MS is Autoimmune? Really?

[Guitar_grrrl]

I saw this recent abstract the other day, and it raises some serious questions.  Why are we going after the immune system with expen$ive medicine$$ when the T and B cell activity are more of a secondary symptom/sign?

    * Ann Neurol. 2009 Dec;66(6):711-3.

Abstract

OBJECTIVE: CD4 T-cell-dependent macrophage activation directed against a myelin or oligodendrocyte antigen is generally thought to be the mechanism causing myelin destruction in multiple sclerosis (MS). However, areas within expanding MS lesions may exhibit prominent oligodendrocyte loss and apoptosis in the absence of infiltrating lymphocytes. The present study was designed to further investigate the inflammatory profile of different regions within rapidly expanding MS lesions. METHODS: Twenty-six active lesions from 11 patients with early MS were serially sectioned and immunostained for T and B cells, plasma cells, ramified microglia, macrophages, monocytes, and CD209-positive dendritic cells. Cell counts were compared in prephagocytic, phagocytic, and immediately postphagocytic areas. RESULTS: Parenchymal T and B cells were largely absent in areas of initial oligodendrocyte loss and in areas of degenerate and dead myelin infiltrated by myelin phagocytes. In contrast, trailing areas of complete demyelination packed with lipid macrophages, and, in some lesions, regenerating oligodendrocytes, showed large numbers of T cells, B cells, and immunoglobulin G (IgG)-positive plasma cells. Lesions in 2 exceptionally early cases contained relatively few T and B cells, and no IgG-positive plasma cells. INTERPRETATION: Early loss of oligodendrocytes is a prominent feature in tissue bordering rapidly expanding MS lesions. Macrophage activity is largely an innate scavenging response to the presence of degenerate and dead myelin. Adaptive immune activity involving T and B cells is conspicuous chiefly in recently demyelinated tissue, which may show signs of oligodendrocyte regeneration. The findings suggest that plaque formation has some basis other than destructive cell-mediated immunity directed against a myelin or oligodendrocyte antigen.

I know this is a super small study, but this raises big red flags for me, and definitely needs further investigation!!  I'm curious to see your thoughts.

Cheers,
Guitar_grrrl

[Guitar_grrrl]

Sorry, I meant to add this idea - I'm really curious about Ibudilast, a new neuron protectant going through the testing hoops right now.

[Guitar_grrrl]

Here's the takeaway from Accelerated Cure Project:

In a recently published study, Australian MS pathologist John Prineas and his colleagues examined autopsy brain tissue of 15 people with MS (11 with early MS) to understand the process by which active MS lesions expand. They examined tissue sections from 10 active lesions using staining methods and microscopy to identify the features of the samples and perform counts of the cells found there. The types of immune cells identified included T cells, B cells, microglia (immune cells of the central nervous system that can become phagocytes, which clean up debris), and dendritic cells (immune cells that display fragments on their surface to activate other immune cells). The study describes what they found in the lesions, working from the outside in:

    * Normal appearing white matter bordering MS lesions: These areas contained activated microglia; antibodies binding to some astrocytes, axons, and oligodendrocytes; and dendritic cells along blood vessels. No T or B cells were present.
    * Outer borders of active MS lesions ("pre-phagocytic"): Decreased numbers of oligodendrocyte cell bodies were seen; remaining oligodendrocytes were sometimes swollen or showed signs of dying. Myelin sheaths were still intact although they were often swollen due to fluid having gotten in between their layers. These areas had a small increase in activated microglia and a small number of T cells.
    * Actively demyelinating areas ("phagocytic"): These sites contained myelin debris which was being taken up by local microglia as well as phagocytes entering the lesion from the bloodstream. A small to moderate increase in the number of T cells was seen in these areas, as well as increased numbers of T and B cells in the space adjacent to blood vessels.
    * Recently demyelinated tissue: These tissues were full of myelin-containing phagocytes. Signs of early remyelination were present including the appearance of small numbers of oligodendrocytes. Numerous T cells were found throughout the area, and large numbers of T cells, B cells, and other immune cells were concentrated around blood vessels (perivascular cuffs).
    * Inactive lesions: As in the outer border of active lesions, the borders of inactive lesions contained activated microglia, and dendritic cells were also found around blood vessels.

In a couple of cases of acute, rapidly fatal MS (disease duration of only 18 or 21 days), the level of inflammation in active lesions was much lower than in the other subjects. Also, the microglia bordering the lesions showed no sign of activation.

The authors interpret their findings to indicate that plaques grow through loss of oligodendrocytes on the plaque border, which is followed by myelin breakdown, scavenging of debris by phagocytes, and infiltration of immune cells such as T cells. What causes the oligodendrocytes to die is not known -- for instance, it could be toxic elements seeping outward from the plaque, factors produced by activated microglia, or something else. The fact that T cells are not abundant in areas where phagocytes are actively scavenging myelin debris suggests that this process is not activated by T cells but instead is initiated by the macrophages themselves, similar to what is seen in injured tissue. The presence of T and B cells in greater numbers in recently demyelinated tissue indicates that these cells are part of the immune system's response to demyelination, as opposed to being a driver of the demyelination. Also, the fact that these cells are present where remyelination is taking place suggests that they don't prevent the regeneration process and may even help it.

Although this study doesn't reveal the critically important initial cause of oligodendrocyte death that drives lesion growth, having a better idea of the sequence of events nevertheless helps enrich our understanding of the disease. It's also interesting that inactive lesions remain surrounded by a sentinel of activated microglia and dendritic cells. Perhaps as these cells build up throughout the course of the disease, they provide a continual inflammatory presence that in time has an additional effect independent of relapses.

Thanks to MSNews reader Rob Swenson for the pointer to this study!

My own takeaway is that our immune system is in there doing damage control.  Why not explore DMDs that DON'T mess with our immune system?

Inquiring Minds...
Guitar_grrrl

[Erin0313]

Wow I became overwhelmed about 2 lines in to that :(

That is one of the bummers of my MS. I need a "smart person" with me at all times to explain things in simple terms.

My mother started a foundation for the research of auto-immune diseases locally last month with a write up in the paper etc. trying to draw donations for the local hospital. In a moment of confusion I said to her I don't think that MS is an auto-immune disease and she was panicked because of course I am the one with MS so I would know right? LOL we had to look it up on the internet to make her feel better.

Oh cog fog you pain in the behind!

Erin :)

[jensequitur]

I've always thought that the immune response was a reaction to the cell damage, rather than the reason for the cell damage - but everybody seemed so sure!