Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Not Due to Anti-mitochondrial Antibodies

Abstract

Metabolic profiling studies have recently indicated dysfunctional mitochondria in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This includes an impaired function of pyruvate dehydrogenase complex (PDC), possibly driven by serum factor(s), which leads to inadequate adenosine triphosphate generation and excessive lactate accumulation. A reminiscent energy blockade is likely to occur in primary biliary cholangitis (PBC), caused by anti-PDC autoantibodies, as recently proposed. PBC is associated with fatigue and post-exertional malaise, also signifying ME/CFS. We herein have investigated whether ME/CFS patients have autoreactive antibodies that could interfere with mitochondrial function. We found that only 1 of 161 examined ME/CFS patients was positive for anti-PDC, while all PBC patients (15/15) presented significant IgM, IgG, and IgA anti-PDC reactivity, as previously shown. None of fibromyalgia patients (0/14), multiple sclerosis patients (0/29), and healthy blood donors (0/44) controls showed reactivities. Anti-mitochondrial autoantibodies (inner and outer membrane) were negative in ME/CFS cohort. Anti-cardiolipin antibody levels in patients did not differ significantly from healthy blood donors. In conclusion, the impaired mitochondrial/metabolic dysfunction, observed in ME/CFS, cannot be explained by presence of circulating autoantibodies against the tested mitochondrial epitopes.

Keywords: AMA; PDC; anti-mitochondrial autoantibodies; anti-pyruvate dehydrogenase complex antibodies; myalgic encephalomyelitis/chronic fatigue syndrome.

Copyright © 2020 Nilsson, Palmer, Apostolou, Gottfries, Rizwan, Dahle and Rosén.

Figures

Figure 1

(A) Anti-pyruvate dehydrogenase complex (anti-PDC) IgG antibody levels in the plasma of healthy blood donors (BD, n = 44), primary biliary cholangitis patients (PBC, n = 15), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients (cohort 1: C1, n = 46, cohort 2: C2, n = 61 and cohort 3: C3, n = 18), myalgic encephalomyelitis/chronic fatigue syndrome with fibromyalgia (ME/CFS+FM) (cohort 1: C1, n = 17 and cohort 3: C3, n = 19), fibromyalgia (FM) patients (cohort 1: C1, n = 11 and cohort 3: C3, n = 3), age-matched healthy blood donors (BD3, n = 15) from cohort 3, and multiple sclerosis (MS) patients (cohort1: C1, n = 29). (B) Immunoblot analysis against human extracted pyruvate dehydrogenase of pooled primary biliary cholangitis (PBC) serum (lanes 1–3), plasma sample from patient #21 with myalgic encephalomyelitis/chronic fatigue syndrome with fibromyalgia (ME/CFS+FM patient (lanes: 4–6), and plasma sample from patient #43 with myalgic encephalomyelitis/chronic fatigue syndrome patient (lanes: 7–9). Samples were found positive for anti-PDC antibodies using the anti-PDC ELISA. Pooled PBC sample and patient #21 (ME/CFS+FM) were found positive for the major autoreactive proteins within the PDC complex, dihydrolipoamide acetyltransferase (E2) and the E3-binding protein (E3BP), whereas patient #43 (ME/CFS) was found negative. (C,D) Anti-PDC antibody levels of IgM and IgA subclass in the same samples as in panel (A). Dotted line represents cut-off levels for each Immunoglobulin subclass. Data are represented as individual points for each subject, overlaid by a horizontal mean group value ± SEM. Multiple group comparisons were analyzed by one-way ANOVA. Statistically significant differences are indicated (p < 0.0001).

Figure 2

Anti-cardiolipin (ACA) antibody levels of IgG (A), IgM (B), and IgA (C) subclasses in the plasma of healthy blood donors and patients in cohort 1. For IgG and IgM the analysis included samples from healthy blood donors (BD, n = 24), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS patients, n = 39), myalgic encephalomyelitis/chronic fatigue syndrome with fibromyalgia (ME/CFS+FM, n = 8) and fibromyalgia (FM, n = 8) patients. For IgA ACA analysis samples included BD (n = 24), ME/CFS patients (n = 39), ME/CSF+FM patients (n = 9), and FM (n = 8) patients. GPL, MPL, and APL correspond to IgG, IgM and IgA phospholipid units, respectively. Dotted lines represent cut-off levels for each subclass. Data are represented as individual points for each subject, overlaid by a horizontal mean group value ± SEM. For IgG and IgM ACA antibody levels, values < 10 U/mL were considered negative, values between 10 and 40 were considered as weak positive and values higher that 40 were considered positive. For IgA ACA, values < 12 U/mL were considered negative. No statistically significant differences were noted.