8536ach07-161-1848/15/028:41 PM Page161mac114Mac114:2 nightshift chapter 7 Major Histocompatibility npl om e VERY MAMMALIAN SPECIES STUDIED TO DATE possesses a tightly linked cluster of genes, the ma- jor histocompatibility complex(MHC), whose products play roles in intercellular recognition and in dis- crimination between self and nonself. The MHC partici- Presentation of Vesicular Stomatitis Virus Peptide(top) and Sendai Virus Nucleoprotein Peptide by Mouse MHC ates in the development of both humoral and Class I molecule H-2K mediated immune responses. While antibodies may react with antigens alone, most T cells recognize antigen only when it is combined with an mhc molecule. furthermore a General Organization and Inheritance of the mHc because MHC molecules act as antigen-presenting struc tures, the particular set of MHC molecules expressed by an MHC Molecules and genes individual influences the repertoire of antigens to which that a Detailed Genomic Map of MHC Genes individuals TH and Tc cells can respond. For this reason, the Cellular distribution of mhc molecules MHC Partly determines the response of an individual to antigens of infectious organisms, and it has therefore been a Regulation of MHC Expression implicated in the susceptibility to disease and in the devel a MHC and Immune Responsiveness opment of autoimmunity. The recent understanding that natural killer cells express receptors for MHC class I antigens a MHC and Disease Susceptibility and the fact that the receptor-MHC interaction may lead to inhibition or activation expands the known role of this gene family(see Chapter 14). The present chapter examines the genes'; their current designation as histocompatibility-2 molecules play in producing an immune response. recognized fully, Snell was awarded the Nobel prize in 1980 for this work The MHC Encodes Three Major General Organization and Classes of molecules Inheritance of the mHc The major histocompatibility complex is a collection of The concept that the rejection of foreign tissue is the result genes arrayed within a long continuous stretch of DNA on of an immune response to cell-surface molecules, now called chromosome 6 in humans and on chromosome 17 in mice histocompatibility antigens, originated from the work of The MHC is referred to as the HLA complex in humans and Peter Gorer in the mid-1930s Gorer was using inbred strains as the H-2 complex in mice. Although the arrangement of of mice to identify blood-group antigens In the course of genes is somewhat different, in both cases the MHc genes are these studies, he identified four groups of genes, designated organized into regions encoding three classes of molecules I through IV, that encoded blood-cell antigens. Work carried (Figure 7-1 out in the 1940s and 1950s by Gorer and George Snell estab- Class I MHC genes encode glycoproteins expressed o lished that antigens encoded by the genes in the group desig- the surface of nearly all nucleated cells; the major nated II took part in the rejection of transplanted tumors function of the class I gene products is presentation of and other tissue. Snell called these genes" histocompatibility peptide antigens to Tc cells
genes”; their current designation as histocompatibility-2 (H-2) genes was in reference to Gorer’s group II blood-group antigens. Although Gorer died before his contributions were recognized fully, Snell was awarded the Nobel prize in 1980 for this work. The MHC Encodes Three Major Classes of Molecules The major histocompatibility complex is a collection of genes arrayed within a long continuous stretch of DNA on chromosome 6 in humans and on chromosome 17 in mice. The MHC is referred to as the HLA complex in humans and as the H-2 complex in mice. Although the arrangement of genes is somewhat different, in both cases the MHC genes are organized into regions encoding three classes of molecules (Figure 7-1): ■ Class I MHC genes encode glycoproteins expressed on the surface of nearly all nucleated cells; the major function of the class I gene products is presentation of peptide antigens to TC cells. chapter 7 ■ General Organization and Inheritance of the MHC ■ MHC Molecules and Genes ■ Detailed Genomic Map of MHC Genes ■ Cellular Distribution of MHC Molecules ■ Regulation of MHC Expression ■ MHC and Immune Responsiveness ■ MHC and Disease Susceptibility Major Histocompatibility Complex E possesses a tightly linked cluster of genes, the major histocompatibility complex (MHC), whose products play roles in intercellular recognition and in discrimination between self and nonself. The MHC participates in the development of both humoral and cellmediated immune responses. While antibodies may react with antigens alone, most T cells recognize antigen only when it is combined with an MHC molecule. Furthermore, because MHC molecules act as antigen-presenting structures, the particular set of MHC molecules expressed by an individual influences the repertoire of antigens to which that individual’s TH and TC cells can respond. For this reason, the MHC partly determines the response of an individual to antigens of infectious organisms, and it has therefore been implicated in the susceptibility to disease and in the development of autoimmunity. The recent understanding that natural killer cells express receptors for MHC class I antigens and the fact that the receptor–MHC interaction may lead to inhibition or activation expands the known role of this gene family (see Chapter 14). The present chapter examines the organization and inheritance of MHC genes, the structure of the MHC molecules, and the central function that these molecules play in producing an immune response. General Organization and Inheritance of the MHC The concept that the rejection of foreign tissue is the result of an immune response to cell-surface molecules, now called histocompatibility antigens, originated from the work of Peter Gorer in the mid-1930s. Gorer was using inbred strains of mice to identify blood-group antigens. In the course of these studies, he identified four groups of genes, designated I through IV, that encoded blood-cell antigens. Work carried out in the 1940s and 1950s by Gorer and George Snell established that antigens encoded by the genes in the group designated II took part in the rejection of transplanted tumors and other tissue. Snell called these genes “histocompatibility Presentation of Vesicular Stomatitis Virus Peptide (top) and Sendai Virus Nucleoprotein Peptide by Mouse MHC Class I Molecule H-2Kb 8536d_ch07_161-184 8/15/02 8:41 PM Page 161 mac114 Mac 114:2nd shift:
8536d_cho7 161-184 8/16/02 12: 09 PM Page 162 mac100 mac 100: 1?/8_tm: 8536d: Goldsby et al./Immunology Se 162 PART II Generation of B-Cell and T-Cell Response VISUALIZING CONCEPTS Mouse H-2 complex III H-2K INF-a products B aB Cproteins TNFB/H-2DH-2L Human HLA complex HLA MHC class DP DQDR C4, C2, BF B C Gene DP DQ DR C'proteins TNF-CL BaBc阝 TNF-B HLA-BHLACHLA-A GURE7-1Simplified organization of the major histocompat- (green) gene products. The class I and class ll gene products bility complex(MHC)in the mouse and human. The MHC is re- shown in this figure are considered to be the classical MHC mol ferred to as the H-2 complex in mice and as the HLA complex in ecules. The class lll gene products include complement(C"pro- humans. In both species the MHC is organized into a number of teins and the tumor necrosis factors(TNF-a and TNF B) a Class II MHC genes encode glycoproteins expressed antigens begin to appear)and from being rejected by ma- nting cells(macrophages, ternal Tc cells dendritic cells, and B cells), where they present processed The two chains of the class li mhc molecules are en- antigenic peptides to TH cells coded by the la and ie regions in mice and by the DP, DQ and DR regions in humans. The terminology is somewhat a Class IlI MHC genes encode, in addition to other confusing, since the D region in mice encodes class I MHC products, various secreted proteins that have immune molecules, whereas the D region(DR, DQ, DP)in humans functions, including components of the complement refers to genes encoding class II MHC molecules! Fortu- system and molecules involved in inflammation nately, the designation D for the general chromosomal loca Class I MHC molecules encoded by the K and D regions in today; the sequence of the entire MHC region is available o tion encoding the human class II molecules is seldom used mice and by the A, B, and C loci in humans were the first the more imprecise reference to region is seldom necessary discovered, and they are expressed in the widest range of As with the class I loci, additional class II molecules en- cell types. These are referred to as classical class I molecules. coded within this region have specialized functions in the complexes also encode class I molecules; these gene.A immune process Additional genes or groups of genes within the H-2 or HLA The class I and class II MHC molecules have common designated nonclassical class I genes Expression of the non- structural features and both have roles in antigen processing classical gene products is limited to certain specific cell By contrast, the class Ill MHC region, which is flanked by the types. Although functions are not known for all of these class I and II regions, encodes molecules that are critical gene products, some may have highly specialized roles in immune function but have little in common with class I or II immunity. For example, the expression of the class I HLA- molecules. Class Ill products include the complement com- G molecules on cytotrophoblasts at the fetal-maternal in- ponents CA, C2, BF(see Chapter 13), and inflammatory cy terface has been implicated in protection of the fetus from tokines, including tumor necrosis factor (TNF)and being recognized as foreign(this may occur when paternal heat-shock proteins(see Chapter 12)
■ Class II MHC genes encode glycoproteins expressed primarily on antigen-presenting cells (macrophages, dendritic cells, and B cells), where they present processed antigenic peptides to TH cells. ■ Class III MHC genes encode, in addition to other products, various secreted proteins that have immune functions, including components of the complement system and molecules involved in inflammation. Class I MHC molecules encoded by the K and D regions in mice and by the A, B, and C loci in humans were the first discovered, and they are expressed in the widest range of cell types. These are referred to as classical class I molecules. Additional genes or groups of genes within the H-2 or HLA complexes also encode class I molecules; these genes are designated nonclassical class I genes. Expression of the nonclassical gene products is limited to certain specific cell types. Although functions are not known for all of these gene products, some may have highly specialized roles in immunity. For example, the expression of the class I HLAG molecules on cytotrophoblasts at the fetal-maternal interface has been implicated in protection of the fetus from being recognized as foreign (this may occur when paternal antigens begin to appear) and from being rejected by maternal TC cells. The two chains of the class II MHC molecules are encoded by the IA and IE regions in mice and by the DP, DQ, and DR regions in humans. The terminology is somewhat confusing, since the D region in mice encodes class I MHC molecules, whereas the D region (DR, DQ, DP) in humans refers to genes encoding class II MHC molecules! Fortunately, the designation D for the general chromosomal location encoding the human class II molecules is seldom used today; the sequence of the entire MHC region is available so the more imprecise reference to region is seldom necessary. As with the class I loci, additional class II molecules encoded within this region have specialized functions in the immune process. The class I and class II MHC molecules have common structural features and both have roles in antigen processing. By contrast, the class III MHC region, which is flanked by the class I and II regions, encodes molecules that are critical to immune function but have little in common with class I or II molecules. Class III products include the complement components C4, C2, BF (see Chapter 13), and inflammatory cytokines, including tumor necrosis factor (TNF) and heat-shock proteins (see Chapter 12). 162 PART II Generation of B-Cell and T-Cell Responses VISUALIZING CONCEPTS FIGURE 7-1 Simplified organization of the major histocompatibility complex (MHC) in the mouse and human. The MHC is referred to as the H-2 complex in mice and as the HLA complex in humans. In both species the MHC is organized into a number of regions encoding class I (pink), class II (blue), and class III (green) gene products. The class I and class II gene products shown in this figure are considered to be the classical MHC molecules. The class III gene products include complement (C) proteins and the tumor necrosis factors (TNF- and TNF-). II III Complex MHC class Region Gene products IA αβ H–2K H–2L C′ proteins H–2D IE αβ TNF-α TNF-β TNF-α TNF-β H–2 I I K IA IE S D III Complex MHC class Region Gene products DQ αβ C′ proteins HLA-B HLA-C HLA-A DR αβ HLA II I DP DQ DR C4, C2, BF B C A Human HLA complex Mouse H-2 complex DP αβ 8536d_ch07_161-184 8/16/02 12:09 PM Page 162 mac100 mac 100: 1268_tm:8536d:Goldsby et al. / Immunology 5e-:
