Pertinence of kappa and lambda recombinant antibodies directed against thyroid peroxidase in thyroid autoimmune disease

Bresson, Damien; Chardès, Thierry; Chapal, Nicolas; Bès, Cédric; Cérutti, Martine; Devauchelle, G.; Bouanani, Majida; Mani, Jean‐Claude; Péraldi-Roux, Sylvie

doi:10.3233/hab-2001-103-403

Cited by 7 publications

(11 citation statements)

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“…Interestingly, these mutants could be classified into two groups, which weakly (TPO 377-386 ) or strongly (TPO 353-363 , TPO 713-720 , TPO 766 -775 ) affected the binding of the anti-TPO aAbs. In contrast to competition studies between anti-TPO mAb and polyclonal patients' sera described previously by our group and others (13,14,25,40,41), where the results could be biased by steric hindrance, the effects of each mutation on the binding of all polyclonal anti-TPO sera studied here resulted in the same pattern for the particular mutation. Similar results were obtained by McLachlan and Rapoport's group (30).…”

Section: Figcontrasting

confidence: 44%

“…Selection of T13-binding Mimotopes by Phage Display Technology-We have demonstrated previously that aAb T13 strongly inhibits the TPO binding of aAb in the sera of patients suffering from AITD (40,41). Moreover, we have shown that aAb T13 does not recognize a linear epitope, 2 thus suggesting the conformational nature of this dominant cognate epitope.…”

Section: Characterization Of Aab T13 Expressed As Whole Igg 1 Inmentioning

confidence: 99%

“…After three washings, the reactivity was revealed with 1 mg/ml of 4-nitrophenyl phosphate in 0.5 M diethanolamine/HCl, pH 9.6, for 1 h at 37°C. Kinetic parameters of aAb T13 were obtained by real time analysis as described previously (41). The aAb T13, expressed as scFv or IgG 1 , inhibits between 7.3 and 100% of the binding to TPO of serum samples from patients with AITD that were tested (40,41).…”

Section: Methodsmentioning

confidence: 99%

“…The T13 aAb was expressed as an entire IgG 1 antibody by using the baculovirus/insect cell system as described (41,43,44). IgG 1 T13 was purified on a protein G affinity column and the concentration determined by the A 280 nm , E 0.1% of 1.40.…”

Section: Methodsmentioning

confidence: 99%

“…We applied this strategy to the identification of the TPO immunodominant epitope involved in thyroid autoimmunity by using the human IDR-specific recombinant IgG 1 aAb T13 derived from antibody phage-displayed libraries obtained from B cells extracted from thyroid tissue of Graves' disease patients (40,41). Four distinct regions, belonging to the MPO-like and CCP-like domains of TPO, delimited the discontinuous IDR, recognized by the human recombinant aAb T13 and identified by sera from patients suffering from Hashimoto's thyroiditis or Graves' disease.…”

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confidence: 99%

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Localization of the Discontinuous Immunodominant Region Recognized by Human Anti-thyroperoxidase Autoantibodies in Autoimmune Thyroid Diseases

Bresson¹,

Cérutti²,

Devauchelle³

et al. 2003

Journal of Biological Chemistry

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The discontinuous immunodominant region (IDR) recognized by autoantibodies directed against the thyroperoxidase (TPO) molecule, a major autoantigen in autoimmune thyroid diseases, has not yet been completely localized. By using peptide phage-displayed technology, we identified three critical motifs, LXPEXD, QSYP, and EX(E/D)PPV, within selected mimotopes which interacted with the human recombinant anti-TPO autoantibody (aAb) T13, derived from an antibody phage-displayed library obtained from thyroid-infiltrating TPO-selected B cells of Graves' disease patients. Mimotope sequence alignment on the TPO molecule, together with the binding analysis of the T13 aAb on TPO mutants expressed by Chinese hamster ovary cells, demonstrated that regions 353-363, 377-386, and 713-720 from the myeloperoxidase-like domain and region 766 -775 from the complement control protein-like domain are a part of the IDR recognized by the recombinant aAb T13. Furthermore, we demonstrated that these regions were involved in the binding to TPO of sera containing TPO-specific autoantibodies from patients suffering from Hashimoto's and Graves' autoimmune diseases. Identification of the IDR could lead to improved diagnosis of thyroid autoimmune diseases by engineering "mini-TPO" as a target autoantigen or designing therapeutic peptides able to block undesired autoimmune responses.Human thyroid peroxidase (TPO), 1 described previously as the "thyroid microsomal antigen" (1), is a membrane-bound enzyme expressed at the apical pole of thyrocytes (2). TPO generates the functional form of thyroglobulin by iodination and coupling of tyrosine residues (3). During autoimmune thyroid diseases (AITD), TPO represents a major target for the immune system (4, 5), leading to high titer TPO-specific autoantibodies (aAbs) in the sera of patients suffering from Hashimoto's thyroiditis and Graves' disease. Besides their role as efficient and early diagnostic markers of AITD, TPO-specific aAbs also act as effector molecules either through modulating antigen presentation to T cells or by mediating thyroid destruction after complement activation or antibody-dependent cell cytotoxicity (6 -12). Alignment studies and structural homologies have shown that TPO is formed by three distinct domains: a myeloperoxidase (MPO)-like, a complement control protein (CCP)-like, and an EGF-like domain, from the N-to the Cterminal extremities (13). Although the structure of each domain has been elucidated in part by three-dimensional modeling (13-16), the full three-dimensional structure of TPO remains unknown, even though low resolution crystals have been obtained (17,18). The flexibility observed for the hinge regions probably make difficult the exact positioning of each domain in relation to the others (15).These observations denote a highly complex structure of TPO, thus explaining the reason why TPO aAbs from patients' sera preferentially recognize discontinuous epitopes on . Different approaches have been used to determine the epitopic regions recognized by anti-TPO aAbs from ...

