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The bovine antibody repertoire
Developmental and Comparative Immunology 30 (2006) 175–186 www.elsevier.com/locate/devcompimm
The bovine antibody repertoire Yaofeng Zhaoa, Stephen M. Jacksonb, Robert Aitkenc,* a
Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska University Hospital at Huddinge, SE-14186 Stockholm, Sweden b Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City OK73104-5046, USA c Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom Available online 12 July 2005
Summary Cattle are able to produce a full range of Ig classes including the long-elusive IgD through rearrangement of their germline genes. Several IgL groupings have been reported but as in several other livestock species (e.g. sheep, rabbits, chickens), rearrangement per se fails to generate significant IgH diversity. This is largely because of the modest number of bovine VH segments that participate in rearrangement and their conserved sequences. Perhaps in compensation, bovine Ig heavy chains carry CDR3 sequences of exceptional length. Processes that operate post-rearrangement to generate diversity remain ill defined as are the location, timing and triggers to these events. Reagents are needed to understand better the maturation of B lymphocytes, their responses to antigens and cytokines, and to provide standards for the quantitation of Ig responses in cattle; recombinant methods may help meet this need as Ab engineering technologies become more widely used. q 2005 Elsevier Ltd. All rights reserved.
1. Introduction When compared with human or murine immunology, present understanding of the processes that shape the bovine Ab repertoire can best be described as patchy: in some areas, detailed information has been gathered but it is still the case that many fundamental aspects remain obscure or ill-defined.
Abbreviations Ab, Antibody; AID, Activation induced cytosine deaminase; CDR, Complementarity-determining region; FR, Framework region; H, Heavy (chain); Ig, Immunoglobulin; IgHC, Immunoglobulin heavy chain constant region; IPP, Ileal Peyer’s patches; L, Light (chain); RSS, Recombination signal sequence; SCID, Severe combined immunodeficiency. * Corresponding author. Tel.: C44 141 330 6659; fax: C44 141 330 4600. E-mail address: [email protected] (R. Aitken). 0145-305X/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.dci.2005.06.012
As will likely become apparent to the reader, the Igs of cattle and sheep are very similar at the molecular level. This has led to speculation that the processes that generate and diversify the humoral repertoires of these animals may share common features. Comparisons of this sort need to be made with some caution because incomplete as present understanding of the bovine antibody repertoire may be, several prominent features are peculiar to cattle. Perhaps most obvious is the tendency for cattle IgH chains to carry CDR3s of exceptional length, a property that is shared with camelids but not with sheep. Inevitably, this review makes periodic reference to studies in sheep when equivalent data is unavailable for cattle; these are subject to the caveat that the superficial resemblance between the immune systems of cattle and other commonly farmed ruminants may disguise fundamental differences.
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2. The germline repertoire 2.1. The bovine heavy chain system 2.1.1. Constant region genes With the recent identification and characterisation of the bovine Cd gene [1], it has become apparent that all the Ab classes found in humans and mice—IgM, IgD, IgG, IgE and IgA—are also present in cows [2–8] (Table 1). The Ig H chain constant region (IgHC) genes have been located on chromosome 21q23-q24 [9,10]. Detailed physical mapping by analysis of BAC clones and long distance-PCR [11] has shown the IgHC genes to be arranged in a contig spanning approximately 150 kb with spacings ranging from 5 kb (m to d) to 34 kb (g1–g2) (Fig. 1). Based on a survey of the bovine EST database at GenBank, it was concluded that the seven functional bovine IgHC genes are expressed at different levels, with transcription of the d, g3 and 3 genes occurring at levels much lower than the others [11]. Whilst the functional bovine IgHC genes have been mapped to chromosome 21q23-q24, a bovine m-like sequence, IGHML1, has
been located on chromosome 11q23 [10,12]. Part of IGHML1 has been recovered from a chromosome 11specific library and sequenced [114]. This has revealed some differences with the IGHC m gene present on chromosome 21. Until recently, it had been thought that cows lacked an IgHC d gene [1,13]. The bovine d gene possesses an exon encoding a CH1 domain that is 96.6% identical to the m CH1 sequence. This is strikingly different to the d gene in human and rodents, and suggests a duplication event occurred during evolution of the bovine IgHC locus. The bovine d gene also possesses a short switch region that is absent in humans and rodents. This makes possible the expression of bovine IgD through genomic rearrangement, directed by the Sm and Sd regions. A further characteristic of bovine IgD is the possibility to express a splice variant lacking the CH2 domain [1]. In this respect, the molecule would resemble at a superficial level IgD from rodent, though it should be noted that in mice and rats, this arises from deletion of the dCH2 exon from the IgHC locus during the course of rodent evolution [14–16].
Table 1 Nomenclature and characteristic features of bovine immunoglobulin heavy chain and light chain constant region genes Ig
Current designation
Symbol
Gene
Gene number
Chromosome location
GenBank accession number
Major features and other information
IgG1
IgG1a IgG1b IgG2a
g1a g1b g2a
IGHG1 IGHG1 IGHG2
1
21q23-q24
1
21q23-q24
!16701 S82409 AAB22784
IgG2b IgG3a
g2b g3a
IGHG2 IGHG3
1
21q23-q24
S82407 U63638
Hinge, Arg218; Thr226 Hinge, Thr218; Pro224; Pro226 CH3; intadomain loop hepatappetide; Arg419 Middle hinge, CH3, Glu419 37 amino acid hinge
IgG3b
g3b
IGHG3
IgA
IgA
a
IGHA
1
21q23-q24
AF109167
IgM IgE
IgM IgE
m 3
IGHM IGHE
1 1
21q23-q24 21q23-q24
AY230207 U63640
IgD
IgD
d
IGHD
1
21q23-q24
AF515672 & AF411240
Light chain
Igl Igk
l k
IGLC IGKC
R4 ?
