Enterovirus-Induced ANT Autoantibodies: the Cause of ME/CFS? Research beginning in the 1980s in Germany on enteroviral heart muscle infections (myocarditis) found evidence of an autoantibody which targets the adenine nucleotide translocator (ANT) protein located on the mitochondrial membrane, and thereby leads to impairment of mitochondrial energy production. The German researchers observed that these ANT autoantibodies are cross-reactive to enterovirus VP capsid protein of coxsackievirus B3. So the researchers suggested that enterovirus may be inducing these autoantibodies by molecular mimicry, as a result of the viral VP capsid protein being molecularly similar to the ANT protein found on mitochondria. To support this claim, they also note that there are homologies in the peptide sequence of the ANT protein and the VP capsid protein of coxsackievirus B3 (such homologies are thought to underpin autoimmunity by molecular mimicry). Because mitochondrial ANT protein plays a crucial role of transporting ATP generated in the mitochondria into the cytosol of the cell, as well as transporting ADP from the cytosol back into the mitochondria for recycling, any dysfunction in the ANT protein, caused by an autoantibody binding to ANT, could severely disrupt energy metabolism. And indeed, the German research found that in coxsackievirus B myocarditis and dilated cardiomyopathy (dilated cardiomyopathy is a further progression of myocarditis), there was a major disturbance in the energy metabolism in the heart muscle. In fact in one guinea pig study, they found the measured energy output from hearts affected by the ANT autoantibody was five times less than the energy output from the hearts of healthy animals. And in addition, ANT autoantibody-affected hearts produced more than double the amount of lactate. So clearly this ANT autoantibody is associated with a very substantial impediment in energy production, as well as increased lactate production. That certainly is beginning to sound like the state of affairs we find in ME/CFS. Implications of ANT Autoantibody Research for ME/CFS The ANT autoantibody research was noted by Professor Peter Behan of Glasgow University, Scotland, who suggested in a paper in 1985 that the ANT autoantibody might be involved in creating the low energy state of ME/CFS. In others words, Prof Behan proposed the following viral-autoimmune etiology for ME/CFS: Enterovirus infection ➤ induces ANT autoantibodies ➤ disrupts mitochondria ➤ leads to ME/CFS Surprisingly, nobody to my knowledge has looked to see if ANT autoantibodies are present in ME/CFS, even though they are linked to enterovirus infections and cause a huge decrease in muscle energy production. However in recent years, evidence indicating the mitochondrial ANT protein is pretty dysfunctional in ME/CFS patients has emerged: the 2009 energy metabolism study of Myhill, Booth and McLaren-Howard (MBM) found that ME/CFS patients have major dysfunctions in their ANT protein — both dysfunctions in the ANT transport of ATP from the mitochondria into the cytosol of the cell, as well as dysfunctions in the ANT transport of ADP from the cytosol into the mitochondria. Thus this MBM study implies that something is affecting ANT in ME/CFS patients. Could that something be ANT autoantibodies? Note that in the MBM study, they refer to the mitochondrial ANT protein as "translocator protein". This adenine nucleotide translocator (ANT) protein incidentally is also known by the names of: ATP/ADP translocator, or ATP/ADP carrier. Furthermore, Fluge and Mella's research, which found that rituximab can improve or cure ME/CFS, also suggests that an autoantibody may be driving ME/CFS. Rituximab deletes all the B-cells in the blood, and so some time after rituximab treatment, the production of autoantibodies will tend to cease. Thus the idea that ANT autoantibodies might be a cause of ME/CFS is consistent with observations that rituximab can improve or cure ME/CFS. ANT Autoantibodies and Calcium Channelopathies