Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model

Abstract

Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.

Full text

February 2018 | Volume 9 | Article 2291
HYPOTHESIS AND THEORY
published: 15 February 2018
doi: 10.3389/fimmu.2018.00229
Frontiers in Immunology | www.frontiersin.org
Edited by:
Simona Zompi,
University of California,
San Francisco, United States
Reviewed by:
DeAunne Denmark,
Open Medical Institute (OMI),
United States
Maureen Hanson,
Cornell University, United States
*Correspondence:
Jonas Blomberg
jonas.blomberg@medsci.uu.se
Specialty section:
This article was submitted to
Microbial Immunology,
a section of the journal
Frontiers in Immunology
Received: 01September2017
Accepted: 26January2018
Published: 15February2018
Citation:
BlombergJ, GottfriesC-G,
ElfaitouriA, RizwanM and RosénA
(2018) Infection Elicited Autoimmunity
and Myalgic Encephalomyelitis/
Chronic Fatigue Syndrome: An
Explanatory Model.
Front. Immunol. 9:229.
doi: 10.3389/fimmu.2018.00229
Infection Elicited Autoimmunity and
Myalgic Encephalomyelitis/Chronic
Fatigue Syndrome: An Explanatory
Model
Jonas Blomberg1*, Carl-Gerhard Gottfries2, Amal Elfaitouri3, Muhammad Rizwan1
and Anders Rosén4
1 Department of Medical Sciences, Uppsala University, Clinical Microbiology, Academic Hospital, Uppsala, Sweden,
2 Gottfries Clinic AB, Mölndal, Sweden, 3 Department of Infectious Disease and Tropical Medicine, Faculty of Public
Health, Benghazi University, Benghazi, Libya, 4 Department of Clinical and Experimental Medicine, Division of Cell
Biology, Linköping University, Linköping, Sweden
Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is
a common, debilitating, disease of unknown origin. Although a subject of controversy
and a considerable scientific literature, we think that a solid understanding of ME/
CFS pathogenesis is emerging. In this study, we compiled recent findings and placed
them in the context of the clinical picture and natural history of the disease. A pattern
emerged, giving rise to an explanatory model. ME/CFS often starts after or during an
infection. A logical explanation is that the infection initiates an autoreactive process,
which affects several functions, including brain and energy metabolism. According to
our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbi-
osis experience a gradual development of Bcell clones prone to autoreactivity. Under
normal circumstances these Bcell offsprings would have led to tolerance. Subsequent
exogenous microbial exposition (triggering) can lead to comorbidities such as fibromy-
algia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may
then lead to immunization against autoantigens involved in aerobic energy production
and/or hormone receptors and ion channel proteins, producing postexertional malaise
and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing
of immunoglobulin variable domains could reveal the evolution of pathogenic clones.
Although evidence consistent with the model accumulated in recent years, there are
several missing links in it. Hopefully, the hypothesis generates testable propositions
that can augment the understanding of the pathogenesis of ME/CFS.
Keywords: chronic fatigue syndrome, myalgic encephalomyelitis, irritable bowel syndrome, postexertional
malaise, autoimmunity
INTRODUCTION
ME/CFS is a common disease of unknown etiology characterized by postexertional malaise (PEM;
a type of fatigability), cognitive disturbance, unrefreshing sleep, autonomic nerve dysfunction, and
a few characteristic comorbidities, see, e.g., Ref. (1–3). It oen starts with an infection and has a
strong tendency to remain a chronic condition.

TABLE 1 | Some outstanding questions regarding ME/CFS, which are addressed
in this conceptual review.
The hypothesis gives rise to several verifiable general questions
• What is the nature of the genetic predisposition?
• Can the infection history of ME/CFS patients be traced?
• Does it differ from those of other diseases, e.g., autoimmune ones?
• Is there a common sequence of infection, postexertional malaise, and comor-
bidity occurrence during ME/CFS pathogenesis?
• Can defects in tolerance development be detected in ME/CFS patients?
• Can the path of Bcell clones from germ line to various autoreactivities be traced
in ME/CFS patients?
• Which autoantibodies can be detected in ME/CFS patients and its comorbidities?
• Can clues to ME/CFS biomarkers be derived from this explanatory model?
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ME/CFS diagnostic criteria have gradually become more
stringent, see, e.g., Ref. (2–7). ese are based on somatic,
oen self-reported symptoms (8, 9). Although oen used inter-
changeably, studies using the “CDC,” (also called the “Fukuda”)
criteria (5) mainly use the term “CFS,” while those using the
“Canada” (3) or International consensus (2) criteria use the
term “ME.” is creates an ambiguity, which may explain
some contradicting results. ere are so far no specic labora-
tory tests (10) for ME/CFS diagnosis. Recently, a committee
recommended a new name for ME/CFS, systemic exhaustion
intolerance disease (SEID) (11, 12) with diagnostic criteria
that emphasize PEM as the central ME/CFS symptom (13).
e disease entity ME/CFS is not uncontroversial. Like many
times before in medical history, psychiatric and somatic
explanations compete with each other. A recent critical review,
which emphasized psychiatric aspects, stated that “there is no
convincing pathogenesis model for CFS” (14). However, in this
review, we forward that evidence for a somatic origin of the
disease is accumulating.
From a research perspective it is important that patients are
diagnosed using strict criteria. A thorough clinical examination
is necessary. It does not matter how sophisticated the analyses
are in a study if patient selection is ambiguous. In the case of
“fatigue” it is important to distinguish ME/CFS fatigue from
other types of fatigue, such as burnout syndrome and depres-
sion, see, e.g., Ref. (15). In ME/CFS, repetition of a physical or
mental exertion can reveal objective evidence of fatigability.
is exertion-elicited fatigue, PEM, is required for the diagnosis
of ME/CFS using the Canadian criteria (3), the International
consensus (2), and the SEID (12), but not using CDC (5) cri-
teria. Although the term “ME/CFS,” encompassing both “ME”
and “CFS,” has a built-in ambiguity it covers much of the current
studies and is operationally judged as the best available concept.
Fatigue similar to PEM also occurs in Sjögren’s syndrome (SS),
primary biliary cholangitis (also named primary biliary cir-
rhosis) (PBC), and systemic lupus erythematosus (SLE). e
relation of ME/CFS to the similar condition Gulf War Illness
(GWI) is uncertain, see, e.g., Ref. (16). However, a recent study
describes a laboratory-based distinction between the two ill-
nesses (17).
Recent ME/CFS reports brought optimism (18). National
Institutes of Health in the US announced that it will prioritize the
disease. Cornerstones are studies on PEM (12, 19) and eects of
immunosuppressive treatment (20–22) although not substanti-
ated in a phase III trial.
ere are several partly competing explanatory models for
ME/CFS, for example; autoimmunity, chronic infection, energy
metabolic defect, imbalance in autonomous nervous system and/
or hormones, and psychosomatic dysfunction. In this laboratory-
oriented review, we present an overview of recent ndings and
attempt to bring a substantial portion of ME/CFS symptoms and
its disease history into one explanatory model. e model draws
analogies from more established autoimmune diseases (even if
much remains to be understood in these too) is based on clinical
experience and on recent immunometabolic results. Clues for
further research are given in Tab l e 1 and as separate statements
in the text.
TRYING TO PLACE IT ALL UNDER ONE
UMBRELLA: A HYPOTHESIS FOR ME/CFS
PATHOGENESIS
We propose a pathogenetic model reminiscent of current think-
ing on the pathogenesis of autoimmunity.
A genetically predisposed person (A) is exposed to successive
infections (B), e.g., in the gastrointestinal tract—manifested as
dysbiosis or irritable bowel syndrome (IBS)—or in the airways,
with microbes carrying epitopes mimicking human self-epitopes,
or microbes which activate autoreactive Bcells to produce the
so-called natural antibodies with non-rearranged germ line
immunoglobulin genes. Such autoreactive Bcells may be deleted
or persist in a state of anergy (C). A proportion of these Bcells
remain in spleen and lymph nodes as memory IgM+, IgA+, or
IgG+ Bcells (D). Individuals dier in time and extent of encoun-
ters with autoreactivity eliciting microbes. Some encounters are
here postulated to give rise to autoantibodies (E) against key
enzymes in energy metabolism hence causing a defective aerobic
energy metabolism and PEM, the central symptom of ME/CFS,
others to bromyalgia (FM), yet others to postural orthostatic
tachycardia syndrome (POTS) or other comorbidities. If the
autoimmunization events are independent of each other they
can occur in any order. If there are cooperativity eects they may
follow a rather specic order (F). e upper case letters refer to
stages in Figures1 and 2.
us, the basic property of ME/CFS patients would be a
defect in tolerance coupled with a chance exposure to microbes
carrying relevant mimicking autoantigen epitopes.
e italicized text of Figure1 shows a hypothetical expla-
nation of the events behind ME/CFS. A known function of
microbes in the gut is to train, from within, the immune
system to recognize and react correctly to microbes (including
bacteria and viruses), which come from the outside (25–29).
e correct reaction includes, among other things, anergy and
unresponsiveness to microbial antigens that cross-react with
self-antigens. It is known that ME/CFS patients oen have IBS
(30–32). In this IBS there is also a modied gut ora (33, 34).
A less symptomatic gut dysbiosis may also occur (33, 35). In
addition, there is also occasional epithelial barrier leakage of
gut microbes. It is reasonable to assume that the innate mucosal
immunity defenses have been breached or that peripheral
tolerance maintenance (training function) of the gut ora has

FIGURE 1 | Approximate course of events during which ME/CFS develops, and overview of the explanatory model. The postulated immunometabolic energy
block is shown as an antibody and a mitochondrion. Italicized text refers to the explanatory model presented under “Trying to place it all under one umbrella.”
Abbreviations are explained in the text.
FIGURE 2 | Mutational fate of a hypothetic germ line immunoglobulin heavy
chain sequence (Vhy) in successive Bcell clones, which gradually expand
their paratope diversity in interplay with gut microbiota, Tcells, and dendritic
cells. If there is a chronic antigen stimulation, sequences more or less close
to germ line sequence may be selected. Resulting Bcells are stored as
memory cells in germinal centers of gut-associated lymph nodes. Some
of the developmental branches end due to clonal anergy or deletion
(tolerization). Others are postulated to descend along a path to autospecificity
due to an abnormality in gut commensal spectrum. An exogenous, triggering,
antigenic stimulation (e.g., infection), eventually leads to overt pathogenic
autospecificity (“evil” Bcell clones, magenta) and ME/CFS. Similar fates of
other Bcell clones, which eventually turn autopathic and give comorbidities,
are indicated under “F.” Characters A–F in bold refer to the stages mentioned
under “Trying to place it under one umbrella.” This figure was inspired by
work on the autoreactive clone VH4-34 (23, 24).
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oen leads to tolerance (36). When there is microleakage toler-
ance may not function properly leading to loss of checkpoints
that normally prevent development of autoreactivity (37–42).
e prole of Bcell subpopulations is dierent in ME/CFS
compared with controls (43). A factor behind that could be
new memory Bcells with autoreactivity, which normally would
be sorted out, arising and persisting. When the body is exposed
to a new infection, these B cells could produce antibodies
which react both to microbe and autoantigen. Autoantibodies
and Tcells that recognize self-peptides can damage cells which
carry autoantigens. is is the so-called mimicry (antigen
similarity) theory behind autoimmune disease (44). Part of the
explanation for ME/CFS would then be the disturbed gut ora
and microleakage from the gut. At the le side of Figure1 is
written “Genetic predisposition.” is is compatible with the
increased frequency of ME/CFS in certain families. Like for
many other common diseases ME/CFS could depend on both
inheritance and environment.
If this hypothesis is correct, a tendency for autoreactivity
would arise gradually, via a changed gut ora and microleakage
from the gut. Aer a decisive immunization event autoim-
munity leading to ME/CFS would arise, as shown in Figure1.
e prerequisites for autoimmunity would arise gradually
because Bcells with a tendency for autoimmunity would arise
aer recurring microleakage across the mucosal barrier of the
gastrointestinal tract inducing a state of chronic inamma-
tion. e normal contact between gut microbes and immune
system occurs at the gut/mucosa interphase. Central tolerance
oen develops by elimination of autoreactive Bcells. However,
a proportion of autoreactive Bcells remain which are kept unre-
sponsive (anergic). When there is microleakage, the mucosal
barrier is bypassed and tolerance may not be maintained.
Autoreactive Bcells can then be activated and dierentiate to
autopathic Bcells.
been disturbed. Normally, the mucosal immune system must
maintain tolerance to harmless foreign antigens including food
and commensal microbes. Presentation of antigens at mucosae