17 ?
!62917 ?
IgG2a (A1) IgG2a (A2) IgG2b/ IgG3
U63639
6 amino acid substitutions; 84 bp, INV3 insert Pst I RFLP generates polynucleotides of 6.0 and 6.3 kb suggestive of sequence of alleles Pst I, EcoR I and BamH I RFLPs show polymorphism suggestive of sequence alleles mCH1 like dCH1 due to mu gene dubplication; Transcribed through class switch recombination directed by the Sd One Cl gene is preferentially used
Y. Zhao et al. / Developmental and Comparative Immunology 30 (2006) 175–186 20 kb µ δ
γ3
γ1
γ2
ε
α
Fig. 1. Organisation of constant region genes at the bovine heavy chain locus. The bar indicates a distance of approximately 20 kb. Data adapted from [11].
The only genes present in multiple copies at the bovine IgHC locus are the g genes. It had been suggested that four g genes might be present in the bovine genome [2,5] but recent studies have shown that only three exist between the d and 3 genes, encoding the IgG1, IgG2 and IgG3, respectively [11]. The fourth g gene proposed by others is most probably a polymorphic allele of g1, g2 or g3. Allotypic variants of g2 have been noted [17] that appear to be able to activate complement to different degrees [18], properties that may impact upon the ability of homozygotic animals to resist bacterial infection [19]. In heterozygotes, co-expression of the allotypes of IgG2 can be observed with some evidence of age-dependent regulation [19]. 2.1.2. The JH locus The bovine Ig JH locus has been located approximately 7 kb upstream of the bovine m gene [1] and found to comprise six JH genes in a stretch of DNA of approximately 1.8 kb (Fig. 2). Two segments, JH1 and JH2, were shown to be potentially functional although there was a strong preference for expression of the former. This is reflected in the frequency with which a single FR4 sequence can be observed in IgH chain cDNA [20–22]. The JH1 and JH2, encoding 15 and 17 amino acids respectively, share a five amino acid VTVSS motif at their 3 0 ends that is very common in mammalian JH genes. In addition to the two functional JH genes, there are also four JH pseudogenes that were identified without either the right RSS or splice site (Fig. 2; Table 2). Studies of bovine Ig H chain cDNA have revealed that a second JH segment can undergo rearrangement at low frequency [22]. This can be distinguished from the coding sequence of the JH1 segment by the substitution of the two R codons for Q and L. The segment has been located to what appears to be a duplicated copy of the JH locus [114] (GenBank
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accession number AY149283). Six JH segments have been identified at this locus; only the fourth and the sixth appeared functional, rearrangement of the sixth creating the alternative sequence noted in cDNA studies [22]. This duplicated JH locus has been mapped to chromosome 11 and is probably contiguous with IGML1. Superficially, the organisation and rearrangement of the bovine JH locus resembles that of the sheep and marked similarities of sequence can be detected. However, the ovine JH1 segment that undergoes frequent rearrangement and the less commonly selected JH2 segment reside at the same locus as is typical of the mammalian Ig system [23]. It thus seems likely that along with the g3 gene [11], this distinctive feature of the bovine Ab system has emerged during the c. 20 million years since cattle and sheep diverged into separate species [24]. 2.1.3. The D locus Partial characterisation of the bovine D locus has been described recently, revealing three D genes in a 2.3 kb DNA region [25]. It is not presently known how far they are located from the bovine JH locus. The sizes of the segments are 42 bp (14 possible codons), 58 bp (19 possible codons) and 148 bp (49 possible codons) respectively (Fig. 3). This finding is consistent with the unusual length of a bovine DQ52 segment located on the upstream flank of both JH loci (Hosseini et al., unpublished data; GenBank accession AY149283). It has been consistently reported that bovine IgH chains possess unusually long CDR3 sequences [20–22,26,27]. This property might thus arise from direct rearrangement of D genes from the germline, although it is still possible that D–D fusion may contribute to the generation of long CDR3s. Although considered extremely unusual in human immunology [28], this process has been observed in chickens [29]. 2.1.4. VH genes. The bovine VH locus has been little studied so the approximate size of the locus and the number of segments present is not known. Also it is not clear if the bovine VH genes are confined to chromosome 21q23-24, upstream from the constant region cluster, or whether as in humans, VH orphons are located elsewhere in the genome [30].
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Fig. 2. Sequence of the bovine JH locus on chromosome 21. Recombination signal sequences are indicated in upper case and underlined for each segment. The coding sequence for each segment is indicated in bold, upper case with the predicted reading frame translated below. Data adapted from [11].
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Table 2 Recombination signal sequences and functionality of the splice sites for segments for segments at the bovine JH locus on chromosome 21. Data adapted from [11] J segment
Nonamer
Spacer
Heptamer
JH-PS1
GGTTTCCGT
21 bp
CACTGTG
No
JH-PS2 JH-PS3 JH-PS4 JH1 JH2
TGTTTTTGT GGTTCATGT GAGCTCTTG GGTTTTTGC GGTTTTTGT
22 bp 23 bp 22 bp 23 bp 22 bp
AGCCATG CCCTCAG CACCGTG CACTGTG CACTGTG
No Yes No Yes Yes
From studies of bovine Ig cDNA sequences, many publications have concluded that a single VH gene family undergoes rearrangement and expression. This gene family is homologous to the murine VH Q-52 and related human families [20–22]. The bovine VH family was designated as BoVH1, and is thought to consist of no more than 20 VH segments [20,31]. Additional data from Southern blotting has indicated that segments from at least three other gene families may be present in the bovine genome [22,31] (Table 3). It is not known whether these segments are able to undergo rearrangement and why they appear to be excluded from the expressed H chain repertoire.
