HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dörner, T. Articles by Lipsky, P. E. Search for Related Content PubMed PubMed Citation Articles by Dörner, T. Articles by Lipsky, P. E.

Delineation of Selective Influences Shaping the Mutated Expressed Human Ig Heavy Chain Repertoire¹

Department of Internal Medicine and Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75235

After Ag exposure, somatic hypermutation and subsequent selection play significant roles in shaping the peripheral B cell repertoire. However, the disparate impact of each process has not been completely delineated. To address this, the mutational patterns of a large panel of productive V_HDJ_H rearrangements of individual human B cells were analyzed and compared with those of a previously reported panel of nonproductive V_HDJ_H rearrangements. The productive V_H rearrangements exhibited a significantly lower mutational frequency and a significantly smaller number of replacement mutations than the nonproductively rearranged genes, suggesting that structural constraints of the Ig molecule and selective influences both impacted the repertoire, militating against replacement mutations. Positive selection favored a mean of four to six replacements in complementarity-determining region 1 (CDR1) and CDR2, and less than two replacements in the framework regions (FRs). In contrast, the negative impact of replacement mutations generated an increased number of silent mutations within both the CDRs and FRs of the productive repertoire accompanied by a net increase in the ratio of replacement to silent mutations in the CDRs compared with that in the FRs. Moreover, there was a negative influence on the distribution of amino acid changes resulting from mutations of highly mutable codons, such as AGY, TAY, GTA, and GCT, preferentially leading to conservative changes in the expressed Ig repertoire. The results are consistent with the conclusion that the expressed repertoire is limited, compared with the potential generated by the mutational machinery, by the dual requirements of avoiding autoreactivity and satisfying structural constraints of an intact Ig molecule.

This article has been cited by other articles:

				N. S. Longo, P. L. Lugar, S. Yavuz, W. Zhang, P. H. L. Krijger, D. E. Russ, D. D. Jima, S. S. Dave, A. C. Grammer, and P. E. Lipsky Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting Blood, April 16, 2009; 113(16): 3706 - 3715. [Abstract] [Full Text] [PDF]

				H. Tian, A. Groner, M. Boes, and L.-a. Pirofski Pneumococcal Capsular Polysaccharide Vaccine-Mediated Protection against Serotype 3 Streptococcus pneumoniae in Immunodeficient Mice Infect. Immun., April 1, 2007; 75(4): 1643 - 1650. [Abstract] [Full Text] [PDF]

				J. J. Bleesing, M. M. Souto-Carneiro, W. J. Savage, M. R. Brown, C. Martinez, S. Yavuz, S. Brenner, R. M. Siegel, M. E. Horwitz, P. E. Lipsky, et al. Patients with Chronic Granulomatous Disease Have a Reduced Peripheral Blood Memory B Cell Compartment. J. Immunol., June 1, 2006; 176(11): 7096 - 7103. [Abstract] [Full Text] [PDF]

				C. L. Morvan, E. Pinaud, C. Decourt, A. Cuvillier, and M. Cogne The immunoglobulin heavy-chain locus hs3b and hs4 3' enhancers are dispensable for VDJ assembly and somatic hypermutation Blood, August 15, 2003; 102(4): 1421 - 1427. [Abstract] [Full Text] [PDF]

				G. S. Shapiro, K. Aviszus, J. Murphy, and L. J. Wysocki Evolution of Ig DNA Sequence to Target Specific Base Positions Within Codons for Somatic Hypermutation J. Immunol., March 1, 2002; 168(5): 2302 - 2306. [Abstract] [Full Text] [PDF]

				R. Marasca, P. Vaccari, M. Luppi, P. Zucchini, I. Castelli, P. Barozzi, A. Cuoghi, and G. Torelli Immunoglobulin Gene Mutations and Frequent Use of VH1-69 and VH4-34 Segments in Hepatitis C Virus-Positive and Hepatitis C Virus-Negative Nodal Marginal Zone B-Cell Lymphoma Am. J. Pathol., July 1, 2001; 159(1): 253 - 261. [Abstract] [Full Text] [PDF]

				M. Dono, S. Zupo, N. Leanza, G. Melioli, M. Fogli, A. Melagrana, N. Chiorazzi, and M. Ferrarini Heterogeneity of Tonsillar Subepithelial B Lymphocytes, the Splenic Marginal Zone Equivalents J. Immunol., June 1, 2000; 164(11): 5596 - 5604. [Abstract] [Full Text] [PDF]

				M. Oprea and T. B. Kepler Genetic Plasticity of V Genes Under Somatic Hypermutation: Statistical Analyses Using a New Resampling-Based Methodology Genome Res., December 1, 1999; 9(12): 1294 - 1304. [Abstract] [Full Text]

				A. R. Thompsett, D. W. Ellison, F. K. Stevenson, and D. Zhu VH Gene Sequences From Primary Central Nervous System Lymphomas Indicate Derivation From Highly Mutated Germinal Center B Cells With Ongoing Mutational Activity Blood, September 1, 1999; 94(5): 1738 - 1746. [Abstract] [Full Text] [PDF]

				S. S. Sahota, R. Garand, R. Mahroof, A. Smith, N. Juge-Morineau, F. K. Stevenson, and R. Bataille VH Gene Analysis of IgM-Secreting Myeloma Indicates an Origin From a Memory Cell Undergoing Isotype Switch Events Blood, August 1, 1999; 94(3): 1070 - 1076. [Abstract] [Full Text] [PDF]