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e frequency of IBS, alterations in microbiome and extent of
microleakage should be further studied in ME/CFS. Attempts to
nd autoreactive Bcells to nd their origin and their evolution
should be made. Maybe it is possible to trace how they evolved
by systematic sequencing of their antigen-binding structures
(paratopes and idiotypes), from germ line to anti-gut microbe to
autoimmune clone?
GENETIC PREDISPOSITION AND
PREMORBID PHENOTYPE
ere is evidence for a strong genetic component in some auto-
immune diseases, such as complement component deciencies
in SLE which may lead to reduced self-antigen elimination.
Likewise, in ME/CFS, autoimmune diseases, for example, thyroid
disease (45), SS (46), and SLE (47), oen occur among relatives
and sometimes among the patients themselves.
Presence of an HLA association is a hallmark of many auto-
immune diseases. It indicates an aberrant immune presentation
to either cytotoxic Tcells (HLA Class I) or T helper cells (HLA
Class II) which predisposes for autoimmunity. One study found
an overrepresentation of HLA Class II DQA1*01, with an odds
ratio of 1.93 (48).
Specic cytokine gene polymorphisms were observed; an
increase of one, for TNFα, and a decrease of one, for IFNγ, were
found in CFS (49).
Recent genome-wide association studies showed an increased
frequency in ME/CFS of single-nucleotide polymorphisms (SNPs),
some isolated, some concentrated to three gene regions: microtu-
bule associated protein 7, CCDC7 (coiled-coil domain containing
7) and a T-cell receptor alpha chain gene (50). e latter may
conne an increased tendency to autoimmunity. e comorbidity
with autoimmune disease or disease having an increased preva-
lence of autoantibodies, e.g., FM (51–57), IBS (58–63), POTS (64),
and hypothyroidism (45, 51, 55, 65–67), also indicate a tendency
for autoimmunity in ME/CFS patients (further detailed in the sec-
tion on autoreactivie B cell clones and autoantibodies, including
Tabl e 4). SS (46) and SLE (47) oen occur among relatives and
sometimes among the patients themselves.
IgG3 and mannose binding lectin deciency were more com-
mon among ME/CFS patients than in controls (102, 103). IgG
subclass deciency is more frequent in ME/CFS than in controls
(104, 105). Such deciencies could increase the risk of recurrent
infections.
In a genetic study concentrating on hormone and hormone
receptor genes, certain TRPM3 and CHRNA2 SNPs were found
to be more common in ME/CFS (106–108).
Are There Also Epigenetic Changes
in ME/CFS?
DNA modication (methylation) of promoters of some genes
associated with immune cell regulation; glucocorticoid recep-
tors, ATPase and IL6 receptor, respectively, was reported to dier
between ME/CFS and controls (109). DNA methylation depends
on the one-carbon metabolism, where ME/CFS changes have
been recorded. Although the reason for such hypomethylation
can only be speculated upon, it is interesting that the combined
action of the vitamins B12 and folic acid play a fundamental role
in providing methyl groups to hundreds of substrates in various
elementary cell processes (see the section “can autoimmunity
explain energy metabolic disturbances and PEM”).
Gene Expression in ME/CFS
In a recent RNA-seq study, there were no specic RNAs expres-
sed in ME/CFS compared with healthy controls and other
chronic diseases (110). In another expression study, prominent
dierentially expressed genes were EIF4G1, EIF2B4, MRPL23,
which control RNA translation, in cytoplasm and/or mitochon-
dria (111). A dierential expression of genes crucial for T-cell
activation and innate response to viruses was also described
(111–114) in CFS.
A novel angle was the report that the pattern in cerebrospi-
nal uid (CSF) and blood of another kind of RNA, the small
regulatory RNAs, diered between ME/CFS, GWI, and controls
(17, 115). Another pattern was found in FM (116). e
pathophysiological roles of the small regulatory RNAs are still
uncertain, but the ndings indicate additional levels of patho-
physiological regulation, which also could provide diagnosti-
cally useful biomarkers.
A prerequisite for calling a disease chronic is duration of at
least 6months. is oen means that one has not been able to
take samples during the period when the disease commenced.
A common situation is that the patients remember that ME/CFS
started with an infection, oen infectious mononucleosis (IM), or
a general virosis-like disease (117). When the acute infection with
fever, myalgia, and swollen lymph nodes and/or cough subsides,
a malaise and fatigability remains. According to the literature
approximately 70% of ME/CFS cases start rather abruptly in this
way. Others have a more gradual debut. e natural history of the
disease should be studied systematically.
In a few cases, ME/CFS appear epidemically, with several
cases being derived from a common index case. Even if epidemic
outbreaks are uncommon it indicates that the disease might be
contagious. Further epidemiological studies are needed.
MANY DIFFERENT INFECTIONS HAVE
BEEN OBSERVED AT THE OUTSET OF
ME/CFS LIKE DISEASE
ere is abundant evidence for infection as a trigger of chronic
fatigue in a more general sense (oen manifested as fatigability)
(68, 72–74, 77–79, 82, 84, 118–128) (Tabl e2). But negative evidence
also exists (129, 130). Some of this evidence is inconclusive (131,
132). Whether all these instances of postinfectious fatigability have
identical properties (e.g., Do they fulll criteria for PEM?; For ME/
CFS?; How chronic are they?; etc.) should be systematically investi-
gated. ese infections can be traced in the patient history, by direct
detection of the microbe(s) (133), or by detection of antibodies to
the microbe(s) (94, 119, 133–146), see, however, Ref. (147).
How oen does it happen that spouses are aicted? is
would advocate a transmissible factor rather than inheritance.
Epstein–Barr virus (EBV) seems to be a frequent trigger of
ME/CFS (also referred to as “postviral fatigue”). Glandular fever

