Monday, 14 August 2017

Seeing is B-lieving

The success of B-cell-depleting therapies tells us that B cells play an important role in driving MS. We don't really understand how - they may be producing antibodies targeted against 'self', they may be recruiting other immune players like T lymphocytes and monocytes, or they may be doing both. 

There are many different types of B cell, each of which has a different set of roles in the immune system. 

So a sensible question to ask is whether the numbers and types of B cell present in the CSF - the spinal fluid - can predict the course of the disease.

A new study asked this question by looking at 128 pwMS and 40 people with other neurological disorders as their control group. They took samples of CSF - spinal fluid - and analysed the different subsets of B cells present. They then correlated this information with clinical details such as disease course and MRI findings.  

The numbers of mature B cells and plasmablasts (the precursors to long-lived antibody-secreting plasma cells) were raised in the group of people with bout-onset forms of MS (CIS, RRMS, SPMS) compared to PPMS and the control group. There was no difference in T cell numbers between the groups. 

CSF lymphocyte counts were not predictive of disability progression, conversion from CIS to RRMS.

This is very interesting. It implies that the CSF B cell profile is 'diagnostic' but not 'prognostic'. CSF B cells may be involved in driving relapses or may be a consequence of a 'leaky' blood-brain barrier in relapse-onset disease. What is odd and intriguing is that CSF B cells were not raised in PPMS. Given the success of ocrelizumab - a B cell depleter - in PPMS it is a bit counter-intuitive that this group did not show any evidence of having high CSF B counts. This may be because only two types of B cells, mature and plasmablasts, were examined here. In fact, the number of B lymphocytes in the CSF of the pwPPMS was slightly raised (although not statistically significant) compared to the control group. Given that the control group were also people with neurologic disorders, many of whom would be expected to have a degree of CNS inflammation, we may be missing a genuine difference here. Further studies are needed to examine the CSF of pwPPMS to determine whether there is a selective increase in specific B cell populations, such as the memory B's.


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Abstract

Background

There is evidence that B cells play an important role in disease pathology of multiple sclerosis (MS). The aim of this prospective observational study was to determine the predictive value of cerebrospinal fluid (CSF) B cell subtypes in disease evolution of patients with MS.

Materials and methods

128 patients were included between 2004 and 2012. Median follow up time was 7.9 years (range 3.3–10.8 years). 10 patients were lost to follow-up. 32 clinically isolated syndrome- (CIS), 25 relapsing remitting MS- (RRMS), 2 secondary progressive MS- (SPMS) and 9 primary progressive MS- (PPMS) patients were included. The control group consisted of 40 patients with other neurological diseases (OND). CSF samples were analyzed for routine diagnostic parameters. B cell phenotypes were characterized by flow cytometry using CD19 and CD138 specific antibodies. Standardized baseline brain MRI was conducted at the time of diagnostic lumbar puncture. Main outcome variables were likelihood of progressive disease course, EDSS progression, conversion to clinical definite MS (CDMS) and relapse rate.

Results

CSF mature B cells (CD19+CD138-) were increased in bout-onset MS compared to PPMS (p<0.05) and OND (p<0.001), whereas plasma blasts (CD19+CD138+) were increased in bout-onset MS (p<0.001) and PPMS (p<0.05) compared to OND. CSF B cells did not predict a progressive disease course, EDSS progression, an increased relapse rate or the conversion to CDMS. Likelihood of progressive disease course (p<0.05) and EDSS (p<0.01) was predicted by higher age at baseline, whereas conversion to CDMS was predicted by a lower age at onset (p<0.01) and the presence of ≥9 MRI T2 lesions (p<0.05).

Conclusion

We detected significant differences in the CSF B cell subsets between different clinical MS subtypes and OND patients. CSF B cells were neither predictive for disease and EDSS progression nor conversion to CDMS after a CIS.