The German researchers found that their ANT autoantibody is also cross-reactive to the calcium channel, and that as this autoantibody binds to the calcium channel, it alters calcium influx into the cell, resulting in calcium channelopathies. Recent research from Australia has now found calcium channelopathies in the natural killer cells of ME/CFS patients. Perhaps an ANT autoantibody might help explain these ME/CFS channelopathies. Grand Unifying Theory of ME/CFS? This idea that ANT autoantibodies may be driving ME/CFS would tie together three characteristics of ME/CFS: its well-researched links to enteroviral infection; its apparent involvement of autoimmunity; and its observed energy metabolism dysfunctions. So this enterovirus-induced ANT autoantibody, if it exists in ME/CFS, could amount to a grand unifying theory of ME/CFS. If ME/CFS Were Caused by ANT Autoantibodies, What Would Be the Treatment? Obviously rituximab is a treatment that should eliminate ANT autoantibodies. And since these ANT autoantibodies appear to arise from a chronic enterovirus infection, elimination of that infection could also treat ME/CFS. Dr John Chia's interferon treatment of enterovirus infections in ME/CFS, which put some patients into remission for 2 to 14 months, indicates that treating enterovirus can be effective. Unfortunately interferon is not viable as a long term treatment, but its one-off efficacy does prove in principle that treating the virus treats ME/CFS. A third speculative approach that might help decrease the possible ANT autoantibodies in ME/CFS involves reducing the cytokine IL-17 and reducing the number of Th17 cells. A 2010 mouse study found that in acute coxsackievirus B3 myocarditis, reducing IL-17 led to a reduction in ANT autoantibodies, which the authors suggested could lead to a novel therapeutic approach for myocarditis. Th17 cells are characterized by the production of IL-17, and in other myocarditis studies, Th17 cells have been linked to the worsening of coxsackievirus B myocarditis, because Th17 seems to promote viral replication. Thus a treatment which decreases Th17 and IL-17 may well reduce ANT autoantibody production. The supplement N-acetyl-glucosamine has been shown to reduce both Th17 and IL-17. There are also several other drugs and supplements which are known to inhibit Th17 and IL-17. Further Details of the ANT Autoantibody Research In terms of how the ANT autoantibody can affect the functioning of the ANT protein on the mitochondrial membrane, the researchers have proposed four possible mechanisms: It's interesting that ANT protein is synthesized in the cytosol of the cell, and then later transported to the mitochondria. So the ANT autoantibodies could bind to the ANT protein while this protein is still in the cytosol. The researchers did try to verify that an antibody had entered the heart muscle cells: There are actually a number of anti-mitochondrial autoantibodies known, see: Anti-mitochondrial antibody. So it is not unusual to have autoantibodies that target parts of mitochondria. A further complexity about ANT protein is that the researchers found a shift in the relative expression of the three ANT protein isoforms (ANT1, ANT2 and ANT3) in myocarditis and dilated cardiomyopathy patients: This increase in ANT1 expression, incidentally, may be detrimental to patients with enterovirus (EV) myocarditis or dilated cardiomyopathy heart infections: So lowered ANT1 expression is linked to elimination of the enterovirus infection. The authors say that ANT1 overexpression influences the expression of other genes that may affect viral replication. Incidentally, if lowered ANT1 expression is associated with spontaneous elimination of enterovirus infection, then conceivably any treatment which reduces ANT1 expression might have useful antiviral effects. A Question I Have One question I have: why does this ANT autoantibody apparently induced by enteroviral heart muscle infection only affect the heart muscle, and not the other