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Review
. 2019 Oct 17;10:997.
doi: 10.3389/fgene.2019.00997. eCollection 2019.

The Camel Adaptive Immune Receptors Repertoire as a Singular Example of Structural and Functional Genomics

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Free PMC article
Review

The Camel Adaptive Immune Receptors Repertoire as a Singular Example of Structural and Functional Genomics

Salvatrice Ciccarese et al. Front Genet. .
Free PMC article

Abstract

The adaptive immune receptors repertoire is highly plastic, with its ability to produce antigen-binding molecules and select those with high affinity for their antigen. Species have developed diverse genetic and structural strategies to create their respective repertoires required for their survival in the different environments. Camelids, until now, considered as a case of evolutionary innovation because of their only heavy-chain antibodies, represent a new mammalian model particularly useful for understanding the role of diversity in the immune system function. Here, we review the structural and functional characteristics and the current status of the genomic organization of camel immunoglobulins (IG) or antibodies, α/ß and γ/δ T cell receptors (TR), and major histocompatibility complex (MHC). In camelid humoral response, in addition to the conventional antibodies, there are IG with "only-heavy-chain" (no light chain, and two identical heavy gamma chains lacking CH1 and with a VH domain designated as VHH). The unique features of these VHH offer advantages in biotechnology and for clinical applications. The TRG and TRD rearranged variable domains of Camelus dromedarius (Arabian camel) display somatic hypermutation (SHM), increasing the intrinsic structural stability in the γ/δ heterodimer and influencing the affinity maturation to a given antigen similar to immunoglobulin genes. The SHM increases the dromedary γ/δ repertoire diversity. In Camelus genus, the general structural organization of the TRB locus is similar to that of the other artiodactyl species, with a pool of TRBV genes positioned at the 5' end of three in tandem D-J-C clusters, followed by a single TRBV gene with an inverted transcriptional orientation located at the 3' end. At the difference of TRG and TRD, the diversity of the TRB variable domains is not shaped by SHM and depends from the classical combinatorial and junctional diversity. The MHC locus is located on chromosome 20 in Camelus dromedarius. Cytogenetic and comparative whole genome analyses revealed the order of the three major regions "Centromere-ClassII-ClassIII-ClassI". Unexpectedly low extent of polymorphisms and haplotypes was observed in all Old World camels despite different geographic origins.

Keywords: Camelus bactrianus; Camelus dromedarius; Camelus ferus; Immunoglobulins; Immunome; Old World camelids; T cell receptors; major histocompatibility complex.

Figures

Figure 1
Figure 1
Schematic representation of the general structure of camel conventional IgG1 and the nonconventional IgG2 and IgG3. The lack of light chain is itself a consequence of the absence of the CH1 domain in the gamma 2 and gamma 3 chains, due to a splicing defect of the CH1 exon. The figure is from IMGT: Camelidae IgG antibodies (http://www.imgt.org/IMGTbiotechnology/Camel_IgG.html#characteristics) with permission of IMGT ®, the international ImMunoGeneTics information system ® (http://www.imgt.org).
Figure 2
Figure 2
Sequence comparison of dromedary TRGV2/5R1S169, and the computed interaction between the genomic TRGV2, its mutated counterpart 5R1S169, and the genomic TRDV4 (modified from Ciccarese et al., 2014). Structural overlapping of TRGV2 (depicted in red), and 5R1S169 clone (depicted in green) with TRDV4 (depicted in blue), is shown. CDR-IMGT regions are framed with colored rectangles according to IMGT standardized colors. IMGT Collier de Perles of 5R1S169 clone is shown (Lefranc et al., 2003; Lefranc, 2011a; Lefranc, 2011b). The protein complex interface was computed by the online tool PDBePISA at the EBI server. (http://www.ebi.ac.uk/msd-srv/prot_int/) and visualized by UCSF Chimera tool (http://www.cgl.ucsf.edu/chimera/).
Figure 3
Figure 3
Schematic representation of the D-J-C clusters within the TRB locus of the different mammalian species modified from Antonacci et al., 2017a. The orthologous and paralogous TRBJ genes are depicted with the same colour as deduced by the phylogenetic analysis. The double colour TRBC3 gene indicates the homologies with the TRBC1 and TRBC2 genes as result of the unequal crossover that generated the new TRB D-J-C cluster in the artiodactyl species (Antonacci et al., 2008; Eguchi-Ogawa et al., 2009).
Figure 4
Figure 4
Phylogenetic tree of the dromedary, wild, and domestic Bactrian camel, human, dog, sheep, and pig TRBV gene sequences. The sequences of the human, dog, sheep, and pig TRBV genes were retrieved from the IMGT database (http://www.imgt.org/), whereas the camel TRBV gene sequences derived from Antonacci et al., 2019. The nucleotide sequences of the V-REGION were combined by adopting two selection criteria: (1) only potential functional and in-frame pseudogenes (excepted for human TRBV1) were included; and (2) only one gene for each of the subgroups was selected for each species. The evolutionary analysis was conducted in MEGA7 (Kumar et al., 2016). The evolutionary history was inferred by using the Maximum Likelihood method based on the Tamura-Nei model (Tamura and Nei, 1993). The tree is drawn to scale, with branch lengths measured in the number of substitutions per site. The analysis involved 181 nucleotide sequences. Codon positions included were 1st+2nd+3rd+Noncoding. All positions containing gaps and missing data were eliminated. The different colours highlight the distribution of the phylogenetic groups corresponding to the 26 camel TRBV subgroups. The gene functionality according to IMGT rules (F, functional; ORF, open reading frame; P, pseudogene) is indicated; nd indicates that the nucleotide sequence of the gene is incomplete and its functionality cannot be defined. The IMGT 6-letter for species (Homsap, Susscr, Oviari, Camdro, Camfer, and Cambac) and 9-letter for subspecies (Canlupfam) standardized abbreviation for taxon is used.
Figure 5
Figure 5
Schematic map of the overall organization of the major histocompatibility complex in Old World camelids, modified from Plasil et al. (2016, 2019).

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