Antibody-dependent cell-mediated cytotoxicity (ADCC) in familial myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

ABSTRACT

Background

Chronic fatigue syndrome (CFS) is an illness of unknown origin that may have familial risks. Low natural killer (NK) lymphocyte activity was proposed as a risk for familial CFS in 1998. Since then, there have been many studies of NK lymphocytes in CFS in general populations but few in familial CFS. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK lymphocytes helps control viral infections. ADCC is affected by variant CD16A receptors for antibody that are genetically encoded by FCGR3A.

Methods

This report characterizes ADCC effector NK cell numbers, ADCC activities, and FCGR3A variants of five families each with 2–5 CFS patients, their family members without CFS and unrelated controls. The patients met the Fukuda diagnostic criteria. We determined: CD16Apositive blood NK cell counts; EC50s for NK cell recognition of antibody; ADCC lytic capacity; FCGR3A alleles encoding CD16A variants, ROC tests for biomarkers, and synergistic risks.

Results

CFS patients and their family members had fewer CD16Apositive NK cells, required more antibody, and had ADCC that was lower than the unrelated controls. CFS family members were predominantly genetically CD16A F/F s for the variant with low affinity for antibodies. ROC tests indicated unsuitability of ADCC as a biomarker for CFS because of the low ADCC of family members without CFS. Familial synergistic risk vs. controls was evident for the combination of CD16Apositive NK cell counts with ADCC capacity.

Conclusions

Low ADCC may be a risk factor for familial CFS. Furthermore, characterization of familial CFS represents an opportunity to identify pathogenic mechanisms of CFS.

GRAPHICAL ABSTRACT

KEYWORDS:

• Chronic fatigue syndrome
• ADCC
• antibody-dependent cell-mediated cytotoxicity
• NK
• CD16A
• family studies

Acknowledgements

We are deeply grateful to the patients and families who made this study possible. Suzanne D. Vernon, Ph.D., at the Bateman Horne Center contributed valuable guidance. Nor Zainal, Ph.D., examined her records to obtain specifics from her study of familial CFS [12]. We thank Roche Pharmaceutical Research & Early Development for obinutuzumab. DNA was isolated by Ms. Laura Meadows and FCGR3A alleles sequenced at the NIH by Stephen K. Anderson, Ph.D. We thank Lynn B. Jorde, Ph.D., University of Utah School of Medicine, for help with the genetic data and Parker Hoshizaki, Terry Woodin, Ph.D., and Stephen K. Anderson, Ph.D. for manuscript editing.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability

Additional clinical information may be obtained upon request.

Additional information

Funding

The research was supported in part by NIH R21 AI117491 awarded to Dr. D Hudig as a co-investigator, by NIH P30 GM GM110767 (Cytometry Center), and by an anonymous generous private donor to the Bateman Horne Center who helped pay for the collection and shipment of blood samples. We would also thank the Nevada INBRE (NIH GM103440) for undergraduate research scholarships (to AP Sung and J-J Tang). The American Association of Immunologists awarded a predoctoral fellowship to AP Sung. Geolocation (Reno, NV and Salt Lake City, UT, U.S.A.)

Notes on contributors

Alexander P. Sung

Alexander P. Sung, M.S., is an MD-PhD student class of 2022 at the University of Nevada, Reno (UNR), School of Medicine (SoM) with Dr. Hudig as his thesis advisor.

Jennifer J.-J. Tang

Jennifer J-J Tang, M.S., is currently a student at the William S. Boyd School of Law, University of Nevada, Las Vegas. She performed research as an M.S. Biotechnology student at UNR.

Michael J. Guglielmo

Michael J. Guglielmo is a research associate II in the Hudig lab and an M.S. student in Biotechnology at UNR.

Julie Smith-Gagen

Julie Smith-Gagen, Ph.D., is an associate professor of Community Health Sciences. She is a member of the American College of Epidemiology. Her current research focuses on diagnostics and treatments for patients with cancers of unknown primary origin.

Lucinda Bateman

Lucinda Bateman, M.D., is a general internist who has specialized in the diagnosis and management of ME/CFS for 20 years. She has participated in many ME/CFS clinical research projects throughout this period.

Lydia Navarrete-Galvan

Lydia Navarrete-Galvan, B.S., is a 2019 UNR graduate with majors in Microbiology and Nutrition. She is currently a research assistant in the Hudig lab and plans to become an MD.

Doug D. Redelman

Doug D. Redelman, Ph.D., deceased. He was a research professor in the Department of Physiology, UNR SoM, a lifelong member of the Am. Assn. of Immunologists, and head of the UNR Cytometry Center.

Dorothy Hudig

Dorothy Hudig, Ph.D., is a professor in the Department of Microbiology and Immunology, UNR SoM and a lifelong member of the Am. Assn. of Immunologists. Her research interests are granzyme serine proteases and cytotoxic T & NK cell-mediated killing. Dr. Hudig is currently working on aspects of serial NK lymphocyte-mediated killing.