8 research outputs found
Complement Activation Is Associated With Disease Severity in Multiple Sclerosis.
BACKGROUND AND OBJECTIVES
Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression.
METHODS
CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient.
RESULTS
CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 0.0001).
DISCUSSION
CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS
Efficacy of Intravenous Immunoglobulin in Neurological Diseases
Owing to its anti-inflammatory efficacy in various autoimmune disease
conditions, intravenous immunoglobulin (IVIG)-pooled IgG obtained from
the plasma of several thousands individuals-has been used for nearly
three decades and is proving to be efficient in a growing number of
neurological diseases. IVIG therapy has been firmly established for the
treatment of Guillain-Barre syndrome, chronic inflammatory demyelinating
polyneuropathy, and multifocal motor neuropathy, either as first-line
therapy or adjunctive treatment. IVIG is also recommended as rescue
therapy in patients with worsening myasthenia gravis and is beneficial
as a second-line therapy for dermatomyositis and stiff-person syndrome.
Subcutaneous rather than intravenous administration of IgG is gaining
momentum because of its effectiveness in patients with primary
immunodeficiency and the ease with which it can be administered
independently from hospital-based infusions. The demand for IVIG therapy
is growing, resulting in rising costs and supply shortages. Strategies
to replace IVIG with recombinant products have been developed based on
proposed mechanisms that confer the anti-inflammatory activity of IVIG,
but their efficacy has not been tested in clinical trials. This review
covers new developments in the immunobiology and clinical applications
of IVIG in neurological diseases
Intravenous immunoglobulin in neurology-mode of action and clinical efficacy
Intravenous immunoglobulin (IVIg)-a preparation of polyclonal serum IgG
pooled from thousands of blood donors-has been used for nearly three
decades, and is proving to be an efficient anti-inflammatory and
immunomodulatory treatment for a growing number of neurological
diseases. Evidence from controlled clinical trials has established IVIg
as a first-line therapy for Guillain-Barre syndrome, chronic
inflammatory demyelinating polyneuropathy and multifocal motor
neuropathy. IVIg is also an effective rescue therapy in some patients
with worsening myasthenia gravis, and is beneficial as a second-line
therapy for dermatomyositis and stiff-person syndrome. IVIg has been
tested in some neurodegenerative disorders, but a controlled study in
Alzheimer disease yielded disappointing results. Despite its widespread
use and therapeutic success, the mechanisms of action of IVIg are poorly
understood. Several hypotheses, based on the function of either the
variable or constant IgG fragments, have been proposed to explain IVIg’s
immunomodulatory activity. This Review highlights emerging data on the
mechanisms of action of IVIg related to its anti-inflammatory activity,
especially that involving the cellular Fc gamma receptors and Fc
glycosylation. We also summarize recent trials in neurological diseases,
discuss potential biomarkers of efficacy, offer practical guidelines on
administration, and provide a rationale for experimental trials in
neuroinflammatory disorders
Highlights from the 2019 European Congress on Treatment and Research in Multiple Sclerosis (ECTRIMS 2019)
The 2019 ECTRIMS Congress, in Stockholm, has had record-breaking figures for both attendance and scientific production. There were 9361 participants from 100 different countries for a total of 1541 abstracts. Upon invitation of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) executive committee, the authors of this meeting report assessed abstracts from all poster and oral presentations for novelty, scientific quality and relevance for basic and clinical multiple sclerosis (MS) research. The objective of this report is to highlight a selection of basic, translational and clinical studies out of the many outstanding projects that were presented. Abstracts and references cited in our report were chosen at the discretion of the authors and all co-authors and the ECTRIMS executive committee agreed on the selection. In the event of discrepancies between the abstract and the uploaded poster or presentation, we aimed to present data derived from the poster or presentation. All abstracts are accessible through the ECTRIMS online library () and also published in this journal (Volume 25 Issue 2_suppl, September 2019; ). A few additional references from the literature were added but were restricted to the ones that authors considered as absolutely required for an optimized understanding of the topics highlighted
Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity
The B cell-depleting IgG1 monoclonal antibody rituximab can persistently
suppress disease progression in some patients with autoimmune diseases.
However, the mechanism underlying these long-term beneficial effects has
remained unclear. Here, we evaluated Ig gene usage in patients with
anti-myelin-associated glycoprotein (anti-MAG) neuropathy, an autoimmune
disease of the peripheral nervous system that is mediated by IgM
autoantibodies binding to MAG antigen. Patients with anti-MAG neuropathy
showed substantial clonal expansions of blood IgM memory B cells that
recognized MAG antigen. The group of patients showing no clinical
improvement after rituximab therapy were distinguished from clinical
responders by a higher load of clonal IgM memory B cell expansions
before and after therapy, by persistence of clonal expansions despite
efficient peripheral B cell depletion, and by a lack of substantial
changes in somatic hypermutation frequencies of IgM memory B cells. We
infer from these data that the effectiveness of rituximab therapy
depends on efficient depletion of noncirculating B cells and is
associated with qualitative immunological changes that indicate
reconfiguration of B cell memory through sustained reduction of
autoreactive clonal expansions. These findings support the continued
development of B cell-depleting therapies for autoimmune diseases
Broader Epstein-Barr virus-specific T cell receptor repertoire in patients with multiple sclerosis
The EBV-specific T cell receptor repertoire is broader in multiple sclerosis patients, even in diseased siblings of discordant monozygotic twin pairs, indicating an ongoing immune response to Epstein-Barr virus in multiple sclerosis patients, which might hold clues for multiple sclerosis pathogenesis and future therapeutic or preventive avenues. Epstein-Barr virus (EBV) infection precedes multiple sclerosis (MS) pathology and cross-reactive antibodies might link EBV infection to CNS autoimmunity. As an altered anti-EBV T cell reaction was suggested in MS, we queried peripheral blood T cell receptor beta chain (TCR beta) repertoires of 1,395 MS patients, 887 controls, and 35 monozygotic, MS-discordant twin pairs for multimer-confirmed, viral antigen-specific TCR beta sequences. We detected more MHC-I-restricted EBV-specific TCR beta sequences in MS patients. Differences in genetics or upbringing could be excluded by validation in monozygotic twin pairs discordant for MS. Anti-VLA-4 treatment amplified this observation, while interferon beta- or anti-CD20 treatment did not modulate EBV-specific T cell occurrence. In healthy individuals, EBV-specific CD8(+) T cells were of an effector-memory phenotype in peripheral blood and cerebrospinal fluid. In MS patients, cerebrospinal fluid also contained EBV-specific central-memory CD8(+) T cells, suggesting recent priming. Therefore, MS is not only preceded by EBV infection, but also associated with broader EBV-specific TCR repertoires, consistent with an ongoing anti-EBV immune reaction in MS