8536d_ cho7 161-184 8/16/02 8: 28 AM Page 163 mac100 mac 100: 129Atm: 8536d: Goldsby et al. Immunology 5e Major Histocompatibility Complex CHAPTER 7 Allelic Forms of mhc genes are Inherited presses both parental alleles at each MHC locus. For exam in Linked Groups Called Haplotypes ple, if an H-2 strain is crossed with an H-2 then the F, in herits both parental sets of alleles and is said to be H-2 As described in more detail later, the loci constituting the ( Figure 7-2a) Because such an Fi expresses the MHC pro MHC are highly polymorphic; that is, many alternative teins of both parental strains on its cells, it is histocompatible forms of the gene, or alleles, exist at each locus among the with both strains and able to accept grafts from either population. The genes of the MHC loci lie close together; for parental strain(see example in Figure 7-2b)However,nei- example, the recombination frequency within the H-2 com- ther of the inbred parental strains can accept a graft from the plex (i.e, the frequency of chromosome crossover events Fi mice because half of the MHC molecules will be foreign to during mitosis, indicative of the distance between given gene the parent. segments)is only 0.5%-crossover occurs only once in every The inheritance of HLA haplotypes from heterozygous 200 mitotic cycles. For this reason, most individuals inherit human parents is illustrated in Figure 7-2c In an outbred the alleles encoded by these closely linked loci as two sets, one population, each individual is generally heterozygous at each from each parent. Each set of alleles is referred to as a haplo- locus. The human hLA complex is highly polymorphic and type. An individual inherits one haplotype from the mother multiple alleles of each class I and class ll gene exist. How- and one haplotype from the father In outbred populations, ever, as with mice, the human MHC loci are closely linked the offspring are generally heterozygous at many loci and will and usually inherited as a haplotype. When the father and express both maternal and paternal MHC alleles. The alleles mother have different haplotypes, as in the example shown are codominantly expressed; that is, both maternal and pater- (Figure 7-2c)there is a one-in-four chance that siblings will nal gene products are expressed in the same cells. If mice are inherit the same paternal and maternal haplotypes and inbred(that is, have identical alleles at all loci), each H-2 lo- therefore be histocompatible with each other; none of the cus will be homozygous because the maternal and paternal offspring will be histocompatible with the parents haplotypes are identical, and all offspring therefore express Although the rate of recombination by crossover is low identical haplotypes. within the HLA, it still contributes significantly to the diver Certain inbred mouse strains have been designated as sity of the loci in human populations.Genetic recombina prototype strains, and the MHC haplotype expressed by tion generates new allelic combinations(Figure 7-2d),and these strains is designated by an arbitrary italic superscript the high number of intervening generations since the ap- (e.g,H-2,H-2). These designations refer to the entire set of pearance of humans as a species has allowed extensive re- inherited H-2 alleles within a strain without having to list combination, so that it is rare for any two unrelated each allele individually(Table 7-1). Different inbred strains individuals to have identical sets of HLa genes may have the same set of alleles, that is the same MHC hap lotype, as the prototype strain. For example, the CBA, AKR, MHC Congenic Mouse Strains Are ldentical The three strains differ, however, in genes outside the H-2 at All Loci Except the MHC Detailed analysis of the H-2 complex in mice was made If two mice from inbred strains having different MHC possible by the development of congenic mouse strains. In haplotypes are bred to one another, the Fi generation inher- bred mouse strains are syngeneic or identical at all genetic its haplotypes from both parental strains and therefore ex- loci. Two strains are congenic if they are genetically identical TABLE 7 2 Haplotypes of some mouse strains H-2 ALLELE Prototype strain Other strains with the same haplotype Haplotype K CBA AKR C3H. B10.BR. C57 k k DBA/2 BALB/C, NZB, SEA, YBR kdbkss Ekdbkskq d C57BL/10(B10) C57BL/6, C57L, C3H SW, LP, 129 b b B10.s S儿L t1 DBA/ STOLI, B10.Q,Allelic Forms of MHC Genes Are Inherited in Linked Groups Called Haplotypes As described in more