Why Mast Cell Issues May Be Somewhat Common, With MC

[tex]

Hi All,

As you may recall, I am personally of the opinion that the syndrome known as microscopic colitis is not due to an overactive immune system , but rather, due to an underactive immune system. Specifically, I believe that our immune systems do not inherently overproduce killer T-cells. Instead, I believe that our problems are due to a deficiency of mediator T-cells, (sometimes referred to as suppressor T-cells), which would otherwise, (if they were present in sufficient/normal numbers), modulate the activity of killer T-cells, and prevent them from generating an autoimmune-type process. Experience tells us that in natural body processes, deficiencies are almost always much more likely to exist, than excesses. Right? Especially in consideration of the effects of the normal aging process.

Anyway, while researching another issue, I happened to come across an old research article that sort of ties in with my position, and in doing so, it illuminates a mechanism by which mast cell issues may be likely to be associated with MC. The primary topic of this research had nothing to do with MC, of course, but an observation stated in the discussion section of the report, caught my eye:

Treatment with cyclophosphamide is known to depress the activity of suppressorT cells and enhance IgE responses (Ishizaka, 1976). In our experiments, the IgE anti-HSV response was greater in the cyclophosphamide-treated mice (Fig. ld). This suggests that anti-virus IgE responses might be particularly prominent in conditions where there is a decrease in suppressor T cells, e.g. in congenital immunodeficient states or secondary to immunosuppressive therapy.

IgE antibodies bind avidly to mast cells and basophils.

The red emphasis is mine, of course.

http://vir.sgmjournals.org/cgi/reprint/64/3/533.pdf

Obviously, if we have an insufficiency, (or worse yet, a deficiency), of suppressor T-cells, then this could open the door to mast cell issues.

Anyone have any thoughts on this - or am I all wet?

Tex

[mbeezie]

Tex,

I suppose that very well could be what activates mast cells. I have had a hunch for awhile that I wasn't alone in my mast cell issues. Dr. Lewey also thinks that mast cell issues are more common than most think but the diagnosis is being missed.

Mary Beth

[TooManyHats]

So when they suppressed the immune system, Mast cells became an issue?

[tex]

So when they suppressed the immune system, Mast cells became an issue?

Sort of, but not exactly, because that wasn't what they were investigating. They simply used the phenomenon of the release of histamine by mast cells, as a vehicle for detecting the presence of IgE within the cells. They were interested in demonstrating that IgE antibodies may play a part in the development of disease connected with virus infections, and measuring histamine release from mast cells, after challenging them in vitro with virus antigens, simply provided them with a way to detect the presence of IgE within cells.

In their words:

Mice immunized with ultraviolet-inactivated herpes simplex virus (HSV) or injected with infectious virus developed IgE-specific antibody to HSV. Cell-bound IgE was detected by measuring the release of histamine from peritoneal mast cells challenged in vitro with virus antigens. Circulating igE antibody was detected by sensitizing rat basophilic leukaemia (RBL-2H3) cells with sera from HSV-immunized mice and then challenging these cells with virus or control antigens to release histamine. IgE antibody may contribute to the pathogenesis of virus infections.

The observation that I quoted in my first post, was made when they noticed that cyclophosphamide-treated mice, (IOW, mice with depressed suppressor T-cell activity), showed a dramatically-increased IgE anti-HSV response, which you can see in figure 1d in their report, (page 535). This observation, however, wasn't a central premise in the goals of their report - it was simply a phenomenon that they happened to notice, so they mentioned it. And I happened to notice it, because it appears to support my theory of the true cause of MC, and coincidentally, it offers a reasonable explanation of why mast cell issues may be somewhat common with MC, (because of the link with a deficiency of suppressor T-cells).

Tex

[Polly]

Interesting, Tex.

I have a question. Has a deficiency of mediator T cells actually been measured? Or is this your theory? I ask because there are so many other possible mechanisms besides just an excess or deficiency of something. Perhaps there is an adequate amount or even an excess, but they are not operating effectively at the cellular level. Sort of like in type II diabetes, where there is adequate circulating insulin, but it doesn't work well at the cellular level.