7 comments:

  1. 1º conclussion Ocb have no real predictive value

    Also this study is al most copy cap this one:

    Multiple sclerosis is a chronic inflammatory and demyelinating disorder of the CNS with an unknown aetiology.
    Although intrathecal immunoglobulin G (IgG) synthesis is a key feature of the disease, little is still known about
    the B cell response in the CNS of multiple sclerosis patients. We analysed the phenotype and kinetics of
    different B cell subsets in patients with multiple sclerosis, infectious disease (IND) and non-inflammatory
    neurological disease (NIND). B cells were detected in the CSF of multiple sclerosis and IND patients, but
    were largely absent in NIND patients. In the CSF, the majority of B cells had a phenotype of memory B cells and
    short-lived plasma blasts (PB); plasma cells were absent from the compartment. The proportion of PB was
    highest in multiple sclerosis patients and patients with acute CNS infection. While PB disappeared rapidly from
    the CSF after resolution of infection in IND patients, these cells were present at high numbers throughout the
    disease course in multiple sclerosis patients. CSF PB numbers in multiple sclerosis patients strongly correlated
    with intrathecal IgG synthesis and inflammatory parenchymal disease activity as disclosed by MRI. This study
    identifies short-lived plasma blasts as the main effector B cell population involved in ongoing active inflammation
    in multiple sclerosis patients

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    Replies
    1. According to the Pender Hypothesis, dysregulation of EBV in memory B-cells is driving the recruitment of cytotoxic T-cells in the CNS resulting in damage to the CNS. Short-lived plasma blasts and subsequent intrathecal Ab production are transient after acute inflammatory episodes. Targeting of CD20+ memory B-cells harboring EBV with autologous T-cell therapy is Phase 1 in Australia. If EBV dysregulation in memory B-cells is driving MS then other strategies to reduce EBV expression could be of benefit. It would seem that CRISPER/cas9 gene editing of EBV in memory B-cells may be worth a look.

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    2. CRISPR:-) gene editing is going to be a hot topic in future therapeutics. Obviously we need to know what sequences are causing the disease in the first place.

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    3. Would agree with all of the above - unfortunately will be a bit of time before CRISPR finds a useful therapeutic application in MS, it's most useful in the context of specific identified disease-causing mutations and we're not quite at that stage yet with MS.

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    4. Dr. Pender in Queensland, Australia seems convinced that uncontrolled EBV in memory B cells is the underlying source of neuroinflammation. As he proceeds with the study we shall see. Here is an interview link from AAN in Boston.
      https://www.id-hub.com/2017/05/05/targeting-epstein-barr-virus-multiple-sclerosis-interview-michael-pender/

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  2. To address the role of the humoral immune system in
    neuroinflammation, we investigated B cell responses in different
    neuroinflammatory diseases in a cross-sectional and
    longitudinal study. We demonstrate that neuroinflammatory
    diseases are characterized by accumulation of B cells in the
    CSF. The main proportion of these B cells express a memory
    phenotype (CD19+CD27+CD138–). Memory B cells remain in
    the CNS compartment for years after infection, suggesting
    that their presence is independent of antigen persistence.
    We also observed a population of CD19+CD27++CD138+
    cells. These cells express high levels of CD38 and HLA-DR
    molecules, which identify them as short-lived PB (phenotype:
    CD19+CD27++CD138+CD38++HLA-DR++) (Odendahl et al.,
    2005). In contrast, PC, which express medium levels of CD38
    and no HLA-DR were largely absent from the CSF (phenotype:
    CD19+/–CD27++CD138+CD38+HLADR–). This finding
    contrasts a recent study, which described increased numbers
    of CD19–CD138+ PC in the CSF of patients with inflammatory
    CNS diseases (Corcione et al., 2004). In our study, predominantly
    short-lived PB were found in the CSF of patients
    with acute neuroinfection or multiple sclerosis. Since PB rapidly
    appear in the CSF following infection but disappear after
    clearance of the pathogen, their presence seems to be strictly
    dependent on the driving antigens. In multiple sclerosis, thePB subset was present throughout the disease course. Remarkably,
    the percentage of PB among all CSF B cells was higher in
    multiple sclerosis patients than all other diseases. Moreover,
    plasma blast numbers in CSF correlate strongly with the
    intrathecal IgG production and the CNS inflammation
    determined by MRI. These findings identify PB as the
    main effector B cell subset in multiple sclerosis

    ReplyDelete
  3. MD, thought it might interest you.

    This study, “Caveolin-1-dependent nanoscale organization of the BCR regulates B- cell tolerance”, was published in the Nature Immunology journal.

    ReplyDelete

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