detail later, the loci constituting the MHC are highly polymorphic; that is, many alternative forms of the gene, or alleles, exist at each locus among the population. The genes of the MHC loci lie close together; for example, the recombination frequency within the H-2 com￾plex (i.e., the frequency of chromosome crossover events during mitosis, indicative of the distance between given gene segments) is only 0.5%—crossover occurs only once in every 200 mitotic cycles. For this reason, most individuals inherit the alleles encoded by these closely linked loci as two sets, one from each parent. Each set of alleles is referred to as a haplo￾type. An individual inherits one haplotype from the mother and one haplotype from the father. In outbred populations, the offspring are generally heterozygous at many loci and will express both maternal and paternal MHC alleles. The alleles are codominantly expressed; that is, both maternal and pater￾nal gene products are expressed in the same cells. If mice are inbred (that is, have identical alleles at all loci), each H-2 lo￾cus will be homozygous because the maternal and paternal haplotypes are identical, and all offspring therefore express identical haplotypes. Certain inbred mouse strains have been designated as prototype strains, and the MHC haplotype expressed by these strains is designated by an arbitrary italic superscript (e.g., H-2a , H-2b ). These designations refer to the entire set of inherited H-2 alleles within a strain without having to list each allele individually (Table 7-1). Different inbred strains may have the same set of alleles, that is the same MHC hap￾lotype, as the prototype strain. For example, the CBA, AKR, and C3H strains all have the same MHC haplotype (H-2k ). The three strains differ, however, in genes outside the H-2 complex. If two mice from inbred strains having different MHC haplotypes are bred to one another, the F1 generation inher￾its haplotypes from both parental strains and therefore ex￾presses both parental alleles at each MHC locus. For exam￾ple, if an H-2b strain is crossed with an H-2k , then the F1 in￾herits both parental sets of alleles and is said to be H-2b/k (Figure 7-2a). Because such an F1 expresses the MHC pro￾teins of both parental strains on its cells, it is histocompatible with both strains and able to accept grafts from either parental strain (see example in Figure 7-2b). However, nei￾ther of the inbred parental strains can accept a graft from the F1 mice because half of the MHC molecules will be foreign to the parent. The inheritance of HLA haplotypes from heterozygous human parents is illustrated in Figure 7-2c. In an outbred population, each individual is generally heterozygous at each locus. The human HLA complex is highly polymorphic and multiple alleles of each class I and class II gene exist. How￾ever, as with mice, the human MHC loci are closely linked and usually inherited as a haplotype. When the father and mother have different haplotypes, as in the example shown (Figure 7-2c) there is a one-in-four chance that siblings will inherit the same paternal and maternal haplotypes and therefore be histocompatible with each other; none of the offspring will be histocompatible with the parents. Although the rate of recombination by crossover is low within the HLA, it still contributes significantly to the diver￾sity of the loci in human populations. Genetic recombina￾tion generates new allelic combinations (Figure 7-2d), and the high number of intervening generations since the ap￾pearance of humans as a species has allowed extensive re￾combination, so that it is rare for any two unrelated individuals to have identical sets of HLA genes. MHC Congenic Mouse Strains Are Identical at All Loci Except the MHC Detailed analysis of the H-2 complex in mice was made possible by the development of congenic mouse strains. In￾bred mouse strains are syngeneic or identical at all genetic loci. Two strains are congenic if they are genetically identical Major Histocompatibility Complex CHAPTER 7 163 TABLE 7-1 H-2 Haplotypes of some mouse strains H-2 ALLELES Prototype strain Other strains with the same haplotype Haplotype K IA IE S D CBA AKR, C3H, B10.BR, C57BR k k k k kk DBA/2 BALB/c, NZB, SEA, YBR d d d d dd C57BL/10 (B10) C57BL/6, C57L, C3H.SW, LP, 129 b b b b bb A A/He, A/Sn, A/Wy, B10.A a k k k dd A.SW B10.S, SJL s s s s ss A.TL t1 s k k kd DBA/1 STOLI, B10.Q, BDP q q q q qq 8536d_ch07_161-184 8/16/02 8:28 AM Page 163 mac100 mac 100: 1268_tm:8536d:Goldsby et al. / Immunology 5e-: