Thyrotropin-Blocking Autoantibodies and Thyroid-Stimulating Autoantibodies: Potential Mechanisms Involved in the Pendulum Swinging from Hypothyroidism to Hyperthyroidism or Vice Versa

被引:158
作者
McLachlan, Sandra M. [1 ]
Rapoport, Basil
机构
[1] Cedars Sinai Med Ctr, Thyroid Autoimmune Dis Unit, Los Angeles, CA 90048 USA
基金
美国国家卫生研究院;
关键词
BINDING INHIBITOR IMMUNOGLOBULINS; TSH RECEPTOR ANTIBODIES; EUTHYROID HASHIMOTOS-THYROIDITIS; HUMAN MONOCLONAL AUTOANTIBODY; L-THYROXINE THERAPY; GRAVES-DISEASE; AUTOIMMUNE-THYROIDITIS; ANTITHYROID DRUGS; KNOCKOUT MICE; A-SUBUNIT;
D O I
10.1089/thy.2012.0374
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Thyrotropin receptor (TSHR) antibodies that stimulate the thyroid (TSAb) cause Graves' hyperthyroidism and TSHR antibodies which block thyrotropin action (TBAb) are occasionally responsible for hypothyroidism. Unusual patients switch from TSAb to TBAb (or vice versa) with concomitant thyroid function changes. We have examined case reports to obtain insight into the basis for "switching." Summary: TBAb to TSAb switching occurs in patients treated with levothyroxine (LT4); the reverse switch (TBAb to TSAb) occurs after anti-thyroid drug therapy; TSAb/TBAb alterations may occur during pregnancy and are well recognized in transient neonatal thyroid dysfunction. Factors that may impact the shift include: (i) LT4 treatment, usually associated with decreased thyroid autoantibodies, in unusual patients induces or enhances thyroid autoantibody levels; (ii) antithyroid drug treatment decreases thyroid autoantibody levels; (iii) hyperthyroidism can polarize antigen-presenting cells, leading to impaired development of regulatory T cells, thereby compromising control of autoimmunity; (iv) immune-suppression/hemodilution reduces thyroid autoantibodies during pregnancy and rebounds postpartum; (v) maternally transferred IgG transiently impacts thyroid function in neonates until metabolized; (vi) a Graves' disease model involving immunizing TSHR-knockout mice with mouse TSHR-adenovirus and transfer of TSHR antibody-secreting splenocytes to athymic mice demonstrates the TSAb to TBAb shift, paralleling the outcome of maternally transferred "term limited" TSHR antibodies in neonates. Finally, perhaps most important, as illustrated by dilution analyses of patients' sera in vitro, TSHR antibody concentrations and affinities play a critical role in switching TSAb and TBAb functional activities in vivo. Conclusions: Switching between TBAb and TSAb (or vice versa) occurs in unusual patients after LT4 therapy for hypothyroidism or anti-thyroid drug treatment for Graves' disease. These changes involve differences in TSAb versus TBAb concentrations, affinities and/or potencies in individual patients. Thus, anti-thyroid drugs or suppression/hemodilution in pregnancy reduce initially low TSAb levels even further, leading to TBAb dominance. In contrast, TSAb emergence after LT4 administration may be sufficient to counteract TBAb inhibition. The occurrence of "switching" emphasizes the need for careful patient monitoring and management. Finally, whole genome screening of relatively rare "switch" patients and appropriate Graves' and Hashimoto's controls could provide unexpected and valuable information regarding the basis for thyroid autoimmunity.
引用
收藏
页码:14 / 24
页数:11
相关论文
共 74 条
[1]   Narrow individual variations in serum T4 and T3 in normal subjects:: A clue to the understanding of subclinical thyroid disease [J].
Andersen, S ;
Pedersen, KM ;
Bruun, NH ;
Laurberg, P .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2002, 87 (03) :1068-1072
[2]  
Blumenthal D. K, 2011, GOODMAN GILMAN PHARM, Vtwelfth, P46
[3]  
Bolton J, 1999, CLIN CHEM, V45, P2285
[4]   Evidence for negative cooperativity among human thyrotropin receptors overexpressed in mammalian cells [J].
Chazenbalk, GD ;
Kakinuma, A ;
Jaume, JC ;
McLachlan, SM ;
Rapoport, B .
ENDOCRINOLOGY, 1996, 137 (11) :4586-4591
[5]   Thyroid-stimulating autoantibodies in Graves disease preferentially recognize the free A subunit, not the thyrotropin holoreceptor [J].
Chazenbalk, GD ;
Pichurin, P ;
Chen, CR ;
Latrofa, F ;
Johnstone, AP ;
McLachlan, SM ;
Rapoport, B .
JOURNAL OF CLINICAL INVESTIGATION, 2002, 110 (02) :209-217
[6]   Low-dose immunization with adenovirus expressing the thyroid-stimulating hormone receptor A-subunit deviates the antibody response toward that of autoantibodies in human Graves' disease [J].
Chen, CR ;
Pichurin, P ;
Chazenbalk, GD ;
Aliesky, H ;
Nagayama, Y ;
McLachlan, SM ;
Rapoport, B .
ENDOCRINOLOGY, 2004, 145 (01) :228-233
[7]   L-THYROXINE THERAPY INDUCES A FALL OF THYROID MICROSOMAL AND THYROGLOBULIN ANTIBODIES IN IDIOPATHIC MYXEDEMA AND IN HYPOTHYROID, BUT NOT IN EUTHYROID HASHIMOTOS-THYROIDITIS [J].
CHIOVATO, L ;
MARCOCCI, C ;
MARIOTTI, S ;
MORI, A ;
PINCHERA, A .
JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION, 1986, 9 (04) :299-305
[8]   GRAVES HYPERTHYROIDISM FOLLOWING PRIMARY HYPOTHYROIDISM - SEQUENTIAL-CHANGES IN VARIOUS ACTIVITIES OF THYROTROPIN RECEPTOR ANTIBODIES [J].
CHO, BY ;
SHONG, YK ;
LEE, HK ;
KOH, CS ;
MIN, HK .
ACTA ENDOCRINOLOGICA, 1989, 120 (04) :447-450
[9]   Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves' disease [J].
Costagliola, S ;
Morgenthaler, NG ;
Hoermann, R ;
Badenhoop, K ;
Struck, J ;
Freitag, D ;
Poertl, S ;
Weglöhner, W ;
Hollidt, JM ;
Quadbeck, B ;
Dumont, JE ;
Schumm-Draeger, PM ;
Bergmann, A ;
Mann, K ;
Vassart, G ;
Usadel, KH .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1999, 84 (01) :90-97
[10]   Thyroid Hormones as Modulators of Immune Activities at the Cellular Level [J].
De Vito, Paolo ;
Incerpi, Sandra ;
Pedersen, Jens Z. ;
Luly, Paolo ;
Davis, Faith B. ;
Davis, Paul J. .
THYROID, 2011, 21 (08) :879-890