For the new ones, the main idea is that there are four patterns of MS (one of them, IV very rare and often ignored), and they represent different pathogenic kinds of MS. Probably the most common, pattern II, is related to EBV while the rest are not.
Patterns I and II lesions show perivenous distribution, sharp borders and macrophages/microglia, and are considered typical autoimmune MS lesions. Pattern III and IV do not show macrophages/microglia and probably will be officially excluded from MS at some point.
(image taken from https://onlinelibrary.wiley.com/doi/ful ... 9485.12498)
- Jan 2019: Immunoadsorption or plasma exchange in steroid‐refractory multiple sclerosis and neuromyelitis optica: They say that immunoadsorption is equally effective than plasma exchange.
- Jan 2019: Brain histopathological study and prognosis in MOG antibody‐associated demyelination: They present two cases of anti-MOG encephalomyelitis, not MS, but similar to tumefactive MS, having lesions belonging at the same time to patterns I and II. This could explain some reports about coexistence of patterns.
-June 2018: Multiple sclerosis pathogenesis: missing pieces of an old puzzle: At least two distinct demyelinating processes may be responsible for lesion genesis in MS; in one the primary target of injury are oligodendrocytes and in the other myelin components.
- June 2018: Mitoxantrone treatment in a patient with multiple sclerosis and pattern III lesions: They report for the first time a successful Mitoxantrone treatment in a patient with specifically determined pattern III lesions.
- April 2018: Differences in the Reponses to Apheresis of patients with histopathologically classified Patterns of MS: Response to apheresis therapy may be associated with immunopathological patterns and thus with pathological mechanisms of lesion development.
- April 2018: Tissue Markers for Acute Multiple Sclerosis Treatment Response—A Step Toward Personalized Medicine: Personalized medicine tries to find the right medicine for each patient. Patterns are considered in this article.
- March 2018: Rescue therapy with alemtuzumab in B cell/antibody-mediated MS They explain that Alemtuzumab works better for pattern II and they identify the B-cells problem with this pattern.
- March 2018: Detailed Characterization of T Cell Receptor Repertoires in Multiple Sclerosis Brain Lesions: Description of the T-cells behaviour in pattern II. Clonal T cell expansions in MS brain lesions allow the identification of T cells that are assumed to be involved in the disease process.
- Jan. 2018: Transcriptional profile and Epstein-Barr virus infection status of laser-cut immune infiltrates from the brain of patients with progressive multiple sclerosis. They say that EBV is strongly related to clonally expanded CD4+ and CD8+ T cells, the ones detected in pattern II brain lesions.
- Jan 2018: Baló’s concentric sclerosis is immunologically distinct from multiple sclerosis: Pattern III MS is a subtype of Balo and not MS: "Pattern III MS is diagnosed ... has only recently been proposed to denote a disease entity distinct from MS based on our observation that those patients are negative for OCB"
- August 2017: Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis: A special test called the MRZ reaction, reported in 60–80% of MS patients was absent in all pattern II or III MS patients tested. Besides Oligoclonal bands were present in nearly all samples from pattern I but only in few samples from patients with patterns II or III.
- May 2017: Sublethal oligodendrocyte injury: A reversible condition in multiple sclerosis?: They explain that pattern III MS could be reversed.
- November 2016: Multiple sclerosis: the upward trajectory continues. Pattern III lesions linked to hypoxia and resposive to oxygen therapy: "Whilst these findings, including the reversal of ongoing hypoxia, need to be verified, they suggest a key role for hypoxia in the pattern III lesions". Available as pdf in http://discovery.ucl.ac.uk/1534337/1/Th ... v-2016.pdf
- October 2016: Complement C3 on microglial clusters in multiple sclerosis occur in chronic but not acute disease: The say that microglia is the culprit in pattern I but not in the others patterns: "In acute MS cases with either pattern II or pattern III lesion pathology we found no evidence of microglial clusters or linear deposits of C3d, suggesting that clusters formation is independent of active demyelination".
- June 2015: Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesions: First functional evidence for arole of Th2/Tc2 cells in pattern II MS, supporting the existence of this pathogenic phenotype.
-Nov. 2008: Unique serum immune signatures characterize immunopathogenic mechanisms of MS. Biomarkers in blood can identify the pathological MS pattern.
- August 2005: Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. First report about a selective treatment. All patients with pattern II but none with patterns I or III, achieved neurological improvement.
