Relationship Between Autoantibody Epitopic Recognition and Immunoglobulin Gene Usage

Overview

Journal Clin Exp Immunol

Publisher Oxford University Press

Specialty Allergy & Immunology

Date 1998 Mar 5

PMID 9486412

Citations 7

Authors

J Guo

R S McIntosh

B Czarnocka

A P Weetman

B Rapoport

S M McLachlan

Affiliations

Soon will be listed here.

Abstract

An immunodominant region recognized by serum autoantibodies has been defined on the autoantigen thyroid peroxidase (TPO) using recombinant human TPO-specific Fab or a panel of mouse MoAbs. We have now analysed the epitopic relationships between the four recombinant Fab that identify the A and B domains of the TPO immunodominant region and (i) the mouse TPO MoAb as well as (ii) nine new TPO-specific Fab isolated independently. Competition between mouse MoAbs and recombinant Fab for binding to 125I-TPO revealed three patterns. First, for MoAbs 15, 59, 64 and 18, TPO binding was virtually abolished (approximately 90%) by Fab which define the A domain of TPO, with less inhibition by B domain Fab. Second, for MoAbs 2, 9 and 47, the Fab competed much less for TPO binding, and, when detectable, inhibition was predominantly with B domain Fab (65-20%). Third, for MoAbs 53, 30, 1, 24 and 40, none of the Fab competed effectively for 125I-TPO binding. Thus, the epitopes for MoAbs 18, 59, 64 and 15 correspond to those of the A domain defined by the human Fab, and the epitopes for MoAbs 2, 9 and 47 correspond to those of the B domain. In the second part of the study, competition studies demonstrated that the epitopes of nine new Fab corresponded to those of the four Fab that define the immunodominant region. For four new Fab, TPO binding was inhibited to a greater extent by B- than by A-domain Fab (65-95% versus <50%). In contrast, for five new Fab the A-domain Fab were more effective inhibitors (approximately 90%) than the B-domain Fab. In addition, consistent with previous observations, all five new Fab with 02/012 kappa L chains, but none of the new Fab with non-O2/O121 chains, interacted with A-domain epitopes. In conclusion, we have established the epitopic relationships between recombinant human Fab and mouse MoAbs that define the TPO immunodominant region on TPO. Further, analysis of recombinant TPO Fab isolated from patients on three continents strengthens the paradigm of a relationship between autoantibody epitopic recognition and immunoglobulin gene usage.

Citing Articles

Localization of the immunodominant region on human thyroid peroxidase in autoimmune thyroid diseases: an update.

Bresson D, Rebuffat S, Peraldi-Roux S J Autoimmune Dis. 2005; 2(1):2.

PMID: 15769293 PMC: 1084359. DOI: 10.1186/1740-2557-2-2.

Superiority of thyroid peroxidase DNA over protein immunization in replicating human thyroid autoimmunity in HLA-DRB1*0301 (DR3) transgenic mice.

Flynn J, Gardas A, Wan Q, Gora M, Alsharabi G, Wei W Clin Exp Immunol. 2004; 137(3):503-12.

PMID: 15320899 PMC: 1809151. DOI: 10.1111/j.1365-2249.2004.02553.x.

Evaluation of conformational epitopes on thyroid peroxidase by antipeptide antibody binding and mutagenesis.

Gora M, Gardas A, Wiktorowicz W, Hobby P, Watson P, Weetman A Clin Exp Immunol. 2004; 136(1):137-44.

PMID: 15030525 PMC: 1809007. DOI: 10.1111/j.1365-2249.2004.02422.x.

Insight into antibody responses induced by plasmid or adenoviral vectors encoding thyroid peroxidase, a major thyroid autoantigen.

Guo J, Pichurin P, Nagayama Y, Rapoport B, McLachlan S Clin Exp Immunol. 2003; 132(3):408-15.

PMID: 12780686 PMC: 1808732. DOI: 10.1046/j.1365-2249.2003.02170.x.

Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers.

Armengol M, Juan M, Lucas-Martin A, Fernandez-Figueras M, Jaraquemada D, Gallart T Am J Pathol. 2001; 159(3):861-73.

PMID: 11549579 PMC: 1850445. DOI: 10.1016/S0002-9440(10)61762-2.

References

Kajita Y, Morgan D, Parkes A, Rees Smith B . Labelling and immunoprecipitation of thyroid microsomal antigen. FEBS Lett. 1985; 187(2):334-8. DOI: 10.1016/0014-5793(85)81271-0. View

Parkes A, McLachlan S, Bird P, Rees Smith B . The distribution of microsomal and thyroglobulin antibody activity among the IgG subclasses. Clin Exp Immunol. 1984; 57(1):239-43. PMC: 1536069. View

Gardas A, Domek H . The effect of sulphydryl reagents on the human thyroid microsomal antigen. J Endocrinol Invest. 1988; 11(5):385-8. DOI: 10.1007/BF03349061. View

Weetman A, Black C, Cohen S, Tomlinson R, Banga J, Reimer C . Affinity purification of IgG subclasses and the distribution of thyroid auto-antibody reactivity in Hashimoto's thyroiditis. Scand J Immunol. 1989; 30(1):73-82. DOI: 10.1111/j.1365-3083.1989.tb01190.x. View

