Autoimmune Graves’ disease
1: J Mol
Endocrinol. 2008 Sep;41(3):145-64. Epub 2008 Jul 7.
FSH and TSH binding to their respective receptors: similarities,
differences and implication for glycoprotein hormone specificity.
Núñez
Miguel R, Sanders
J, Chirgadze
DY, Blundell
TL, Furmaniak
J, Rees
Smith B.
FIRS Laboratories, RSR Ltd., Parc Ty Glas, Llanishen,
Cardiff CF14 5DU, UK.
The crystal structures of the
leucine-rich repeat domain (LRD) of the FSH receptor (FSHR) in complex with
FSH and the TSH receptor (TSHR) LRD in complex with the thyroid-stimulating
autoantibody (M22) provide opportunities to assess the molecular basis of
the specificity of glycoprotein hormone-receptor binding. A comparative
model of the TSH-TSHR complex was built using the two solved crystal
structures and verified using studies on receptor affinity and activation.
Analysis of the FSH-FSHR and TSH-TSHR complexes allowed identification of
receptor residues that may be important in hormone-binding specificity.
These residues are in leucine-rich repeats at the two ends of the FSHR and
the TSHR LRD structures but not in their central repeats. Interactions in
the interfaces are consistent with a higher FSH-binding affinity for the
FSHR compared with the binding affinity of TSH for the TSHR. The higher
binding affinity of porcine (p)TSH and bovine (b)TSH for human (h)TSHR
compared with hTSH appears not to be dependent on interactions with the
TSHR LRD as none of the residues that differ among hTSH, pTSH or bTSH
interact with the LRD. This suggests that TSHs are likely to interact with
other parts of the receptors in addition to the LRD with these non-LRD
interactions being responsible for affinity differences. Analysis of
interactions in the FSH-FSHR and TSH-TSHR complexes suggests that the
alpha-chains of both hormones tend to be involved in the receptor
activation process while the beta-chains are more involved in defining
binding specificit
Hum
Antibodies. 2004;13(4):119-29.
Evidence for two discontinuous regions on the thyrotropin receptor
involved in the binding of the monoclonal antibody 34A.
Bresson
D, Laune
D, Chardès
T, Charreire
J, Bès
C, Bouanani
M, Péraldi-Roux
S.
Autoimmune Disease Unit, Cedars-Sinai Research
Institute, and University of California School of Medicine, Los Angeles, CA
90048, USA.
The human thyrotropin receptor
(hTSHR) is a major autoantigen in thyroid autoimmunity. The aim of this
study was to localize the discontinuous epitope recognized by the
anti-hTSHR monoclonal antibody (mAb) 34A. We used the phage-displayed
peptide technology and selected thirteen 34A-specific mimotopes which could
be grouped into four families according to their sequence homologies.
Mimotope sequence alignments on the primary sequence of hTSHR allowed us to
identify regions 88-100 (family I homologous motif Tx(8)FYNL) and 276-281
(family IV homologous motif DxSYPS) as being putative parts of the
discontinuous epitope recognized by the mAb 34A. Interestingly, by using
the Spot method, TSH was also found to interact with peptides bearing amino
acids from these two regions, suggesting their involvement in TSH/TSHR
interaction. Moreover these data are in agreement with the ability of the
mAb 34 to displace TSH binding to its receptor. In addition, purified IgG
from nine patients with Graves' disease were able to specifically recognize
family I-specific mimotopes, whereas those from healthy donors did not.
Taken together, our data suggest the involvement of regions 88-100 and
276-281 in the epitope recognized by mAb 34A as well as purified IgG from
patients' sera and provide a basis for rational guided mutagenesis.
Autoimmunity. 2004 Sep-Nov;37(6-7):51520.
Characterization of a recombinant Yersinia enterocolitica
lipoprotein; implications for its role in autoimmune response against
thyrotropin receptor.
Gangi
E, Kapatral
V, El-Azami
El-Idrissi M, Martinez
O, Prabhakar
BS.
Department of Microbiology and Immunology, College of
Medicine, University of Illinois at Chicago, 60612, USA.
