ReviewThe human antibody repertoire to infectious agents: implications for disease pathogenesis
Introduction
Throughout life, the mammalian immune system is confronted with a variety of exogenous antigens. Not only is the number of endogenous bacteria higher than that of the cells of the mammalian host, but there is also a never-ceasing introduction of exogenous infectious agents, mainly through the respiratory and gastrointestinal tracts. In addition to being more numerous than their mammalian host, infectious agents have a much shorter generation time and their genotypic diversity is higher than that of the mammal. Highly polymorphic bacteria include the exogenous organisms Streptococcus pyogenes, Borrelia species and Neisseria meningitidis, and the endogenous bacteria Escherichia coli and Helicopter pylori (Spratt and Maiden, 1999); and the HIV and influenza virus are notorious for their high variability (Hahn et al., 1986). Despite these common encounters, the immune system efficiently copes with this microbial diversity and only a fraction of colonized hosts will generally develop infection and disease. The first arm to be deployed in the defense is the innate immune system, capable of rapidly identifying infectious agents. This engagement is followed by the adaptive arm of the immune system with its humoral and cellular responses capable of, not only, responding to, but also, remembering the exogenous encounters. Antibodies are at the front-line of these defense mechanisms against pathogens. By virtue of their potential to recognize essentially all possible antigens with high specificity and affinity, they act in concert with cellular immunity to control infectious diseases. However, little is known about the mechanisms that govern the selection of the genes encoding human antibodies to infectious agents and several questions await elucidation. Do different B cell clonotypes with different phenotypes and functions specify distinct subsets of the repertoire that are involved in the various effector arms of the immune system? How is the preimmune repertoire shaped to generate a molecular template upon which somatic diversification operates? What is the precise genetic composition of the B cell repertoire involved in generation of neutralizing and enhancing antibodies? Recently, the complete structure of the human immunoglobulin (Ig) loci has now been elucidated (Corbett et al., 1997, Matsuda et al., 1998, Zachau, 1993) and the molecular characteristics of human monoclonal antibodies to a series of infectious agents have been reported. This novel knowledge provides insight into the mechanisms that shape the human antibody repertoire and has implications with regard to engagement of the humoral arm of the immune system and to designing vaccination strategies. The aim of this article is to provide a brief survey of recently recognized concepts and to discuss them in a critical perspective.
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Human antibody gene diversification
In order to appreciate the reasoning that lies behind the antibody selection processes that operate during exposure of the immune system to infectious agents, it is necessary to first review briefly the molecular events that take place throughout human B cell development. Several mechanisms operate during differentiation of B lymphocytes to create sufficient diversity for recognition of the huge number of different antigenic specificities. A functional human Ig molecule is encoded by genes that
Novel antibody-mediated protection mechanisms
The outcome of the interactions between the immune system and pathogens is influenced by factors linked to the invader, such as cytopathogenicity, kinetics, and cell and tissue tropism, and by the efficacy of the immune defense engaged, including innate (complement, neutrophils, macrophages) and adaptive immunity (T and B lymphocytes). Antibodies recognize linear and conformational epitopes on proteins, carbohydrates and other pathogen-derived antigens and the specificity is determined by the
Innate and acquired protective antibodies
The first isotype to be expressed during infection is IgM that acts as an early defense mechanism against mucosal and systemic pathogens. Interestingly, two types of IgM co-exist in the humoral repertoire. The first, called natural IgM, is secreted by B-1 lymphocytes, exists prior to antigen stimulation and is generally polyreactive with both self and exogenous antigens (Zouali, 2002b), suggesting that it may contribute to innate immune responses. More recently, it was demonstrated that natural
Pathogen polymorphism and immune diversity
It has long been recognized that pathogens are living entities, but it was initially thought that they are monomorphic. Even Robert Koch was convinced that each disease was caused by a single invariant microbial species. However, it has become clear that infectious agents inexorably evolve and change and, for some of them, constantly emerging variants with modified antigen specificity, host affinity and virulence are encountered. For example, bacteria have elaborated mechanisms to mutate,
Diversity of the antibody repertoire to pathogens
Since each antibody V region displays a distinct genetic signature specified by the uniqueness of the structure of its H- and L-chain V regions, characterization of the genes encoding antibodies provides a useful approach for study of their nature and origin. Ig V genes can serve as markers in clonal analysis because unique combinations of VH, D and JH or VL and JL gene elements are formed in the primary repertoire and are generally conserved during the ontogeny of B cell clones, and the
Dominant expression of Ig variable genes to pathogens
In contrast to what is seen with other infectious agents, there is a relatively restricted antibody response to the polysaccharide (PS) of H. influenzae serotype b (Hib), an encapsulated bacterium responsible for major cases of meningitis of young children in industrialized countries. Since protection against the invasive disease caused by Hib is conferred principally by antibodies to the bacterial capsule polysaccharide, the Hib PS antibody repertoire has been studied extensively by a number
Implications of Ig gene-directed immunodominance
The exact reasons for the phenomenon of dominance of certain V genes in some antibody repertoires remain unclear, but the view that antibody V genes have been retained in the germline because of their capacity to accommodate pathogen-derived antigens and, hence, to impart a protective role against foreign invaders is of particular interest in this context. However, most antigens will not have an opportunity to exert such a strong selective pressure on the germline repertoire. It has been
Expression of Ig repertoire to pathogens throughout development
It is generally thought that the fetal repertoire provides a primary gene pool that serves as the base from which somatic diversification generates paratopes able to recognize antigenic motifs of the external environment with a high affinity. Evidence is mounting that not only the diversification of the immunoglobulin repertoire with respect to gene usage (Shiokawa et al., 1999) and CDRH3 composition (Bauer et al., 2002) but also the antibody response to some antigens is acquired in a
Ig repertoire defects and disease susceptibility
VH gene polymorphism is common in the human population (Sasso et al., 1995). The largest VH subgroup, VH3, in particular, is highly heterogeneous and several alleles have been described for some of its members. Since VH3 gene subgroup products are frequently the targets of interaction with infectious agents, one may suggest that pathogens may play an important role in maintaining or even promoting the development of Ig gene polymorphisms. As for other loci, such variability, by increasing the
Acknowledgements
MZ is supported by the Institut National de la Recherche et de la Santé Médicale (INSERM, Paris, France) and by grants from Fondation pour la Recherche Médicale (Paris), Agence Nationale de Recherches sur le SIDA (ANRS, Paris), and Ensemble Contre le SIDA (SIDACTION, Paris). MO is supported by the Crafoord Foundation and the Swedish Research Council.
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