The direct deleterious effect of Th17 cells in the nervous system compartment in multiple sclerosis and experimental autoimmune encephalomyelitis: one possible link between neuroinflammation and neurodegeneration

Bălaşa, Rodica; Maier, Smaranda; Bărcuțean, Laura; Stoian, Adina; Moţăţăianu, Anca

doi:10.2478/rrlm-2020-0005

Cited by 12 publications

(9 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As cladribine is an important member of immune reconstruction therapies, it is mandatory to determine what type of lymphocytes undergo this reconstruction process and what types are spared. In clinical practice there is no rebound of MS clinical or MRI activity even after recovery of T cell count, suggesting a degree of qualitative change after treatment with cladribine in the adaptive immune response ( 3 , 61 , 62 ).…”

Section: Discussionmentioning

confidence: 99%

“…Activated T cells (CD3+) are capable of mounting an autoimmune response against myelin components, penetrating the blood-brain barrier, proliferating and subsequently secreting pro-inflammatory cytokines. These cytokines stimulate microglia, macrophages, astrocytes and B cells, resulting in demyelination and neurodegeneration ( 2 , 3 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

et al. 2021

View full text Add to dashboard Cite

BackgroundMultiple sclerosis (MS) is an incurable autoimmune disease mediated by a heterogeneous T cell population (CD3+CD161+CXCR3−CCR6+IFNγ−IL17+, CD3+CXCR3+CCR6+IFNγ+IL17+, and CD3+CXCR3+IFNγ+IL17− phenotypes) that infiltrates the central nervous system, eliciting local inflammation, demyelination and neurodegeneration. Cladribine is a lymphocyte-depleting deoxyadenosine analogue recently introduced for MS therapy as a Disease Modifying Drug (DMD). Our aim was to establish a method for the early identification and prediction of cladribine responsiveness among MS patients.MethodsAn experimental model was designed to study the cytotoxic and immunomodulatory effect of cladribine. T cell subsets of naïve relapsing-remitting MS (RRMS) patients were analyzed ex vivo and in vitro comparatively to healthy controls (HC). Surviving cells were stimulated with rh-interleukin-2 for up to 14days. Cell proliferation and immunophenotype changes were analyzed after maximal (phorbol myristate acetate/ionomycin/monensin) and physiological T-cell receptor (CD3/CD28) activation, using multiparametric flow cytometry and xMAP technology.ResultsEx vivo CD161+Th17 cells were increased in RRMS patients. Ex vivo to in vitro phenotype shifts included: decreased CD3+CCR6+ and CD3+CD161+ in all subjects and increased CD3+CXCR3+ in RRMS patients only; Th17.1 showed increased proliferation vs Th17 in all subjects; CD3+IL17+ and CD3+IFNγ+IL17+ continued to proliferate till day 14, CD3+IFNγ+ only till day 7. Regarding cladribine exposure: RRMS CD3+ cells were more resistant compared to HC; treated CD3+ cells proliferated continuously for up to 14 days, while untreated cells only up to 7 days; both HC/RRMS CD3+CXCR3+ populations increased from baseline till day 14; in RRMS patients vs HC, IL17 secretion from cladribine-treated cells increased significantly, in line with the observed proliferation of CD3+IL17+ and CD3+IFNγ+IL17+ cells; in both HC/RRMS, cladribine led to a significant increase in CD3+IFNγ+ cells at day 7 only, having no further effect at day14. IFNγ and IL17 secreted in culture media decreased significantly from ex vivo to in vitro.ConclusionsCD3+ subtypes showed different responsiveness due to selectivity of cladribine action, in most patients leading to in vitro survival/proliferation of lymphocyte subsets known as pathogenic in MS. This in vitro experimental model is a promising tool for the prediction of individual responsiveness of MS patients to cladribine and other DMDs.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The brain CT scan performed in 2009 revealed generalized white matter disorder with diffuse hypodensities, ventriculomegaly, and the presence of cavum septi pellucidi. The brain MRI scan performed in 2022 highlighted the rapid progression of cerebral, cerebellar, and vermis atrophy, with cerebral hyperintensities similar to demyelinating lesions present in the pons, middle cerebral peduncles, bilateral hemispheric supratentorial white matter (without fulfilling the demyelinating or autoimmune CNS disease criteria), and marked right hippocampus atrophy [ 33 , 34 , 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant—Our Experience and Systematic Review of the Literature