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Section: Figcontrasting

confidence: 44%

Section: Characterization Of Aab T13 Expressed As Whole Igg 1 Inmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Localization of the Discontinuous Immunodominant Region Recognized by Human Anti-thyroperoxidase Autoantibodies in Autoimmune Thyroid Diseases

Bresson¹,

Cérutti²,

Devauchelle³

et al. 2003

Journal of Biological Chemistry

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The human anti-thyroid peroxidase autoantibody repertoire in Graves' and Hashimoto's autoimmune thyroid diseases

et al. 2002

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Human anti-thyroid peroxidase (TPO) autoantibodies (aAb) are generated during autoimmune thyroid diseases (AITD). Within recent years, increasing knowledge of the TPO-specific aAb repertoire, gained mainly by the use of combinatorial library methodology, has led to the cloning and sequencing of around 180 human anti-TPO aAb. Analysis of the immunoglobulin (Ig) variable (V) genes encoding the TPO aAb in the ImMunoGeneTics database (IMGT) (http://imgt.cines.fr) reveals major features of the TPO-directed aAb repertoire during AITD. Heavy chain VH domains of TPO-specific aAb from Graves' disease patients preferentially use D proximal IGHV1 genes, whereas those from Hashimoto's thyroiditis are characterized more frequently by IGHV3 genes, mainly located in the middle of the IGH locus. A large proportion of the anti-TPO heavy chain VH domains is obtained following a VDJ recombination process that uses inverted D genes. J distal IGKV1 and IGLV1 genes are predominantly used in TPO aAb. In contrast to the numerous somatic hypermutations in the TPO-specific heavy chains, there is only limited amino acid replacement in most of the TPO-specific light chains, particularly in those encoded by J proximal IGLV or IGKV genes, suggesting that a defect in receptor editing can occur during aAb generation in AITD. Among the predominant IGHV1 or IGKV1 TPO aAb, conserved somatic mutations are the hallmark of the TPO aAb repertoire. The aim of this review is to provide new insights into aAb generation against TPO, a major autoantigen involved in AITD.

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Immunoglobulin light-chain genes in the rhesus macaque II: lambda light-chain germline sequences for subgroups IGLV1, IGLV2, IGLV3, IGLV4 and IGLV5

et al. 2005

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The combined processes of immunoglobulin (IG) gene rearrangement and somatic hypermutation allow for the creation of an extremely diverse antibody repertoire. Knowledge of the germline sequence of the IG genes is required so that hypermutation and the affinity matured humoral response can be properly studied. Variable region genes can be arranged into subgroups; in humans, there are 11 IGLV subgroups and 6 IGKV subgroups. The rhesus macaque (Macaca mulatta) is a relevant non-human primate model for human immunological systems. A number of macaque IGHV, IGHD and IGHJ genes have already been reported. We have also previously reported a number of macaque IGKV genes. Here we report the isolation of new macaque IGLV genes by polymerase chain reaction amplification from macaque genomic DNA using primers based on the human sequences. Nine IGLV1, 10 IGLV2, 21 IGLV3, 5 IGLV4 and 7 IGLV5 germline genes for the macaque were found, the open-reading frames of which exhibit high homology to their human counterparts (>89.3, >88.6, >89.0, >94.7 and >87.1%, respectively).

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Pertinence of kappa and lambda recombinant antibodies directed against thyroid peroxidase in thyroid autoimmune disease

Cited by 7 publications

References 0 publications

Localization of the Discontinuous Immunodominant Region Recognized by Human Anti-thyroperoxidase Autoantibodies in Autoimmune Thyroid Diseases

Localization of the Discontinuous Immunodominant Region Recognized by Human Anti-thyroperoxidase Autoantibodies in Autoimmune Thyroid Diseases

The human anti-thyroid peroxidase autoantibody repertoire in Graves' and Hashimoto's autoimmune thyroid diseases

Immunoglobulin light-chain genes in the rhesus macaque II: lambda light-chain germline sequences for subgroups IGLV1, IGLV2, IGLV3, IGLV4 and IGLV5

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