C. Medesan et al., COMPARATIVE-STUDIES OF RAT IGG TO FURTHER DELINEATE THE FC-FCRN INTERACTION SITE, European Journal of Immunology, 28(7), 1998, pp. 2092-2100
Recent data have indicated that the MHC class I-related receptor, FcRn
, regulates the half-lives of serum IgG in addition to its known role
in transferring IgG from mother to young. In the current study, the ac
tivity of rat IgG (rIgG) isotypes in FcRn-mediated functions has been
analyzed. The serum half-life and maternofetal transfer in mice decrea
sed in the order rIgG2a > rIgG1 > rIgG2c > rIgG2b. This decrease in ac
tivity correlates well with reduced binding affinity for soluble mouse
FcRn, and site-directed mutagenesis of a recombinant Fc-hinge fragmen
t has been used to investigate the molecular basis for the differences
in activities of the rIgG. Analysis of the serum half-lives of the mu
tated Fc-hinge fragments demonstrated that, in addition to Ile253, His
310, His435 and His436 that were identified in earlier studies, amino
acids at positions 257, 307 and 309 play a role in building the FcRn i
nteraction site of IgG. The study also excludes the involvement of ami
no acids in a fourth loop located at the CH2-CH3 domain interface that
encompasses residues 386-387 in FcRn binding. Sequence differences at
positions 257, 307 and 309 between rlgG most likely account for the r
educed affinity of rIgG2b and IgG2c relative to rIgG1 and rIgG2a for b
inding to FcRn.