Functional 5 0 splice site
2.2. The bovine light chain system The bovine L chain repertoire is dominated by lambda chains [32], and their encoding genes have been assigned to bovine chromosome 17 [33] (Table 1). There are probably more than four Cl genes in the bovine lambda locus, although it appears that one is preferentially utilized [34]. It has been suggested that cattle also express kappa light chains at a low level [35,36] but very little is known about this L chain locus. Based on sequence similarity, the bovine lambda L chain variable sequences are divided into Vl1, Vl2, Vl3 [37,38], the Vl1 group being further divisible
Fig. 3. Sequence of three bovine D segments. Recombination signal sequences are indicated in upper case and underlined for each segment. The coding sequence for each segment is indicated in upper case and separated from the recombination signal sequences by a space for better clarity. Data adapted from [25].
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Table 3 Nomenclature of bovine immunoglobulin heavy chain and light chain variable region genes Gene
Gene family
VH
BoVH1 BoVH2? Vl1 Vl2 Vl3 ?
Vl
Vk
Subgroup
? Vl1x (Vl1a, Vl1b, Vl1c), Vl1d, Vl1e
?
into subgroups according to characteristic sequences in the FRs and the length of CDR1 (Table 3). It has been suggested that H chains carryinging CDR3 sequences of exceptional length are preferentially paired with lambda chains from one of the Vl1 subgroups [39].
3. Antibody composition of serum and secretions Reagents for the detection of bovine IgM, IgG1, IgG2 and IgA are available from commercial distributors such as Serotoc, VMRD and Bethyl Labs. Individual investigators have generated reagents that permit the discrimination of the allotypes of IgG2 [18,40] and the detection of bovine IgE [41]. Some organisations (e.g. Bethyl Labs) are able to supply purified Ig to allow quantitation of these classes in test materials through a simple capture ELISA. These assays can determine the composition of serum, colostrum, milk or other fluids. Under normal circumstances, the serum contains undetectable levels of IgE and IgA may be present at hundreds of micrograms per ml [42]. In contrast, IgM and IgG1 and IgG2 are typically present at mg per ml concentrations (IgM c. 3 mg per ml, IgG1 and IgG2 c. 10 mg per ml the former usually exceeding the latter), IgG1 rising to exceed 60 mg per ml in hyperimmunized animals. As the major secretory subclass, the concentration of IgG1 in colostrum can exceed 100 mg per ml and in milk it is usually present at levels up to 10 times that of the other Ig classes [42]. The quantitation of antigen-specific responses can only be achieved with complex and timeconsuming competition immunoassays. Given these constraints, it is unsurprising that antigen-specific responses are more usually measured on a relative
Gene number
Chromosome location
References
% 20 ?
21q23-q24 21q23-q24
31, 22 31, 33 38, 39
S30
17
?
?
35
basis against reference sera or pre-immune samples [41]. This situation seems likely to change as recombinant antibody technologies start to make greater impact. For example, in unpublished studies, a single-chain Ab isolated against a bacterial target by phage display has been fused to bovine IgHC sequences and expressed in transfected mammalian cells to produce an antigen-specific IgG1 construct for ELISA standardisation (Aitken et al., unpublished data). Whilst reagents such as these have an obvious value in monitoring the progress of an Ab response, they may also find a role in standardising passive therapies based upon bovine immunoglobulins [43].
4. Lymphogenesis and the pre-immune repertoire The emergence of IgMCB cells can be detected in the bovine spleen early in gestation [44]. Ig rearrangement has also been detected in the spleen and several other organ systems during foetal development using PCR [45]. In sheep, foetal splenectomy has shown that the precursor populations from which the B cell repertoire emerges can be derived from other - potentially multiple - sites of early B cell accumulation [46]. The long CDR3 sequences that characterise bovine Ab H chains have been detected in foetal lymphoid cDNA [22,27] and there is some evidence of preferential use of subgroups of light chains [39] and intra-heavy chain disulphide bridging to aid the stabilisation of these rearrangement products [26]. It thus appears that these are properties intrinsic to the bovine Ig system and do not emerge through antigen-driven processes. It is widely assumed that development of the Ab repertoire in maturing bovine B cells is heavily
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dependent upon events in the gut-associated lymphoid tissue during foetal development and in the weeks and months after birth [47]. Data in support of this model is fragmentary and largely based upon the perceived similarities between cattle and sheep. Population of the ileal Peyer’s patches (IPP) during development of the bovine foetus and the formation of follicles have been documented and shown to be oligoclonal [48,49]. Ig diversification in individual follicles has been traced back to these founder clones [45]. In sheep, entry to the IPP takes place during a relatively short window of time during gestation, a period that can be defined by injecting anti-IgM antibodies to deplete founder clones before they undergo significant expansion in the IPP [50]. Evidence has been gathered of high rates of B cell proliferation in the bovine IPP around time of birth and although levels of apoptosis are likely high [51], this appears insufficient to explain the relative stability in total cell numbers [52]. This is consistent with emigration to the periphery [53]. As the bovine Ab repertoire is founded upon a single family of VH segments of very limited diversity and frequent use of one JH segment [20–22], rearrangement per se is incapable of generating significant levels of H chain diversity. The nature of the diversification process in cattle remains ill defined. Evidence suggestive of gene conversion has been gathered from studies of the lambda L chain system [34,37] whereas other studies of the pre-immune repertoire have favoured somatic hypermutation as the diversification mechanism [22]. In the sheep, the long-held view has been that the latter drives diversification of the pre-immune repertoire in the IPP and that after birth, emigration and later involution of the organ releases diversified B cells to population the lymphoid system [54–56]. Recent work in the sheep has discovered that the number and diversity of VL segments in the germline is greater than previously supposed [57]. Ig L chain rearrangement may therefore be able to generate some of the diversity previously attributed to somatic hypermutation. Whatever the nature of the process in cattle, increasing levels of immunoglobulin diversity become detectable in peripheral lymphoid tissue with age [22,45]. This is accompanied by a rise in the endogenous synthesis of antibody from undetectable levels at birth [58] to levels in the peripheral circulation that are immunologically
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significant 1–2 weeks after birth [59] and later [60]. In other animals dependent upon gut-associated lymphoid tissue for the generation of the antibody repertoire, lymphopoiesis declines sharply post partum [61]. The same is likely to be true of cattle [62] but this has yet to be formally demonstrated. As there is limited transfer across the bovine placenta from dam to foetus, the possibilities for maternal influence over the developing antibody repertoire are limited [42]. However, maternal and environmental factors are likely to play prominent roles, post partum. The neonatal diet and its composition can affect leukocyte function at a fundamental level [63,64] but bovine colostrum also has marked immunomodulatory properties. Aside from suppression of the endogenous capacity of the neonate to respond immunologically, it has been shown that colostrum promotes the elimination of B cells expressing IgG subclasses, or at least downregulation of these markers at the cell surface [58]. The mechanism of this effect is unclear. Work particularly with the rabbit has emphasised the impact of the intestinal microflora on diversification of the neonatal antibody repertoire [65–67]. It will be interesting to see whether similar events provide the trigger for diversification of the bovine Ab repertoire in the environment of the IPP.
