Similarity and divergence in the development and expression of the mouse and human antibody repertoires

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Abstract

Over the past twenty years diverse groups in Northeast Asia, Western Europe, and North America have competed to map, sequence, and characterize the immunoglobulin loci of mouse and man. Now that this work is near completion, it has become evident that the human and mouse germline repertoires share broad similarities in gene composition, organization, and other general principles. In spite of these similarities, the repertoires expressed by adult mice and humans are distinct and differ from each other in detail. In both species the mechanisms used to create repertoire diversity appear designed to generate a random range of antigen binding sites. However, a detailed analysis reveals significant constraints in the sequence and amino acid composition of the third complementarity region of the H chain (CDR-H3), which lies at the center of the antigen binding site. The mechanisms used to regulate the composition of the repertoire, their significance to the development and maintenance of immune competence, and the contribution of violation of normal repertoire boundaries to the development of diseases of immune function remain foci of ongoing investigation.

Introduction

The ability of the adaptive immune system to recognize and neutralize novel antigens rests on the ability of lymphocytes to create highly diversified antigen receptor repertoires [1], [2], [3], [4], [5]. The B cell antigen receptor, immunoglobulin or Ig, is a heterodimeric protein composed of two heavy (H) and two light (L) chains. In mouse and human, the Ig H chain and the two types of Ig L chains, κ and λ, are each encoded by multigene families. Each H and L chain can be divided into a constant (C) domain that defines effector function and a variable (V) domain that determines antigen specificity or affinity [reviewed in [6], [7]]. The C domains are germline encoded, whereas V domains are created by means of a complex series of gene rearrangement events that occur de novo in developing B cells [1], [6], [8], [9], [10], [11].

Section snippets

The immunoglobulin gene loci

The IgH, Igκ, and Iλ loci are located on separate chromosomes. Homologous mouse and human loci share a certain similarity in their general organization, but significant differences in detail that have occurred over 70 million years of evolution have major effects on the composition of the final expressed repertoire.

The human κ locus, on chromosome 2p11.2, contains approximately 76 gene segments [12]. This locus, as well as the λ and H chain loci, is still evolving; and the detritus of evolution

V domain structure

Each newly formed V domain contains four intervals of relatively constant sequence (termed frameworks or FRs) that are separated from each other by three hypervariable intervals (termed complementarity determining regions or CDRs) (Fig. 5). The FRs encode the anti-parallel strands that make up the core β-barrel structure of the V domain, as well as the loops that are proximal to the C domain. Together the FR2s, which are V encoded, and FR4s, which are J encoded, of the H and L chains create the

B cell development

B cell differentiation follows a similar pathway in mouse and human. Progression along this pathway is most often depicted as a linear process that is defined by the regulated assembly of immunoglobulin (Fig. 6). Assembly begins in the H chain locus [27], [28]. The initiation of DH→JH joining defines the pro-B cell. In-frame VH→DJ rearrangement allows production of cytoplasmic μ chain, defining the early pre-B cell. The successful association of μ with ψLC correlates with the downregulation of

The ontogeny of B cell development

Humans take approximately 38 weeks for complete gestation, and pre-B cells can first be detected at 7–8th week of gestation in the embryonic liver. Immature B cells can be observed approximately one week later [11], [33]. From the 9th through the 12th week of gestation, immature B cells form the majority of the B cells in the lymphoid organs. After the 13th week of gestation, the majority of the B cells express both IgM and IgD on their cell surface [11], and plasma cells can be detected as

Controlled diversification of the antibody repertoire and of the adaptive immune response

Although B cells and plasma cells can be detected at a fairly early stage in fetal development, the ability to respond to specific antigens is restricted at the earliest stages of life, and is subsequently acquired in a controlled, stepwise fashion [37], [38], [39], [40]. The programmed acquisition of antigen specificities appears to be a fundamental property of the developing immune system in jawed vertabrates, with multiple species, including mouse and human, following similar, albeit not

Regulation of CDR-H3 diversity

The germline complexity of the DH and JH loci is significantly greater in human than mouse, and this complexity is further enhanced by detailed regulation of the mechanisms of antibody diversification [66]. Unlike mouse, the patterns of DH and JH utilization in human differ as a function of developmental age (Fig. 7). D7–27 (DQ52) contributes to the majority of first trimester transcripts and remains at high frequency in second trimester transcripts, but represents only a small fraction in

Constraints on the hydrophobicity of CDR-H3

Although the mechanisms used to generate CDR-H3 appear designed to create diversity at random, comparative studies of immunoglobulins from all jawed vertebrates have shown that the amino acid composition of this interval is highly biased [73], [74], [75]. Tyrosine, is ten-fold over-represented in CDR-H3 repertoires when compared to protein sequence in general, and tyrosine and glycine typically provide 40–50% of the amino acids in CDR-H3 [69]. This bias yields an CDR-H3 repertoire enriched for

Shared general principles, but divergent expressed repertoires

The extensive similarities between mouse and human in the sequence of individual V, D and J gene segments coupled with the similarities in the overall amino acid composition of CDR-H3 raised the question of whether the antibody repertoire in mice might represent a subset of that observed in human [69]. This question was especially addressed to that segment of the human H chain repertoire that shares CDR-H3 length distribution with mouse. A related question was whether the narrow length

Summary

Although at first glance the antibody repertoire appears to be the random product of gene rearrangement, closer inspection reveals evidence of a process of regulated diversification; with major differences between fetus and adult. Human and mouse fetal sequences share some striking similarities as well as significant differences in both the regulation of the process and in the composition of their fetal antibody repertoires. With increasing age the mouse and human repertoires increasingly

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