Gene Expression Profiling in Fibromyalgia Indicates an Autoimmune Origin of the Disease and Opens New Avenues for Targeted Therapy

Abstract

Fibromyalgia is a chronic disorder characterized by widespread pain and by several non-pain symptoms. Autoimmunity, small fiber neuropathy and neuroinflammation have been suggested to be involved in the pathogenesis of the disease. We have investigated the gene expression profile in peripheral blood mononuclear cells obtained from ten patients and ten healthy subjects. Of the 545,500 transcripts analyzed, 1673 resulted modulated in fibromyalgic patients. The majority of these genes are involved in biological processes and pathways linked to the clinical manifestations of the disease. Moreover, genes involved in immunological pathways connected to interleukin-17 and to Type I interferon signatures were also modulated, suggesting that autoimmunity plays a role in the disease. We then aimed at identifying differentially expressed Long non-coding RNAs (LncRNAs) functionally connected to modulated genes both directly and via microRNA targeting. Only two LncRNAs of the 298 found modulated in patients, were able to target the most highly connected genes in the fibromyalgia interactome, suggesting their involvement in crucial gene regulation. Our gene expression data were confirmed by real time PCR, by autoantibody testing, detection of soluble mediators and Th-17 polarization in a validation cohort of 50 patients. Our results indicate that genetic and epigenetic mechanisms as well as autoimmunity play a pivotal role in the pathogenesis of fibromyalgia.

Application of Salivary Biomarkers in the Diagnosis of Fibromyalgia

“…IL-6 is involved in the onset and persistence of pain, and elevated levels have been found in patients with chronic pathological pain [ 118 , 119 ]. Many studies have described increased serum/plasma IL-6 levels in FM patients [ 5 , 91 , 96 , 97 , 98 , 99 ], and these have even been correlated with the intensity of pain [ 100 ]. Elevated levels of this biomolecule have also been observed in skin biopsies from FM patients [ 95 ] and in their peripheral blood mononuclear cells [ 92 ], which was found to be related to hyperalgesia, fatigue, and depression.…”

“…This pro-inflammatory cytokine is produced by Th-17 cells and participates in inflammatory processes, promoting the production of chemokines and granulocyte colony-stimulating factors and mobilizing immune cells to infection sites [ 112 , 124 ]. Elevated serum levels of this cytokine have been widely reported in FM patients [ 99 , 106 ], and some authors have related its presence to characteristic symptoms of the disease, such as anxiety [ 125 ] and pain [ 126 ].…”

Etiology, Pathogenesis, Diagnosis, and Treatment of Fibromyalgia Syndrome

“…It is also noted that high levels of CD4+ T cells produced by circulating IL-17 and of serum cytokines such as TGF-beta, IL-6, IL-21 and IL-23 that promote Th17 differentiation, survival and expansion in fibromyalgic patients, therefore settling the gene expression signature and the presence of a continuing inflammation. This study also found two uncharacterized LncRNAs that aim, and regulate networks of genes that are included in numerous characteristics of fibromyalgia through their miRNA [5]. Diagnosis of fibromyalgia is not that easy because the disease is described as multifactorial, and very little information is known about the causes of the disease.…”

Extra-Articular Manifestations and Comorbidities in Psoriatic Disease: A Journey Into the Immunologic Crosstalk

“…Immunologic alterations are added to genetic, hormonal, environmental, and neural factors and can contribute to the development of an inflammatory state ( 151 ). Interestingly, a very recent genetic study investigated the gene expression profile in patients with FM, finding that most of modulated genes belonged to the IL-17 pathway and to the type I IFN signatures, suggesting an autoimmune component for this disease ( 152 ). These data corroborate the findings of increased serum levels of pro-inflammatory cytokines, such as IL-1, IL-6 and IL-17, found in patients with FM ( 153 ).…”