Re: Fine-Tuning of T Lymphocytes in Autoimmunity.htm

[Guest guest]

, thanks, but you've got to be kidding! I have a masters degree

but no idea what the point of this article is. Do tell.

I've never had a positive thyroid antibody test; this was the first

time my antibodies were tested. That's why I was wondering if I DID

have Hashis 20 years ago -- as Dr. Rind hypothesized -- or if my

thyroid problems are resulting from adrenal fatigue that developed

on is own (not due to Hashis).

I pulled out the metabolic scorecard symptoms and blood test results

matrix from Dr. Rind and marked for each item whether I fall into

the adrenal category, mixed, or thyroid. So far I have 27 for

adrenal, 18 for mixed, and 7 for thyroid, so I am thinking that

maybe I never had Hashis, just chronic fatigue (adrenal) syndrome

that worsened over the years and made me mildly hypothyroid. This

would explain some of the differences I have from the group, such as

most of you have high cholesterol, but mine is abnormally low. Most

of you have frequent colds and flu; I practically never do.

By the way, Rind says cold hands and feet are an adrenal symptom,

NOT thyroid! This flies in the face of everything I've seen but

only points to how inconnected our glands on the HPA axis are.

Best,

> Fine-Tuning of T Lymphocytes in AutoimmunityThis, I believe is the

breakthrough answer to that question puzzling someone here about why

her particular autoimmune antibodies can no longer be detected,

whereas, in some people they keep going up, plus having a much

longer slower destruction period for yrs and yrs. This is the

common denominator I believe that a lot of us have been banking on

that consolidates almost ALL autoimmune diseases. If you don't get

dizzy deciphering all this technical medical jibberish, then you'll

still see the commonality. This is very exciting to me!

Autoantibodies have puzzled us sort of on a now-you-see-it-now-you-

don't basis. Of course, we know the bottom line is that we just

want to feel better, and sometimes it seems unreachable, but we're

getting there, within this generation I think.

>

>

> Texas

>

>

>

>

>

>

>

>

> My Homepage|Log Out

>

> December 16, 2003

>

>

>

>

>

>

> In This Article

>

> References

>

>

>

>

>

> From Clinical Endocrinology

>

> Fine-Tuning of T Lymphocytes in

Autoimmunity: Genetic Association of CTLA-4 Variants and Graves'

Disease Revisited

> Posted 12/08/2003

>

> Klaus Badenhoop; Christian Seidl

>

> T lymphocytes are the key effector cells in

immune-mediated endocrine disorders such as type 1 diabetes, Graves'

and 's disease or Hashimoto's thyroiditis. The activation of

T lymphocytes is tuned by signals that are regulated by the T cell

receptor (TCR) and the interplay of costimulatory receptors CD28

with the B7 ligands on antigen presenting cells (APCs). The

cytotoxic T lymphocyte antigen 4 (CTLA-4) is expressed on activated

T cells and inhibits further activation by binding to the

costimulatory molecules B7.1 and B7.2 of the APC (Carreno & ,

2002). This leads to downregulation of the other costimulatory

molecule's CD28-induced effects on intracellular signalling of the

TCR (Riley et al., 2002). This negative regulation is based upon

inhibition of extracellular signal-regulated kinase (ERK) activation

as well as by sequestration of B7 ligands (Carreno et al., 2000).

How this attenuation of the T lymphocyte activation is achieved

depends on the quantitative and kinetic expression and also the

abundance of the ligand B7.1 (Carreno & , 2002). As only 5%

of the T cell's CTLA-4 content is expressed on the cell surface,

subtle differences may lead to severe consequences. Thus,

variability in the function of this costimulatory molecule makes it

a prime candidate for disease susceptibility in autoimmune

disorders. In fact, polymorphisms of CTLA-4 have been shown to

confer susceptibility to several autoimmune diseases: type 1

diabetes mellitus, Graves' disease, Hashimoto's thyroiditis,

's disease, rheumatoid arthritis (Seidl et al., 1998),

systemic lupus erythematosus (Hudson et al., 2002) and multiple

sclerosis (Maurer et al., 2002).