Autoimmune Graves' disease (GD), which is characterized
by hyperthyroidism, is mediated by autoantibodies to the thyrotropin
receptor (TSHR). Yersinia enterocolitica (Y.e.) has been shown to produce a
lipoprotein (LP) that can cross-react with the TSHR and thus can act as a
potential trigger of thyroid autoimmunity. In this study, to further
characterize LP, we cloned the LP gene from Y. enterocolitica and expressed
a recombinant LP. This recombinant LP was mitogenic for C3H/HeJ (LPS
hyporesponsive) B cells and induced production and secretion of significant
levels of IL-6 from splenocytes. A mouse antibody generated against the
recombinant LP cross-reacted with TSHR as shown by western blot analysis.
FACS analysis of splenocytes from mice immunized with LP revealed that LP
could induce increased expression of B7.1 and B7.2. The immunomodulatory
effects of LP including up-regulation of B7.1 and B7.2 coupled with its
ability to induce antibodies that can cross-react with the TSHR showed
several potential mechanisms by which it can cause breakdown of self-tolerance
to TSHR.
PMID:
15621579 [PubMed - indexed for MEDLINE
|
1: J Mol
Endocrinol. 2008 Sep;41(3):145-64. Epub 2008 Jul 7. FSH and TSH binding to their respective receptors: similarities,
differences and implication for glycoprotein hormone specificity.
Núñez
Miguel R, Sanders
J, Chirgadze
DY, Blundell
TL, Furmaniak
J, Rees
Smith B. FIRS Laboratories, RSR Ltd., Parc Ty Glas, Llanishen,
Cardiff CF14 5DU, UK. The crystal structures of the leucine-rich repeat domain (LRD) of the FSH receptor (FSHR) in complex with FSH and the TSH receptor (TSHR) LRD in complex with the thyroid-stimulating autoantibody (M22) provide opportunities to assess the molecular basis of the specificity of glycoprotein hormone-receptor binding. A comparative model of the TSH-TSHR complex was built using the two solved crystal structures and verified using studies on receptor affinity and activation. Analysis of the FSH-FSHR and TSH-TSHR complexes allowed identification of receptor residues that may be important in hormone-binding specificity. These residues are in leucine-rich repeats at the two ends of the FSHR and the TSHR LRD structures but not in their central repeats. Interactions in the interfaces are consistent with a higher FSH-binding affinity for the FSHR compared with the binding affinity of TSH for the TSHR. The higher binding affinity of porcine (p)TSH and bovine (b)TSH for human (h)TSHR compared with hTSH appears not to be dependent on interactions with the TSHR LRD as none of the residues that differ among hTSH, pTSH or bTSH interact with the LRD. This suggests that TSHs are likely to interact with other parts of the receptors in addition to the LRD with these non-LRD interactions being responsible for affinity differences. Analysis of interactions in the FSH-FSHR and TSH-TSHR complexes suggests that the alpha-chains of both hormones tend to be involved in the receptor activation process while the beta-chains are more involved in defining binding specificit Hum
Antibodies. 2004;13(4):119-29. Evidence for two discontinuous regions on the thyrotropin receptor
involved in the binding of the monoclonal antibody 34A.
Bresson
D, Laune
D, Chardès
T, Charreire
J, Bès
C, Bouanani
M, Péraldi-Roux
S. Autoimmune Disease Unit, Cedars-Sinai Research
Institute, and University of California School of Medicine, Los Angeles, CA
90048, USA. The human thyrotropin receptor
(hTSHR) is a major autoantigen in thyroid autoimmunity. The aim of this
study was to localize the discontinuous epitope recognized by the
anti-hTSHR monoclonal antibody (mAb) 34A. We used the phage-displayed
peptide technology and selected thirteen 34A-specific mimotopes which could
be grouped into four families according to their sequence homologies.
Mimotope sequence alignments on the primary sequence of hTSHR allowed us to
identify regions 88-100 (family I homologous motif Tx(8)FYNL) and 276-281
(family IV homologous motif DxSYPS) as being putative parts of the
discontinuous epitope recognized by the mAb 34A. Interestingly, by using
the Spot method, TSH was also found to interact with peptides bearing amino
acids from these two regions, suggesting their involvement in TSH/TSHR
interaction. Moreover these data are in agreement with the ability of the
mAb 34 to displace TSH binding to its receptor. In addition, purified IgG
from nine patients with Graves' disease were able to specifically recognize
family I-specific mimotopes, whereas those from healthy donors did not.
Taken together, our data suggest the involvement of regions 88-100 and
276-281 in the epitope recognized by mAb 34A as well as purified IgG from
patients' sera and provide a basis for rational guided mutagenesis. Autoimmunity. 2004 Sep-Nov;37(6-7):51520. Characterization of a recombinant Yersinia enterocolitica
lipoprotein; implications for its role in autoimmune response against
thyrotropin receptor.