Pattern III MS (distal oligodendrogliopathy) could be reversed:
Sublethal oligodendrocyte injury: A reversible condition in multiple sclerosis?
http://onlinelibrary.wiley.com/doi/10.1 ... 24944/full
Degeneration of oligodendroglial distal processes (pattern III) has been identified as an early event in multiple sclerosis (MS) lesion development. Our objective was to further define the development of the “dying-back” oligodendrocyte lesion in situ and to model the development and potential reversibility of such responses using dissociated cultures of adult human brain-derived oligodendrocytes.
In situ analyses were performed on glutaraldehyde-fixed thin sections of clinically acute and pathologically active cases of MS. In vitro studies were conducted using adult human brain-derived oligodendrocytes challenged by metabolic stress conditions (low nutrient/glucose).
In situ analyses indicated a spectrum of myelin changes in the presence of morphologically intact oligodendrocytes; these included degeneration of the inner cytoplasmic tongue with increasing sizes of intramyelinic bleb formation that could result in radial fractures of the myelin sheath. Macrophages with ingested myelin fragments were identified only once the fragmentation was established. In vitro studies indicated that oligodendrocyte process retraction, which was linked to reduced glycolytic respiratory activity, is reversible until a critical time point. Subsequent cell death was not linked to caspase-3–dependent programs. Gene expression studies conducted at the latest reversible time point revealed reduced expression of pathways associated with cell process outgrowth and myelination, as well as with metabolic activity.
Our findings reveal the potential to protect and possibly restore myelin elaborated by existent oligodendrocytes in early and evolving MS lesions, and suggest the necessity of ongoing studies of the mechanisms underlying subsequent adult human oligodendrocyte cell death.
Type II pattern impressively responsible to alemtuzumab:
http://journals.sagepub.com/doi/abs/10. ... 6418759895
Alemtuzumab exerts its clinical efficacy by its specific pattern of depletion and repopulation of different immune cell subsets. Recently, single cases of multiple sclerosis patients who developed severe exacerbation after the first alemtuzumab application, accompanied by re-appearance of peripheral B cells, were reported. Here we present a case with underlying B cell-driven multiple sclerosis that impressively improves after alemtuzumab, although peripheral B cell repopulation took place. Our detailed clinical, histopathological, imaging and immunological data suggest that alemtuzumab can act as an effective rescue treatment in highly active B cell-driven and antibody/complement-mediated multiple sclerosis type II patients.
Full pdf available at http://journals.sagepub.com/doi/pdf/10. ... 6418759895
A description of the fisiopathology of the T-cells in the MS pattern II:
https://onlinelibrary.wiley.com/doi/ful ... 2/acn3.218
Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesions
Multiple sclerosis (MS) is a disease of the central nervous system with marked heterogeneity in several aspects including pathological processes. Based on infiltrating immune cells, deposition of humoral factors and loss of oligodendrocytes and/or myelin proteins, four lesion patterns have been described. Pattern II is characterized by antibody and complement deposition in addition to T‐cell infiltration. MS is considered a T‐cell‐mediated disease, but until now the study of pathogenic T cells has encountered major challenges, most importantly the limited access of brain‐infiltrating T cells. Our objective was to identify, isolate, and characterize brain‐infiltrating clonally expanded T cells in pattern II MS lesions.
We used next‐generation sequencing to identify clonally expanded T cells in demyelinating pattern II brain autopsy lesions, subsequently isolated these as T‐cell clones from autologous cerebrospinal fluid and functionally characterized them.
We identified clonally expanded CD8+ but also CD4+ T cells in demyelinating pattern II lesions and for the first time were able to isolate these as live T‐cell clones. The functional characterization shows that T cells releasing Th2 cytokines and able to provide B cell help dominate the T‐cell infiltrate in pattern II brain lesions.
Our data provide the first functional evidence for a putative role of Th2/Tc2 cells in pattern II MS supporting the existence of this pathogenic phenotype and questioning the protective role that is generally ascribed to Th2 cells. Our observations are important to consider for future treatments of pattern II MS patients.
