Antibodies in the CSF may be secondary to damage

Brändle SM, Obermeier B, Senel M, Bruder J, Mentele R, Khademi M, Olsson T, Tumani H, Kristoferitsch W, Lottspeich F, Wekerle H, Hohlfeld R, Dornmair K. Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins. Proc Natl Acad Sci U S A. 2016 Jun 20. pii: 201522730. [Epub ahead of print]

Oligoclonal Ig bands (OCBs) of the cerebrospinal fluid are a hallmark of multiple sclerosis (MS), a disabling inflammatory disease of the central nervous system (CNS). OCBs are locally produced by clonally expanded antigen-experienced B cells and therefore are believed to hold an important clue to the pathogenesis. However, their target antigens have remained unknown, mainly because it was thus far not possible to isolate distinct OCBs against a background of polyclonal antibodies. To overcome this obstacle, we copurified disulfide-linked Ig heavy and light chains from distinct OCBs for concurrent analysis by mass spectrometry and aligned patient-specific peptides to corresponding transcriptome databases. This method revealed the full-length sequences of matching chains from distinct OCBs, allowing for antigen searches using recombinant OCB antibodies. As validation, we demonstrate that an OCB antibody from a patient with an infectious CNS disorder, neuroborreliosis, recognized a Borrelia protein. Next, we produced six recombinant antibodies from four MS patients and identified three different autoantigens. All of them are conformational epitopes of ubiquitous intracellular proteins not specific to brain tissue. Our findings indicate that the B-cell response in MS is heterogeneous and partly directed against intracellular autoantigens released during tissue destruction. In addition to helping elucidate the role of B cells in MS, our approach allows the identification of target antigens of OCB antibodies in other neuroinflammatory diseases and the production of therapeutic antibodies in infectious CNS diseases.

The inside of the cell is not normally seen by antibodies, but when a cell dies or is killed its content are liberated and then seen by the immune system and soin this study they take B cells from the CNS of some people with MS, they make the antibodies they produce and find that they are reacting to the contents of cells, suggesting that they are seconday to the disease process and not due to the cause. So not all of the antibodies in the spinal fluid may be informative. 

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  • So it would be self immunity result of the true cause of MS? Is self immunity cause of MS by a defect in the lymphocytes? It seems q T cells driving the autoimmune attack and the B cells the drive or not?…
    And if it is a consequence, against whom is this attack, or rather, who are these self heterogeneous antigens? The study cites who are these self antigens?

  • That's interesting. Didn't Prof G also suggest that with a truly effective DMT, the OGBs would go away? So this study reinforces the idea that persistent OGBs indicate ongoing disease activity, even when everything else is NEDA?

  • What about the leaky blood vessels that is implicated in Parkinson's and other degenerative diseases of the brain?

  • The question was in for another publication…
    About this publication MD then you would say that the major problem of MS is in Microglia in Innate Immunity, and not necessarily in lymphocytes? These lymphocytes would only be recruited for the Innate Immunity calls to the site, as in the studies there was no myelin found …

  • SO why does this not happen in the periphery? Cells die and are replaced all the time in the body – why do we not get peripheral auto-antibodies to intra-cellular proteins?

    • Good question.
      Simple answer is I am not sure I can give a good answer.

      In the periphery I.e. outside the brain there are immunological mechanisms that kill off immune responses to the inside of cells if they are regularly seen in the thymus. So immune responses to cell contents may not happen.

      Why this happens in cns disease is an interesting one

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