Stoian,

Bajko,

Bălașa

et al. 2024

Biomolecules

View full text Add to dashboard Cite

Background: Developmental and epileptic encephalopathies (DEE) encompass a group of rare diseases with hereditary and genetic causes as well as acquired causes such as brain injuries or metabolic abnormalities. The phosphofurin acidic cluster sorting protein 2 (PACS2) is a multifunctional protein with nuclear gene expression. The first cases of the recurrent c.625G>A pathogenic variant of PACS2 gene were reported in 2018 by Olson et al. Since then, several case reports and case series have been published. Methods: We performed a systematic review of the PUBMED and SCOPUS databases using Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Our search parameters included DEE66 with a pathogenic PACS2 gene p.Glu209Lys mutation published cases to which we added our own clinical experience regarding this pathology. Results: A total of 11 articles and 29 patients were included in this review, to which we added our own experience for a total of 30 patients. There was not a significant difference between sexes regarding the incidence of this pathology (M/F: 16/14). The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait. Facial dysmorphism and other organs’ involvement were also frequently reported. Brain MRIs evidenced anomalies of the posterior cerebellar fossa, foliar distortion of the cerebellum, vermis hypoplasia, white matter reduction, and lateral ventricles enlargement. Genetic testing is more frequent in children. Only 4 cases have been reported in adults to date. Conclusions: It is important to maintain a high suspicion of new pathogenic gene variants in adult patients presenting with a characteristic clinical picture correlated with radiologic changes. The neurologist must gradually recognize the distinct evolving phenotype of DEE66 in adult patients, and genetic testing must become a scenario with which the neurologist attending adult patients should be familiar. Accurate diagnosis is required for adequate treatment, genetic counseling, and an improved long-term prognosis.

show abstract

“…BBB disruption is not only directly and immediately deleterious in MS pathology by allowing the entrance of proinflammatory cells into the CNS, it may also have delayed secondary effects on MS resulting from the continuous self-maintained proinflammatory and neurodegenerative effects of some cells. As an example, the Th 17 cells, with the high expression of granzyme B, attain increased migratory capacity on arrival in the CNS and continue to stimulate demyelination and extensive axonal degeneration through the following: (1) direct interaction with myelin oligodendrocyte glycoprotein; (2) Th 17 cells secretion of IL-17 and IL-21 and the stimulation of the development of ectopic lymphoid structures; and (3) a decrease in the remyelinating processes by the inhibition of oligodendrocytes [44,45].…”

Section: Metabolic Changes In Bbb Cellsmentioning

confidence: 99%

Reviewing the Significance of Blood–Brain Barrier Disruption in Multiple Sclerosis Pathology and Treatment

Bălaşa

Barcutean

Mosora

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

The disruption of blood–brain barrier (BBB) for multiple sclerosis (MS) pathogenesis has a double effect: early on during the onset of the immune attack and later for the CNS self-sustained ‘inside-out’ demyelination and neurodegeneration processes. This review presents the characteristics of BBB malfunction in MS but mostly highlights current developments regarding the impairment of the neurovascular unit (NVU) and the metabolic and mitochondrial dysfunctions of the BBB’s endothelial cells. The hypoxic hypothesis is largely studied and agreed upon recently in the pathologic processes in MS. Hypoxia in MS might be produced per se by the NVU malfunction or secondary to mitochondria dysfunction. We present three different but related terms that denominate the ongoing neurodegenerative process in progressive forms of MS that are indirectly related to BBB disruption: progression independent of relapses, no evidence of disease activity and smoldering demyelination or silent progression. Dimethyl fumarate (DMF), modulators of S1P receptor, cladribine and laquinimode are DMTs that are able to cross the BBB and exhibit beneficial direct effects in the CNS with very different mechanisms of action, providing hope that a combined therapy might be effective in treating MS. Detailed mechanisms of action of these DMTs are described and also illustrated in dedicated images. With increasing knowledge about the involvement of BBB in MS pathology, BBB might become a therapeutic target in MS not only to make it impenetrable against activated immune cells but also to allow molecules that have a neuroprotective effect in reaching the cell target inside the CNS.

show abstract

The direct deleterious effect of Th17 cells in the nervous system compartment in multiple sclerosis and experimental autoimmune encephalomyelitis: one possible link between neuroinflammation and neurodegeneration

Cited by 12 publications

References 43 publications

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant—Our Experience and Systematic Review of the Literature

Reviewing the Significance of Blood–Brain Barrier Disruption in Multiple Sclerosis Pathology and Treatment

Contact Info

Product

Resources

About