5. Bovine B cell responses It is self-evident that the response of bovine B cells to antigen depends upon multiple factors. It is beyond the scope of this review to detail this large area of work but influences include the characteristics of cells that initially present antigen [68–71], which B cell activation pathway is triggered [72,73], and the balance of cytokines present in the local environment [74–78]. It is notable that polarised TH1 and TH2 responses that are observed in murine responses to antigen have only been consistently seen in a number of chronic bovine infections [79]. Novel regulatory factors have been identified [80] and thus mouse models of cytokine action need to be extrapolated to bovine immunology with care. Markers for bovine B cells are emerging [81–84]. With some exceptions [85], these tend to be expressed on B cells detectable in the periphery and good
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markers for the early stages of B cell differentiation are presently lacking. One feature of bovine B cells that merits particular mention is the expression of CD5 on a subset of peripheral blood B lymphocytes [36,86,87]. The proportion of B cells expressing this marker in cattle appears higher than in laboratory animals [88]. Similar B cell populations can be observed in sheep [89]. Bovine CD5CB cells can be infected with Theileria [90] and infection with bovine leukemia virus leads to persistent lymphocytosis [91]. Trypanosome infection also increases their representation in the peripheral blood [92]. The significance of this cell population viz a viz murine CD5CB cells is uncertain [93], but their prominence and the failure of early attempts to detect IgD at the surface of bovine B cells [13] has led to speculation that many B lymphocytes in cattle–perhaps a majority–are of the B-1 lineage [13,62]. Such extreme polarisation may be unlikely but it is notable that Ig rearrangement in cattle takes place during foetal development, and that the expression of polyreactive Ig is detectable, becoming common during certain infections [26,94,95]. These properties are at least consistent with the behaviour of B-1 cells. Studies with mice also show the biased usage of VH segments in CD5CB cells [96,97], another interesting parallel with events in cattle. The observation that different activating signals impact upon the expression of CD5 [72] indicates that the CD5C phenotype is more likely an induced differentiation state than the end product of a definite B cell lineage [88]. The identification of a ligand for bovine CD5 will doubtless assist a better understanding of these processes [98].
6. Future directions Although significant gaps exist in present understanding of the bovine Ig repertoire and its development, this situation is likely to improve in the near future. In part, clarification will come from exploitation of developments in human and murine immunology. To take one topical example, the identification of AID as a crucial factor in the processes of somatic hypermutation and class switching has triggered substantial activity in the immunological community at large [99]. Since AID contributes to somatic hypermutation and gene
conversion [99,100], tracking its expression in bovine tissues offers the chance to identify the location and timing of Ig diversification in cattle without bias towards either of the competing models for the diversification mechanism. The release of the first draft of the chicken genome in the Spring of 2004 heralds a new era for research on animals of economic importance; efforts to sequence the bovine genomic will facilitate the identification of enzymes, cytokines and surface markers involved in immunity, an enterprise that has previously been reliant upon protein purification [101,102] or serological crossreaction [83,84]. In applied areas of bovine immunology, there remains a basic requirement for standards for the quantitation of Ab responses and controlling cytokines. The use of recombinant methods is starting to impact in this area [103,104] and the application of antibody engineering methods [105] offers the chance to develop reagents to measure antigen-specific responses on a quantitative basis rather than in relation to pre-immune titres. Reagents of this sort may also find applications in therapy [106]. The study of immunology in large animals has definite benefits [107] aside from the intrinsic interest and economic importance of this group of animals but there is no doubt that working with these species brings with it logistical and cost problems. This may explain why several of the key areas of Ig diversification are better understood for sheep than they are for cattle. Some investigators have explored the use of the SCID mouse into which bovine B cells can be successfully grafted [108–111]. These might provide a more experimentally amenable system for studies of lymphopoeisis but it is inevitable that at some stage, data will need to be validated against events in the natural host. There is an obvious linkage between a better understanding of the bovine B cells repertoire and disease resistance and onwards to the economics of dairy and beef production. The application of cloning technology to cattle [112] may offer the chance to manipulate enhanced levels of disease resistance into the animal. Cloning methods have already led to the generation of transgenic cattle able to express human antibodies [113]. The future thus holds many exciting challenges for those willing to join this branch of veterinary immunology.