The present invention relates to methods and kits for diagnosing multiple sclerosis (MS) in a subject. Particularly, the present invention relates to methods and kits for diagnosing a subtype of MS in a subject, the subtype selected from relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and a pathologic sub-type of MS lesions selected from Pattern I and Pattern II MS lesion
Differences in the Reponses to Apheresis Therapy of Patients With 3 Histopathologically Classified Immunopathological Patterns of Multiple Sclerosis
https://jamanetwork.com/journals/jamane ... irect=true
Importance Plasma exchange and immunoadsorption are second-line apheresis therapies for patients experiencing multiple sclerosis relapses. Early active multiple sclerosis lesions can be classified into different histopathological patterns of demyelination. Pattern 1 and 2 lesions show T-cell– and macrophage–associated demyelination, and pattern 2 is selectively associated with immunoglobulin and complement deposits, suggesting a humoral immune response. Pattern 3 lesions show signs of oligodendrocyte degeneration. Thus it is possible that pathogenic heterogeneity might predict therapy response.
Objective To evaluate the apheresis response in relation to histopathologically defined immunopathological patterns of multiple sclerosis.
Design, Setting and Participants This single-center cohort study recruited 69 patients nationwide between 2005 and 2016. All included patients had a diagnosis of early active inflammatory demyelination consistent with multiple sclerosis; were classified into patterns 1, 2, or 3 based on brain biopsy analysis; and underwent apheresis treatments. Patients who had concomitant severe disease, neuromyelitis optica, or acute disseminated encephalomyelitis were excluded.
Main Outcomes and Measures The primary therapy outcome was a functionally relevant improvement of the relapse-related neurological deficit. Radiological and Expanded Disability Status Scale changes were secondary outcome parameters.
Results The mean (SD) age of patients was 36.6 (13.3) years; 46 of the 69 participants (67%) were female. Overall, 16 patients (23%) exhibited pattern 1 lesions, 40 (58%) had pattern 2 lesions, and 13 (19%) had pattern 3 lesions. A functional therapy response was observed in 5 of the 16 patients with pattern 1 disease (31%) and 22 of the 40 patients with pattern 2 disease (55%), but none of the 13 patients with pattern 3 disease exhibited improvement (pattern 2 vs 3 P < .001). Radiological improvements were found in 4 (25%), 22 (56%), and 1 (11%) of patients with patterns 1, 2, and 3, respectively. The respective rates of response measured by changes in Expanded Disability Status Scale scores were 25%, 40%, and 0%. Brainstem involvement was a negative predictive factor for the functional therapy response (logarithmic odds ratio [logOR], −1.43; 95% CI, −3.21 to 0.17; P = .03), while immunoadsorption (as compared with plasma exchange) might be a positive predictive factor (logOR, 3.26; 95% CI, 0.75 to 8.13; P = .01).
Conclusions and Relevance This cohort study provides evidence that the response to apheresis treatment is associated with immunopathological patterns. Patients with both patterns 1 and 2 improved clinically after apheresis treatment, but pattern 2 patients who showed signs of a humoral immune response benefited most. Apheresis appears unlikely to benefit patients with pattern 3 lesions.
"Histopathological studies have demonstrated at least three different lesion patterns [...]. Pattern I show T cell and macrophage infiltration. Pattern II is defined by additional antibody and complement deposition Pattern III is characterized by distal oligodendrogliopathy [...]. These findings raise the possibility that MS, a diagnosis currently based mainly on phenotypical, namely clinical and radiological features, may in fact be a pathologically heterogeneous syndrome rather than a single disease entity. Importantly, two recent studies demonstrated intraindividual homogeneity and persistence of pattern I, II and III lesions over time further corroborating the notion that lesion pathology may rather define pathogenetically distinct entities than reflect stage-dependent processes in the development of lesions"
Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis
https://jneuroinflammation.biomedcentra ... 017-0929-z
Background: The diagnosis of multiple sclerosis (MS) is currently based solely on clinical and magnetic resonance imaging features. However, histopathological studies have revealed four different patterns of lesion pathology in patients diagnosed with MS, suggesting that MS may be a pathologically heterogeneous syndrome rather than a single disease entity.
Objective: The aim of this study was to investigate whether patients with pattern I MS differ from patients with pattern II or III MS with regard to cerebrospinal fluid (CSF) findings, especially with reference to intrathecal IgG synthesis, which is found in most patients with MS but is frequently missing in MS mimics such as aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-IgG-positive encephalomyelitis.
