We measured the peripheral blood cytokines IL-6, IL-8, and IL-10 in the carriers of the FMR1 premutation and in control individuals, and found that carriers had significantly higher levels of the anti-inflammatory cytokine IL-10. Concentrations of IL-10 significantly correlated with the number of CGG repeats, whereas the concentrations of proinflammatory cytokines IL-6 and IL-8 did not.
IL-10 is a key orchestrator of the immune system with potent anti-inflammatory effects. An increase in IL-10 concentration in the peripheral blood was previously demonstrated in other neurodegenerative disorders, such as PD and HD [26, 27]. Although it is less severe, FXTAS shares features with HD including trinucleotide-repeat expansions, the presence of intranuclear inclusions, abnormal movements and cognitive decline. HD-specific trinucleotide-repeat expansions are thought to primarily cause accumulation of the abnormal polyglutamine-containing proteins , unlike FXTAS repeats that affect the 5′-UTR of FMR1 mRNA. It is tempting to speculate that an accumulation of the expanded mRNA, which was also reported in HD, plays a role in the activation of specific immune pathways involved in these types of diseases.
In our study, we did not find a significant increase in the concentration of proinflammatory cytokines IL-6 and IL-8 in peripheral blood, as observed in the blood as well as in the brain of patients affected by AD, PD, and HD [29, 30]. Bjorkqvist and colleagues compared plasma levels of numerous cytokines in HD patients and observed that the combination of plasma IL-6, IL-8, and IL-10 levels could very efficiently differentiate between HD expansion carriers (premanifest and manifest) and controls . We did not have symptomatic FXTAS patients available for our analysis, and future studies would be necessary to identify if and how the immune status of these individuals changes in the presence of symptoms. However, as shown in Figure 2, we do observe a strong correlation between IL-6 and IL-8 concentrations (r = 0.79), whereas the correlation with IL-10 concentrations is weaker (r = 0.64 and r = 0.58, respectively).
IL-10 is secreted by various cell types: different T-cell subsets, macrophages, dendritic cells, B cells, mast cells, and eosinophils [31–33]. The increased IL-10 levels observed in FMR1 premutation carriers could therefore be due to activation of immune cells, as well as a direct consequence of IL-10 gene overexpression in PBMCs. Specifically, the FMR1 gene is expressed in PBMCs ; therefore the expression of the pathological repeats could alter intrinsic properties of PBMCs and lead to the increased IL-10 production. In general, cells expressing FMR1 mRNA containing more than 55 CGG repeats were shown to have growth defects, abnormal distribution of lamin and enhanced expression of stress proteins ; these could potentially trigger an increase of IL-10 production in many diverse immune cells. Further studies will be needed to elucidate the precise mechanism of IL-10 production.
Deregulation of IL-10 was associated with various diseases, such as cancer, rheumatoid arthritis, systemic lupus erythematosus, asthma, infectious disorders, and so forth , where both overexpression and IL-10 deficiency were shown to have a pathophysiological significance. Most often enhanced expression of IL-10 is beneficial for the individuals due to the activation of anti-inflammatory mechanisms, although a detrimental effect of IL-10 overexpression was demonstrated in a mouse model that subsequently developed a demyelinating peripheral neuropathy . Although FXTAS patients show a reduction of brain myelin content that is also associated with neuronal loss , it is hard to say whether this is somehow related to the observed increase of IL-10 levels in peripheral blood.
The relationship between increased concentrations of IL-10 in the peripheral blood of FXTAS patients and central nervous system pathology remains unknown. Pathological changes in the nervous system and increased IL-10 levels in peripheral blood could be independent consequences of CGG-repeat expression in these different compartments. Alternatively, inflammatory activation may originate in the central nervous system, with immunomodulators crossing the brain–blood barrier and reaching the peripheral circulation.
Levels of IL-10 discriminate premutation carriers from controls and may represent a valuable early biomarker. The design of this study including asymptomatic young carriers did not permit any correlation with the progression of the disease. Longitudinal studies including carriers affected with FXTAS are required to address this question.