Love,

Polly

[tex]

Polly,

I'm not aware of any research that involved TREG measurements specifically for patients with MC. However, there is a lot of information available about this issue for various types of other autoimmune diseases.

This would probably be a worthwhile read, if we had access to the entire article:

Here, we discuss the role of cytokines and costimulatory molecules in the generation, maintenance, and function of Tregs. We also summarize evidence for the involvement of Tregs in controlling autoimmune diseases, including type 1 diabetes, experimental autoimmune encephalomyelitis, and inflammatory bowel disease.

The red emphasis is mine, of course, in all of these quotes.

http://www.ncbi.nlm.nih.gov/pubmed/15790360

The article at the following link contains a lot of good information:

Strategies to support TREGs in autoimmune diseases are considered an intriguing new approach for using to suppress the inflammatory process, by manipulating both the function and number of TREGs. It is believed that protocols for such manipulation have the therapeutic potential to induce tolerance in patients with autoimmune diseases, because in mice with collagen-induced arthritis, depletion of TREGs caused rapid progression, but early joint damage could be reversed by the transfer of isolated and ex vivo-proliferated TREGs.108 Other animal models of autoimmunity show similar results.109,110

* Children with thymic hypoplasia as a result of the 22q.2 deletion syndrome display an impaired TREG generation and have an increased risk of developing an autoimmune disorder.75
* Patients with a mutation of the transcription factor autoimmune regulator (AIRE) have a defective expression of tissue-specific self-antigens in thymus, leading to autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED).76 In mice, AIRE deficiency is associated with a reduced generation of TREGs, which may hold true also for humans.77
* Reduction of thymic activity has been reported in patients with multiple sclerosis78 and rheumatoid arthritis,79 who show a reduced number of T-cell receptor excision circles (Trec), indicating a reduced thymic output.80,81 The number of Trecs exponentially declines also with aging, and reduction of Trecs in young patients with autoimmune diseases indicates therefore an ‘early aging’ of the thymus. As TREG function declines with thymic senescence,82 it is conceivable that the induction of TREGs in the ‘early aged’ thymus of patients with autoimmune diseases is less efficient, and non-regulatory T cells bearing an autoreactive TCR may escape the thymic selection process more frequently.83

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1782226/

This article, about autoimmune gastritis, contains some good info, also:

http://www.jimmunol.org/content/181/12/8209.full.pdf

Your suspicions may be correct, though, in certain cases, (provided the conclusions reached in the article at the following link are valid). This article claims that autoimmune thyroid disease, for example, is an exception:

Conclusions: Although T regulatory cells are abundant in inflamed thyroid tissue, they are apparently unable, in most cases, to down-modulate the autoimmune response and the tissue damage seen in AITD. (J Clin Endocrinol Metab 91: 3639–3646, 2006)

http://jcem.endojournals.org/cgi/reprint/91/9/3639.pdf

Here's some older research:

Although uncontrolled clones of autoreactive T cells play a central role in the pathogenesis of autoimmunity, another mechanism potentially involved in many autoimmune diseases is deficiency of suppressor T cells, most notably those belonging to the antiidiopeptide TH3/Tr1 TCD4+CD25+(high) subset. Failure of suppressor mechanisms may be in part primary, due to defective positive selection of suppressor T cells in the thymus, and in part acquired, secondary to chronic infections promoted by deficiencies in innate immunity.

http://www.ncbi.nlm.nih.gov/pubmed/15474387

And another example where TREG measurements were apparently made, in a case study concerning suppressor T-cell deficiency in primary sclerosing cholangitis:

http://www.springerlink.com/content/g5144446v1588n12/

If MC weren't perceived as a "red-headed stepchild" by so many segments of the medical community, maybe someone would make some TREG counts for MC patients.

Love,
Tex

[klhale]

OK Tex, how/where do I get some of those T Cells?

I need em' bad!

karen

[tex]

I need em' bad!

I suspect we all do.

Tex