Fine-Tuning of T Lymphocytes in Autoimmunity.htm

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This, 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

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December 16, 2003

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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.

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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@...

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

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