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The bovine antibody repertoire Yaofeng Zhaoa, Stephen M. Jacksonb, Robert Aitkenc,* a
Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska University Hospital at Huddinge, SE-14186 Stockholm, Sweden b Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City OK73104-5046, USA c Division of Infection and Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom Available online 12 July 2005
Summary Cattle are able to produce a full range of Ig classes including the long-elusive IgD through rearrangement of their germline genes. Several IgL groupings have been reported but as in several other livestock species (e.g. sheep, rabbits, chickens), rearrangement per se fails to generate significant IgH diversity. This is largely because of the modest number of bovine VH segments that participate in rearrangement and their conserved sequences. Perhaps in compensation, bovine Ig heavy chains carry CDR3 sequences of exceptional length. Processes that operate post-rearrangement to generate diversity remain ill defined as are the location, timing and triggers to these events. Reagents are needed to understand better the maturation of B lymphocytes, their responses to antigens and cytokines, and to provide standards for the quantitation of Ig responses in cattle; recombinant methods may help meet this need as Ab engineering technologies become more widely used. q 2005 Elsevier Ltd. All rights reserved.
1. Introduction When compared with human or murine immunology, present understanding of the processes that shape the bovine Ab repertoire can best be described as patchy: in some areas, detailed information has been gathered but it is still the case that many fundamental aspects remain obscure or ill-defined.
Abbreviations Ab, Antibody; AID, Activation induced cytosine deaminase; CDR, Complementarity-determining region; FR, Framework region; H, Heavy (chain); Ig, Immunoglobulin; IgHC, Immunoglobulin heavy chain constant region; IPP, Ileal Peyer’s patches; L, Light (chain); RSS, Recombination signal sequence; SCID, Severe combined immunodeficiency. * Corresponding author. Tel.: C44 141 330 6659; fax: C44 141 330 4600. E-mail address: [email protected] (R. Aitken). 0145-305X/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.dci.2005.06.012
As will likely become apparent to the reader, the Igs of cattle and sheep are very similar at the molecular level. This has led to speculation that the processes that generate and diversify the humoral repertoires of these animals may share common features. Comparisons of this sort need to be made with some caution because incomplete as present understanding of the bovine antibody repertoire may be, several prominent features are peculiar to cattle. Perhaps most obvious is the tendency for cattle IgH chains to carry CDR3s of exceptional length, a property that is shared with camelids but not with sheep. Inevitably, this review makes periodic reference to studies in sheep when equivalent data is unavailable for cattle; these are subject to the caveat that the superficial resemblance between the immune systems of cattle and other commonly farmed ruminants may disguise fundamental differences.
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2. The germline repertoire 2.1. The bovine heavy chain system 2.1.1. Constant region genes With the recent identification and characterisation of the bovine Cd gene [1], it has become apparent that all the Ab classes found in humans and mice—IgM, IgD, IgG, IgE and IgA—are also present in cows [2–8] (Table 1). The Ig H chain constant region (IgHC) genes have been located on chromosome 21q23-q24 [9,10]. Detailed physical mapping by analysis of BAC clones and long distance-PCR [11] has shown the IgHC genes to be arranged in a contig spanning approximately 150 kb with spacings ranging from 5 kb (m to d) to 34 kb (g1–g2) (Fig. 1). Based on a survey of the bovine EST database at GenBank, it was concluded that the seven functional bovine IgHC genes are expressed at different levels, with transcription of the d, g3 and 3 genes occurring at levels much lower than the others [11]. Whilst the functional bovine IgHC genes have been mapped to chromosome 21q23-q24, a bovine m-like sequence, IGHML1, has
been located on chromosome 11q23 [10,12]. Part of IGHML1 has been recovered from a chromosome 11specific library and sequenced [114]. This has revealed some differences with the IGHC m gene present on chromosome 21. Until recently, it had been thought that cows lacked an IgHC d gene [1,13]. The bovine d gene possesses an exon encoding a CH1 domain that is 96.6% identical to the m CH1 sequence. This is strikingly different to the d gene in human and rodents, and suggests a duplication event occurred during evolution of the bovine IgHC locus. The bovine d gene also possesses a short switch region that is absent in humans and rodents. This makes possible the expression of bovine IgD through genomic rearrangement, directed by the Sm and Sd regions. A further characteristic of bovine IgD is the possibility to express a splice variant lacking the CH2 domain [1]. In this respect, the molecule would resemble at a superficial level IgD from rodent, though it should be noted that in mice and rats, this arises from deletion of the dCH2 exon from the IgHC locus during the course of rodent evolution [14–16].
Table 1 Nomenclature and characteristic features of bovine immunoglobulin heavy chain and light chain constant region genes Ig
Current designation
Symbol
Gene
Gene number
Chromosome location
GenBank accession number
Major features and other information
IgG1
IgG1a IgG1b IgG2a
g1a g1b g2a
IGHG1 IGHG1 IGHG2
1
21q23-q24
1
21q23-q24
!16701 S82409 AAB22784
IgG2b IgG3a
g2b g3a
IGHG2 IGHG3
1
21q23-q24
S82407 U63638
Hinge, Arg218; Thr226 Hinge, Thr218; Pro224; Pro226 CH3; intadomain loop hepatappetide; Arg419 Middle hinge, CH3, Glu419 37 amino acid hinge
IgG3b
g3b
IGHG3
IgA
IgA
a
IGHA
1
21q23-q24
AF109167
IgM IgE
IgM IgE
m 3
IGHM IGHE
1 1
21q23-q24 21q23-q24
AY230207 U63640
IgD
IgD
d
IGHD
1
21q23-q24
AF515672 & AF411240
Light chain
Igl Igk
l k
IGLC IGKC
R4 ?
