Patterns thread: Selective treatment for the four patterns

A forum to discuss research on the origins of MS and its development.

Patterns thread: Selective treatment for the four patterns

Postby frodo » Sun Nov 26, 2017 4:04 am

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

Objective

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.

Methods

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).

Results

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.

Interpretation

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.
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Re: Patterns thread: Selective treatment for the four patter

Postby frodo » Mon Apr 23, 2018 5:47 am

Type II pattern impressively responsible to alemtuzumab:

http://journals.sagepub.com/doi/abs/10. ... 6418759895

Abstract

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
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Re: Patterns thread. Pattern II mechanism.

Postby frodo » Mon Apr 23, 2018 5:57 am

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

Objective

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.

Methods

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.

Results

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.

Interpretation

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.
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Patterns thread. Microarray for diagnosis

Postby frodo » Mon Apr 23, 2018 6:05 am

Patent for diagnosis of the MS subtype, able to discriminate patterns I and II:

https://patents.google.com/patent/US9267945B2/en

Abstract

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
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Re: Patterns thread: Selective treatment for the four patter

Postby frodo » Thu Apr 26, 2018 3:30 am

Patterns I and II (specially pattern II) responsive to plasmapheresis. Pattern I unresponsive. This is just the last of several reports in this sense.

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

Abstract

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.
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Re: Patterns thread: Selective treatment for the four patter

Postby frodo » Thu May 10, 2018 1:54 am

As introduction they say:

"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.
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Pattern II: T-cells description

Postby frodo » Thu May 10, 2018 2:07 am

Pattern II: Description of the T-cells behaviour:

Detailed Characterization of T Cell Receptor Repertoires in Multiple Sclerosis Brain Lesions

https://www.frontiersin.org/articles/10 ... 00509/full

Extracts:

[...] 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.
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Re: Pattern II: T-cells description

Postby frodo » Thu May 10, 2018 2:18 am

Complement C3 on microglial clusters in multiple sclerosis occur in chronic but not acute disease

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[...]
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Re: Pattern II: T-cells description

Postby frodo » Thu May 10, 2018 2:23 am

About a pattern III experimental model:

Normobaric hyperoxia protects against demyelination in an experimental model of pattern III multiple sclerosis lesions

http://discovery.ucl.ac.uk/1465736/
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Re: Pattern III separation proposal

Postby frodo » Tue May 29, 2018 12:00 am

Pattern III MS proposed to be set appart from classical 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 (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"

Source:

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 [9]. 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’ [30].
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Personalized medicine and patterns

Postby frodo » Tue May 29, 2018 3:39 am

Personalized medicine: At present, treatment of multiple sclerosis (MS) relapses is far from personalized medicine: most patients receive 1 or 2 courses of corticosteroids, with treatment of unresponsive relapses escalating to apheresis (either plasma exchange or immunoabsorption).1,2 Predictors of response to either corticosteroids or plasma exchange are limited.

Tissue Markers for Acute Multiple Sclerosis Treatment Response—A Step Toward Personalized Medicine

https://jamanetwork.com/journals/jamane ... ct/2670431
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Mitoxantrone effective in pattern III

Postby frodo » Mon Jun 11, 2018 10:56 pm

Mitoxantrone treatment in a patient with multiple sclerosis and pattern III lesions

https://onlinelibrary.wiley.com/doi/abs ... cen3.12466

Abstract
Background


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.

Case presentation

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.

Conclusion

Mitoxantrone therapy along with steroid pulses could potentially be considered as a therapeutic option for pattern III lesions.
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Re: Mitoxantrone effective in pattern III

Postby NHE » Mon Jun 11, 2018 11:09 pm

frodo wrote:Conclusion

Mitoxantrone therapy along with steroid pulses could potentially be considered as a therapeutic option for pattern III lesions.

Mitoxantrone's cardiotoxicity limits its usefulness.
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Pattern II related to the new discovery of GDP-L-fucose synt

Postby frodo » Mon Oct 22, 2018 7:39 am

We can see what the team that found the new auto-antibody (GDP-L-fucose synthase) was doing when they found it. It is related to the four "luccchinetti patterns". They had just focused in the pattern II, which it was clearly autoimmune for them. Therefore it seems that this discovery only applies to them (they speak about HLA DRB3 immunocompatibility, or DRB3*02:02 Multiple Sclerosis Patients)

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.
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