TABLE 2 | Long-standing fatigue, or fatigability, after an infection.
Microbe Infection Diagnostic term Approximate % of fatigued post infection Reference
Epstein–Barr virus Infectious mononucleosis Postviral fatigue 11% (6months); 4% (12months) (68, 69)
Coxiella burnetii Q fever Post Q fever fatigue 10–20% (6–12months) (69–71)
Giardia lamblia Giardiasis Post Giardia fatigue <1% (12months) (72, 73)
Ross River virus Ross River virus infection Post Ross River fatigue 11% (6months); 9% (12months) (69, 74)
Chikungunya virus Chikungunya virus infection Post Chikungunya fatigue (often together
with arthralgia)
20% over background (≥12months) (75, 76)
West Nile virus West Nile virus infection Post West Nile fatigue 31% (6months) (77–79)
Dengue virus Dengue fever Post Dengue fatigue 8% (2months) (80, 81)
Ebola virus Ebola hemorrhagic fever Post Ebola fatigue Not clear, at least 10% (6months) (82, 83)
SARS corona virus Severe acute respiratory syndrome Post SARS syndrome Approximately 22/400=6% (≥12months) (84)
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(127), also called IM, is most frequently caused by EBV. A rea-
sonably specic laboratory test for IM (the “Mono” test) is based
on heterophilic antibodies, which bind to carbohydrate antigens
on non-human erythrocytes (148–150). If infectious triggers of
ME/CFS are investigated, a positive Mono test provides an oen
recorded marker. Other infections are oen not diagnosed as
objectively. EBV belongs to the herpes virus family. It can infect
and remain latent in B cells. At primary infection, EBV trig-
gers massive activation of multiple Bcell clones each secreting
monoclonal antibodies which are coded by immunoglobulin
heavy and light (IGH and IGL) chain genes with unique vari-
able [immunoglobulin heavy chain variable (IGHV) and IGLV]
genes, with the so-called complementarity-determining regions.
e result is a polyclonal B cell stimulation, with massive
release of natural antibodies, including autoreactive antibodies.
Besides Bcell growth stimulation, EBV stimulates production
of EBI3, one of two chains of the tolerance-control heterodimer
cytokines IL27 and IL35 (151). us, EBV is deeply inuencing
immune functions. EBV is also coding for antigens with highly
repetitive structure (e.g., Gly–Ala–Gly–Ala repeats in EBNA1).
is may be a source for antigenic mimicry and development
of autoreactivity. Both the B cell growth stimulation and such
antigenic mimicry make EBV a prime suspect of inducing
autoreactivity. ere is a correlation between occurrence of IM
and the autoimmune diseases MS (152–154) and SLE (155–158).
How EBV is involved, be it frequent reactivations of latent EBV
or defects in the Tcell and NKcell surveillance mechanisms
against the virus, is not clear, but the presence of EBV, and the
immune response to it, should be compared in ME/CFS, MS,
and SLE, see Ref. (134).
Summarizing, EBV is especially interesting as a facilitator
of autoreactivity. Some autoantibodies may have an origin in a
mimicry between EBV antigen and self-antigens. EBV is a ubiq-
uitous virus. EBV can stimulate thousands of Bcells to produce
thousands of dierent antibodies, each with its own unique
antigen-binding site. It oen occurs as an eliciting factor trig-
gering ME/CFS, in this case referred to as “postviral fatigue.” As
mentioned, it stimulates growth of a wide variety of Bcells, and it
has viral proteins that can give rise to autoantibodies (159, 160).
Transmissibility is a microbial property. Most ME/CFS cases
are sporadic (118). However, there are a few recorded outbreaks,
where healthy ME/CFS patient contacts developed symptoms of
the disease (118, 161), forming ME/CFS outbreaks in ME/CFS,
indicating a transmissible agent.
Many observations support that a condition similar to ME/
CFS occurs in approximately 10% of those who had Q fever, an
infection with the bacterium Coxiella burnetii (69, 70, 74) which
oen occurs in outbreaks. Q fever is unevenly spread throughout
the world. ME/CFS is more widespread. Q fever is therefore
unlikely to be a common cause of ME/CFS, globally.
A chronic postinfectious fatigue/fatigability reminiscent of
PEM occurs aer a number of life-threatening virus infections
(Ta bl e 2 ). ere is not much antigenic similarity between these
infective agents. Many infections which fundamentally challenge
or reorganize the immune system give rise to a persistent, perhaps
autoimmune, malfunctioning state.
Note that the number of ME/CFS cases triggered by severe
zoonotic infections such as Ebola must be very small, on a global
scale. Besides IM, mild respiratory infections like those caused by
mycoplasma (162–168) and chlamydia (164, 169, 170), or general
infections due to parvovirus B19 (136, 171) and herpes 6 and 7
(133), have been mentioned, although the diagnostic evidence is
not strong.
Although much remains unclear before the role of infection in
autoimmunity is understood, there are diseases where a known
antigenic challenge triggers autoimmune disease, an infection
(172) or a vaccination. Surprisingly oen it is the brain that is the
target for this autoimmunity (Table3).
In addition to commonly known microbes (virus, bacteria,
and protozoa), a large number of new ones have been discovered
during the last 5years (171, 173–179). Many of them are viruses
which do not cause any known disease. We need to keep an eye
on these microbes. Maybe there are some among them which can
precipitate ME/CFS?
In these examples of infection elicited autoimmunity, the
microbial antigen mimics epitope(s) on human cells. Such
microbial epitopes may either be small molecules, like lipids, or
added to proteins posttranslationally (172), randomly similar
sequences, repetitive sequence motifs, or highly conserved anti-
genic structures.
An example of the former mechanism (posttranslational anti-
genic modication) is PBC. e antibodies are directed against a
small fatty acid molecule, lipoic acid, added posttranslationally to
a protein in the pyruvate dehydrogenase (PDH) enzyme complex.
PDH is part of the energy producing machinery at the surface of
mitochondria (180, 181), and governs the transition from glycoly-
sis (anaerobic energy metabolism) to the tricarboxylic acid cycle
and respiratory chain (aerobic energy metabolism), occurring