17 ?
!62917 ?
IgG2a (A1) IgG2a (A2) IgG2b/ IgG3
U63639
6 amino acid substitutions; 84 bp, INV3 insert Pst I RFLP generates polynucleotides of 6.0 and 6.3 kb suggestive of sequence of alleles Pst I, EcoR I and BamH I RFLPs show polymorphism suggestive of sequence alleles mCH1 like dCH1 due to mu gene dubplication; Transcribed through class switch recombination directed by the Sd One Cl gene is preferentially used
Y. Zhao et al. / Developmental and Comparative Immunology 30 (2006) 175–186 20 kb µ δ
γ3
γ1
γ2
ε
α
Fig. 1. Organisation of constant region genes at the bovine heavy chain locus. The bar indicates a distance of approximately 20 kb. Data adapted from [11].
The only genes present in multiple copies at the bovine IgHC locus are the g genes. It had been suggested that four g genes might be present in the bovine genome [2,5] but recent studies have shown that only three exist between the d and 3 genes, encoding the IgG1, IgG2 and IgG3, respectively [11]. The fourth g gene proposed by others is most probably a polymorphic allele of g1, g2 or g3. Allotypic variants of g2 have been noted [17] that appear to be able to activate complement to different degrees [18], properties that may impact upon the ability of homozygotic animals to resist bacterial infection [19]. In heterozygotes, co-expression of the allotypes of IgG2 can be observed with some evidence of age-dependent regulation [19]. 2.1.2. The JH locus The bovine Ig JH locus has been located approximately 7 kb upstream of the bovine m gene [1] and found to comprise six JH genes in a stretch of DNA of approximately 1.8 kb (Fig. 2). Two segments, JH1 and JH2, were shown to be potentially functional although there was a strong preference for expression of the former. This is reflected in the frequency with which a single FR4 sequence can be observed in IgH chain cDNA [20–22]. The JH1 and JH2, encoding 15 and 17 amino acids respectively, share a five amino acid VTVSS motif at their 3 0 ends that is very common in mammalian JH genes. In addition to the two functional JH genes, there are also four JH pseudogenes that were identified without either the right RSS or splice site (Fig. 2; Table 2). Studies of bovine Ig H chain cDNA have revealed that a second JH segment can undergo rearrangement at low frequency [22]. This can be distinguished from the coding sequence of the JH1 segment by the substitution of the two R codons for Q and L. The segment has been located to what appears to be a duplicated copy of the JH locus [114] (GenBank
177
accession number AY149283). Six JH segments have been identified at this locus; only the fourth and the sixth appeared functional, rearrangement of the sixth creating the alternative sequence noted in cDNA studies [22]. This duplicated JH locus has been mapped to chromosome 11 and is probably contiguous with IGML1. Superficially, the organisation and rearrangement of the bovine JH locus resembles that of the sheep and marked similarities of sequence can be detected. However, the ovine JH1 segment that undergoes frequent rearrangement and the less commonly selected JH2 segment reside at the same locus as is typical of the mammalian Ig system [23]. It thus seems likely that along with the g3 gene [11], this distinctive feature of the bovine Ab system has emerged during the c. 20 million years since cattle and sheep diverged into separate species [24]. 2.1.3. The D locus Partial characterisation of the bovine D locus has been described recently, revealing three D genes in a 2.3 kb DNA region [25]. It is not presently known how far they are located from the bovine JH locus. The sizes of the segments are 42 bp (14 possible codons), 58 bp (19 possible codons) and 148 bp (49 possible codons) respectively (Fig. 3). This finding is consistent with the unusual length of a bovine DQ52 segment located on the upstream flank of both JH loci (Hosseini et al., unpublished data; GenBank accession AY149283). It has been consistently reported that bovine IgH chains possess unusually long CDR3 sequences [20–22,26,27]. This property might thus arise from direct rearrangement of D genes from the germline, although it is still possible that D–D fusion may contribute to the generation of long CDR3s. Although considered extremely unusual in human immunology [28], this process has been observed in chickens [29]. 2.1.4. VH genes. The bovine VH locus has been little studied so the approximate size of the locus and the number of segments present is not known. Also it is not clear if the bovine VH genes are confined to chromosome 21q23-24, upstream from the constant region cluster, or whether as in humans, VH orphons are located elsewhere in the genome [30].
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Fig. 2. Sequence of the bovine JH locus on chromosome 21. Recombination signal sequences are indicated in upper case and underlined for each segment. The coding sequence for each segment is indicated in bold, upper case with the predicted reading frame translated below. Data adapted from [11].
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Table 2 Recombination signal sequences and functionality of the splice sites for segments for segments at the bovine JH locus on chromosome 21. Data adapted from [11] J segment
Nonamer
Spacer
Heptamer
JH-PS1
GGTTTCCGT
21 bp
CACTGTG
No
JH-PS2 JH-PS3 JH-PS4 JH1 JH2
TGTTTTTGT GGTTCATGT GAGCTCTTG GGTTTTTGC GGTTTTTGT
22 bp 23 bp 22 bp 23 bp 22 bp
AGCCATG CCCTCAG CACCGTG CACTGTG CACTGTG
No Yes No Yes Yes
From studies of bovine Ig cDNA sequences, many publications have concluded that a single VH gene family undergoes rearrangement and expression. This gene family is homologous to the murine VH Q-52 and related human families [20–22]. The bovine VH family was designated as BoVH1, and is thought to consist of no more than 20 VH segments [20,31]. Additional data from Southern blotting has indicated that segments from at least three other gene families may be present in the bovine genome [22,31] (Table 3). It is not known whether these segments are able to undergo rearrangement and why they appear to be excluded from the expressed H chain repertoire.
