Increased cerebrospinal fluid albumin and immunoglobulin A fractions forecast cortical atrophy and longitudinal functional deterioration in relapsing-remitting multiple sclerosis

Kroth, Julia; Ciolac, Dumitru; Fleischer, Vinzenz; Koirala, Nabin; Krämer, Julia; Luessi, Felix; Bittner, Stefan; González‐Escamilla, Gabriel; Zipp, Frauke; Meuth, Sven G.; Groppa, Sergiu

doi:10.1177/1352458517748474

Cited by 14 publications

(15 citation statements)

References 26 publications

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“…Although serum levels of IgG and IgM were not importantly modified, IgA significantly decreased over time in response to DMF treatment. This is an important observation as a recent report has demonstrated a relationship between CSF IgA levels and IgA CSF/serum quotient, and cerebral atrophy and EDS in MS patients ( 34 ). Moreover, given the importance of several cytokines, particularly IFNγ, in the IgG subclass switch process ( 35 , 36 ), changes in IgG subclass profile (decrease in IgG3 and IgG2) in the serum of our DMF-treated patients favor a role of the Tfh subpopulations shift and their secreted cytokines in the DMF treatment effect.…”

Section: Discussionsupporting

confidence: 56%

Relapsing–Remitting Multiple Sclerosis Is Characterized by a T Follicular Cell Pro-Inflammatory Shift, Reverted by Dimethyl Fumarate Treatment

et al. 2018

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Multiple sclerosis (MS) is considered a T cell-mediated autoimmune disease, although several evidences also demonstrate a B cell involvement in its etiology. Follicular T helper (Tfh) cells, a CXCR5-expressing CD4+ T cell subpopulation, are essential in the regulation of B cell differentiation and maintenance of humoral immunity. Alterations in circulating (c)Tfh distribution and/or function have been associated with autoimmune diseases including MS. Dimethyl fumarate (DMF) is a recently approved first-line treatment for relapsing–remitting MS (RRMS) patients whose mechanism of action is not completely understood. The aim of our study was to compare cTfh subpopulations between RRMS patients and healthy subjects and evaluate the impact of DMF treatment on these subpopulations, relating them to changes in B cells and humoral response. We analyzed, by flow cytometry, the distribution of cTfh1 (CXCR3+CCR6−), cTfh2 (CXCR3−CCR6−), cTfh17 (CXCR3−CCR6+), and the recently described cTfh17.1 (CXCR3+CCR6+) subpopulations of CD4+ Tfh (CD45RA−CXCR5+) cells in a cohort of 29 untreated RRMS compared to healthy subjects. CD4+ non-follicular T helper (Th) cells (CD45RA−CXCR5−) were also studied. We also evaluated the effect of DMF treatment on these subpopulations after 6 and 12 months treatment. Untreated RRMS patients presented higher percentages of cTfh17.1 cells and lower percentages of cTfh2 cells consistent with a pro-inflammatory bias compared to healthy subjects. DMF treatment induced a progressive increase in cTfh2 cells, accompanied by a decrease in cTfh1 and the pathogenic cTfh17.1 cells. A similar decrease of non-follicular Th1 and Th17.1 cells in addition to an increase in the anti-inflammatory Th2 subpopulation were also detected upon DMF treatment, accompanied by an increase in naïve B cells and a decrease in switched memory B cells and serum levels of IgA, IgG2, and IgG3. Interestingly, this effect was not observed in three patients in whom DMF had to be discontinued due to an absence of clinical response. Our results demonstrate a possibly pathogenic cTfh pro-inflammatory profile in RRMS patients, defined by high cTfh17.1 and low cTfh2 subpopulations that is reverted by DMF treatment. Monitoring cTfh subsets during treatment may become a biological marker of DMF effectiveness.

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Section: Discussionsupporting

confidence: 56%

Relapsing–Remitting Multiple Sclerosis Is Characterized by a T Follicular Cell Pro-Inflammatory Shift, Reverted by Dimethyl Fumarate Treatment

et al. 2018

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“…Because previous studies associated increased QAlb with higher disability in patients with MS, 7,8 we explored indicators of CNS damage in our cohort of 121 patients with MS using 2 promising biomarkers: NF-L, a cytoskeletal component of neurons that is very abundant in axons, 17 and it has been associated with BBB integrity, 18 and CHI3L1, a glycoprotein secreted by activated glia. 19 Our results demonstrated that the intrathecal quantity of both biomarkers was statistically higher in the CSF of patients with increased QAlb (figure 2D), and their amount correlated with QAlb and with each other as already reported 20 ( figure 2E).…”

Section: Markers Of Cns Damage In Patients With Ms With Increased Qalbmentioning

confidence: 99%

“…Supporting such an association between CNS damage and changes in BBB permeability, it has been observed that high QAlb and other CSF markers of compromised BBB integrity in patients with MS are accompanied by brain atrophy and faster increase in disability. 7,8 To better understand BBB permeability in MS and its putative association with CNS damage and systemic inflammation, we performed a detailed characterization of CSF and paired blood samples that included immunophenotyping and lipidomics.…”

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confidence: 99%

Altered CSF Albumin Quotient Links Peripheral Inflammation and Brain Damage in MS