TABLE 3 | Autoimmune syndromes secondary to infections–association/hypothetical relationship.
Disease Microbe Type of microbe Mimicry (likely structure) Reference
Postinfectious encephalitis Measles, Varicella-zoster, etc. Virus Anti-myelin oligodendrocyte
glycoprotein and unknown antigens
(85, 86)
Guillain–Barré syndrome Campylobacter (primarily)
and Zika virus
Bacterium
and virus
Gangliosides; unknown antigen (87, 88)
“Nodding disease” Onchocerca volvulus Worm Unknown antigen (89)
Pediatric autoimmune neuropsychiatric
disorders associated with streptococcal
infection (PANDAS)
Streptococcus infections,
i.e., strep throat or scarlet fever
Bacterium Carbohydrate antigens? (90)
Multiple sclerosis Epstein–Barr virus and other
pathogens
Virus and bacteria Myelin basic protein, proteolipid protein,
and myelin oligodendrocyte glycoprotein
(91, 92)
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inside mitochondria. Lipoylation is a posttranslational modica-
tion, which also occurs in a few bacteria, such as Novosphingobium
(182). Gut infection with Novosphingobium is a possible cause of
PBC. e PBC patients have a PEM reminiscent of the PEM of
ME/CFS. Likewise, periodontal infection with Aggregatibacter,
which citrullinates its own as well as human proteins, may provide
the nal trigger for rheumatoid arthritis (183).
An example of the latter mechanism (conserved epitopes)
is a family of highly conserved proteins, which are present in
both humans and microbes, called “heat shock proteins” (HSP).
Antibodies against HSPs occur in many oen studied autoim-
mune diseases, for example, MS and SLE (94, 184–188). We found
a higher frequency and levels of antibodies against a specic
portion of HSP60 in ME/CFS patients (94). Even though HSP60
is a mitochondrial protein it is unknown if these antibodies can
inuence mitochondrial function.
IMMUNOLOGICAL ASPECTS OF ME/CFS
How does autoreactivity develop? Much remains to be learned.
e adaptive portion of the immune system (B and Tcells) has a
formidable task, to distinguish “self” from “non-self,” i.e., autoan-
tigens from antigens of invading microbes. Aer an infection
the immune response is initially relying on players of the innate
immune system with natural antibodies, receptors for pathogen-
associated molecular patterns, danger-associated molecular
patterns, and DNA sensors for exogenous pathogens. However,
within a few weeks the immune system acquires a higher preci-
sion with the developing adaptive immune B and Tcells ensuring
that only the targeted microbe is destroyed. e target selection
(and tolerance development) may go wrong. Some microbial
targets are very similar to self-molecules. is is the basis for the
so-called molecular mimicry theory, although the evolutionary
lines for microbes and humans diverged long ago. ere are still
some structures, such as HSP, which have hardly changed at all
since then. An immune defense against them thus constitutes a
risk of promoting an autoreactive response.
So-called “natural antibodies,” which occur in all persons and
mostly are of IgM nature, oen both poly- and autoreactive, are
produced by a CD20+, CD27+, and CD43+ subset of Bcells
(189). One function of these natural antibodies is scavenging of
dead/apoptotic, damaged and infected cells. Only sometimes do
they result in disease. In a healthy person, Bcells that can produce
autoantibodies oen rest in an “anergic” state and do not produce
their potentially damaging antibodies. ey can be activated by
the so-called “cell danger” signals. Bcells which produce natural
IgM have regulatory functions (190). Such “innate” immune cells
which are on the border of auto- and alloreactivity may be start-
ing points for development of autoimmune disease.
Disturbance in the composition of the gut microbiome, dys-
biosis, has been detected in several diseases (33–35, 86, 191–195).
A major function of the microbiome probably is to train the
immune system (e.g., Tcells, Bcells, and dendritic cells) with a
large variety of antigens. Disturbance in it may lead to a defective
immune repertoire and imbalance of tolerance induction (196).
As the tools for studying microbiota gradually become more pre-
cise, the possibility of more or less specic changes in microbiota
predisposing to autoreactivity is increasingly being addressed.
is is the case for type 1 diabetes (27, 197, 198), multiple sclerosis
(199), rheumatoid arthritis (200), SLE (201), Behcet’s syndrome
(202), autoimmune gastritis (203), and ankylosing spondylitis
(204). ME/CFS patients also seem to have aberrations in their
gut microbiota (33, 192, 205, 206).
A symptomatic variant of gut dysbiosis, IBS (207), a common
comorbidity in ME/CFS, may inuence mucosal tolerance induc-
tion. Indeed, ME/CFS with IBS was suggested to be a distinct
subset of ME/CFS (208).
It is conceivable that if the mucosal barrier also is broken by
microleakage (28, 34, 37, 41, 192, 209–210), tolerance develop-
ment may become impaired, facilitating development of autore-
activity (37–42, 211–213). Autoimmunity oen seems to be a hit
and run phenomenon. However, a chronic underlying infection
cannot be excluded, also in the ME/CFS case (214, 215).
e hypothesis presented in Figure 2 is based on ndings
regarding the IGHV gene sequence VH4-34 (23, 24) in SLE.
It elaborates the immunoevolutionary aspect of Figure 1.
Its explanatory model is similar to current thinking regarding
the pathogenesis of autoimmune disease. It tries to clarify the
genesis of autoreactive Bcell clones from germ line to patho-
genicity. e original specicity conferred to a B cell and
immunoglobulin by VH4-34 is anti-branched lactosamine
containing carbohydrates. is then gradually mutates, prob-
ably due to exposure to epitopes from commensal gut bacteria.
e original specicity exists in the beginning of a mutational
walk in the Vh genetic maze, an example of epistasis, where one
mutation facilitates other mutations during avidity maturation.

TABLE 4 | Occurrence of autoantibodies in ME/CFS and some of its comorbidities.a
Disease (frequency in ME/CFS),
reference
Antigen to which autoantibody occurs more often than in controls
Phospholipid Carbohydrate Hormone Hormone receptor Ion channel protein Other protein
ME/CFS Cardiolipin (54) Ganglioside (54)β-Adrenergic and
muscarinic cholinergic
(93)
HSP60 (94)
Fibromyalgia (35–73%) (95) Potassium channel
transporter (96, 97)
(hypo)Thyroidism (thyroiditis
by cytology, 40%, wide definition
of chronic fatigue) (98)
Thyroperoxidase
(45)
Thyroid-stimulating
hormone (99)
Postural orthostatic tachycardia
syndrome and/or orthostatic
hypotension (27%) (100)
Acetylcholine (101) Calcium channel
transporter (101)
Irritable bowel syndrome
(35–90%) (30–32)
Vinculin and cytolethal
distending toxin B (58)
aThe list is not complete. More studies are needed to obtain better statistics. Some of these autoantibodies have the potential to become diagnostic biomarkers. Abbreviations are
explained in the text.
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Other unknown antigenic stimulations then give rise to various
autoantibodies, some with anti-DNA specicity. We hypoth-
esize that pathogenic autoantibodies in ME/CFS are created by a
similar mechanism. us, we postulate that a genetically predis-
posed person gets a deranged gut microbiome which gives rise
to apathogenic Bcells with a weak autospecicity. ey are not
eliminated due to a defective tolerance induction. Finally, these
clones are given an antigenic stimulation from an exogenous
infection which yields pathogenic Bcell clones. us, memory
Bcell clones with a paratope spectrum derived from germline
and subsequent exposure to commensal microbes, e.g., in gut,
may be an important intermediary step before development of
outright autoimmunity. It should be possible to follow the path
to autopathic clones by isolation and sequencing the variable
immunoglobulin chains in B lymphocytes in ME/CFS, like what
was done with VH4-34.
Autoreactive B Cell Clones and
Autoantibodies in ME/CFS
Several autoantibodies have been found in ME/CFS (54, 93,
94, 216–222), and some of its comorbidities (Tabl e 4 ). is is
circumstantial evidence for ME/CFS being an autoimmune con-
dition. Especially interesting are the results where an increased
frequency of antibodies to certain hormone receptors was found
(93). Several ME/CFS symptoms may be explainable by receptor
interference from such autoantibodies.
In autoimmune conditions with pathological autoantibodies,
erroneously activated and mutated B cells are the root of the
evil (Figure2). ese should be studied in detail (43). One can
envisage large scale sequencing of immunoglobulin gene vari-
able domains of such clones to dene aberrant specicities, with
autoreactivity. A characteristic variation in Bcell subsets (43) has
been described in ME/CFS.
is should be studied systematically. At which time point did
these diseases manifest themselves, before or aer the ME/CFS
started? How large is the frequency of autoantibodies in patients
with these conditions, preferably measured simultaneously in
an antigen matrix? Maybe there are autoimmunity biomarkers
which could be used for ME/CFS diagnosis?
Cytokine Patterns in Blood and CSF
in ME/CFS
e immune system is engaged in ME/CFS (220). Several studies
have found changes in cytokine pattern in blood and CSF, and in
expression of cytokine genes (223–231), especially aer exercise
(232–238), concomitant with an increase in reactive oxygen spe-
cies (ROS) levels and a decrease of HSP70 concentration (239),
oen in connection with a “are,” an acute exacerbation of ME/
CFS symptoms (237, 238). A diculty is that cytokine patterns
(Tabl e 5) are inherently variable. e cytokine proles may be
dierent in dierent stages of the disease (225, 240).
A more permanent dysregulation of cytokines in plasma has
also been reported (223, 225, 226, 228, 230, 243), see Tab le  5.
A correlation with disease duration was seen (225, 242). A meta-
analysis showed that an increased level of TGFβ in plasma in
ME/CFS versus controls was the most consistent nding (227).
Cytokines in CSF were also deranged in ME/CFS (224, 228).
Tabl e 5 is a compilation from recent publications on cytokine
abnormalities in ME/CFS. A recent meta-analysis concluded that
many of the reported ndings are not reproducible (227). is
could reect dierent levels of physical activity, the volatile nature
of cytokine levels and methodological problems, such as collec-
tion, handling, and preparation of samples. ere could also be a
heterogeneity within the ME/CFS group which blurs the patterns,
see, e.g., Ref. (224, 234).
Whether there are cytokine changes aer exercise peculiar to
ME/CFS is a related subject (244). A recent meta-analysis con-
cluded that complement factor C4a split products, oxidative stress
markers and leukocyte expression of IL10 and toll-like receptor 4
genes are reproducibly dierent from controls in ME/CFS (233).
However, there may be subgroups within the ME/CFS group with
radically dierent reactions to exercise. A clear-cut dierence in

