Fatigue, sleep, and autoimmune and related Disorders, by Mark R Zielinski, David M Systrom and Noel R Rose in Front. Immunol., 06 August 2019 [doi.org/10.3389/fimmu.2019.01827]


Review article abstract:

Profound and debilitating fatigue is the most common complaint reported among individuals with autoimmune disease, such as systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, celiac disease, chronic fatigue syndrome, and rheumatoid arthritis.

Fatigue is multi-faceted and broadly defined, which makes understanding the cause of its manifestations especially difficult in conditions with diverse pathology including autoimmune diseases. In general, fatigue is defined by debilitating periods of exhaustion that interfere with normal activities. The severity and duration of fatigue episodes vary, but fatigue can cause difficulty for even simple tasks like climbing stairs or crossing the room.

The exact mechanisms of fatigue are not well-understood, perhaps due to its broad definition. Nevertheless, physiological processes known to play a role in fatigue include oxygen/nutrient supply, metabolism, mood, motivation, and sleepiness—all which are affected by inflammation. Additionally, an important contributing element to fatigue is the central nervous system—a region impacted either directly or indirectly in numerous autoimmune and related disorders.

This review describes how inflammation and the central nervous system contribute to fatigue and suggests potential mechanisms involved in fatigue that are likely exhibited in autoimmune and related diseases.

Future Directions

There are several areas of research and logistics that need to be established to understand the exact mechanisms of fatigue and sleep in autoimmune diseases. First, a detailed description of particular types of fatigue needs to be established in the clinic. This can be achieved, in part, with more precise medical coding. Second, there needs to be standardized questionnaires and diagnostic tests that can more precisely indicate the determents observed from fatigue. This will provide insight into the types of fatigue that are observed with the pathogenesis of the autoimmune disorders.

Understanding the neurocircuitry of fatigue and its relationship between inflammation and autoimmune diseases is also needed. This area can aid in understanding the manifestation of types and severity of fatigue found in autoimmune patients. Since inflammation and metabolism are implicated in fatigue and impairments are found in these in autoimmune disorders, a detailed understating of the mechanisms of these systems, unique cells, and brain areas are lacking in autoimmune research.

More information on interactions between circadian timing and sleep/wake state or sleep loss, alterations in neuronal activity, and normal daily functioning that affect fatigue is required. And there needs to be a better understanding of the relationship between the vagal afferents in modulating brain inflammation to induce fatigue is needed. More research is also necessary for understanding the relationship between vasohemodynamics and fatigue in autoimmune disease.

Additionally, several autoimmune diseases are associated with disproportionately greater incidence and disease severity in particular genders and little information is known regarding the relationship of fatigue with these gender differences (373). The relationship of gender to fatigue in autoimmune disease should be a topic for future research.

An autoimmune disease involves multiple interactions between genetics and environmental factors. Most autoimmune-related disorders are more prevalent in monozygotic twins vs. dizygotic twins or siblings, indicating the involvement of genetics in disease development. Furthermore, genome wide association studies (GWAS) have found several genetic loci and small nucleotide polymorphisms that are associated with specific autoimmune disease prevalence.

Interestingly, proteins encoded by genes that are involved in inflammatory mechanisms including NF-κB, apoptosis, Toll-like receptor, and immune complexes are described in autoimmune and related disorders. Nevertheless, a number of autoimmune diseases exhibit similar genetic modifications, which likely contributes to the higher incidence of multiple autoimmune diseases found in individuals with autoimmune disorders and potentially similar disease characteristics including fatigue. Indeed, larger data sets (i.e., >10,000 individuals) are finding new associations of inflammatory mechanism I with impairments in respiratory function and sleep (374). Several inflammatory gene small nucleotide polymorphisms have been implicated in fatigue including TNF-α, IL-1β, IL-6, and IFN-γ (375).

Nevertheless, a high amount of the heritability of the genetics behind autoimmune and related disorders remains unexplained. In recent years, researchers, agencies, and governments, such as the British Biobank, Trans-Omics for Precision Medicine (TOPMED), and the Million Veteran Program have begun assembling very large sample populations that are giving enough statistical power to unmask genetic links between diseases.


In summary, fatigue is a major early finding in individuals with autoimmune diseases, and inflammation is a contributing factor relating to this impairment, one that affects the ability of people to perform daily activities, work, and thus their overall well-being. Recent research reveals a relationship between types of fatigue and certain brain areas, cell types, and phenotypes that mediate the symptoms observed.

In addition, inflammatory molecules that are enhanced in the periphery with specific types of autoimmune disease can alter brain inflammation and neurocircuitry affecting fatigue. Consequently, immunomodulatory agents and drugs targeting inflammatory pathways could serve to treat fatigue occurring in autoimmune and related diseases. Understanding the mechanisms behind fatigue will not only aid individuals with autoimmune diseases but could also benefit transplant recipients, cancer patients, and infectious disease patients who experience debilitating fatigue


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