Molecular bases of genetic diversity and evolution of the immunoglobulin heavy chain variable region (IGHV) gene locus in leporids

Abstract

The rabbit has long been a model for studies of the immune system. Work using rabbits contributed both to the battle against infectious diseases such as rabies and syphilis, and to our knowledge of antibodies' structure, function, and regulated expression. With the description of rabbit Ig allotypes, the discovery of different gene segments encoding immunoglobulins became possible. This challenged the “one gene-one protein” dogma. The observation that rabbit allotypic specificities of the variable regions were present on IgM and IgG molecules also led to the hypothesis of Ig class switching. Rabbit allotypes contributed to the documentation of phenomena such as allelic exclusion and imbalance in production of allelic gene products. During the last 30 years, the rabbit Ig allotypes revealed a number of unique features, setting them apart from mice, humans and other mammals. Here, we review the most relevant findings concerning the rabbit IGHV. Among these are the preferential usage of one VH gene in VDJ rearrangements, the existence of trans-species polymorphism in the IGHV locus revealed by serology and confirmed by sequencing IGHV genes in Lepus, the unusually large genetic distances between allelic lineages and the fact that the antibody repertoire is diversified in this species only after birth. The Whole Genome Sequence of rabbit, plus re-sequencing of additional strains and related genera, will allow further evolutionary investigations of antibody variation. Continued research will help define the roles that genetic, allelic and population diversity at antibody loci may play in host-parasite interactions.

Multi-parameter exploration of HIV-1 virus-like particles as neutralizing antibody immunogens in guinea pigs, rabbits and macaques

“…S6A). Rabbits may be preferable as small animal models (Pan et al, 2013; Pinheiro et al, 2011) because they lack this serum background problem and also react better with conserved targets that may ultimately be important for the development of nAbs of any breadth. However, it is important to point out that the VH family diversity in both rabbits and guinea pigs is quite limited compared to primates and that their antibody diversity is generated principally by gene conversion, contrasting with the largely combinatorial origins of IgG diversity in primates (somatic hypermutation is also used in all cases).…”

“…Their sophisticated features, however, raise questions about whether model species used for vaccine testing have sufficient germline immunoglobulin repertoire complexity to develop similar nAbs (Pinheiro et al, 2011). This uncertainty calls for the continued testing of nAb vaccine candidates in multiple animal models.…”

The non-pathogenic Australian rabbit calicivirus RCV-A1 provides temporal and partial cross protection to lethal Rabbit Haemorrhagic Disease Virus infection which is not dependent on antibody titres

“…In addition, another study shows that adoptive transfer of polyclonal RHDV-positive serum can prevent lethal RHD in susceptible adult rabbits [49]. Future studies are clearly warranted shedding more light into the respective parts that cellular immunity, antibodies, but also immunogenetics [50] play in the protection and cross protection from lethal RHDV infection.…”

Hematopoiesis in the equine fetal liver suggests immune preparedness

“…Species with limited combinatorial diversity including swine (Butler et al 2006; Butler et al 2011), sheep (Reynaud et al 1995), cattle (Kaushik et al 2009; Koti et al 2010; Saini and Kaushik 2002; Verma and Aitken 2012) depend more on junctional diversity and post-recombination processes such as somatic hypermutation. Chickens utilize somatic gene conversion (Reynaud et al 1989), while rabbits use both somatic hypermutation and gene conversion to diversify their Ig repertoires (Becker and Knight 1990; Pinheiro et al 2011). …”