Immune System Dysfunction

Immune abnormalities are among the most consistently documented features of ME/CFS and likely play a central role in disease pathogenesis. The 2024 NIH deep phenotyping study by Walitt et al. provided the most comprehensive characterization to date of specific immune abnormalities, including characteristic B cell population shifts and sex-specific patterns of immune dysregulation (Walitt et al. 2024). This chapter provides a comprehensive examination of immune dysfunction across the innate and adaptive immune systems, inflammatory mediators, and potential autoimmune mechanisms.

As discussed in Chapter Energy Metabolism and Mitochondrial Function, immune activation is metabolically costly and may contribute to the bioenergetic crisis in ME/CFS. The neuroinflammatory mechanisms described here connect to autonomic and cardiovascular dysfunction (Chapter Cardiovascular Dysfunction) and neurological impairment (Chapter Neurological and Neurocognitive Dysfunction). Understanding immune dysfunction is thus essential for a comprehensive model of ME/CFS pathophysiology. Chapter Integrative Models and Multi-System Pathophysiology synthesizes these cross-system connections, examining how immune dysfunction participates in self-reinforcing pathophysiological cycles (Section Unifying Mechanisms Across Systems).

NoteChapter Roadmap: How to Use This Chapter

For patients: read the innate and adaptive immunity overviews, then the summary integrated model to understand why immune dysfunction drives fatigue and post-exertional symptoms.

For caregivers: read the summary integrated model and the immune-activation section to grasp the biological basis of crashes. The immunosenescence and molecular sections can be skimmed.

For clinicians: read the cytokines, immune-activation, and autoimmunity sections relevant to the presentation, plus the allergy/mast-cell and viral-reactivation sections for comorbid differentials. The lichen-sclerosus section is a niche marker — low priority.

For researchers: read the emerging-research-directions and pregnancy-immunology sections, and the summary integrated model. These cross-link to Chapter Integrative Models and Multi-System Pathophysiology.

1 Contents

• Innate Immunity
• Adaptive Immunity
• Immunosenescence and Accelerated Immune Aging
• Cytokines and Inflammatory Mediators
• Immune Activation and Inflammation
• Viral Reactivation and Persistence
• Autoimmunity in ME/CFS
• Connections to Allergies and Mast Cell Activation
• Virus-Induced Endothelial Senescence
• Immune Remodeling: Beyond Activation
• Summary: Integrated Model of Immune Dysfunction
• Emerging Research Directions in Immune Dysregulation
• Pregnancy Immunology and ME/CFS
• Lichen Sclerosus as a Shared Immune Terrain Marker

References

Walitt, Brian, Komudi Singh, Samuel R LaMunion, Mark Hallett, Sandra Jacobson, Kong Chen, Yoshihisa Enose-Akahata, et al. 2024. “Deep Phenotyping of Post-Infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.” Nature Communications 15 (1): 907. https://doi.org/10.1038/s41467-024-45107-3.