>

> The CTLA-4 gene is located on human chromosome

2q33 – an immunologically important region with the two receptor

genes CD28 and ICOS in its vicinity. Comparative genomic analyses

show a high degree of conservation that indicates the importance in

immune function (Ling et al., 2001). Only few CTLA-4 variants have

been described that consist of at least three polymorphic residues.

These informative polymorphisms form haplotypes of CTLA-4 that have

been shown by transmission distortion test (TDT) to be responsible

for susceptibility to, and also protection from, autoimmune disease

(Marron et al., 1997; Donner et al., 1998). These haplotypes can be

detected by allele detection in the promoter (C/T-318), exon 1

Thr17Ala (A G49nt) and the microsatellite (ATn repeat in the 3'-

untranslated region) variant by standard polymerase chain reaction

(PCR) typing [restriction fragment length polymorphism (RFLP) and

sequencing analysis]. Whereas the promoter and microsatellite

variants might confer regulatory differences, the exon 1 allele is

situated in the signal peptide. Until recently, little was known

about the functional implications of genomic CTLA-4 variation. Of

special interest, therefore, is the recent mapping of the

susceptibility locus to the 6.1 kb 3'-region of the CTLA-4 gene that

was correlated with lower mRNA of its soluble alternative splice

variant (Ueda et al., 2003).

>

> Three further recent reports shed new light on

the function of different CTLA-4 signal peptides. In two studies it

was shown that isolated peripheral T lymphocytes of CTLA-4 Ala17

homozygotes display enhanced proliferation and cytokine production

after stimulation with allogenic or dendritic cells compared with T

cells from CTLA-4 Thr17 homozygotes (Kouki et al., 2000; Mäurer et

al., 2002). In addition, a defect in targeting of CTLA-4 to the cell

surface was demonstrated in CTLA-4 Ala17 individuals by confocal

microscopy (Anjos et al., 2002). The signal peptide undergoes

cotranslational cleavage in the endoplasmic reticulum (ER) and is

therefore not in the mature protein. Thus the signal peptide variant

might alter the intracellular processing of the peptide chain. Anjos

et al. (2002) addressed this issue by comparing the two variants in

in vitro translation assays as well as their glycosylation. They

observed differences in the intracellular to cell surface expression

partitioning between the two alleles and incomplete glycosylation of

the CTLA-4 Ala17 allele. Furthermore, the cell surface/total CTLA-4

Thr17 was higher than in CTLA-4 Ala17 cells, rendering this allele

less efficient in processing the molecule to the cell surface. This

would explain the allele's consistent association with autoimmunity.

A less efficient function of CTLA-4 (one-third less CTLA-4 on the

cell surface in Ala17 homozygotes than in Thr homozygotes) could

promote T lymphocyte proliferation leading to autoimmune disease.

Some clinical sequels in such Ala17 homozygotes have been observed

in Graves' disease: TSH-receptor autoantibodies persisted longer

whereas patients with the Thr17 allele had shorter intervals until

remission in a recent study from Japan (Kinjo et al., 2002). Other

clinical correlations of the CTLA-4 dimorphism include higher free

thyroxine levels in Ala17 homozygous Graves' disease patients, thus

correlating with the severity of thyrotoxicosis (Heward et al.,

1999), as well as thyroid-associated ophthalmopathy (TAO) as shown

earlier (Vaidya et al., 1999) and now again in an enlarged cohort of

patients (Vaidya et al., 2003). Among their most recent group of

patients, a high proportion (43%) was affected by TAO (NOSPECS class

III or worse). Whereas the stronger association of CTLA-4 Ala17 with

TAO in comparison to Graves' disease without eye involvement has

only been observed by the Newcastle group and also an Italian group

(Buzzetti et al., 1999), others could not find that difference

(Allahabadia et al., 2001; Bednarczuk et al., 2003). This may be due

to patient selection but indicates that other factors – genetic and

nongenetic – interact with CTLA-4 to promote TAO pathogenesis.

Nevertheless, TAO is a severe complication and - in the early

stages – a difficult to define comorbidity of Graves' disease, which

may explain why some studies could not detect differences in

patients with and without TAO. Also in multiple sclerosis the Ala17

allele was found to be more prevalent in patients with the primary

progressive form of demyelination (Maurer et al., 2002). Considering

all these facts together, the CTLA-4 Ala17 appears to be a general

risk factor for autoimmunity not specific for a particular disease.