Ruf J, Toubert M, Czarnocka B, Ferrand M, Carayon P . Relationship between immunological structure and biochemical properties of human thyroid peroxidase. Endocrinology. 1989; 125(3):1211-8. DOI: 10.1210/endo-125-3-1211. View

Finke R, Seto P, Rapoport B . Evidence for the highly conformational nature of the epitope(s) on human thyroid peroxidase that are recognized by sera from patients with Hashimoto's thyroiditis. J Clin Endocrinol Metab. 1990; 71(1):53-9. DOI: 10.1210/jcem-71-1-53. View

Davies D, Padlan E, Sheriff S . Antibody-antigen complexes. Annu Rev Biochem. 1990; 59:439-73. DOI: 10.1146/annurev.bi.59.070190.002255. View

Portolano S, Seto P, Chazenbalk G, Nagayama Y, McLachlan S, Rapoport B . A human Fab fragment specific for thyroid peroxidase generated by cloning thyroid lymphocyte-derived immunoglobulin genes in a bacteriophage lambda library. Biochem Biophys Res Commun. 1991; 179(1):372-7. DOI: 10.1016/0006-291x(91)91380-u. View

Libert F, Ludgate M, Dinsart C, Vassart G . Thyroperoxidase, but not the thyrotropin receptor, contains sequential epitopes recognized by autoantibodies in recombinant peptides expressed in the pUEX vector. J Clin Endocrinol Metab. 1991; 73(4):857-60. DOI: 10.1210/jcem-73-4-857. View

10.

Finke R, Seto P, Ruf J, Carayon P, Rapoport B . Determination at the molecular level of a B-cell epitope on thyroid peroxidase likely to be associated with autoimmune thyroid disease. J Clin Endocrinol Metab. 1991; 73(4):919-21. DOI: 10.1210/jcem-73-4-919. View

11.

McLachlan S, Rapoport B . The molecular biology of thyroid peroxidase: cloning, expression and role as autoantigen in autoimmune thyroid disease. Endocr Rev. 1992; 13(2):192-206. DOI: 10.1210/edrv-13-2-192. View

12.

Portolano S, Chazenbalk G, Seto P, Hutchison J, Rapoport B, McLachlan S . Recognition by recombinant autoimmune thyroid disease-derived Fab fragments of a dominant conformational epitope on human thyroid peroxidase. J Clin Invest. 1992; 90(3):720-6. PMC: 329922. DOI: 10.1172/JCI115943. View

13.

Chazenbalk G, Portolano S, Russo D, Hutchison J, Rapoport B, McLachlan S . Human organ-specific autoimmune disease. Molecular cloning and expression of an autoantibody gene repertoire for a major autoantigen reveals an antigenic immunodominant region and restricted immunoglobulin gene usage in the target organ. J Clin Invest. 1993; 92(1):62-74. PMC: 293532. DOI: 10.1172/JCI116600. View

14.

Portolano S, McLachlan S, Rapoport B . High affinity, thyroid-specific human autoantibodies displayed on the surface of filamentous phage use V genes similar to other autoantibodies. J Immunol. 1993; 151(5):2839-51. View

15.

Chazenbalk G, Costante G, Portolano S, McLachlan S, Rapoport B . The immunodominant region on human thyroid peroxidase recognized by autoantibodies does not contain the monoclonal antibody 47/c21 linear epitope. J Clin Endocrinol Metab. 1993; 77(6):1715-8. DOI: 10.1210/jcem.77.6.7505290. View

16.

Cox J, Tomlinson I, Winter G . A directory of human germ-line V kappa segments reveals a strong bias in their usage. Eur J Immunol. 1994; 24(4):827-36. DOI: 10.1002/eji.1830240409. View

17.

Nishikawa T, Costante G, Prummel M, McLachlan S, Rapoport B . Recombinant thyroid peroxidase autoantibodies can be used for epitopic "fingerprinting" of thyroid peroxidase autoantibodies in the sera of individual patients. J Clin Endocrinol Metab. 1994; 78(4):944-9. DOI: 10.1210/jcem.78.4.7512572. View

18.

Costante G, Portolano S, Nishikawa T, Jaume J, Chazenbalk G, Rapoport B . Recombinant thyroid peroxidase-specific autoantibodies. II. Role of individual heavy and light chains in determining epitope recognition. Endocrinology. 1994; 135(1):25-30. DOI: 10.1210/endo.135.1.7516865. View

19.

Prummel M, Portolano S, Costante G, Rapoport B, McLachlan S . Isolation and characterization of a monoclonal human thyroid peroxidase autoantibody of lambda light chain type. Mol Cell Endocrinol. 1994; 102(1-2):161-6. DOI: 10.1016/0303-7207(94)90109-0. View

20.

Hexham J, Partridge L, Furmaniak J, Petersen V, Colls J, Pegg C . Cloning and characterisation of TPO autoantibodies using combinatorial phage display libraries. Autoimmunity. 1994; 17(3):167-79. DOI: 10.3109/08916939409010651. View