Immune Dysregulation as a Cause of Autoinflammation in Fragile X Premutation Carriers: Link between FMRI CGG Repeat Number and Decreased Cytokine Responses

Careaga, Milo; Rose, Destanie R.; Tassone, Flora; Berman, Robert F.; Hagerman, Randi J.; Ashwood, Paul

doi:10.1371/journal.pone.0094475

Cited by 25 publications

(30 citation statements)

References 38 publications

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“…Notably, an increase in IL-10 secretion by PBMC in the absence of immune challenge was described in FMR1 premutation carriers [30]. Furthermore, a decreased cytokine secretion response was observed in LPS-stimulated PBMC from individuals carrying the FMR1 premutation [31]. This suggests that dysregulation in the FMR1 gene could alter immune responsiveness under yet to be defined conditions.…”

Section: Reduced Levels Of Pro-inflammatory Chemokines In Fxs Patientsmentioning

confidence: 95%

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

et al. 2020

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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.

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Section: Reduced Levels Of Pro-inflammatory Chemokines In Fxs Patientsmentioning

confidence: 95%

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

et al. 2020

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“…This included reductions in the cytokines IL-12(p40) and IL-1α, MCP-1 and INFγ, IL-1α and TNFα in unstimulated monocytes and peripheral blood lymphocytes, respectively. Subtle immune deficiencies were observed in both female and male CGG KI mice that were similar to those seen in human female PM carriers, suggesting that human male carriers may be immunologically affected as well (Careaga et al, 2014). This hypothesis is supported by observations by Marek et al .…”

Section: What Have Mouse Models Taught Us About Fxtas?mentioning

confidence: 79%

“…In addition to the numerous pathologies associated with FMR1 CGG-expansions, immunological issues have been reported in carriers as well (Careaga et al, 2014; Marek et al, 2012; Winarni et al, 2012). This has been particularly evident in female PM carriers, who were found to be at higher risk for developing autoimmune conditions when compared with controls (Winarni et al, 2012).…”

Section: What Have Mouse Models Taught Us About Fxtas?mentioning

confidence: 99%

What has been learned from mouse models of the Fragile X Premutation and Fragile X-associated tremor/ataxia syndrome?

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Careaga

Berman

2016

The Clinical Neuropsychologist

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Objective To describe in this review how research using mouse models developed to study the Fragile X premutation (PM) and Fragile X-associated tremor/ataxia syndrome (FXTAS) have contributed to understanding these disorders. PM carriers bear an expanded CGG trinucleotide repeat on the Fragile X Mental Retardation 1 (FMR1) gene, and are at risk for developing the late-onset neurodegenerative disorder FXTAS. Conclusions Much has been learned about these genetic disorders from the development and study of mouse models. This includes new insights into the early cellular and molecular events that occur in PM carriers and in FXTAS, the presence of multi-organ pathology beyond the CNS, immunological dysregulation, unexpected synthesis of a potentially toxic peptide in FXTAS (i.e., FMRpolyG), and evidence that the disease process may be halted or reversed by appropriate molecular therapies given early in the course of disease.

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“…Case reports suggest that such an association is likely 78 , perhaps as a consequence of increased oxidative stress and/or inflammation in the CNS, the psychological stress caused by having the autoimmune condition in addition to FXTAS, or the additional dysregulation of the immune system that exacerbates inflammation. Cytokines and chemokines are dysregulated in individuals with premutation alleles, and this dysregulation worsens with age and leads to lower activity of the immune system than in age-matched controls without the premutation 88 . This progression of immune dysregulation in FXTAS is probably related to immune-mediated disorders, frequent infections, and low activity of the cancer surveillance system 89,90 .…”

Section: Novel Features Of Fxtasmentioning

confidence: 99%

Fragile X-associated tremor/ataxia syndrome — features, mechanisms and management

2016

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Many physicians are unaware of the many phenotypes associated with the fragile X premutation, an expansion in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene that consists of 55-200 CGG repeats. The most severe of these phenotypes is fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in the majority of ageing male premutation carriers but in fewer than 20% of ageing women with the premutation. The prevalence of the premutation is 1 in 150-300 females, and 1 in 400-850 males, so physicians are likely to see people affected by FXTAS. Fragile X DNA testing is broadly available in the Western world. The clinical phenotype of FXTAS at presentation can vary and includes intention tremor, cerebellar ataxia, neuropathic pain, memory and/or executive function deficits, parkinsonian features, and psychological disorders, such as depression, anxiety and/or apathy. FXTAS causes brain atrophy and white matter disease, usually in the middle cerebellar peduncles, the periventricular area, and the splenium and/or genu of the corpus callosum. Here, we review the complexities involved in the clinical management of FXTAS and consider how targeted treatment for these clinical features of FXTAS will result from advances in our understanding of the molecular mechanisms that underlie this neurodegenerative disorder. Such targeted approaches should also be more broadly applicable to earlier forms of clinical involvement among premutation carriers.

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Immune Dysregulation as a Cause of Autoinflammation in Fragile X Premutation Carriers: Link between FMRI CGG Repeat Number and Decreased Cytokine Responses

Cited by 25 publications

References 38 publications

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

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

What has been learned from mouse models of the Fragile X Premutation and Fragile X-associated tremor/ataxia syndrome?

Fragile X-associated tremor/ataxia syndrome — features, mechanisms and management

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