Comparative studies of rat IgG to further delineate the Fc:FcRn interaction site.
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 activity of rat IgG (rIgG) isotypes in FcRn-mediated functions has been analyzed. The serum half-life and maternofetal transfer in mice decreased in the order rIgG2a > rIgG1 > rIgG2c > rIgG2b. This decrease in activity correlates well with reduced binding affinity for soluble mouse FcRn, and site-directed mutagenesis of a recombinant Fc-hinge fragment has been used to investigate the molecular basis for the differences in activities of the rIgG. Analysis of the serum half-lives of the mutated Fc-hinge fragments demonstrated that, in addition to Ile253, His310, His435 and His436 that were identified in earlier studies, amino acids at positions 257, 307 and 309 play a role in building the FcRn interaction site of IgG. The study also excludes the involvement of amino 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 rIgG most likely account for the reduced affinity of rIgG2b and IgG2c relative to rIgG1 and rIgG2a for binding to FcRn.
Department of Microbiology and Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas 75235-8576, USA.
C
C
Medesan
P
P
Cianga
M
M
Mummert
D
D
Stanescu
V
V
Ghetie
E S
ES
Ward
D000818:Animals; D005260:Female; D006207:Half-Life; D007074:Immunoglobulin G / Q000378:metabolism*; D007132:Immunoglobulin Isotypes / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D051379:Mice; D011247:Pregnancy; D051381:Rats; D011961:Receptors, Fc / Q000378:metabolism*
D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D011961:Receptors, Fc