Wednesday, 6 December 2017

Yet more data supports the B memory Cell idea

I can hear you saying, "Oh no not another B-cell paper!". However, this is where the action is. It is the B-cell and not the T-cell. Do you agree or disagree? Have your say. 

Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patients.
Eggers EL, Michel BA, Wu H, Wang SZ, Bevan CJ, Abounasr A, Pierson NS, Bischof A, Kazer M, Leitner E, Greenfield AL, Demuth S, Wilson MR, Henry RG, Cree BA, Hauser SL, von Büdingen HC.
JCI Insight. 2017 Nov 16;2(22). pii: 92724. doi: 10.1172/jci.insight.92724. [Epub ahead of print

A role of B cells in multiple sclerosis (MS) is well established, but there is limited understanding of their involvement during active disease. Here, we examined cerebrospinal fluid (CSF) and peripheral blood (PB) B cells in treatment-naive patients with MS or high-risk clinically isolated syndrome. Using flow cytometry, we found increased CSF lymphocytes with a disproportionate increase of B cells compared with T cells in patients with gadolinium-enhancing (Gd+) lesions on brain MRI. Ig gene heavy chain variable region (Ig-VH) repertoire sequencing of CSF and PB B cells revealed clonal relationships between intrathecal and peripheral B cell populations, which could be consistent with migration of B cells to and activation in the CNS in active MS. In addition, we found evidence for bystander immigration of B cells from the periphery, which could be supported by a CXCL13 gradient between CSF and blood. Understanding what triggers B cells to migrate and home to the CNS may ultimately aid in the rational selection of therapeutic strategies to limit progression in MS.

In active disease there are more B cells accumulating in the CNS....but what are they?

CSF lymphocytes are dominated by T cells, but B cells are disproportiona...

Yes you guessed it they are B memory Cells. 

The population is the Class Switched memory B cell, There were also more plasma cells (did these come from memory cell population).

The finding that increased CSF B cells were linked to the presence of Gadolinium (Gd) lesions on brain MRI suggested their association with disease activity in MS and raised the question whether there are clonal relationships between CSF B cell subsets and their PB counterparts. 

Interestingly, they found evidence peripherally antigen-stimulated B cells may have migrated to the CSF compartment where they became activated to further mature into antibody-secreting CD27 high B cells.

They found clonally related CD27hi PCs (plasmablasts/plasma cells) in blood and CSF that were also related to Ig class-switched-memory B cells in the same compartments. 

Given that CD27hi PCs are likely restricted to their compartment (as evidenced by their low CXCR5 expression), and the persistence of memory B cells in MS CSF and CNS in general, parallel maturation of preexisting class switched memory B cells on both sides of the blood-brain barrier may have occurred following a peripheral immune activating event. 

The presence of clonal relationships between memory B cells and plasma cells in the CSF and CSF Ig-VH clusters containing related IgM-VH and IgG-VH also support local B cell activation and subsequent maturation and class-switch recombination.

They did find naive CSF B cells with clonally related counterparts in the periphery, naive B cells do not seem to become stimulated intrathecally to mature to memory B cells.

So its B memory Cells

Peripheral immune activation can lead to intrathecal immune stimulation, either via antigen nonspecific (A; e.g., via cytokines during an infectious disease) or antigen-specific (B; via preformed CD27+IgD SM) mechanisms. This immune activation involves B and T cells, as supported by our flow cytometry findings and those of others (24) (Figures 1–3), and leads to B cell activation, modification of the B cell receptor (somatic hypermutation [SHM]; Ig-class switch recombination [CSR]) and B cell maturation (C). B cell influx and intrathecal B cell expansion are supported by Ig-RepSeq (Figures 5 and 6). These immune mechanisms support MS disease activity (evidenced by Gd+ MRI lesions; example from patient 57514) and lead to increased production of CXCL13 (D), which, in turn, also attracts CD27 B cells to the CNS/CSF compartment (E). These CD27 B cells may not have been involved in the initial peripheral immune triggering event; rather, their migration to the CNS could be a nonspecific event. Activated CD27+ B cells, once in the CNS, may further mature to antibody-secreting plasmablasts/plasma cells and may home to ectopic lymphoid sites (F). We found no evidence for CD27 IgD+ B cells maturing to antigen-specific CD27+ B cell subset; the fate of naive B cells in CSF remains unknown (G). It is important to note that several steps described in this model remain hypothetical and subject of future research.


  1. It is my understanding that a memory B cell is specific to one thing.

    Does a memory B cell remember last months cold only or does it remember last months cold, the flu jab and chicken pox etc?

    1. You're correct Aidan the memory B cell is specific for one antigen but in some cases the antigen might not be specific to a particular pathogen and in some cases there can be cross-reactivity with human antigens too. It's complex!

  2. Typo? "B cells" repeated later in the paragraph quoted below. You said you had a bee in your bonnet....

    I *really do* want to get Andrew Straneri going on the research idea - SPCI - Smart Phone Cognition Index.

