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J. Biol. Chem., Vol. 282, Issue 18, 13917-13927, May 4, 2007

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The Immunoglobulin Heavy Chain Constant Region Affects Kinetic and Thermodynamic Parameters of Antibody Variable Region Interactions with Antigen^*

Marcela Torres, Narcis Fernández-Fuentes, András Fiser, and Arturo Casadevall¹

From the Departments of Microbiology & Immunology and Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461

A central dogma in immunology is that antibody specificity is a function of the variable (V) region. However serological analysis of IgG₁, IgG_2a, and IgG_2b switch variants of murine monoclonal antibody (mAb) 3E5 IgG₃ with identical V domains revealed apparent specificity differences for Cryptococcus neoformans glucuronoxylomannan (GXM). Kinetic and thermodynamic binding properties of mAbs 3E5 to a 12-mer peptide mimetic of GXM revealed differences in the affinity of these mAbs for a monovalent ligand, a result that implied that the constant (C) region affects the secondary structure of the antigen binding site, thus accounting for variations in specificity. Structural models of mAbs 3E5 suggested that isotype-related differences in binding resulted from amino acid sequence polymorphisms in the C region. This study implies that isotype switching is another mechanism for generating diversity in antigen binding and that isotype restriction of certain antibody responses may reflect structural constraints imposed by C region on V region binding. Furthermore, isotype affected the polyreactivity of V region identical antibodies, implying a role for C region in determining self-reactivity.

Received for publication, January 23, 2007 , and in revised form, March 2, 2007.

^* This work was supported by Grants AI33774, AI33142, and HL59842 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1S-3S and Tables 1S and 2S.

¹ To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Forchheimer Bldg., Rm. 411, Bronx, NY 10461. Tel.: 7180-430-2811; Fax: 7180-430-8701; E-mail: casadeva{at}aecom.yu.edu.

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