TABLE 5 | A selective list of cytokines whose concentrations were reported to change in ME/CFS.
Cytokine Body fluid Up- or downregulation Reference Comment
TGFαSerum +(225)
TGFβSerum +(226, 227) Most consistent finding, although one inconclusive (241)
TNFαSerum +(225) Elevated early after debut
IFN-γSerum +(225) Elevated early after debut
IL1αSerum +(225) Elevated in early stage of ME/CFS
Eotaxin-1 (CCL11) Serum −, +(225, 226) Positively correlated with severity and low early after debut
Eotaxin-2 (CCL24) Serum +(223)
Leptin Serum −(230) Inversely correlated with severity
IL13 Serum +(226) Positively correlated with severity
IL6 Serum +(242) Elevated early after debut
IL7 Serum −(223)
IL8 Serum +(242) Elevated early after debut
IL10 Cerebrospinal fluid −(228)
IL16 Serum −(223)
IL17A Serum +(225) Elevated early after debut
VEGFαSerum −(223)
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gene expression aer exercise between ME/CFS patients which
have POTS comorbidity, and those who do not, was found (234).
e activity of the so-called natural killer cells is also changed
(231, 244–248) in ME/CFS. However, a negative report came
recently (249). e latter may be due to methodological dier-
ences. Both kinds of immune change (cytokines and immune cell
activity) are potential biomarkers and should be studied more.
Is There a General Defect in Tolerance
Development in ME/CFS?
Tolerance induction is a major property of the gut mucosal
immune system (196). A special kind of T helper cells, Treg, medi-
ate mucosal tolerance, and anergy of tolerized Bcell clones, via
IL10 and TGFβ. It may be more than a coincidence that a change
in TGFβ levels in serum was the most consistent cytokine change
in ME/CFS versus controls (Table5).
A defective tolerance development could in principle be
detectable as a tendency to develop autoimmune disease in ME/
CFS. e comorbidity between ME/CFS and better studied auto-
immune disorders such as SS (250), SLE, and multiple sclerosis
(251) is an indication of this. Fatigability, which may or may not
be related to the PEM of ME/CFS (252–255), occurs as a major
symptom in some autoimmune (6, 184, 256–261), mitochondrial
(262, 263) and infectious (264) diseases. Immunostimulation,
e.g., with Staphylococcal vaccine, theoretically could induce
tolerance to autoepitopes involved in ME/CFS pathogenesis
(265–267). It was reported to be eective in ME/CFS in a double-
blind study (267). Symptom relief paralleled anti-staphylococcal
antibody presence (266), arguing for impaired development
of tolerance to autoepitopes of microbial origin in ME/CFS.
Further studies are needed.
A strong argument for Bcell-mediated autoimmunity in ME/
CFS has been the rituximAab eect (20, 22). Around 60% of
patients improved aer a lag period. Rituximab is a monoclonal
antibody directed against CD20, a surface antigen expressed on
the majority of Bcells. ey are killed when the antibody binds to
them. However, in a recent phase III trial there was no statistically
signicant eect observed (Mella, personal communication).
Until results of the trial are published, it is not known whether
this was due to a major placebo, or a minor rituximab, eect.
CD20 is mainly present on Bcells, but is neither expressed on
immature Bcells nor on most antibody producing cells such as
plasmablasts and plasma cells (268). Part of the problem may be
the subjective estimation of symptoms, prone to overestimation
of placebo eects. In future double-blind studies of treatments
for ME, objective symptom measures should be used to a larger
extent. Another confounding factor may be heterogeneity within
the ME/CFS patients although they were diagnosed according to
the Canada criteria. Detailed studies are strongly recommended.
Unpublished phase I and II studies have shown improvement
in ME/CFS patients aer treatment with the more unspecic
immunosuppressant cyclophosphamide (Fluge, personal com-
munication). It is another sign of autoimmunity contributing to
ME/CFS.
In autoimmunity dependent on autoantibodies, the errone-
ously activated Bcells are the root of the evil.
Increased Frequency of Lymphomas
in ME/CFS
Chronic immune stimulation increases the risk for Bcell lym-
phomas. is happens in many autoimmune diseases. In accord-
ance with the autoimmune hypothesis for ME/CFS presented
here, CFS patients have a greater risk of Bcell non-Hodgkin
lymphomas, in particular marginal zone lymphoma (OR=1.88,
95% CI = 1.38–2.57), compared with sex and age matched
controls (269).
In summary, the evidence for autoimmunity in ME/CFS is
indirect or circumstantial. It rests on the eect of immunosup-
pression (although unsubstantiated in a double-blind trial) of
anti-CD20, comorbidities with known autoimmunity (thyroiditis,
thyroidism) or possible autoimmunity (FM, POTS, IBS), prob-
able improvement aer immunostimulation, and an increased
frequency of certain autoantibodies and of Bcell lymphomas.
Of the Witebsky–Rose criteria for autoimmunity (270), direct;
transfer of disease by antibody, and indirect; transfer of disease
by cells to SCID mice, induction of disease by autoantigen,