Functional 5 0 splice site
2.2. The bovine light chain system The bovine L chain repertoire is dominated by lambda chains [32], and their encoding genes have been assigned to bovine chromosome 17 [33] (Table 1). There are probably more than four Cl genes in the bovine lambda locus, although it appears that one is preferentially utilized [34]. It has been suggested that cattle also express kappa light chains at a low level [35,36] but very little is known about this L chain locus. Based on sequence similarity, the bovine lambda L chain variable sequences are divided into Vl1, Vl2, Vl3 [37,38], the Vl1 group being further divisible
Fig. 3. Sequence of three bovine D segments. Recombination signal sequences are indicated in upper case and underlined for each segment. The coding sequence for each segment is indicated in upper case and separated from the recombination signal sequences by a space for better clarity. Data adapted from [25].
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Table 3 Nomenclature of bovine immunoglobulin heavy chain and light chain variable region genes Gene
Gene family
VH
BoVH1 BoVH2? Vl1 Vl2 Vl3 ?
Vl
Vk
Subgroup
? Vl1x (Vl1a, Vl1b, Vl1c), Vl1d, Vl1e
?
into subgroups according to characteristic sequences in the FRs and the length of CDR1 (Table 3). It has been suggested that H chains carryinging CDR3 sequences of exceptional length are preferentially paired with lambda chains from one of the Vl1 subgroups [39].
3. Antibody composition of serum and secretions Reagents for the detection of bovine IgM, IgG1, IgG2 and IgA are available from commercial distributors such as Serotoc, VMRD and Bethyl Labs. Individual investigators have generated reagents that permit the discrimination of the allotypes of IgG2 [18,40] and the detection of bovine IgE [41]. Some organisations (e.g. Bethyl Labs) are able to supply purified Ig to allow quantitation of these classes in test materials through a simple capture ELISA. These assays can determine the composition of serum, colostrum, milk or other fluids. Under normal circumstances, the serum contains undetectable levels of IgE and IgA may be present at hundreds of micrograms per ml [42]. In contrast, IgM and IgG1 and IgG2 are typically present at mg per ml concentrations (IgM c. 3 mg per ml, IgG1 and IgG2 c. 10 mg per ml the former usually exceeding the latter), IgG1 rising to exceed 60 mg per ml in hyperimmunized animals. As the major secretory subclass, the concentration of IgG1 in colostrum can exceed 100 mg per ml and in milk it is usually present at levels up to 10 times that of the other Ig classes [42]. The quantitation of antigen-specific responses can only be achieved with complex and timeconsuming competition immunoassays. Given these constraints, it is unsurprising that antigen-specific responses are more usually measured on a relative
Gene number
Chromosome location
References
% 20 ?
21q23-q24 21q23-q24
31, 22 31, 33 38, 39
S30
17
?
?
35
basis against reference sera or pre-immune samples [41]. This situation seems likely to change as recombinant antibody technologies start to make greater impact. For example, in unpublished studies, a single-chain Ab isolated against a bacterial target by phage display has been fused to bovine IgHC sequences and expressed in transfected mammalian cells to produce an antigen-specific IgG1 construct for ELISA standardisation (Aitken et al., unpublished data). Whilst reagents such as these have an obvious value in monitoring the progress of an Ab response, they may also find a role in standardising passive therapies based upon bovine immunoglobulins [43].
4. Lymphogenesis and the pre-immune repertoire The emergence of IgMCB cells can be detected in the bovine spleen early in gestation [44]. Ig rearrangement has also been detected in the spleen and several other organ systems during foetal development using PCR [45]. In sheep, foetal splenectomy has shown that the precursor populations from which the B cell repertoire emerges can be derived from other - potentially multiple - sites of early B cell accumulation [46]. The long CDR3 sequences that characterise bovine Ab H chains have been detected in foetal lymphoid cDNA [22,27] and there is some evidence of preferential use of subgroups of light chains [39] and intra-heavy chain disulphide bridging to aid the stabilisation of these rearrangement products [26]. It thus appears that these are properties intrinsic to the bovine Ig system and do not emerge through antigen-driven processes. It is widely assumed that development of the Ab repertoire in maturing bovine B cells is heavily
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dependent upon events in the gut-associated lymphoid tissue during foetal development and in the weeks and months after birth [47]. Data in support of this model is fragmentary and largely based upon the perceived similarities between cattle and sheep. Population of the ileal Peyer’s patches (IPP) during development of the bovine foetus and the formation of follicles have been documented and shown to be oligoclonal [48,49]. Ig diversification in individual follicles has been traced back to these founder clones [45]. In sheep, entry to the IPP takes place during a relatively short window of time during gestation, a period that can be defined by injecting anti-IgM antibodies to deplete founder clones before they undergo significant expansion in the IPP [50]. Evidence has been gathered of high rates of B cell proliferation in the bovine IPP around time of birth and although levels of apoptosis are likely high [51], this appears insufficient to explain the relative stability in total cell numbers [52]. This is consistent with emigration to the periphery [53]. As the bovine Ab repertoire is founded upon a single family of VH segments of very limited diversity and frequent use of one JH segment [20–22], rearrangement per se is incapable of generating significant levels of H chain diversity. The nature of the diversification process in cattle remains ill defined. Evidence suggestive of gene conversion has been gathered from studies of the lambda L chain system [34,37] whereas other studies of the pre-immune repertoire have favoured somatic hypermutation as the diversification mechanism [22]. In the sheep, the long-held view has been that the latter drives diversification of the pre-immune repertoire in the IPP and that after birth, emigration and later involution of the organ releases diversified B cells to population the lymphoid system [54–56]. Recent work in the sheep has discovered that the number and diversity of VL segments in the germline is greater than previously supposed [57]. Ig L chain rearrangement may therefore be able to generate some of the diversity previously attributed to somatic hypermutation. Whatever the nature of the process in cattle, increasing levels of immunoglobulin diversity become detectable in peripheral lymphoid tissue with age [22,45]. This is accompanied by a rise in the endogenous synthesis of antibody from undetectable levels at birth [58] to levels in the peripheral circulation that are immunologically
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significant 1–2 weeks after birth [59] and later [60]. In other animals dependent upon gut-associated lymphoid tissue for the generation of the antibody repertoire, lymphopoiesis declines sharply post partum [61]. The same is likely to be true of cattle [62] but this has yet to be formally demonstrated. As there is limited transfer across the bovine placenta from dam to foetus, the possibilities for maternal influence over the developing antibody repertoire are limited [42]. However, maternal and environmental factors are likely to play prominent roles, post partum. The neonatal diet and its composition can affect leukocyte function at a fundamental level [63,64] but bovine colostrum also has marked immunomodulatory properties. Aside from suppression of the endogenous capacity of the neonate to respond immunologically, it has been shown that colostrum promotes the elimination of B cells expressing IgG subclasses, or at least downregulation of these markers at the cell surface [58]. The mechanism of this effect is unclear. Work particularly with the rabbit has emphasised the impact of the intestinal microflora on diversification of the neonatal antibody repertoire [65–67]. It will be interesting to see whether similar events provide the trigger for diversification of the bovine Ab repertoire in the environment of the IPP.
