Sunday, 29 April 2012

Research Autoimmunity without a cell in sight


Sádaba MC, Tzartos J, Paíno C, García-Villanueva M, Alvarez-Cermeño JC, Villar LM, Esiri MM.Axonal and oligodendrocyte-localized IgM and IgG deposits in MS lesions. J Neuroimmunol. 2012 Apr 23. [Epub ahead of print]

BACKGROUND: Recent findings support the important role of antibodies in multiple sclerosis (MS) physiopathology. Thus, local IgG synthesis is a hallmark of the disease, and intrathecal IgM synthesis associates with a poor disease outcome.
METHODOLOGY: The aim of this study was to investigate the presence of IgM (contains five IgG like molecules that are weak binder to targets) and IgG (usually strong bindiers to targets) in demyelinating lesions using high sensitivity immunohistochemistry techniques in necropsies from fourteen MS patients, four controls without neurological disease and four cases with non MS CNS inflammatory disease.
RESULTS: IgG and IgM were absent in controls. Conversely, we found IgM in about 50% and IgG in 75% of MS patients. The presence of IgM and IgG antibodies was independent of disease duration, clinical disease type or lesion stage. IgM and IgG were present in acute, chronic active and chronic inactive lesions. Double immunofluorescence showed that IgM and IgG were detected on axons and oligodendrocytes in demyelinated areas. Moreover, we observed immunoglobulin deposits on oligodendrocytes in NAWM in some cases. IgG and IgM colocalized with complement C3b on demyelinated axons and oligodendrocytes and antibody-antigen immunocomplexes were detected in foamy macrophages in active lesion areas. These findings were absent from cases of non-neurological disease and cases with non-MS CNS inflammatory disease.
CONCLUSIONS:These observations provide further evidence on the role of antibodies, complement and macrophages in plaque development, and strongly suggest they can induce axonal injury, an important cause of disability in MS. They may provide novel therapeutic strategies to limit tissue degeneration in the disease.



                              Complement cascade (yes it is complicated)

Much has been made about the John Prineus studies of oligodendrocyte damage without the presence of lymphocytes (white blood cells). However they don't need to be near the damage if their function is to help B cells to secrete antibodies that can travel widely throughout the central nervous system, once it passed the blood brain barrier or is secreted inside the brain. The presence of antibody (IgG and IgM) and complement (cascade of molecules that end up punching holes via the membrane attack complex in cells to kill them or can provide a signal for macrophages or microglia to engulf (Opinsinization) the target expressing complement). 



There is an immunology lession that needs to be given. The fact that it is present in normal appearing white matter, which is seemingly normal tissue, suggests that this could be an early event in lesion formation and that normal appearing white matter may be destined to become the pre-active lesion (see espresso pathology posts)

2 comments:

  1. How do they punch holes into cells? Do they secrete an acid or something, or do they chew into it (improbable, I know)?

    I have always been curious as to how myelin is destroyed in MS.

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  2. I have updated the post abit with an extra figure to show how the pore is formed, it is abit like inserting a drain and then the "life blood" of the cell flows out. This is via the membrane attack complex of complement small proteins and is activated by certain types of antibodies binding to a cell or it being infected with certain molecules.

    However there other ways of killing such as via direct killer cell contact such as using perforin (http://en.wikipedia.org/wiki/Perforin) and granzymnes. The perforin is again another pore forming compound that is used to get the granyzmnes into cells so they commit cell death.

    There are even more ways of killing cells.

    Some cells could chew into it this is what macrophages do, they have molecules that recognise antibodies (called Fc receptors) and complement (Complement receptors) and these are used as ways of ingesting what the the antibodies and complement are bound to. They have digesting enzymnes (like acids) that help in this digestion (http://en.wikipedia.org/wiki/Phagocytosis).

    If an oligodendrocyte is killed it is not here to make myelin. This is the problem and we know of many differnt ways this can happen, but which one is the most important is not yet clear.

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