FIGURE 3 | Metabolites and enzymes that are reportedly changed in ME/CFS. Molecules localized in energy metabolic organelles (peroxisome and mitochondrion),
and the whole cell, are shown in pink if increased in abundance and green if decreased in abundance. Changes may sometimes be visible only after exercise. The
blue “X” indicates a metabolic block implicated in ME/CFS (275). Normally functioning mitochondria convert oxygen to water through the respiratory chain. If the
aerobic energy production is impaired, some oxygen can be converted to hydrogen peroxide and reactive oxygen species (ROS). PPP is the pentose phosphate
pathway, an alternative pathway for energy production from carbohydrates. It produces the antioxidant NADPH. Together with glutathione, a product of one-carbon
metabolism, NADPH controls ROS accumulation (“Redox ctrl”). A panel including some of the marked molecules may be useful as biomarker for ME/CFS.
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identication of antibodies within lesions, genetic predisposition,
autoantibodies or self-reactive Tcells, a few (genetic predisposi-
tion and increased frequency of autoantibodies) are partially
fullled. Much work remains.
CAN AUTOIMMUNITY EXPLAIN ENERGY
METABOLIC DISTURBANCES AND PEM?
e objective measurement of energy metabolism by repeated
cardiopulmonary exercise testing revealed a defective aerobic
energy production in ME/CFS (19). is is manifested as an
abnormal fatigability. Fatigability, which may or may not be
related to the PEM of ME/CFS (252–255), occurs as a major
symptom in some autoimmune (6, 184, 256–261), mitochondrial
(262, 263) and infectious (264) diseases. It remains to be studied
how unique the PEM of ME/CFS is.
Several observations indicate that the oxygen dependent
(aerobic) energy metabolism is disturbed in ME/CFS (8, 19,
262, 271–273) (Figure3; Tab l e 6 ). at disturbance may be the
reason for PEM. Mitochondria are the main producers of energy.
ey derive from α-proteobacteria which, over one billion years
ago, were taken up into eukaryotic cells, see, e.g., Ref. (274).
It is not unreasonable to guess that an immune defense against
an infecting bacterium can cause collateral damage to mitochon-
dria. While there must be protective mechanisms against this
(e.g., tolerization), they may not always work.
A new dimension for understanding ME/CFS was added
by recent publications (275, 279, 280, 282, 284). ey revealed
profound metabolic dierences between ME/CFS patients and
controls. Some of these changes may derive from an abnormal
mitochondrial function in ME/CFS. Whether these abnormali-
ties have an autoimmune origin is not known.
Evidence for Inhibition of Key Energy
Metabolic Processes in ME/CFS
A number of reports indicate a metabolic disturbance, indicative
of mitochondrial dysfunction (19, 273, 275, 276, 279, 280, 282,
284–286) in ME/CFS. Evidence points to a defective aerobic
energy metabolism. e aerobic energy metabolism (TCA+res-
piratory chain) gives an around 10-fold higher yield of ATP per
glucose molecule than the anaerobic metabolism. ere are
similarities with PBC, a model of autoantibody mediated energy
blockade (180, 287–292). In analogy with PBC, where IgG were
found to be energy inhibitory, circulating energy inhibitors have
been found in ME/CFS (275), although their molecular nature is
unknown. e demonstration of such inhibitors has the potential

TABLE 6 | Potential energy metabolic biomarkers for ME/CFS.
Metabolic role Metabolite or protein Body fluid Gain (+) or loss (−) in
ME/CFS vs healthy controls
Reference Comment
One-carbon metabolism Taurine Blood −(276)
Homocysteine Cerebrospinal
fluid (CSF)
+(277)
Oxidation Reactive oxygen species
(peroxide, etc.)
Serum +(239, 278) Measured using thiobarbituric
acid reactive substances
Amino acid metabolism
(anaplerotic amino acids)
Leucine, isoleucine,
phenylalanine, and tyrosine
Blood −(275)
Urea cycle and amino
acid metabolism
Citrulline Blood and urine −(279)
Ornithine Blood and urine +(279)
Lipid metabolism Phospholipids, including
cardiolipin
Blood −(280)
Acyl carnitine Blood −(276, 280)
(Glyco)sphingolipids Blood −(280)
Glycolysis Lactate Blood and CSF
(muscle)
+(271, 275, 281) Higher after exercise
(physical and mental)
Tricarboxylic acid
cycle (TCA)
Isocitrate Blood −(279)
TCA Succinate Blood and urine −(282)
TCA Aconitate hydratase protein Saliva +(283)
ATP synthase protein Saliva +(283)
ATP translocase Saliva −(283)
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to explain the disease and create ecient diagnostic tests. It would
be logical if, like in PBC, these circulating inhibitors turned out to
be immunoglobulins, presumably directed against mitochondrial
proteins.
It is an important research task to compare PEM of PBC with
the PEM of ME/CFS, and PEM-like fatigability in other diseases.
Fibromyalgia is a common comorbidity of ME/CFS, which
also occurs in several established autoimmune conditions
(55, 293–298). e delineation of ME/CFS from FM is sometimes
not straightforward. FM muscle displays metabolic abnormalities
(299, 300) reminiscent of those observed in ME/CFS. Besides the
comorbidity, there seem to be both common (myalgia, muscle
metabolic abnormalities, increased frequency of autoantibod-
ies) and distinct (PEM, cognitive disturbance) aspects of these
conditions.
Can a Defective Energy Metabolism Also
Explain the Cognitive Disturbances?
A decient energy supply may also cause cognitive disturbance
in ME/CFS (195). It can be elicited by both physical and mental
(301, 302) activity. In analogy with accumulation of lactate in
serum and muscle aer exercise, increased concentrations of
lactate in CSF have been found in ME/CFS (281, 303) and the
related condition GWI (304). ME/CFS-specic changes in the
CSF proteome which included accumulation of complement
components, a sign of antibody activity, were also described (305).
Homocysteine is part of the one-carbon metabolism, which
was reported to be deranged in ME/CFS patients, perhaps
as a compensation for other energy metabolic disturbances.
Homocysteine levels in CSF are a widely used marker of
reduced cognition. In 1997, an investigation of homocysteine
and vitamin B12 in CSF of patients who fulfilled the criteria
of both FM and chronic fatigue syndrome was carried out.
In comparison with a large healthy control group, all eleven
patients in the study had increased homocysteine levels in
CSF, although the blood levels were usually not increased. The
CSF-B12 level appeared to be generally low. The high CSF-
homocysteine and low CSF-B12 levels correlated significantly
with ratings of mental fatigue. The results were at the time
interpreted as suggesting a block of inflow over the blood
brain barrier of B12 and/or folic acid (277). The derangement
in one-carbon metabolism is supported by 20years’ experience
of vitamin B12 and B9 treatment in ME/CFS patients, which
tends to diminish impaired cognition (“brain fog”) (306). It is
not immediately evident why the one-carbon metabolic path-
way would change after a block of aerobic energy production.
The genesis of this metabolic aberration in ME/CFS should be
further studied.
e state of the one-carbon metabolism also has profound
epigenetic consequences. Both DNA and histone methylation
depend on the availability of S-adenosyl-methionine.
How Are Metabolic Disturbances
Related to the Flare after Exercise?
e “are” is a central event aer exercise, accounting for much
of the malaise in PEM.
A link between mitochondrial dysfunction and innate
immune dysregulation is suggested by recent immunometabolic
ndings which demonstrate that the energy producing organelles
(mitochondria and peroxisomes) are coupled via mitochondrial