5. Bovine B cell responses It is self-evident that the response of bovine B cells to antigen depends upon multiple factors. It is beyond the scope of this review to detail this large area of work but influences include the characteristics of cells that initially present antigen [68–71], which B cell activation pathway is triggered [72,73], and the balance of cytokines present in the local environment [74–78]. It is notable that polarised TH1 and TH2 responses that are observed in murine responses to antigen have only been consistently seen in a number of chronic bovine infections [79]. Novel regulatory factors have been identified [80] and thus mouse models of cytokine action need to be extrapolated to bovine immunology with care. Markers for bovine B cells are emerging [81–84]. With some exceptions [85], these tend to be expressed on B cells detectable in the periphery and good
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markers for the early stages of B cell differentiation are presently lacking. One feature of bovine B cells that merits particular mention is the expression of CD5 on a subset of peripheral blood B lymphocytes [36,86,87]. The proportion of B cells expressing this marker in cattle appears higher than in laboratory animals [88]. Similar B cell populations can be observed in sheep [89]. Bovine CD5CB cells can be infected with Theileria [90] and infection with bovine leukemia virus leads to persistent lymphocytosis [91]. Trypanosome infection also increases their representation in the peripheral blood [92]. The significance of this cell population viz a viz murine CD5CB cells is uncertain [93], but their prominence and the failure of early attempts to detect IgD at the surface of bovine B cells [13] has led to speculation that many B lymphocytes in cattle–perhaps a majority–are of the B-1 lineage [13,62]. Such extreme polarisation may be unlikely but it is notable that Ig rearrangement in cattle takes place during foetal development, and that the expression of polyreactive Ig is detectable, becoming common during certain infections [26,94,95]. These properties are at least consistent with the behaviour of B-1 cells. Studies with mice also show the biased usage of VH segments in CD5CB cells [96,97], another interesting parallel with events in cattle. The observation that different activating signals impact upon the expression of CD5 [72] indicates that the CD5C phenotype is more likely an induced differentiation state than the end product of a definite B cell lineage [88]. The identification of a ligand for bovine CD5 will doubtless assist a better understanding of these processes [98].
6. Future directions Although significant gaps exist in present understanding of the bovine Ig repertoire and its development, this situation is likely to improve in the near future. In part, clarification will come from exploitation of developments in human and murine immunology. To take one topical example, the identification of AID as a crucial factor in the processes of somatic hypermutation and class switching has triggered substantial activity in the immunological community at large [99]. Since AID contributes to somatic hypermutation and gene
conversion [99,100], tracking its expression in bovine tissues offers the chance to identify the location and timing of Ig diversification in cattle without bias towards either of the competing models for the diversification mechanism. The release of the first draft of the chicken genome in the Spring of 2004 heralds a new era for research on animals of economic importance; efforts to sequence the bovine genomic will facilitate the identification of enzymes, cytokines and surface markers involved in immunity, an enterprise that has previously been reliant upon protein purification [101,102] or serological crossreaction [83,84]. In applied areas of bovine immunology, there remains a basic requirement for standards for the quantitation of Ab responses and controlling cytokines. The use of recombinant methods is starting to impact in this area [103,104] and the application of antibody engineering methods [105] offers the chance to develop reagents to measure antigen-specific responses on a quantitative basis rather than in relation to pre-immune titres. Reagents of this sort may also find applications in therapy [106]. The study of immunology in large animals has definite benefits [107] aside from the intrinsic interest and economic importance of this group of animals but there is no doubt that working with these species brings with it logistical and cost problems. This may explain why several of the key areas of Ig diversification are better understood for sheep than they are for cattle. Some investigators have explored the use of the SCID mouse into which bovine B cells can be successfully grafted [108–111]. These might provide a more experimentally amenable system for studies of lymphopoeisis but it is inevitable that at some stage, data will need to be validated against events in the natural host. There is an obvious linkage between a better understanding of the bovine B cells repertoire and disease resistance and onwards to the economics of dairy and beef production. The application of cloning technology to cattle [112] may offer the chance to manipulate enhanced levels of disease resistance into the animal. Cloning methods have already led to the generation of transgenic cattle able to express human antibodies [113]. The future thus holds many exciting challenges for those willing to join this branch of veterinary immunology.
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