    Given that CD27hi PCs are likely restricted to their compartment (as evidenced by their low CXCR5 expression), and the persistence of memory B cells in MS CSF and CNS in general, parallel maturation of preexisting class switched memory B cells B cells on both sides of the blood-brain barrier may have occurred following a peripheral immune activating event.

  3. As someone with MS and not a scientist, I'm afraid I am struggling to understand this post. Please could someone briefly summarise with a few simple bullet points - thank you.

    1. Anon 11:24:
      MS patients are routinely screened with MRi and Gadolinium contrast medium. Gadolinium enhancing lesions seen on MRi is telling of inflammatory activity.

      Study main points:
      - In patients with Gad+ lesions, there is an increase of B cells in the spinal fluid.
      - The increase is mainly due to Memory B cells that are class switched (Which means mainly IgG+ B cells, in the case of MS).
      - These memory B cells that are found in CSF can also be found in the blood (clones). This is determined by sequencing the B cell receptors.

  4. Very nice paper

    Since this is only CIS and RRms patients would this b cells patterns

    between Pb and Cns in Gd+ and Gd- patients would still apply in

    later stages or during the disease course?

    This study is in contrast, patients with advance disease

    Abstract T cells are considered pivotal in the pathology
    of multiple sclerosis (MS), but their function and antigen
    specificity are unknown. To unravel the role of T cells in
    MS pathology, we performed a comprehensive analysis on T
    cells recovered from paired blood, cerebrospinal fluid (CSF),
    normal-appearing white matter (NAWM) and white matter
    lesions (WML) from 27 MS patients with advanced disease
    shortly after death. The differentiation status of T cells in
    these compartments was determined by ex vivo flow cytometry
    and immunohistochemistry. T-cell reactivity in shortterm
    T-cell lines (TCL), generated by non-specific stimulation
    of T cells recovered from the same compartments, was
    determined by intracellular cytokine flow cytometry. Central
    memory T cells predominated in CSF and effector memory
    T cells were enriched in NAWM and WML. WML-derived
    T cells represent chronically activated T cells expressing
    a cytotoxic effector phenotype (CD95L and granzyme
    B) indicative for local antigenic stimulation (CD137). The
    same lesions also contained higher CD8+
    T-cell frequencies
    expressing co-inhibitory (TIM3 and PD1) and co-stimulatory
    (ICOS) T-cell receptors, yet no evidence for T-cell
    senescence (CD57) was observed. The oligoclonal T-cell
    receptor (TCR) repertoire, particularly among CD8+
    cells, correlated between TCL generated from anatomically
    separated WML of the same MS patient, but not between
    paired NAWM and WML. Whereas no substantial T-cell
    reactivity was detected towards seven candidate human MSassociated
    autoantigens (cMSAg), brisk CD8+
    T-cell reactivity
    was detected in multiple WML-derived TCL towards
    autologous Epstein–Barr virus (EBV) infected B cells (auto-
    BLCL). In one MS patient, the T-cell response towards
    autoBLCL in paired intra-lesional TCL was dominated by
    TCRVβ2+CD8+ T cells, which were localized in the parenchyma
    of the respective tissues expressing a polarized TCR
    and CD8 expression suggesting immunological synapse formation
    in situ. Collectively, the data suggest the involvement
    of effector memory cytotoxic T cells recognizing antigens
    expressed by autoBLCL, but not the assayed human cMSAg,
    in WML of MS patients

    The current study provides novel insights into the phenotypic
    and functional characteristics of the T-cell response in
    CSF and (non-)affected brain tissue of MS patients. Three
    main findings are reported. First, T cells in MS lesions
    are predominantly CD8+
    cells expressing a cytotoxic
    effector phenotype indicative for local antigenic stimulation.
    Second, T cells cultured from WML in four of nine
    MS patients recognize autoBLCL. This reactivity was profound
    in TCL generated from AL and mAIL. Third, no
    substantial T-cell reactivity was observed towards seven
    human cMSAg in CSF- and brain tissue-derived TCL of
    MS patients expressing the major MS-associated HLA risk
    alleles HLA-A*03, -DRB1*15 and -DRB1*13.

    This study is at the other end of the spectrum
    27 MS patients
    (median age 59 years, range 35–95 years) at autopsy with
    a median post-mortem interval of 9.6 h (range 4.8–14 h)
    (Online Resource 1). All patients had advanced disease
    (median disease duration 25 years, range 10–54 years),
    expanded disability status scale >6 and the majority had
    primary or secondary progressive MS (22 of 25, 88%).
    Leading cause of death was legally granted euthanasia for
    11 of 27 (44%) patients.


  5. Ok. We're being told this for last 5 years. You've convinced me and thousands of other regular readers of this blog. So how do we use this information to cure ms?

    1. But the scientists haven't got it yet. A thick bunch I hear you say;-)

  6. Dr Hauser

    In the primary progressive MS trial, there was a statistically significant reduction of disability accumulation confirmed at 12 weeks with ocrelizumab compared with placebo. But the effect size was an only 24% relative reduction in disability progression. So extremely effective against new white matter plaques, extremely effective against new clinical relapses, but only partially effective against progressive disability accumulation.



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