to aphthous ulcers, but covering a larger area. He also suffered from chronic fatigue and joint pain and frequently had upper respiratory tract infections. I met him when I was a resident in allergology.

Why was the diagnosis so difficult?

He did not fit into the usual categories of autoimmune diseases or rheumatic conditions. There was no known history of such immune disorders among his parents or in his wider family. So we didn’t suspect that he had inherited anything. 

What do you do when faced with a case like this?

For those patients who are susceptible to infections and constantly feel fatigued, the first step is to take a blood test and measure their antibodies. As neither the blood count nor the antibody levels were abnormal in our patient, we took a closer look at the composition of his immune cells. Nowadays, we can analyze the subgroups of immune cells in great detail from a single blood sample. 

When did you realize something quite unusual might be happening here?

The only thing that stood out with him was that a very specific group of T cells was more abundant relative to other immune cells, a state that remained stable for years. We had no explanation for the abundance of these particular cells. It was clear that we were dealing with something as yet unknown. As part of our research, we then performed a genetic analysis of these specific T cells and compared them to the conventional T cells, which of course he also has. We were looking for differences in the genome sequence.

What did you find?

Only in these specific T cells did he have a mutation in a gene that regulates cell division and activation. The mutation caused these T cells to become overactive and to divide more frequently. This led us to the hypothesis that this mutation had occurred by chance in a precursor cell of this T-cell group. And these overactive T cells then disrupted the immune system to such an extent that he developed the symptoms in question. 

What’s so special about this case?

It is well known that genetic changes do not necessarily affect all cells of an organism. Experts refer to these as “mosaic mutations,” meaning that the body is like a mosaic of cells with localized differences in their genetic sequences. In most of the examples we know today, such mosaic mutations affect, for example, all T and B cells, or the group to which red blood cells, platelets and other white blood cells belong. For the first time, we show an in-depth immunological characterization of a mosaic mutation that affects only this single immune cell subgroup. 

You are describing the case history of a single patient. Are there more cases like this?

We suspect that many unexplained immune disorders could be attributed to such mosaic mutations. We are still in the early stages of exploring the field of these mosaic-like immune disorders. At the University Center for Immunology, we currently have a research cohort of 670 patients, whose cases we are investigating to find the cause of their immune disorders. Our latest work shows that several of these individuals have similar chronic augmented proportions of these specific T cells. We’re still awaiting the results of their genetic analysis.

Why have these diseases been overlooked for so long?

It is mainly due to the technical capabilities of genetic sequencing. These have become much better, faster and more affordable in recent decades. However, standard genetic analyses may miss such mosaics because the group of affected cells is relatively small and gets lost in the blood sample. The correct diagnosis can only be reached by isolating the affected cells and examining them separately.

So you were able to provide your patient with answers. But were you able to help him in the end?

In fact, there is a drug that we were able to offer the patient, which he has now been taking for seven years. It acts precisely where the signaling pathway in the specific T cells is overactive. Since then, the proportion of affected T cells in the patient’s blood has slowly returned to normal. Certain symptoms have improved significantly as a result, and the peeling of the oral mucosa and infections have decreased significantly. But not all symptoms have disappeared. Chronic fatigue, in particular, has persisted. 

Why hasn’t the treatment eliminated all the symptoms?

There are still many unknowns when it comes to chronic fatigue specifically. In the case of this patient, we can only surmise that certain biological responses to years of dysregulation cannot simply be eradicated once the molecular problem is resolved.

What do your findings mean for other patients with unexplained inflammation or immune disorders?

This case shows that a detailed analysis often helps us understand the underlying problem. And even more importantly, it helps us choose the right medication. There are drugs that target many different structures, but which one to use depends very much on the molecular cause of the problem, and not just on the symptoms present. There are patients who have very similar symptoms to this patient, but with a different disease mechanism. In their case, the same medication might not help at all. We also learn a great deal from such cases about the immune system and the function of individual types of immune cells.

How must diagnostic procedures evolve so that more patients with unexplained symptoms can get answers?

Our diagnostic services are under pressure, not least due to healthcare costs. Our aim is to understand the clinical pictures of our patients and to apply personalized treatments. We will not achieve this without modern diagnostics. For those affected, this can be crucial: they not only receive a diagnosis for their condition, but ideally also treatment that targets the underlying cause. Identifying the cause and tackling it at its source can ultimately cost the healthcare system less than the long-term treatment of many individual symptoms. 

Original Publication