Methods: Findings from 68 lumbar punctures in patients who underwent brain biopsy as part of their diagnostic work-up and who could be unequivocally classified as having pattern I, pattern II or pattern III MS were analysed retrospectively.
Results: Oligoclonal bands (OCBs) were present in 88.2% of samples from pattern I MS patients but in only 27% of samples from patients with pattern II or pattern III MS (P < 0.00004); moreover, OCBs were present only transiently in some of the latter patients. A polyspecific intrathecal IgG response to measles, rubella and/or varicella zoster virus (so-called MRZ reaction) was previously reported in 60–80% of MS patients, but was absent in all pattern II or III MS patients tested (P < 0.00001 vs. previous cohorts). In contrast, the albumin CSF/serum ratio (QAlb), a marker of blood–CSF barrier function, was more frequently elevated in samples from pattern II and III MS patients (P < 0.002). Accordingly, QAlb values and albumin and total protein levels were higher in pattern II and III MS samples than in pattern I MS samples (P < 0.005, P < 0.009 and P < 0.006, respectively).
Conclusions: Patients with pattern II or pattern III MS differ significantly from patients with pattern I MS as well as from previous, histologically non-classified MS cohorts with regard to both intrathecal IgG synthesis and blood–CSF barrier function. Our findings strongly corroborate the notion that pattern II and pattern III MS are entities distinct from pattern I MS.
Detailed Characterization of T Cell Receptor Repertoires in Multiple Sclerosis Brain Lesions
https://www.frontiersin.org/articles/10 ... 00509/full
[...] three demyelinating lesions that had different location and inflammatory activity, were obtained from a secondary progressive (SP)MS patient with pattern II demyelinating lesions (22), for whom we had the unique opportunity to have access to peripheral blood mononuclear cells (PBMCs) and CSF cells prior to death and also autopsy brain tissue[...]
Clonal T cell expansions in MS brain lesions allow the identification of T cells that are assumed to be involved in the disease process [...]
It is important to note that the three demyelinating brain lesions analyzed in this study were from a single SPMS patient with pattern II demyelinating lesions (22), and therefore, one may not be able to extrapolate our results to patients with other clinical forms of MS or other demyelinating patterns[...]
Pattern II demyelination is associated with macrophages and T cell inflammation, as well as prominent deposition of antibody/complement complexes at sites of active myelin destruction
[...]and the ability of several of these CSF-TCCs to release Th2 cytokines and help B cells in pattern II demyelination (22), strongly support their pathogenic role and also underline the value of cDNA TRBV-seq of active lesions to identify pathogenic cells.
In conclusion, MS brain lesions, at least in a SPMS patient with pattern II demyelination, independently of their proximity or inflammatory activity, contain CD4+ and CD8+ clonally expanded clonotypes that may play a role in disease pathogenesis.
https://onlinelibrary.wiley.com/doi/ful ... glia.23090
[...]White matter lesions of cases with acute MS were classified into patterns I–IV, as previously described (Lucchinetti et al., 2000). Of the 10 acute MS cases included in the present study, 5 showed active lesions resembling the hypoxia‐like pattern III lesions, and 5 showed active lesions with pattern II pathology (Table 1). Evidence of complement activation in and around the lesions has been previously shown for the MS cases with pattern II pathology[...]
[...]In acute MS cases with either pattern II or pattern III lesion pathology we found no evidence of microglial clusters or linear deposits of C3d, suggesting that clusters formation is independent of active demyelination. In the periplaque white matter, microglia showed a sparse distribution and a resting morphology, as indicated by the thin appearance of IBA‐1+ ramifications and the low immunoreactivity for CD68[...]
"Pattern III MS is diagnosed on the basis of histopathological features, some of which suggest ischemia-mediated tissue damage, and has only recently been proposed to denote a disease entity distinct from classical MS based on our observation that patients with ‘pattern III’ lesions are typically negative for OCB (oligoclonal bands)".
"While probably overrepresented in biopsy/autopsy samples, ‘pattern III MS’ must be a rare disease in the general MS population given that OCB are highly frequent in MS"
Baló’s concentric sclerosis is immunologically distinct from multiple sclerosis: results from retrospective analysis of almost 150 lumbar punctures
https://jneuroinflammation.biomedcentra ... 017-1043-y
Finally, at least some patients with BCS may suffer from what has been called ‘pattern III’ MS. ‘Pattern III’ MS is diagnosed on the basis of histopathological features, some of which suggest ischemia-mediated tissue damage, and has only recently been proposed to denote a disease entity distinct from classical MS based on our observation that patients with ‘pattern III’ lesions are typically negative for OCB . While probably overrepresented in biopsy/autopsy samples, ‘pattern III MS’ must be a rare disease in the general MS population given that OCB are highly frequent in MS. So far, lesions showing the typical histopathological characteristics of ‘pattern III’ lesions have been reported in 12 patients with ‘concentric demyelination’ .
Tissue Markers for Acute Multiple Sclerosis Treatment Response—A Step Toward Personalized Medicine
https://jamanetwork.com/journals/jamane ... ct/2670431
https://onlinelibrary.wiley.com/doi/abs ... cen3.12466
Brain biopsies of multiple sclerosis patients identified three intraindividually stable lesion patterns. Apart from beneficial effects of plasma exchange in patients with type II lesions, little is known about how multiple sclerosis lesion histology could guide therapeutic decisions.
Here, we report on a 53‐year‐old male patient with polysymptomatic cerebral syndrome as the first episode of multiple sclerosis. Brain biopsy showed an inflammatory demyelinating lesion with apoptotic oligodendrocytes and a loss of myelin‐associated glycoprotein, pathological features typical for pattern III lesions. High‐dose steroids and immunosuppressive treatment with mitoxantrone led to a substantial improvement of disability and long‐term clinical stability.
Mitoxantrone therapy along with steroid pulses could potentially be considered as a therapeutic option for pattern III lesions.
- Volunteer Moderator
- Posts: 5045
- Joined: Sat Nov 20, 2004 3:00 pm
- Has thanked: 1 time
- Been thanked: 5 times
Mitoxantrone's cardiotoxicity limits its usefulness.frodo wrote:Conclusion
Mitoxantrone therapy along with steroid pulses could potentially be considered as a therapeutic option for pattern III lesions.
https://www.multiplesclerosis.uzh.ch/en ... pedra.html
Autoantigens and disease heterogeneity
Our research aims are:
The identification of the antigen specificity and functional phenotype of autoreactive CD8+ T cells that are clonally expanded in the brains of MS patients with distinct phenotypes, e.g. 'Lucchinetti/Brück/Lassmann type 2' disease, which is characterized by T cell infiltration, antibody- and complement deposition
Addressing in a larger number of patients if the antigens identified under aim above are related to specific MS phenotypes.
Multiple sclerosis is a chronic inflammatory disease, which leads to focal plaques of demyelination and tissue injury in the CNS. The structural and immunopathological patterns of demyelination suggest that different immune mechanisms may be involved in tissue damage. In a subtype of lesions, which are mainly found in patients with acute fulminant multiple sclerosis with Balo's type concentric sclerosis and in a subset of early relapsing remitting multiple sclerosis, the initial myelin changes closely resemble those seen in white matter stroke (WMS), suggesting a hypoxia-like tissue injury. Since mitochondrial injury may be involved in the pathogenesis of such lesions, we analysed a number of mitochondrial respiratory chain proteins in active lesions from acute multiple sclerosis and from WMS using immunohistochemistry.
Functionally important defects of mitochondrial respiratory chain complex IV [cytochrome c oxidase (COX)] including its catalytic component (COX-I) are present in Pattern III but not in Pattern II multiple sclerosis lesions. The lack of immunohistochemically detected COX-I is apparent in oligodendrocytes, hypertrophied astrocytes and axons, but not in microglia.
The profile of immunohistochemically detected mitochondrial respiratory chain complex subunits differs between multiple sclerosis and WMS. The findings suggest that hypoxia-like tissue injury in Pattern III multiple sclerosis lesions may be due to mitochondrial impairment.
Free full text.
- Similar Topics
- Last post
- 0 Replies
- 812 Views
Last post by frodo
Wed Feb 28, 2018 4:34 am
- 0 Replies
- 689 Views
Last post by frodo
Tue Jul 10, 2018 2:06 am
- 0 Replies
- 992 Views
Last post by seeva
Tue May 01, 2018 11:29 pm
- 0 Replies
- 410 Views
Last post by Petr75
Sat Oct 06, 2018 10:04 am
- 0 Replies
- 742 Views
Last post by seeva
Wed May 09, 2018 2:18 am