autoimmune disorders and MG

Philip Deitiker pdeitik at
Tue Apr 7 13:27:00 EST 1998

On Mon, 6 Apr 1998 21:17:35 -0400, "M." <margaret at>

>Hi - I was wondering if any of you could help me with a school project...
>Does anyone know what specific autoimmune disorders are associated with
>myasthenia gravis?  I have found several sources that say that there *are*
>associated disorders, but none specify *what* they are.

First off let me say that my perspective is that of a biochemist and
not of a cellular immunologist or neurobiologist. My background has
been the biochemistry and evolution of muscle and immunity at the
molecular level. So alot of the clinical phenomena, don't quote me. 

MG is not a single disease but a collection of several types of
diseases, in many (I believe 2/3rds)  patients MG is associated with
thymoma, about half of these thymectomy can correct MG in half it has
little affect. There is the belief that the disease in thymomic
patients is triggered by overexpression of AChR (Acetyl choline
receptor) in the thymus. 
  MG can also be segragated in age of onset, there is late onset
disease and early onset disease. Early onset disease is typically
found at higher frequencies in females vs. males. 

General Foundation for Autoimmune Disease: There is the hypothesis
that recogntion of self vs. non-self antigens results from the long
term discrimination of antigen concentrations present from MHC bearing
cells to T-cells within three ranges. The lowest range is either the
result of low affinity to MHC Class I or II antigens of low amounts of
antigens. The intermediate range is concentrations of intermediate
affinity and amounts, and the high range is either antigens in great
abundance for long periods or those with high affinity for MHC.

The lowest range is not stimulatory because there is simply not enough
T-cell/APC contact to serve stimulation of T-cells, these epitopes are
ignored. Within the intermediate range antigens are frequently
stimulatory to T-cell expansion and helper T-cells aid in the growth
and differentiation of antigen specific B-cells over time helping of
T-cells can turn into suppression. Within the highest range antigens
(self and non-self quickly become tolerized by the body) self antigens
are tolerated very early in life.

What can _possibly_  make a self antigen that was tolerated or ignored
become recognized as non-self.

Overexpression of an previosly ignored antigen or epitope.
Overexpression of a predisposed MHC receptor (by, say, gamma inteferon
expression) within the vicinity of cells expressing a particular
Exposure of antigens normally hidden to cellular immunity.
Mimicry of an antigen by a foreign pathogen.
Directing of professional APC by the binding of cross reactive
antibodies (induced by infection) to a self antigen.
Changes in immunity (DTH response and adrenergic system) with age,
diet, change of circumstances, environmental in predisposed
Change in exposure to allergens and invironmental antigens.

------------ End of general.

 Progression of myastenia gravis:

 For whatever reason, either overexpression or triggering via foreign
antigen mimicry (T or B cell), or overexpression of MHC ( which
frequently can result as conseqeuncy of intrinsic detection of cancers
frequent later on in life) the peptide alpha chain region 140 to 170
of human AChR is presented to T-cells and this stimulates the
expansion of helper T-cells. There are 2 HLA loci which associate with
disease, HLA DQ and HLA DR (there is a japanese group which claim
early onset-female association with DP), these loci may act
independently to cause disease, each presenting the peptide of the
approx. region 146-162. The strongest association is with HLA DQ (at
present). For a review of HLA antigen diversity see Marsh and Bodmer,
European Journal of Immunogenetics, 1994, 21, 519-551 (and later). If
you are intested in how predisposed MHC may evolve see Parham and
Ohta, Science 1996.You may also have to read up on the process of gene
The basic problem with alot of the correlation between MHC and disease
is that some studies where done based on serotyping (extremely
inaccurate), RFLP analysis (slightly better) and Sequencing based
techniques. There may be evolutionary elements to the disease we
simply haven't detected yet. 
  There is an excellant mouse model for MG called EAMG, and alot of
works done by the authors  Ashizawa, Atassi, Chella-Davis, Cristadoss,
Infante, Oshima M., and Shenoy. These authors found that the
recombination event in mice which converted B6 mice into BM12 (three
residues at IA beta) that made BM12 (derived strictly from B6) animals
not predisposed to EAMG. B6/BM12 F1 show a much ~75% lower
predispostion toward EAMG compared to B6. Thus the mouse model shows a
clear mediation of disease by MHC and MHC dose affect. In humans
specific DQ alpha/beta combinations are associated with disease, and
homozygotes of a specific alpha/beta combination may show the highest
association of disease for this loci. Chella-Davis and colleages have
presented some work on the use of human---> mouse transgenics. Their
results are intriguing.

     There are four AChR autodeterminants (regions which show
inordinantly high amounts of Ab reactivity) found in MG, AChR alpha
12-27, 111-126, 122-138, 183-198. 111-138 is the most frequent  and
likely the result of its proximity to region 146-162. The antibodies
to AChR do 2 things. 

1. They bind to the receptor and distort activity. 
2. They facilitate the attack of lymphocytes on muscle tissue.
(although when and how lymphocytes penetrate the motor endplate is

Thus there are two associated physiological changes,
1. Diminution of the motor response mediated by the neuromuscular
2. Destruction of myofibrils, atrophy of muscle, facilitation of the
disorganization and distruction of muscle as a result normal activity.

  As stated above there are other immunological factors which play
into autoimmune diseases and specifically MG. MHC receptors, DTH
responses, T-cell responsiveness and many other factors can act to
make an individual more or less predisposed _if they have a
potentially mediating MHC_. These factors are, in turn, influenced by
what is going on in the body as a whole. There is some concern that
T-cell repertiore and class and subclass behavior vs. repertoire are
importnat factors; however, i question this because most studies show
a great deal of plasticity in the types of antigens that each T-cell
subclass can recognize. There could be specific genetic lesions which
could alter this conclusion though.  As mention above thymoma can be
thought of as an autoimmune disorder. There are other some other
things which correlate with MG patients but are as yet unpublished

To summerize:  what they are probably talking about when they say
autoimmune disorders are autoreactive CD4+ T-helper cells and
unusually high amounts of autoreactive antibodies to the muscarinic
acetyl choline receptor. They could also be talking about invasion of
the neuromuscular junction of autoreactive APC (antigen presenting
cells) and other types cell directed immunity (less established). 
Hope this helps. 


<pdeitik at>

More information about the Immuno mailing list