Intrathecal, Not Systemic Inflammation Is Correlated With Multiple Sclerosis Severity, Especially in Progressive Multiple Sclerosis.

Published on Nov 22, 2019in Frontiers in Neurology2.889
· DOI :10.3389/FNEUR.2019.01232
Joshua L. Milstein1
Estimated H-index: 1
(NIH: National Institutes of Health),
Christopher Barbour4
Estimated H-index: 4
(NIH: National Institutes of Health)
+ 2 AuthorsBibiana Bielekova34
Estimated H-index: 34
(NIH: National Institutes of Health)
Objective: To test the hypothesis that Multiple Sclerosis (MS) patients have increased peripheral inflammation compared to healthy donors and that this systemic activation of the immune system, reflected by acute phase reactants (APRs) measured in the blood, contributes to intrathecal inflammation, which in turn contributes to the development of disability in MS. Methods: Eight serum APRs measured in a prospectively-collected cross-sectional cohort with a total of 51 healthy donors and 291 untreated MS patients were standardized and assembled into related biomarker clusters to derive global measures of systemic inflammation. The resulting APR clusters were compared between diagnostic categories and correlated to equivalently-derived cerebrospinal fluid (CSF) biomarkers of innate and adaptive immunity. Finally, correlations were calculated between biomarkers of systemic and intrathecal inflammation and MS severity measures, which predict future rates of disability progression. Results: While two blood APR clusters were elevated in MS patients, only one exhibited a weak correlation with MS severity. All CSF inflammation clusters, except CSF albumin, correlated with at least one measure of MS severity, with biomarkers of humoral adaptive immunity exhibiting the strongest correlations, especially in Progressive MS. Conclusion: Systemic inflammation does not appear to be strongly associated with intrathecal inflammation in MS. Positive correlations between markers of intrathecal inflammation, especially of humoral immunity, with MS severity measures support a pathogenic role of intrathecal (compartmentalized) inflammation in central nervous system tissue destruction, including in Progressive MS.
📖 Papers frequently viewed together
14 Citations
1 Citations
#1Jeppe Romme Christensen (UCPH: University of Copenhagen)H-Index: 15
#2Mika KomoriH-Index: 14
Last. Finn Sellebjerg (UCPH: University of Copenhagen)H-Index: 61
view all 7 authors...
Background:Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation.Objective:To vali...
12 CitationsSource
#1Lohith Madireddy (UCSF: University of California, San Francisco)H-Index: 14
#2Nikolaos A. Patsopoulos (Harvard University)H-Index: 38
Last. Sergio E. BaranziniH-Index: 61
view all 64 authors...
Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases ...
34 CitationsSource
#1Benjamin Turner (Royal London Hospital)H-Index: 1
#2Bruce A.C. Cree (UCSF: University of California, San Francisco)H-Index: 66
Last. Stephen L. Hauser (UCSF: University of California, San Francisco)H-Index: 115
view all 11 authors...
Objective The efficacy and safety of ocrelizumab, versus interferon (IFN) β-1a, for the treatment of relapsing multiple sclerosis (RMS) from the identically designed OPERA I (NCT01247324) and OPERA II (NCT01412333) phase III studies has been reported; here we present subgroup analyses of efficacy endpoints from the pooled OPERA I and OPERA II populations.
22 CitationsSource
#1Mykolas Bendorius (UDS: University of Strasbourg)H-Index: 3
#2Chrystelle Po (UDS: University of Strasbourg)H-Index: 7
Last. Hélène Jeltsch-David (UDS: University of Strasbourg)H-Index: 8
view all 4 authors...
It took decades to arrive at the general consensus dismissing the notion that the immune system is independent of the central nervous system. In the case of uncontrolled systemic inflammation, the relationship between the two systems is thrown off balance and results in cognitive and emotional impairment. It is specifically true for autoimmune pathologies where the central nervous system is affected as a result of systemic inflammation. Along with boosting circulating cytokine levels, systemic i...
23 CitationsSource
#1Ahmed AbdelhakH-Index: 8
#2André Huss (University of Ulm)H-Index: 11
Last. M. OttoH-Index: 8
view all 5 authors...
While neurofilament light chain (NfL) measurement in serum is a well-established marker of neuroaxonal damage in multiple sclerosis (MS), data on astroglial markers in serum are missing. In our study, glial fibrillary acid protein (GFAP) and NfL were measured in cerebrospinal fluid (CSF) and serum of MS patients and patients with other non-inflammatory neurological diseases (OND) using the Simoa technology. Clinical data like age, gender, expanded disability status scale (EDSS) and MRI findings ...
55 CitationsSource
#1Tiffany R. Anderson (UH: University of Hawaii)H-Index: 10
#2Charles H. Fletcher (UH: University of Hawaii)H-Index: 36
Last. Jade M. S. Delevaux (UH: University of Hawaii)H-Index: 8
view all 6 authors...
Planning community resilience to sea level rise (SLR) requires information about where, when, and how SLR hazards will impact the coastal zone. We augment passive flood mapping (the so-called “bathtub” approach) by simulating physical processes posing recurrent threats to coastal infrastructure, communities, and ecosystems in Hawai‘i (including tidally-forced direct marine and groundwater flooding, seasonal wave inundation, and chronic coastal erosion). We find that the “bathtub” approach, alone...
