A Proteomics Study from the Center

By Anthony L. Komaroff, MD

Proteomics uses new technologies—that have become available in the last two decades—to precisely identify large numbers of proteins and measure their levels. The measurement is made in some compartment of the body: the blood, the spinal fluid, a particular organ, even within a single cell. These new technologies make it possible to take a sample from the compartment, like a small sample of blood, and to accurately measure the levels of hundreds, even thousands, of different proteins in that sample, relatively inexpensively and rapidly.

In the “old days”—way back in the 20th Century—scientists often had to be content with measuring the levels of one protein at a time. Since proteins typically interact with large numbers of other proteins and other types of molecules, you often didn’t learn much by measuring one protein at a time. A great strength of the Columbia Center for Infection and Immunity, where the Center for Solutions for ME/CFS is housed, and its collaborating facility at the University of Pennsylvania – Epigenetics Institute, is the ability to measure large numbers of molecules at the same time, and to study how they interact.

What did the latest study from the Center show?

Basically, two things:

• There appears to be a distinctive “signature” of a small group of proteins that distinguishes people with ME/CFS from healthy people;
• The proteins involved in that “signature” are primarily involved in the immune response—particularly the response of immune cells called B cells—to infections, and the response seen in autoimmune diseases.

It is possible that the “signature” that has been found might some day become a diagnostic test for ME/CFS. A perfect diagnostic test for a disease (in this case, ME/CFS) has two essential elements:

• It must have no “false negatives”: the test result can never be negative (“normal”) in a person who really does have the disease.
• It must have no “false positives”: the test result can never be positive (“abnormal”) in a person who does not really have the disease.

There are very few perfect diagnostic tests in medicine, but there are many that come pretty close to perfection. For the signature that the Center’s study has identified to become a diagnostic test it will need to be tested again:

• In larger numbers of people with ME/CFS from all over the world to determine whether the test has a very low false negative rate;
• In large numbers of people with diseases other than ME/CFS that also can cause the hallmark symptoms of ME/CFS—fatigue, post-exertional malaise, unrefreshing sleep, cognitive impairment, orthostatic intolerance—to determine whether the test has a very low false positive rate in those diseases.

The new study is consistent with prior studies that have found abnormalities related to B cells in people with ME/CFS. B cells are white blood cells, also called lymphocytes, that are important in the response of the immune system to foreign invaders, like infectious agents. In particular, B cells ultimately lead to the production of antibodies—antibodies to fight infectious agents, and auto-antibodies that are seen in autoimmune diseases.

Does this study have implications for treatment?

The study—like most studies—seeks to identify what is going wrong in the body of people with this illness. The reason for this is not just because the answer might be interesting, but because the answer might provide a target to shoot at with a treatment.

In this case, the study may prompt scientists to test more ways to quiet overactive B cells (some past attempts have failed), particularly the production of autoantibodies. Also, if further studies can identify the antigens that the activated immune system is activated by, these results may reveal underlying toxins, infectious agents, or other foreign molecules that can themselves be targeted.

Medical researchers sometimes are called “disease detectives.” If you think of research as detective work, then the cause of a disease is the criminal. This research has not definitively found the criminal that causes ME/CFS, but the research does strongly suggest the neighborhood where the criminal is likely to be hiding.

Milivojevic M, Che X, Bateman L, Cheng A, Garcia BA, Hornig M, Huber M, Klimas NG, Lee B, Lee H, Levine S, Montoya JG, Peterson DL, Komaroff AL, Lipkin WI. Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS. PLoS ONE 15(7): e0236148.