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2015 ; 100
(6
): E871-5
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Evidence that TSH Receptor A-Subunit Multimers, Not Monomers, Drive Antibody
Affinity Maturation in Graves Disease
#MMPMID25856215
Rapoport B
; Aliesky HA
; Chen CR
; McLachlan SM
J Clin Endocrinol Metab
2015[Jun]; 100
(6
): E871-5
PMID25856215
show ga
CONTEXT: The TSH receptor (TSHR) A-subunit shed from the cell surface contributes
to the induction and/or affinity maturation of pathogenic TSHR autoantibodies in
Graves' disease. OBJECTIVE: This study aimed to determine whether the quaternary
structure (multimerization) of shed A-subunits influences pathogenic TSHR
autoantibody generation. DESIGN: The isolated TSHR A-subunit generated by
transfected mammalian cells exists in two forms; one (active) is recognized only
by Graves' TSHR autoantibodies, the second (inactive) is recognized only by mouse
monoclonal antibody (mAb) 3BD10. Recent evidence suggests that both Graves' TSHR
autoantibodies and mAb 3BD10 recognize the A-subunit monomer. Therefore, if the
A-subunit monomer is an immunogen, Graves' sera should have antibodies to both
active and inactive A-subunits. Conversely, restriction of TSHR autoantibodies to
active A-subunits would be evidence of a role for shed A-subunit multimers, not
monomers, in the pathogenesis of Graves' disease. Therefore, we tested a panel of
Graves' sera for their relative recognition of active and inactive A-subunits.
RESULTS: Of 34 sera from unselected Graves' patients, 28 were unequivocally
positive in a clinical TSH binding inhibition assay. None of the latter sera, as
well as 8/9 sera from control individuals, recognized inactive A-subunits on
ELISA. In contrast to Graves' sera, antibodies induced in mice, not by shedding
from the TSHR holoreceptor, but by immunization with adenovirus expressing the
free human A-subunit, were directed to both the active and inactive A-subunit
forms. CONCLUSIONS: The present study supports the concept that pathogenic TSHR
autoantibody affinity maturation in Graves' disease is driven by A-subunit
multimers, not monomers.