The Thyroid-Stimulating Antibody of Graves&amp;rsquo; Disease: Evidence for Restricted Heterogeneity

Zakarija, M.

doi:10.1159/000179266

Cited by 43 publications

(22 citation statements)

References 24 publications

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“…A remarkable property of TSAb is that the activity is often confined to antibodies with only a single class of light chain. Although two studies (6,7) reported that in most cases (17 out of 19 in total) only the lambda light chain was found in TSAb, we have found a more mixed pattern (8), in which some TSAb are lambda light chain restricted, some are kappa light chain restricted, and some are apparently unrestricted. Overall however, these results indicate that in many patients with Graves' disease there is restricted heterogeneity in the use of light chains by T §Ab, which contrasts the unrestricted light chain heterogeneity of thyroglobulin (Tg) and microsomal antigen/ thyroid peroxidase (M/TPO) antibodies (9).…”

Section: Introductioncontrasting

confidence: 82%

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Thyroid-stimulating antibody activity between different immunoglobulin G subclasses.

Weetman¹,

Yateman²,

Ealey³

et al. 1990

J. Clin. Invest.

133

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To investigate the distribution of thyroid-stimulating antibody (TSAb) activity between IgG subclasses, sera from 11 patients with Graves disease (including the National Institute of Biological Standards and Control (NIBSC) Research Standard, long acting thyroid stimulator-B) were fractionated by chromatography on affinity columns of monoclonal IgG subclass antibodies or protein A to deplete all but a single subclass. The resulting fractions were 98% or more pure for a single subclass. In all 11 patients, TSAb activity appeared to be confined to the IgG, fraction as determined by cAMP production on addition of the fractions to the FRTL-5 rat thyroid cell line. In all of eight specimens from seven patients so tested, the whole serum activity was recovered in the IgG, fraction, after adjusting for the recovery of the isotype from the column. TSAb activity in one serum comprised both lambda and kappa light chains but was IgG1 restricted. This IgG subclass restriction was not found when the same fractions were tested for thyroglobulin, microsomal/thyroid peroxidase, or tetanus toxoid antibody activity. Together with previous results showing marked restriction of both light chain usage and isoelectric point of TSAb, these results support the idea that Graves' disease may be the result of an oligo-or possibly monoclonal response at the B cell level. (J. Clin. Invest. 1990. 86:723-727.)

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Section: Introductioncontrasting

confidence: 82%

“…Bioactivity ofTSAb requires the appropriate physical combination of both heavy and light chains (6,10), suggesting that restriction oflight chain type might be accompanied by restriction of heavy chain isotype. That TSAb may not be polyclonal is of importance in understanding the etiology of the disease.…”

Section: Introductionmentioning

confidence: 99%

Thyroid-stimulating antibody activity between different immunoglobulin G subclasses.

Weetman¹,

Yateman²,

Ealey³

et al. 1990

J. Clin. Invest.

133

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“…These authors suggested that this was evidence in favor of the "forbidden clone" hypothesis. Earlier, a report by Zakarija (12) had also provided evidence for what appeared to be relative oligoclonal restriction in autoantibodies occurring in the serum ofGraves' disease patients. The present study was therefore directed at an examination of thyroid-stimulating antibodies (TsAb) as measured in a sensitive in vitro bioassay for their possible kappa or lambda restriction.…”

Section: Introductionmentioning

confidence: 95%

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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“…The Ab response to TSHR is therefore diverse in terms of epitope recognition and function. Earlier studies on TSAbs have indicated a restricted clonal response to TSHR with TSAbs confined to IgG 1 isotype and l-L chain usage (2)(3)(4). Recent genetic studies in inbred mice strains have implicated the IGH V region gene locus in TSAb development (5,6).…”

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confidence: 99%

Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

Hargreaves

Grasso

Hampe

et al. 2013

The Journal of Immunology

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Graves’ disease results from thyroid-stimulating Abs (TSAbs) activating the thyrotropin receptor (TSHR). How TSAbs arise from early precursor B cells has not been established. Genetic and environmental factors may contribute to pathogenesis, including the bacterium Yersinia enterocolitica. We developed two pathogenic monoclonal TSAbs from a single experimental mouse undergoing Graves’ disease, which shared the same H and L chain germline gene rearrangements and then diversified by numerous somatic hypermutations. To address the Ag specificity of the shared germline precursor of the monoclonal TSAbs, we prepared rFab germline, which showed negligible binding to TSHR, indicating importance of somatic hypermutation in acquiring TSAb activity. Using rFab chimeras, we demonstrate the dominant role of the H chain V region in TSHR recognition. The role of microbial Ags was tested with Y. enterocolitica proteins. The monoclonal TSAbs recognize 37-kDa envelope proteins, also recognized by rFab germline. MALDI-TOF identified the proteins as outer membrane porin (Omp) A and OmpC. Using recombinant OmpA, OmpC, and related OmpF, we demonstrate cross-reactivity of monoclonal TSAbs with the heterogeneous porins. Importantly, rFab germline binds recombinant OmpA, OmpC, and OmpF confirming reactivity with Y. enterocolitica. A human monoclonal TSAb, M22 with similar properties to murine TSAbs, also binds recombinant porins, showing cross-reactivity of a spontaneously arising pathogenic Ab with Y. enterocolitica. The data provide a mechanistic framework for molecular mimicry in Graves’ disease, where early precursor B cells are expanded by Y. enterocolitica porins to undergo somatic hypermutation to acquire a cross-reactive pathogenic response to TSHR.

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The Thyroid-Stimulating Antibody of Graves’ Disease: Evidence for Restricted Heterogeneity

Cited by 43 publications

References 24 publications

Thyroid-stimulating antibody activity between different immunoglobulin G subclasses.

Thyroid-stimulating antibody activity between different immunoglobulin G subclasses.

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

Yersinia enterocolitica Provides the Link between Thyroid-Stimulating Antibodies and Their Germline Counterparts in Graves’ Disease

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