Reduced serum levels of pro-inflammatory chemokines in fragile X syndrome

Abstract

Background: Fragile X syndrome (FXS) is the most frequent cause of inherited intellectual disability and the most commonly identified monogenic cause of autism. Recent studies have shown that long-term pathological consequences of FXS are not solely confined to the central nervous system (CNS) but rather extend to other physiological dysfunctions in peripheral organs. To gain insights into possible immune dysfunctions in FXS, we profiled a large panel of immune-related biomarkers in the serum of FXS patients and healthy controls. Methods: We have used a sensitive and robust Electro Chemi Luminescence (ECL)-based immunoassay to measure the levels of 52 cytokines in the serum of n = 25 FXS patients and n = 29 healthy controls. We then used univariate statistics and multivariate analysis, as well as an advanced unsupervised clustering method, to identify combinations of immune-related biomarkers that could discriminate FXS patients from healthy individuals. Results: While the majority of the tested cytokines were present at similar levels in FXS patients and healthy individuals, nine chemokines, CCL2, CCL3, CCL4, CCL11, CCL13, CCL17, CCL22, CCL26 and CXCL10, were present at much lower levels in FXS patients. Using robust regression, we show that six of these biomarkers (CCL2, CCL3, CCL11, CCL22, CCL26 and CXCL10) were negatively associated with FXS diagnosis. Finally, applying the K-sparse unsupervised clustering method to the biomarker dataset allowed for the identification of two subsets of individuals, which essentially matched the FXS and healthy control categories. Conclusions: Our data show that FXS patients exhibit reduced serum levels of several chemokines and may therefore exhibit impaired immune responses. The present study also highlights the power of unsupervised clustering methods to identify combinations of biomarkers for diagnosis and prognosis in medicine.

Disrupted Association of Sensory Neurons With Enveloping Satellite Glial Cells in Fragile X Mouse Model

“…Third, signaling pathways which are down-regulated in SGCs of Fmr1 KO mice are primarily linked to inflammatory and cytokine response. This is consistent with findings of cytokine imbalance in FXS individuals ( Van Dijck et al, 2020 ), children with autism ( Yu et al, 2020 ) and the growing evidence that neuro-inflammatory mechanisms may contribute to the pathogenesis of FXS as well as other autism-associated disorders ( Di Marco et al, 2016 ; Yu et al, 2020 ). This observation is particularly intriguing in a view of a growing number of reports that cytokines may specifically interact with neuronal ion channels regulating excitability ( Viviani et al, 2007 ; Schafers and Sorkin, 2008 ).…”

“…Downregulated pathways were related to response to cytokine stimulus and inflammatory response ( Figure 5B and Table 2 ). These downregulated pathways are consistent with the reduced serum levels of pro-inflammatory chemokines in FXS individuals ( Van Dijck et al, 2020 ). Interestingly, the chemokine Ccl2 was downregulated in both SGC and macrophages in Fmr1 KO mice compared to WT ( Supplementary Tables 4 , 6 ), and is also reduced in the serum of FXS patients ( Van Dijck et al, 2020 ).…”

COVID-19 Infection in a Patient With Fragile-X Syndrome

“…A recent study showed that FXS does not only affect the central nervous system but additionally causes other physiologic dysfunctions including changes in immune-related biomarkers. The study showed that patients with FXS have reduced serum levels of several chemokines including chemokine (c-x-c motif) ligand 10 (CXCL-10), which is a pro-inflammatory cytokine [7]. Therefore, a person with FXS may have impaired immunity and may be more susceptible to infectious diseases.…”

An “Omic” Overview of Fragile X Syndrome

“…Interestingly, FXS leukocytes did not display any alteration in cytokine production when solely stimulated with LPS [ 148 ]. However, two studies have shown that circulating levels of several pro-inflammatory cytokines are actually decreased in FXS serum and plasma [ 149 , 150 ]. Despites being somewhat contradictory, those reports strongly suggest the existence of immune dysfunctions in FXS.…”