Gangi
E, Kapatral
V, El-Azami
El-Idrissi M, Martinez
O, Prabhakar
BS. Department of Microbiology and Immunology, College of
Medicine, University of Illinois at Chicago, 60612, USA. Autoimmune Graves' disease (GD), which is characterized
by hyperthyroidism, is mediated by autoantibodies to the thyrotropin
receptor (TSHR). Yersinia enterocolitica (Y.e.) has been shown to produce a
lipoprotein (LP) that can cross-react with the TSHR and thus can act as a
potential trigger of thyroid autoimmunity. In this study, to further
characterize LP, we cloned the LP gene from Y. enterocolitica and expressed
a recombinant LP. This recombinant LP was mitogenic for C3H/HeJ (LPS
hyporesponsive) B cells and induced production and secretion of significant
levels of IL-6 from splenocytes. A mouse antibody generated against the
recombinant LP cross-reacted with TSHR as shown by western blot analysis.
FACS analysis of splenocytes from mice immunized with LP revealed that LP
could induce increased expression of B7.1 and B7.2. The immunomodulatory
effects of LP including up-regulation of B7.1 and B7.2 coupled with its
ability to induce antibodies that can cross-react with the TSHR showed
several potential mechanisms by which it can cause breakdown of self-tolerance
to TSHR. PMID:
15621579 [PubMed - indexed for MEDLINE |
Thyroid. 2006 Nov;16(11):1085-9.
Effects of a thyroid-stimulating human monoclonal autoantibody (M22)
on functional activity of LH and FSH receptors.
Tonacchera
M, Ferrarini
E, Dimida
A, Agretti
P, De
Marco G, Pinchera
A, Sanders
J, Evans
M, Richards
T, Furmaniak
J, Smith
BR.
Department of Endocrinology,
Centre of Excellence for the Study of Damage to the Nervous and Endocrine
Systems Produced by Environmental, Alimentary, and Pharmacological Agents,
AmbiSEN, University of Pisa, Pisa, Italy, Via Paradisa 2, 56124 Pisa, Italy.
OBJECTIVE: The glycoprotein
hormones luteinizing hormone (LH), follicle-stimulating hormone (FSH), and
thyrotropin (TSH) show low-level cross-reactivity between their respective
receptors (R). Patient serum autoantibodies to the thyrotropin receptor (TSHR)
do not appear to cross-react with the luteinizing hormone receptor (LHR) or
follicle-stimulating hormone receptor (FSHR), although the concentrations of
autoantibody with which it is feasible to carry out experiments of this type
are limited. Consequently, we have studied the effects of high doses of the thyroid-stimulating
human monoclonal autoantibody (M22) on the LHR and FSHR. DESIGN: Chinese
Hamster ovary (CHO) cells stably expressing the TSHR, LHR, and FSHR and
purified M22 IgG preparations were used in the study. METHODS: CHO-TSHR,
CHO-LHR, and CHO-FSHR cells were incubated with bovine TSH (0.1-25mU/mL), human
recombinant chorionic gonadotropin (hCG; 0.5-10mU/mL) or human recombinant FSH
(100-5000mU/mL) or with M22 IgG (0.001-5.0 microg/mL), and the extracellular
cyclic AMP was measured by radioimmunoassay. RESULTS: Cyclic AMP levels
increased in a dose-dependent manner after incubation of CHO-TSHR cells with
TSH or M22 IgG, and on a molar basis the effects of TSH and M22 were similar.
Cyclic AMP stimulation was not detectable in CHO-LHR and CHO-FSHR cells after
incubation with M22 IgG, whereas incubation with hCG or FSH, respectively,
caused dose-dependent cyclic AMP stimulation. On a molar basis, concentrations
of M22 IgG approximately 100x those of FSH causing clear stimulation were
ineffective with CHO-FSHR cells. Similarly, molar concentration of M22 IgG
20,000x those of hCG causing clear stimulation had no effect on CHO-LHR cells.
CONCLUSIONS: This study shows that at relatively high concentrations, M22 IgG
is unable to stimulate cyclic AMP levels in CHO-LHR or CHO-FSHR cells,
suggesting that TSHR autoantibodies have greater specificity for the TSHR than
TSH itself.
PMID: 17123334 [PubMed - indexed