HLA-DR3 and HLA-DR5 Associated Thyrotoxicosis-Two Different Types of Toxic Diffuse Goiter*

Schleusener, H.; Schernthaner, G.; Mayr, Wolfgang R.; Kotulla, P.; Bogner, U.; Finke, R.; Meinhold, H.; Koppenhagen, K; Wenzel, Klaus

doi:10.1210/jcem-56-4-781

Cited by 83 publications

(27 citation statements)

References 35 publications

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“…The association of the 8-kb Eco RI CX allele with Graves' disease described here is of considerable interest and probably should now be analyzed with respect to HLA-DR or immunoglobulin Gm or Km allelic distributions similar to those which have been performed in the past (39)(40)(41)(42)(43). On the basis of the findings presented here, it would now appear appropriate to again examine additional markers on lambda Ig light chains such as those recently described (44) for a possible correlation to the CX genotypic profiles described in the present study.…”

Section: Discussionmentioning

confidence: 82%

Kappa/lambda immunoglobulin distribution in Graves' thyroid-stimulating antibodies. Simultaneous analysis of C lambda gene polymorphisms.

Williams

Marshall²,

Kilpatrick³

et al. 1988

J. Clin. Invest.

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From patients with untreated Graves' disease 11 sera showing high cAMP release in the FRTL-5 cell assay were studied for relative proportions of kappa or lambda Ig molecules showing cAMP releasing activity. Immunoabsorption of y-globulins was performed using monoclonal murine anfi-kappa or antilambda antibodies linked to cyanogen bromide-activated sepharose. Specific kappa-or lambda-adsorbed fractions were also eluted from immunoabsorbents using chaotrophic thiocyanate buffers and equilibrated with pH 7.4 low salt buffer by dialysis. Immunoabsorption and elution experiments showed that five Graves' sera contained predominant cAMP-releasing activity within lambda Ig fractions, whereas two Graves' sera showed predominant cAMP-releasing activity in kappa Ig fractions. Four sera showed cAMP release approximately equally divided between kappa and lambda Ig both after immunoabsorption and specific anti-kappa or anti-lambda eluates were studied.CX genotypes were examined by Southern blotting and restriction fragment length polymorphism analysis of Eco RIdigested genomic DNA from 158 patients with Graves' disease in parallel with 112 normal controls and 29 patients with autoimmune hypothyroidism. Notable shifts in proportions of 8/8 and 18/18 genotypes were present when Graves' patients were compared with normal controls. Allelic frequencies and ratios of genotype 8 to 18 were significantly different (P < 0.05) when Graves' patients were compared either to normal controls or to patients with autoimmune hypothyroidism.

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Section: Discussionmentioning

confidence: 82%

Kappa/lambda immunoglobulin distribution in Graves' thyroid-stimulating antibodies. Simultaneous analysis of C lambda gene polymorphisms.

Williams

Marshall²,

Kilpatrick³

et al. 1988

J. Clin. Invest.

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“…One interesting feature of many peptides identified was their theoretical "promiscuity", that is, their capability to bind to many different HLA-DR alleles, which may be related to autoreactive TCR degeneracy. In fact, DR association with thyroid diseases is not very high, despite the preference for DR3 (37)(38)(39)(40). The main associated alleles are DR3 (DRB1*0301) and DR5 (DRB1*1101).…”

Section: Discussionmentioning

confidence: 98%

Thyroglobulin Peptides Associate In Vivo to HLA-DR in Autoimmune Thyroid Glands

Muixí

Carrascal

Álvarez

et al. 2008

The Journal of Immunology

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Endocrine epithelial cells, targets of the autoimmune response in thyroid and other organ-specific autoimmune diseases, express HLA class II (HLA-II) molecules that are presumably involved in the maintenance and regulation of the in situ autoimmune response. HLA-II molecules thus expressed by thyroid cells have the “compact” conformation and are therefore expected to stably bind autologous peptides. Using a new approach to study in situ T cell responses without the characterization of self-reactive T cells and their specificity, we have identified natural HLA-DR-associated peptides in autoimmune organs that will allow finding peptide-specific T cells in situ. This study reports a first analysis of HLA-DR natural ligands from ex vivo Graves’ disease-affected thyroid tissue. Using mass spectrometry, we identified 162 autologous peptides from HLA-DR-expressing cells, including thyroid follicular cells, with some corresponding to predominant molecules of the thyroid colloid. Most interestingly, eight of the peptides were derived from a major autoantigen, thyroglobulin. In vitro binding identified HLA-DR3 as the allele to which one of these peptides likely associates in vivo. Computer modeling and bioinformatics analysis suggested other HLA-DR alleles for binding of other thyroglobulin peptides. Our data demonstrate that although the HLA-DR-associated peptide pool in autoimmune tissue mostly belongs to abundant ubiquitous proteins, peptides from autoantigens are also associated to HLA-DR in vivo and therefore may well be involved in the maintenance and the regulation of the autoimmune response.

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“…The genetic susceptibility of these diseases is thought to be polygenic. It has been reported that major histocompatibility complex (MHC) gene [4,5], cytotoxic T lymphocyte antigen-4 (CTLA-4) gene [6][7][8], interferong (IFN-g) gene [9,10] and tumor necrosis factor-a (TNF-a) gene [11] polymorphisms are associated with GD and GO. However, none of these associations have been fully confirmed.…”

mentioning

confidence: 99%

A C/T Polymorphism in the 5' Untranslated Region of the CD40 Gene Is Associated with Later Onset of Graves' Disease in Japanese

et al. 2005

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Abstract. Graves' disease (GD) is an autoimmune disorder with genetic predisposition. CD40, which stimulates lymphocyte proliferation and differentiation, is an important immunomodulator and is expressed in the thyroid follicular cells as well as antigen-presenting cells. A single nucleotide polymorphism (SNP) at position -1 of the Kozak sequence of the CD40 gene has been reported to be associated with the development of GD. The aim of the present study was to investigate whether CD40 gene polymorphism confers susceptibility to GD in Japanese. CD40 gene polymorphisms were studied in Japanese GD patients (n = 324) and healthy control subjects without anti-thyroid autoantibodies or a family history of autoimmune disorders (n = 229). A C/T polymorphism at position -1 of the CD40 gene was measured using the polymerase chain reaction restriction fragment length polymorphism. There was no significant difference in allele or genotype frequency of the CD40 SNP between GD and control subjects. There was a significant decrease in the TT genotype frequency in the GD patients, who developed GD after 40 years old, than those under 40 year of age. These data suggest that the SNP of CD40 gene is associated with susceptibility to later onset of GD in Japanese.

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HLA-DR3 and HLA-DR5 Associated Thyrotoxicosis-Two Different Types of Toxic Diffuse Goiter*

Cited by 83 publications

References 35 publications

Kappa/lambda immunoglobulin distribution in Graves' thyroid-stimulating antibodies. Simultaneous analysis of C lambda gene polymorphisms.

Kappa/lambda immunoglobulin distribution in Graves' thyroid-stimulating antibodies. Simultaneous analysis of C lambda gene polymorphisms.

Thyroglobulin Peptides Associate In Vivo to HLA-DR in Autoimmune Thyroid Glands

A C/T Polymorphism in the 5' Untranslated Region of the CD40 Gene Is Associated with Later Onset of Graves' Disease in Japanese

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