Genomic variation leading to altered function of the negative

downregulator of T lymphocyte activation is a consistent risk factor

possibly contributing to the severity of an autoimmune disease. Its

modulation – experimentally tried in animal models of

transplantation – may lead to novel treatment strategies. Therefore,

functional studies of the CTLA-4 gene in the thyroid have high

priority.

>

>

> CLICK HERE for subscription information about

this journal.

>

>

> Reprint Address

>

> Klaus Badenhoop, Medical Department I, Division

of Endocrinology and Department of Immunohaematology, University

Hospital furt am Main, Theodor Stern Kai 7, D 60590 furt,

Germany. E-mail: badenhoop@e...

>

>

>

> --------------------------------------------------------------

>

>

>

>

> Klaus Badenhoop and Christian Seidl, Medical

Department I, Division of Endocrinology; and Department of

Immunohaematology, University Hospital furt am Main, furt,

Germany

>

>

>

> Clin Endocrinol 59(5):555-557, 2003. © 2003

Blackwell Publishing

>

>

>

>

>

>

>

> Related Resources

> Clinical articles on this topic

>

> Join a Discussion with your colleagues

>

>

>

>

>

>

> SEARCH

>

>

>

> Medscape DrugInfo

>

> MEDLINE

>

> Advanced Search

>

>

>

> • About Medscape • Privacy & Ethics • Terms of Use •

Help • WebMD Health

>

>

>

> All material on this website is protected by copyright,

Copyright © 1994-2003 by Medscape. This website also contains

material copyrighted by 3rd parties. Medscape requires Netscape or

Microsoft browsers in versions 5 or higher.

[Guest guest]

Thanks, , for your explanation. FYI I have really bad

allergies. Best,

> The point of this article was about your question about not having

the

> autoimmune antibodies present. This study pointed this out,

having to do

> with these chromosomes, genetic expressions of certain things or

situations

> extending from these chromosomes. One of the things that it did

point out

> is the reasons for some people expressing high autoimmune

antibodies for

> long extended periods of time, and others nada. Of course, you

could very

> well be having adrenal exhaustion or underactive adrenals, and

we're

> thinking that most people who have long ongoing stressors probably

do,

> frankly. This alone can cause less immunity to viruses and

allergies,

> etc...but you say that you never catch colds, flu, don't have

allergies and

> the like. That's more typical of hypothyroidism, so the

information says.

> Me, I am definitely hypo, and I catch everything that comes

along. However,

> it could very have to do with circumstances, being as I work the

nursing

> floor with many immune-compromised patients who do catch these

things

> easily. All this aside, one of the main things the study points

out is why

> those antibodies may not still be there in some persons later on

in life. I

> don't necessarily understand alleles, but I get the meaning of

what it's

> saying if I muddle thru it long enough.

>

>

>

> Re: Fine-Tuning of T Lymphocytes in

Autoimmunity.htm

>

>

> > , thanks, but you've got to be kidding! I have a masters

degree

> > but no idea what the point of this article is. Do tell.

> >

> > I've never had a positive thyroid antibody test; this was the

first

> > time my antibodies were tested. That's why I was wondering if I

DID

> > have Hashis 20 years ago -- as Dr. Rind hypothesized -- or if my

> > thyroid problems are resulting from adrenal fatigue that

developed

> > on is own (not due to Hashis).

> >

> > I pulled out the metabolic scorecard symptoms and blood test

results

> > matrix from Dr. Rind and marked for each item whether I fall into

> > the adrenal category, mixed, or thyroid. So far I have 27 for

> > adrenal, 18 for mixed, and 7 for thyroid, so I am thinking that

> > maybe I never had Hashis, just chronic fatigue (adrenal) syndrome

> > that worsened over the years and made me mildly hypothyroid.

This

> > would explain some of the differences I have from the group,

such as

> > most of you have high cholesterol, but mine is abnormally low.

Most

> > of you have frequent colds and flu; I practically never do.

> >

> > By the way, Rind says cold hands and feet are an adrenal symptom,

> > NOT thyroid! This flies in the face of everything I've seen but

> > only points to how inconnected our glands on the HPA axis are.

> >

> > Best,

> >

> >