Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis

Abstract

BackgroundNumerous cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS), but studies are often limited to whole blood (WB) or peripheral blood mononuclear cells (PBMCs), thereby omitting important information about the cellular origin of the cytokines. Knowledge about the relation between blood and cerebrospinal fluid (CSF) cell expression of cytokines and the cellular source of CSF cytokines is even more scarce.MethodsWe studied gene expression of a broad panel of cytokines in WB from relapsing-remitting multiple sclerosis (RRMS) patients in remission and healthy controls (HCs). Subsequently we determined the gene expression of the dysregulated cytokines in isolated PBMC subsets (CD4+, CD8+T-cells, NK-cells, B-cells, monocytes and dendritic cells) from RRMS patients and HCs and in CSF-cells from RRMS patients in clinical relapse and non-inflammatory neurological controls (NIND).ResultsRRMS patients had increased expression of IFN-gamma (IFNG), interleukin (IL) 1-beta (IL1B), IL7, IL10, IL12A, IL15, IL23, IL27, lymphotoxin-alpha (LTA) and lymphotoxin-beta (LTB) in WB. In PBMC subsets the main sources of pro-inflammatory cytokines were T- and B-cells, whereas monocytes were the most prominent source of immunoregulatory cytokines. In CSF-cells, RRMS patients had increased expression of IFNG and CD19 and decreased expression of IL10 and CD14 compared to NINDs. CD19 expression correlated with expression of IFNG, IL7, IL12A, IL15 and LTA whereas CD14 expression correlated with IL10 expression.ConclusionsUsing a systematic approach, we show that expression of pro-inflammatory cytokines in peripheral blood primarily originates from T- and B-cells, with an important exception of IFNG which is most strongly expressed by NK-cells. In CSF-cell studies, B-cells appear to be enriched in RRMS and associated with expression of pro-inflammatory cytokines; contrarily, monocytes are relatively scarce in CSF from RRMS patients and are associated with IL10 expression. Thus, our findings suggest a pathogenetic role of B-cells and an immunoregulatory role of monocytes in RRMS.

Decreased Level of sRAGE in the Cerebrospinal Fluid of Multiple Sclerosis Patients at Clinical Onset

“…Both IL-6 and IL-1α have been implicated in the pathogenesis of neuroinflammation in MS [5,31,32,33], and, in accordance with our results, associated with early MS. On the other hand, we found that the expression of IL-10, a potent anti-inflammatory cytokine, was lower in PBMCs of MS patients, concordant with several studies of neuroinflammatory disorders [5,15,33]. IL-10 could be induced by type I IFN in monocytes, macrophages and CD4+ T lymphocytes [19], and represents an important negative feedback mechanism to downregulate uncontrolled production of proinflammatory cytokines (IL-1β, IL-6, IL-17, TNF-α), protecting brain homeostasis [5,16,33]. …”

“…Using cultured synovial fibroblasts and macrophages, it was shown that HMGB1 exhibits enhanced proinflammatory activity by binding to cytokines, specifically IL-1β and TNF-α [29,30]. Therefore, we proposed that inflammation may be potentiated by a complex formation of HMGB1 with IL-1β and TNF-α, found to be elevated in the CSF of RR-MS patients [5,16], but our study could not detect an increase in any of these molecules. The lack of difference compared with control samples indicates that the described pathogenic mechanism is not important for MS at the disease onset.…”

“…Gene expression studies of brain tissue and peripheral blood (PBL) from MS patients have shown deregulated expression of cytokines, chemokines and transcription factors related to immune activation [2,16], but the relation between the peripheral immune system and neuroinflammation is still not well understood. In contrast to other studies, which mostly investigated the cytokine profile in the advanced stages of MS, we aimed to assess systemic and cerebrospinal fluid (CSF) changes in patients with MS at the clinical onset of the disease.…”

Body fluid biomarkers in multiple sclerosis: how far we have come and how they could affect the clinic now and in the future

“…For instance, Satoh et al . identified aberrant expression of apoptosis and DNA damage-regulating genes in MS PBMC, wheres Romme-Christianson and colleagues identified cytokine expression profiles in CSF and whole blood (WB) in RRMS patients [86,87]. Hecker et al .…”

Network-based analysis of differentially expressed genes in cerebrospinal fluid (CSF) and blood reveals new candidate genes for multiple sclerosis

“…Furthermore, peripheral blood mononuclear cells (PBMCs) are being considered as an easily accessible and informative source of biological material in MS transcriptome studies (Achiron et al, 2004; Bomprezzi et al, 2003; Singh et al, 2007). In this line, it has been reported that the study linking peripheral and CSF immune responses were essential to understand the immunopathogenesis of MS (Christensen et al, 2012). …”