IL-10 deserves a special mentioning because of its diverse CFS significance under different conditions and experiments. Consistent with previous studies, a 1-year longitudinal study didn't show persistent cytokine findings either (10.1186/1479-5876-10-88
). Persistent, however, was a reduced NK cell activity. Moreover, their term 2 data shows a correlation between reduced mitogen-induced IL-10 levels and a normalization of IL-2, IFN-γ, and TNF-α levels. This indicates that the season of the year might influence an exclusive common factor of these cytokines' deviations in the studied long-term CFS patients. Under this assumption, inconsistent single-term findings are not surprising. A study on exercise-induced IL-10 showed that IL-10 gene expression increases while its concentration remains relatively unaffected (pmid:24974723
). This indicates that IL-10 might need to be differentiated to become a reliable biomarker for CFS. Another study on Cerebrospinal Fluids (CSF) of CFS patients determined IL-10 to be the only among 27 cytokines that showed significantly reduced concentrations in CSF compared to controls (10.1155/2015/929720
). Contrary to the assessment of Yang et al. that IL-10 would be supported as a positively correlating marker by the majority of CFS authors, I could not confirm this by reading through the referenced literature. Even though significant, the results are completely inconsistent amongst each other.
In an effort to cross-reference the role of IL-10 in EBV infections, vIL-10 has to be mentioned. vIL-10 has similar homology to the human IL-10 variant (hIL-10) but differs in certain pathway functions. vIL-10 is not an exclusive feature of EBV but is also encoded by other viruses, especially types of herpes (10.1128/JVI.01098-09
). A great difference between hIL-10 and vIL-10 is the significantly compromised STAT3 phosphorylation of vIL-10, which can lead to elevated immune-inflammatory feedback. The IC50 of vIL-10 on hIL-10's pSTAT3 signaling is almost reached at about half of the overall IL-10 concentration, which is also the lower boundary of vIL-10 alone. This means that at >50% IL-10 concentration, there is 1/4 - 1/3 of the expected pSTAT3 signaling as one would expect by an undifferentiated IL-10 measurement.
A study on vIL-10 in the context of System Lupus Erythematosus (SLE) showed that vIL-10 can be found in significantly higher concentrations in SLE patients (10.3389/fimmu.2018.02198
). SLE is significantly associated with EBV in multiple ways (e.g. antibody levels) (10.1007/s10238-018-0535-0
). There is also initial evidence for EBV to cause SLE (pmid:17121489
). Jog et al. further showed that vIL-10 correlates with IgA antibodies to EBV viral capsid antigen. This is an indicator for EBV reactivations. vIL-10 doesn't seem to directly correlate with hIL-10, though. This means that vIL-10 would not explain any deviations of measured hIL-10 levels if research actually differentiates overall IL-10. But the inhibition of the STAT3 phosphorylation would limit hIL-10's regulatory effect on monocytes.
The survey on vIL-10 summarizes multiple of the exclusive effects of the viral IL-10 homolog (10.1128/JVI.01098-09
). According to their summary, the immunosuppressive properties of vIL-10 provide EBV enhanced survivability in the human organism. In contrast to hIL-10, vIL-10 also lacks the stimulatory capability of thymocyte and mast cell proliferation, as well as MHC II surface expression on B cells. Besides the 1000-fold lower IL-10R1 affinity, vIL-10 also showed an equally reduced potential of inhibiting IL-2 (pmid:8992974
). Moreover, the BCRF1 gene also showed great inhibitory effects on IFN-y synthesis in human PBMCs (10.1126/science.2173142
). According to Slobedman et al. opinion, EBV's gain of the BCRF1 gene, which encodes the IL-10 homology, most likely enhances latent infection.
Interestingly, hIL-10 antibodies, as they are common in pathology for determining IL-10 levels are not completely specific to hIL-10. A western blot showed a certain affinity to vIL-10 (10.3389/fimmu.2018.02198
). In total, vIL-10 probably shows rather low concentrations in the blood. Unfortunately, I could not find any data to relatively quantify both homologs in test groups beyond arbitrary units. However, EBV doesn't need wide systemic proliferation for systemic symptoms to happen. Localized residues would be sufficient as a trigger after exertion when IL-10 proliferation is naturally amplified, as it has been shown with athletic controls (pmid:24974723
). After all, this might be the reason for the elevated gene expression but this is speculative. I imagine that this localized immune-suppressive dynamic of vIL-10 could be a catalyst for true reactivations and new infections of all kinds of pathogens. Surprisingly, the same vIL-10 dynamic has been shown for CAEBV (10.1086/517260
), which means impaired NK cell activity, a lack of cytotoxicity, and reduced IFN-γ levels.
Given the assumption that vIL-10 plays a role in EBV-induced CFS, IFN-γ would be a physiological and desirable response, despite the fatigue that it induces. Similarly, NK cell and cytotoxic support would be adverse to the relatively new BCRF1 adaptation of the EBV virus. EBV mutants that lack BCRF1 and BNLF2a - the two genes responsible for vIL-10's synthesis - can not sufficiently evade pre-latent and lytic immune response for an encoding of latent genes into further lymphocytes (10.1371/journal.ppat.1002704
). Even though a therapy that targets vIL-10 might not be able to eliminate viral residues, it might block the reactivating process (i.e. the lytic phase) of EBV and thereby inhibit the further proliferation of EBV's latent B cell reservoir (10.1016/j.virusres.2010.08.012
). One theoretical consideration would be the use of vIL-10-targeted monoclonal antibodies since they would not show any affinity towards hIL-10. Common IL-10 antibodies most likely will not work, though, because of the higher affinity to hIL-10. This only works in vitro with knockout concentrations.
Increased TGF-β levels would further support the latent-lytic reactivation of EBV (10.1128/JVI.01197-10
), but also impair NK cell activity (not count) due to its complementary function with IL-10. This dynamic has been shown to be part of the pathogenesis of HIV (10.1186/s12879-018-2991-2
), and to affect the energy metabolism, including glycolysis (10.3389/fimmu.2018.01364
). Hence, a normalization of TGF-β levels might be beneficial when they are elevated.
First and foremost, the question is if vIL-10 can be detected in the EBV subgroup of CFS patients. The similarities with the pathology of CFS are remarkable. This includes effects on IL-1β, IL-2, NK cell activity, cytotoxicity, particularly the gradually declining IFN-γ levels that occasionally seem to flare up again or remain mildly elevated for CFS patients. Unfortunately, I could not find any data on JAK/STAT3 signaling in CFS patients to support this theory, which would be the next-best indicator I presume.