organs? The researchers found that in dilated cardiomyopathy patients, there was significant binding to heart ANT protein, whereas little or no binding was found on kidney ANT protein or liver ANT protein. So the ill effects of the ANT autoantibody seem to be restricted to the heart. Although the enterovirus infection itself is located in the heart, I am not really clear why the ANT autoantibodies that this infection induces (which are manufactured by the B-cell-derived plasma cells in the blood circulation) do not also disrupt the ANT protein in the mitochondria of the cells of other organs in the body. Perhaps @Jonathan Edwards might know of a mechanism which keeps the autoimmune effects of ANT autoantibodies restricted to the heart muscle, in the case of enteroviral myocarditis and dilated cardiomyopathy. Terminology Note that when reading the studies, the adenine nucleotide translocator (ANT) has many synonyms, including: adenine nucleotide translocase, translocator protein, ATP/ADP translocator, ADP/ATP translocator, ATP/ADP translocase, and ATP/ADP carrier. Even Wikipedia is confused about these synonyms, as there appears to be two Wikipedia articles on the same subject under different synonyms: Adenine nucleotide translocator and ADP/ATP translocase. References  Significance of the adenine nucleotide translocator in the pathogenesis of viral heart disease. Schultheiss HP, Schulze K, Dörner A. Mol Cell Biochem. 1996 Oct-Nov;163-164:319-27. Full paper here.  The role of the ADP/ATP carrier in the pathogenesis of viral heart disease. Schulze K, Schultheiss HP. Eur Heart J. 1995 Dec;16 Suppl O:64-7. Full paper here.  Disturbance of the myocardial energy metabolism in dilated cardiomyopathy due to autoimmunological mechanisms. Schultheiss HP. Circulation. 1993 May;87(5 Suppl):IV43-8.  Disturbance of myocardial energy metabolism in experimental virus myocarditis by antibodies against the adenine nucleotide translocator. Schulze K, Witzenbichler B, Christmann C, Schultheiss HP. Cardiovasc Res. 1999 Oct;44(1):91-100. Full paper here.  Antibodies to ADP-ATP carrier--an autoantigen in myocarditis and dilated cardiomyopathy--impair cardiac function. Schulze K, Becker BF, Schauer R, Schultheiss HP. Circulation. 1990 Mar;81(3):959-69. Full paper here.  The postviral fatigue syndrome--an analysis of the findings in 50 cases. Behan PO, Behan WM, Bell EJ. J Infect. 1985 May;10(3):211-22. Full paper here.  Chronic fatigue syndrome and mitochondrial dysfunction. Myhill S, Booth NE, McLaren-Howard J. Int J Clin Exp Med. 2009 2(1):1-16. Full paper here.  Antibody-mediated enhancement of calcium permeability in cardiac myocytes. Schultheiss HP, Kühl U, Janda I, Melzner B, Ulrich G, Morad M. J Exp Med. 1988 Dec 1;168(6):2105-19. Full paper here.  Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels. Nguyen T, Johnston S, Clarke L, Smith P, Staines D, Marshall-Gradisnik S. Clin Exp Immunol. 2017 Feb;187(2):284-293. Full paper here.  Neutralization of IL-17 inhibits the production of anti-ANT autoantibodies in CVB3-induced acute viral myocarditis. Yuan J, Yu M, Lin QW, Cao AL, Yu X, Dong JH, Wang JP, Zhang JH, Wang M, Guo HP, Liao YH. Int Immunopharmacol. 2010 Mar;10(3):272-6. Full paper here.  N-acetylglucosamine inhibits T-helper 1 (Th1)/T-helper 17 (Th17) cell responses and treats experimental autoimmune encephalomyelitis. Grigorian A, Araujo L, Naidu NN, Place DJ, Choudhury B, Demetriou M. J Biol Chem. 2011 Nov 18;286(46):40133-41. Full paper here.  Adenine nucleotide translocase 1 expression affects enterovirus infection in human and murine hearts. Kühl U, Ebermann L, Lassner D, Klingel K, Klumpe I, Winter J, Zeichhardt H, Schultheiss HP, Dörner A. Int J Cardiol. 2014 Apr 1;172(3):e449-52. Full paper here.  The antigenic characteristics and the significance of the adenine nucleotide translocator as a major autoantigen to antimitochondrial antibodies in dilated cardiomyopathy. Schultheiss HP, Schwimmbeck P, Bolte HD, Klingenberg M. Adv Myocardiol. 1985;6:311-27.