Puthenparampil

Tomas-Ojer

Hornemann

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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ObjectiveCNS damage can increase the susceptibility of the blood-brain barrier (BBB) to changes induced by systemic inflammation. The aim of this study is to better understand BBB permeability in patients with MS and to examine whether compromised BBB integrity in some of these patients is associated with CNS damage and systemic inflammation.MethodsRoutine CSF measurements of 121 patients with MS were analyzed including number and type of infiltrating cells, total protein, lactate, and oligoclonal bands, as well as intrathecal production of immunoglobulins and CSF/serum quotients for albumin, immunoglobulins, and glucose. In addition, in a subcohort of these patients, we performed ex vivo immunophenotyping of CSF-infiltrating and paired circulating lymphocytes using a panel of 13 monoclonal antibodies, we quantified intrathecal neurofilament light chain (NF-L) and chitinase 3-like 1 (CHI3L1), and we performed intrathecal lipidomic analysis.ResultsPatients with MS with abnormal high levels of albumin in the CSF showed a distinct CSF cell infiltrate and markers of CNS damage such as increased intrathecal levels of NF-L and CHI3L1 as well as a distinct CSF lipidomic profile. In addition, these patients showed higher numbers of circulating proinflammatory Th1 and Th1* cells compatible with systemic inflammation. Of interest, the abnormally high levels of albumin in the CSF of those patients were preserved over time.ConclusionsOur results support the hypothesis that CNS damage may increase BBB vulnerability to systemic inflammation in a subset of patients and thus contribute to disease heterogeneity.

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“…Thus, individual patients' stratification to therapy response or failure is warranted. Importantly, easy to obtain and measure immunological markers of therapy response are extremely necessary to minimize tissue damage and long-term functional impairment (10, 32). Therefore, here the goal was to stratify patients as responders to DMF therapy by linking cellular responses to clinical, structural MRI and brain network dynamics.…”

Section: Discussionmentioning

confidence: 99%

“…At the same time, markers predicting the favorable response to a specific DMD are under meticulous development but are not yet validated for clinical pathways. Mainly, MRI parameters are regarded as surrogate measures of treatment response to DMDs, although cerebrospinal fluid (CSF) or peripheral blood immune response may also be a valuable biomarker (10). In this respect, treatment response to dimethyl fumarate (DMF) was reflected by reduced counts of CD4+ and CD8+ T cells in patients without disease activity (11–13).…”

Section: Introductionmentioning

confidence: 99%

Selective Brain Network and Cellular Responses Upon Dimethyl Fumarate Immunomodulation in Multiple Sclerosis

et al. 2019

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Background: Efficient personalized therapy paradigms are needed to modify the disease course and halt gray (GM) and white matter (WM) damage in patients with multiple sclerosis (MS). Presently, promising disease-modifying drugs show impressive efficiency, however, tailored markers of therapy responses are required. Here, we aimed to detect in a real-world setting patients with a more favorable brain network response and immune cell dynamics upon dimethyl fumarate (DMF) treatment. Methods: In a cohort of 78 MS patients we identified two thoroughly matched groups, based on age, disease duration, disability status and lesion volume, receiving DMF ( n = 42) and NAT ( n = 36) and followed them over 16 months. The rate of cortical atrophy and deep GM volumes were quantified. GM and WM network responses were characterized by brain modularization as a marker of regional and global structural alterations. In the DMF group, lymphocyte subsets were analyzed by flow cytometry and related to clinical and MRI parameters. Results: Sixty percent (25 patients) of the DMF and 36% (13 patients) of the NAT group had disease activity during the study period. The rate of cortical atrophy was higher in the DMF group (−2.4%) compared to NAT (−2.1%, p < 0.05) group. GM and WM network dynamics presented increased modularization in both groups. When dividing the DMF-treated cohort into patients free of disease activity ( n = 17, DMF R ) and patients with disease activity ( n = 25, DMF NR ) these groups differed significantly in CD8+ cell depletion counts (DMF R : 197.7 ± 97.1/μl; DMF NR : 298.4 ± 190.6/μl, p = 0.03) and also in cortical atrophy (DMF R : −1.7%; DMF NR : −3.2%, p = 0.01). DMF R presented reduced longitudinal GM and WM modularization and less atrophy as markers of preserved structural global network integrity in comparison to DMF NR and even NAT patients. Conclusions: NAT treatment contributes to a reduced rate of cortical atrophy compared to DMF therapy. However, patients under DMF treatment with a stronger CD8+ T cell depletion present a more favorable response in terms of cortical integrity and GM and WM network responses. Our findings may serve as basis for the development of personalized treatment paradigms.

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Increased cerebrospinal fluid albumin and immunoglobulin A fractions forecast cortical atrophy and longitudinal functional deterioration in relapsing-remitting multiple sclerosis

Abstract: CSF markers of blood-brain barrier integrity and specific immune response forecast emerging gray matter pathology and disease progression in MS.

Cited by 14 publications

References 26 publications

Relapsing–Remitting Multiple Sclerosis Is Characterized by a T Follicular Cell Pro-Inflammatory Shift, Reverted by Dimethyl Fumarate Treatment

Relapsing–Remitting Multiple Sclerosis Is Characterized by a T Follicular Cell Pro-Inflammatory Shift, Reverted by Dimethyl Fumarate Treatment

Altered CSF Albumin Quotient Links Peripheral Inflammation and Brain Damage in MS

Selective Brain Network and Cellular Responses Upon Dimethyl Fumarate Immunomodulation in Multiple Sclerosis

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