30 CitationsSource
#1Jason Stein (NIH: National Institutes of Health)H-Index: 3
#2Quangang Xu (NIH: National Institutes of Health)H-Index: 3
Last. Bibiana Bielekova (NIH: National Institutes of Health)H-Index: 34
view all 8 authors...
Although B cell depletion is an effective therapy of multiple sclerosis (MS), the pathogenic functions of B cells in MS remain incompletely understood. We asked whether cerebrospinal fluid (CSF) B cells in MS secrete different cytokines than control-subject B cells and whether cytokine secretion affects MS phenotype. We blindly studied CSF B cells after their immortalization by Epstein-Barr Virus (EBV) in prospectively-collected MS patients and control subjects with other inflammatory-(OIND) or ...
5 CitationsSource
#1Rui Li (UPenn: University of Pennsylvania)H-Index: 29
#2Kristina R. Patterson (UPenn: University of Pennsylvania)H-Index: 11
Last. Amit Bar-Or (UPenn: University of Pennsylvania)H-Index: 92
view all 3 authors...
There is growing recognition that B cell contributions to normal immune responses extend well beyond their potential to become antibody-producing cells, including roles at the innate–adaptive interface and their potential to modulate the responses of other immune cells such as T cells and myeloid cells. These B cell functions can have both pathogenic and protective effects in the context of central nervous system (CNS) inflammation. Here, we review recent advances in the field of multiple sclero...
147 CitationsSource
Summary Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactiv...
349 CitationsSource
#1Keenan A. Walker (Johns Hopkins University)H-Index: 12
#2Ron C. Hoogeveen (Johns Hopkins University)H-Index: 60
Last. Rebecca F. Gottesman (Johns Hopkins University)H-Index: 72
view all 8 authors...
Objective: To clarify the temporal relationship between systemic inflammation and neurodegeneration, we examined whether a higher level of circulating inflammatory markers during midlife was associated with smaller brain volumes in late life using a large biracial prospective cohort study. Methods: Plasma levels of systemic inflammatory markers (fibrinogen, albumin, white blood cell count, von Willebrand factor, and Factor VIII) were assessed at baseline in 1,633 participants (mean age 53 [5] ye...
55 CitationsSource
Cited By5
#1Edgar Meinl (LMU: Ludwig Maximilian University of Munich)H-Index: 65
#2Markus Krumbholz (University of Tübingen)H-Index: 36
BAFF and APRIL regulate B cell homeostasis by binding to their three receptors BAFFR, BCMA and TACI. The complexity of this system is further increased by shedding of these three receptors; this reduces signaling due to the display of less surface receptors. Further, soluble forms, sBCMA and sTACI, were detected in body fluids and serve as biomarker in malignancies, autoimmune diseases and immunodeficiencies. sBCMA and sTACI function as decoys blocking BAFF and APRIL. BCMA is a promising therape...
Objectives null To evaluate the long-term effects of natalizumab (NTZ) on different features of intrathecal immunoglobulin (Ig) synthesis in patients with multiple sclerosis (MS) and to quantify the expression of α4-integrin in stages of B-cell maturation. null Methods null We combined a cross-sectional (49 NTZ-treated MS patients, mean treatment duration 5.1 years, and 47 untreated MS patients) and a longitudinal study (33 patients with MS before and during NTZ, mean treatment duration: 4.8 yea...
1 CitationsSource
Multiple sclerosis (MS)-related inflammation can be divided into lesional activity, mediated by immune cells migrating from the periphery to the central nervous system (CNS) and non-lesional activity, mediated by inflammation compartmentalized to CNS tissue. Lesional inflammatory activity, reflected by contrast-enhancing lesions (CELs) on the magnetic resonance imaging (MRI), is effectively inhibited by current disease modifying therapies (DMTs). While, the effect of DMTs on non-lesional inflamm...
#1V S Krasnov (First Pavlov State Medical University of St. Peterburg)
#2Yu M Kolontareva (Novartis)H-Index: 1
Siponimod is a selective modulator of sphingosine-1-phosphate (S1P) receptors of types 1 and 5, registered in the Russian Federation for the treatment of patients with secondary progressive multiple sclerosis (SPMS), regardless of the presence or absence of exacerbations. The effectiveness of the drug in comparison with placebo was demonstrated in patients with SPMS in the international clinical trial EXPAND (phase III). This review devotes actual problems in the treatment of patients with SPMS,...
#1Roberta Magliozzi (Imperial College London)H-Index: 25
#2Valentina Mazziotti (University of Verona)H-Index: 3
Last. Massimiliano Calabrese (University of Verona)H-Index: 45
view all 9 authors...
Background Intrathecal immunoglobulin M (IgM) synthesis has been demonstrated in the early disease stages of multiple sclerosis (MS) as a predictor factor of a worsening disease course. Similarly, increased cerebrospinal fluid (CSF) molecules related to B-cell intrathecal activity have been associated with a more severe MS progression. However, whether CSF levels of IgM are linked to specific inflammatory and clinical profile in MS patients at the time of diagnosis remains to be elucidated. Meth...
2 CitationsSource