ABSTRACT
Abstract ................................................................................................. 132 6.1 Introduction .................................................................................. 132 6.2 Step 1: Limited V-Gene Usage and Suppression of
B Lymphopoiesis in the Bone Marrow ........................................ 133 6.2.1 Arrest of B Lymphopoiesis Early in Ontogeny ................ 135 6.2.2 Mechanism of Arrest of B Lymphopoiesis ...................... 137 6.3 Step 2: Galt and The Generation of a Pre-Immune
Antibody Repertoire .................................................................... 138 6.3.1 GALT as the Site of Development of the Primary Antibody
Repertoire ......................................................................... 140 6.3.2 Requirement of Microbiota for GALT Development and
Generation of the Primary Antibody Repertoire .............. 141 6.3.3 Bacterial Molecules that Contribute to GALT
Development .................................................................... 145 6.3.4 Endogenous Molecules Required for GALT Development....147 6.4 Galt and the Maintenance of B Cells ........................................... 150 6.5 Model For Generating a Pre-Immune Antibody Repertoire ........ 151 6.6 Two-Step Mechanism for Generating a Pre-Immune
Antibody repertoire in Species other than Rabbits ...................... 152 6.7 Conclusion ................................................................................... 154 Keywords .............................................................................................. 154 References ............................................................................................. 155
ABSTRACT
Animals use different strategies to generate a preimmune antibody repertoire. In rabbits, relatively little antibody diversity is generated by combinatorial joining of V(D)J genes at the immunoglobulin heavy chain (IgH) locus due to predominant rearrangement of a single VH gene. Instead, progenitor cells produced in the bone marrow during B cell lymphopoiesis migrate to gut-associated lymphoid tissues (GALT) where they extensively proliferate and diversify their Ig genes by somatic hypermutation and gene conversion mechanisms in response to stimulation by the intestinal microbiota. Recent studies have identified bacterial molecules that contribute to, as well as endogenous molecules required for B cell proliferation and somatic diversification of Ig genes in GALT. In addition to generating a preimmune antibody repertoire in the presence of limited VH gene usage during B cell development, rabbits are presented with an additional challenge of maintaining B cell populations throughout life, as B lymphopoiesis arrests in adult rabbits. Increasing evidence suggests that GALT also plays a key role in maintaining peripheral B cell populations in the absence of ongoing lymphopoiesis. In this chapter, we provide a detailed description of the key experiments and data demonstrating that antibody diversity in rabbits is generated by a two-step mechanism.
