Tuesday, 3 November 2015

More B cells...

Ligocki AJ, Rivas JR, Rounds WH, Guzman AA, Li M, Spadaro M, Lahey L, Chen D, Henson PM, Graves D, Greenberg BM, Frohman EM, Sally Ward E, Robinson W, Meinl E, White CL 3rd, Stowe AM, Monson NL.

A Distinct Class of Antibodies May Be an Indicator of Gray Matter Autoimmunity in Early and Established Relapsing Remitting Multiple Sclerosis Patients. 

ASN Neuro. 2015 Oct 21;7(5). pii: 1759091415609613. doi: 10.1177/1759091415609613.

We have previously identified a distinct class of antibodies expressed by B cells in the cerebrospinal fluid (CSF) of early and established relapsing remitting multiple sclerosis (RRMS) patients that is not observed in healthy donors. These antibodies contain a unique pattern of mutations in six codons along VH4 antibody genes that we termed the antibody gene signature (AGS). In fact, patients who have such B cells in their CSF are identified as either having RRMS or developing RRMS in the future. As mutations in antibody genes increase antibody affinity for particular antigens, the goal for this study was to investigate whether AGS(+) antibodies bind to brain tissue antigens. Single B cells were isolated from the CSF of 10 patients with early or established RRMS. We chose 32 of these B cells that expressed antibodies enriched for the AGS for further study. We generated monoclonal full-length recombinant human antibodies (rhAbs) and used both immunological assays and immunohistochemistry to investigate the capacity of these AGS(+) rhAbs to bind brain tissue antigens. AGS(+) rhAbs did not recognize myelin tracts in the corpus callosum. Instead, AGS(+) rhAbs recognized neuronal nuclei and/or astrocytes, which are prevalent in the cortical gray matter. This pattern was unique to the AGS(+) antibodies from early and established RRMS patients, as AGS(+) antibodies from an early neuromyelitis optica patient did not display the same reactivity. Prevalence of CSF-derived B cells expressing AGS(+) antibodies that bind to these cell types may be an indicator of gray matter-directed autoimmunity in early and established RRMS patients.

 Figure: The definition of MS by Poser before the McDonald.

B cells are currently the go to cells in MS, but what is it about the antibodies that they produce in MS that is distinct from those without MS? In fact we know from practice that depletion of B cells can help in RRMS, and plasmapharesis which removes circulating antibodies can help in some patients. When blood from MS patients has been added to cultures containing astrocytes, oligodendrocytes (myelin forming cells), and neurones in the lab they have resulted in damage to these cells.

Here the authors say that the characteristic of the antibody heavy chain variable regions genes in B cells predicts the development of RRMS by 85-94% accuracy. These antibody genes appear to have developed mutations in the variable regions at an excessive rate compared to normals. The authors have called this feature of the MS antibody genes AGS. When B cells in MS CSF accumulate these mutations in their antibody genes (AGS+), their antibodies have higher affinities for certain antigens, namely neuronal neuclei of cortical grey matter. Can this explain the extent of grey matter vs white matter (26.5% vs 6.5%) lesions in MS? And the dominance of grey matter atrophy in MSers with greater disease activity?

Can elimination of the AGS+ plasma cells in the CSF become a targeted therapy for slowing down cognitive decline in MSers? Do we have the technology for this?

6 comments:

  1. Will then the B cells and T cells are therefore attracted to the CNS by this "call" of myeloid cells (mainly monocytes and macrophages)? http://m.medicalxpress.com/news/2015-11-innate-immune-modulates-severity-multiple.html

    ReplyDelete
    Replies
    1. No one has quite figured out which comes first i.e. do the cells enter from the blood stream after being activated in the rest of the body, or if it's the activation of innate immune system which attracts these cells in. B cell lymphoid follicles in the virchow-robbin spaces are a relatively new discovery and there is a strong link between these and SPMS.

      Delete
  2. I have the same question, I read somewhere that the B cells can cross the BBB. So a guess would be that the bad B cells cross the BBB and then do something that calls in the T cells.

    ReplyDelete
    Replies
    1. Please see above. It used to be taught in med school when I trained that the brain was an immune privileged area, it is now known that the it is known that the brain is under immunological surveillance. Neutrophils (not as well as monocytes), monocytes, lymphocytes (T and B cells) all cross back and forth across the BBB. Now with the reporting of the glymphatic system, this may be another source whereby antigens can get into the brain to stimmulate the humoral immune response.There is also data to suggest that activated T cells enter the brain pretty randomly and unless they recognise a specific antigen they exit! One thing is sure, although cells can transmigrate across the BBB, unless it's leaky it would be difficult for the antibodies to get through, which means the B cells must be getting in or they're already there.

      Delete
  3. Is this the affinity maturation gone awry?

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.