Discovery of a new immune biomarker for chronic fatigue syndrome

On April 27, the research group led by Director Wakiro Sato, Specially Appointed Research Director Takashi Yamamura, and colleagues of the Department of Immunology at the National Institute of Neuroscience of the National Center of Neurology and Psychiatry (NCNP) published their discovery of new immune abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), as well as its potential blood diagnostic marker. ME/CFS is a chronic disease of unknown cause that makes it difficult to lead a normal daily life due to its symptoms, such as strong fatigue and memory/attention impairment. By analyzing B cell receptors (BCRs), which are a type of lymphocyte receptors (BCR repertoire analysis), the research group found increased expression of certain BCRs in patients with ME/CFS. The findings of this study, published in the international scientific journal Brain Behavior and Immunity, are expected to lead to the establishment of an objective diagnostic method for ME/CFS.

ME/CFS is a disease of unknown cause that makes daily life difficult due to various symptoms, such as strong fatigue and weakness that do not improve with sleep or rest for a long period of time, decreased concentration, and cognitive and literacy impairment, and it is characterized by an extreme exacerbation of symptoms after exertion, such as work, study, and housework. Therefore, ME/CFS is easily confused with psychiatric disorders, such as depression. Symptoms, such as the continuation of a slight grade fever and hypersensitivity to sound, light, and smell, are common, and they are more likely to be complicated by severe pain across the whole body (similar to fibromyalgia), abdominal pain, diarrhea, and irritable bowel syndrome with persistent constipation. Diagnosis of ME/CFS is difficult as general blood tests and MRI do not detect its abnormalities, and it has no curative treatment.

A sudden onset due to cold symptoms, such as fever, is common, and the action of viruses and bacteria on the immune system is thought to be important for its onset. Outbreaks after a large-scale infectious disease epidemic have also been reported, and recent cases include one following SARS infection in Canada and Hong Kong in 2003. The onset of ME/CFS has been seen after exposure to toxic substances or trauma, both of which are thought to affect the immune system. Furthermore, removal of B cells, a type of lymphocyte, was reported to be effective in some patients with ME/CFS.

Previously, the research group used diffusion kurtosis imaging to detect abnormalities of the disease. Therefore, viewing ME/CFS as a neuroimmune disease, they searched for biomarkers for ME/CFS in the present study. Specifically, they collected blood samples from 37 patients diagnosed with ME/CFS at the NCNP Hospital who met the diagnostic criteria and were judged to be typical patients of ME/CFS. To investigate the characteristics of their B cells, the research group analyzed the frequency distribution of BCR types and plasmablasts, a type of B cell. The average age of the participants was approximately 40 years, of whom females accounted for 70-80% of patients and approximately 10 years had passed, on average, since the onset of their ME/CFS. In addition, the onset in approximately half of the patients was triggered by infectious diseases, and approximately half of the patients had immune system diseases, such as allergies.

B cells, along with T cells, are responsible for the acquired immune system, responding to a wide variety of pathogens to produce antibodies, present antigens to T cells, and produce cytokines. B cells have BCRs on the surface that correspond to the antibodies, and they are activated upon binding the antigens. The response to diverse antigens is achieved by generating diverse BCRs by mechanisms such as gene rearrangement. In addition, BCRs are composed of polypeptides encoded by three genes (IGHV, IGHD, and IGHJ). The collection of BCRs in each individual is known as the BCR repertoire, and BCRs can be classified into BCR families using genes as indicators. Comprehensive analysis of BCR genes allows analysis of the frequency of various types of BCR families in individual B cells, and the increased expression of certain BCR families has been found to correlate with infectious diseases and autoimmune diseases.

Thus, the research group analyzed, via next-generation sequencing, the BCR repertoire of the patients with ME/CFS in comparison to that of healthy subjects (23 individuals).

Results revealed differences in the BCR repertoire between the patients and healthy subjects. The expression of the BCR families of IGHV1-3, IGHV3-30, IGHV3-30-3, IGHV3-49, IGHD1-26, and IGHJ6 was significantly increased in patients with ME/CFS. Furthermore, their statistical analysis based on this finding showed that ME/CFS could be diagnosed using the expression of these BCR families with a probability of more than 80% when combined with conventional diagnostic criteria. They also confirmed the reproducibility of the findings in another cohort with comparable numbers of patients with ME/CFS and healthy subjects. Furthermore, since the onset in approximately half of the patients who participated in the study was triggered by infectious diseases, the research group examined the correlation between the infectious disease and the BCR family, which revealed an association with IGHV3-30 and IGHV3-30-3. ME/CFS in patients with the expression of these BCR families was triggered by infectious diseases, and they had a relatively short post-onset period.

In addition, a comparison of the frequency of B cells between the patients and healthy subjects using flow cytometry analysis showed that the frequency of B cells was significantly higher in the patients than in healthy subjects and that the frequency of plasmablasts, a type of B cell, increased in 20% of patients. Comprehensive gene expression analysis of patient-derived plasmablasts revealed the enhanced function of interferon-induced genes. Interferon is produced in the body due to viral infections, but it was shown that this function may be chronically activated in the plasmablasts of patients with ME/CFS.

Long term effects of COVID-19 are thought to include the development of ME/CFS. The findings of this study are expected to lead to the development of therapeutic approaches for ME/CFS.