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TABLE 7 | How do recent findings fit into the explanatory model?
Proposed step Finding Degree of fit with presented
explanatory model
Genetic predisposition GWAS: ME/CFS-specific single-nucleotide polymorphisms
in microtubule associated protein 7, CCDC7, and TCRα (50)
HLA: increase in DQA1*01 (48)
IgG subclass deficiency (102–105)
Imperfect, needs deeper study
Presence of transmissible agent
not excluded
Changes in microbiota Reduced overall diversity (34, 191, 192)
Divergence more concentrated to certain taxa (33, 35)
Imperfect, needs deeper study
Gut microleakage Increased lipopolysaccharide (LPS), LPS-binding protein,
and sCD14 in blood (34, 192)
Imperfect, needs deeper study
Autoantibodies Yes, but maybe not disease specific (see Table4) Imperfect, needs deeper study
Triggering antigenic challenge Epstein–Barr virus infection is a common trigger, some
other infections also (see Table2)
Imperfect. Retrospective diagnosis
of infections is often problematic
Autopathic Bcell clones Removal of Bcells by anti-CD20 or other immunosuppressants
improves 50–60% of ME/CFS patients in phase I–II trials (20–22)
Increased frequency of Bcell lymphomas in ME/CFS patients (269)
Larger study with as objective measures
as possible is necessary. Autologous
bone marrow transplantation could
give additional evidence
Defective tolerization
of autoreactive Bcell clones
Increased frequency of autoimmune disorders and comorbidities
in ME/CFS patients
Effect of microbial immune modulation (266, 321, 322)
Imperfect, needs deeper study
Disturbance of energy
metabolism
Clear evidence of energy metabolic disturbance (275, 276, 279, 280) Imperfect. Needs more observations,
especially with reference to exercise
Autoimmunity causing energy
metabolic disturbance
Circulating energy inhibitory factors demonstrated
(like in primary biliary cirrhosis) (275, 292)
Molecular nature of inhibitors is unknown.
If they are immunoglobulins, can they reach
intracellular targets?
antiviral signaling protein, a signaling molecule, to the inamma-
some, which can orchestrate release of inammatory cytokines
(307–314). Another sign of mitochondrial derangement in ME/
CFS is the occurrence of ROS in serum, measured as increase
in thiobarbituric acid reactive substances or decrease of reduced
ascorbic acid (239, 278). ese tests may also become part of a
biomarker panel for ME/CFS. It was recently shown that oxida-
tion of a critical cysteine residue in pyruvate kinase M2, one of
the enzymes of the pyruvate dehydrogenase complex (PDC), can
lead to a block in pyruvate production, potentially mimicking an
autoimmune block of PDC activity (315, 316). us, although
the pattern of metabolic changes in ME/CFS is compatible with
a PDH block (275) (blue X in Figure3), possibly of autoimmune
origin, the block could also be caused by ROS (317), frequently
increased in ME/CFS. ROS are produced in four places in the cell;
NADPH oxidase (in Figure3), peroxisomes and in respiratory
chain complexes I and III (318). ROS production can be evoked
by starvation (319) and respiratory complex I malfunction
(320). ROS inuence glutathione levels and indirectly the whole
one-carbon metabolism. It could be a key player in ME/CFS
pathogenesis. e origin and pathobiology of ROS in ME/CFS
should be investigated.
HOW WELL DO CLINICAL AND
LABORATORY DATA FIT INTO THE
EXPLANATORY MODEL?
As shown in Tab le7, much work remains before the autoimmune
nature of ME/CFS can be considered established.
WHICH FACTS DO NOT FIT INTO THE
EXPLANATORY MODEL?
Even if ME/CFS is of autoimmune origin, is it the metabolic
block (275) or the autoantibodies to hormone receptors (93)
which are most important for pathogenesis?
e mechanism behind the are aer exercise (238) is
obscure. Maybe a mitochondrial defect can lead to an increased
activity in the innate immune network.
e disturbance in one-carbon metabolism (277, 280) may
or may not be related to the disturbed transition between
glycolysis and TCA cycle. It is indicative of a wider metabolic
derangement than a block of PDH (275) would be expected to
lead to. ere are several papers on hormones (322), including
glucocorticoids (257) and transient receptor potential channel
hormones (222), and their receptors (106, 107, 109), in ME/
CFS. It is conceivable that parts of the autonomic dysfunction
can be explained in this way.
CONCLUSION
ME/CFS is a challenge for the patients, for medical research
and ethics, for all of public health, and for society. The intensi-
fied hunt for scientific evidence explaining ME/CFS has large
consequences for many thousands of people. Many of the
published results need repetition. But as shown in this article
the signs that autoimmunity and energy metabolic deficiency
is involved in the disease have increased. A hypothetical
but logical path, from gastrointestinal tract dysbiosis, to

12
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Frontiers in Immunology | www.frontiersin.org February 2018 | Volume 9 | Article 229
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e recently intensied research on ME/CFS yielded many
biomarker candidates, as mentioned in this study. e main
consequence of this work is that the proposition that there is
no logical somatic explanatory model for ME/CFS (14) can be
refuted. However, like for virtually all autoimmune diseases, the
explanatory model has several tentative steps which need further
exploration. e elucidation of the molecular nature of circulat-
ing metabolic inhibitors in ME/CFS (275) is a central question.
If they turn out to be immunoglobulins, they may directly yield
diagnostically useful biomarkers and an explanation of the
mechanism underlying ME/CFS.
e risk of giving a hypothetical unifying explanation, as in
this study, is that hypothesis can be perceived as fact, and that it
inuences the perception of the disease. But contacts with ME/
CFS patients and those who care for them have convinced us
that most can handle the uncertainty that hypotheses involve.
Without hypotheses we cannot direct the acquisition of further
knowledge of ME/CFS.
AUTHOR CONTRIBUTIONS
JB conceived of the paper and wrote most of it. C-GG added
substantial parts especially regarding the clinical aspects. AE
participated in the writing. She is writing a book on ME/CFS, her
comprehensive knowledge was valuable. MR participated in the
writing. He concentrated on checking references. AR contributed
substantially, especially regarding the immunological aspects.
ACKNOWLEDGMENTS
e authors thank Dr. Geraldine Cambridge for fruitful discus-
sions on mechanisms of ME/CFS pathogenesis and Dr. Lucinda
Bateman for discussions on clinical aspects of ME/CFS.
FUNDING
e authors thank the SolveME/CFS Initiative, the Swedish
ME Association, the Open Medicine Foundation (project
no. 1011454), and the Uppsala Academic Hospital (Grant
FOU2017-0039) for economic support, as well as the Invest in
ME Foundation, London, for travel grants. e funders did not
inuence the research or the manuscript in any way.

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