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 complex (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 haplotype. 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 paternal gene products are expressed in the same cells. If mice are inbred (that is, have identical alleles at all loci), each H-2 locus 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 haplotype, 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 inherits haplotypes from both parental strains and therefore expresses both parental alleles at each MHC locus. For example, if an H-2b strain is crossed with an H-2k , then the F1 inherits both parental sets of alleles and is said to be H-2b/k (Figure 7-2a). Because such an F1 expresses the MHC proteins 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, neither 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. However, 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 diversity of the loci in human populations. Genetic recombination generates new allelic combinations (Figure 7-2d), and the high number of intervening generations since the appearance of humans as a species has allowed extensive recombination, 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. Inbred 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-:
8536d_cho7_161-184 8/16/02 12: 09 PM Page 164 mac100 mac 100: 1/8_tm: 8536d: Goldsby et al./ Immunology 5e (a) Mating of inbred mouse strains with different MHC haplotypes Homologous chromosomes with MHC loci The letters b/b designate a mouse homozy H-2b parent H-2 parent gous for the H-2b MHC haplotype, k/k ho- mozygous for the H-2 haplotype, and b/ka heterozygote. Because the MHC loci are dosely linked and inherited as a set, the MHC haplotype of F1 progeny from the mat ing of two different inbred strains can be pre dicted easily.(b) Acceptance or rejection of FI progeny (H-2b/) skin grafts is controlled by the MHC type of b/k the inbred mice. The progeny of the cross be tween two inbred strains with different mhc haplotypes(H-2 and H-25) will express both (b) Skin transplantation between inbred mouse strains with same or different MHC haplotypes haplotypes(H-2b/)and will accept grafts from either parent and from one anoth Parental recipient Skin graft donor Progeny recipient Neither parent strain will accept grafts from the offspring.(c) Inheritance of HLA haplo- types in a hypothetical human family. In hu- mans, the paternal HLA haplotypes are arbitrarily designated A and B, maternal C and D. Because humans are an outbred b/k species and there are alleles at each HLA locus, the alleles comprising the haplo- types must be determined by typing parents and progeny.(d)The genes that make up aplotype in the hypothec family in(c)are shown along with a new hap- type that arose from recombination(R)of →口 b/k Paren Progeny (c) Inheritance of HLA haplotypes in a typical human family (d) A new haplotype (R) arises from recombination Parents o HLA Alleles B C DR DQ DP C/D A17 Haplotypes c3 44 w4 4 13 /C A/D B/R B/C B/D
(a) Mating of inbred mouse strains with different MHC haplotypes b/b b/b b/b b/b b/k b/k k/k k/k k/k b/k F1 progeny (H-2b/k) H-2 H-2k parent b parent Homologous chromosomes with MHC loci (b) Skin transplantation between inbred mouse strains with same or different MHC haplotypes Parental recipient Skin graft donor Parent Progeny recipient b/b b/k b/k k/k Progeny b/b k/k b/k k/k Parent (c) Inheritance of HLA haplotypes in a typical human family Parents Progeny A/B C/D A/C A/D B/C B/D B/R (d) A new haplotype (R) arises from recombination of maternal haplotypes 1 7 w3 2 1 1 ABC HLA Alleles DR DQ DP 2 8 w2 3 2 2 3 44 w4 4 1 3 11 35 w1 7 3 4 3 A Haplotypes B C D 5e R 44 w4 734 2 FIGURE 7-2 (a) Illustration of inheritance of MHC haplotypes in inbred mouse strains. The letters b/b designate a mouse homozygous for the H-2b MHC haplotype, k/k homozygous for the H-2k haplotype, and b/k a heterozygote. Because the MHC loci are closely linked and inherited as a set, the MHC haplotype of F1 progeny from the mating of two different inbred strains can be predicted easily. (b) Acceptance or rejection of skin grafts is controlled by the MHC type of the inbred mice. The progeny of the cross between two inbred strains with different MHC haplotypes (H-2b and H-2k ) will express both haplotypes (H-2b/k) and will accept grafts from either parent and from one another. Neither parent strain will accept grafts from the offspring. (c) Inheritance of HLA haplotypes in a hypothetical human family. In humans, the paternal HLA haplotypes are arbitrarily designated A and B, maternal C and D. Because humans are an outbred species and there are many alleles at each HLA locus, the alleles comprising the haplotypes must be determined by typing parents and progeny. (d) The genes that make up each parental haplotype in the hypothetical family in (c) are shown along with a new haplotype that arose from recombination (R) of maternal haplotypes. 8536d_ch07_161-184 8/16/02 12:09 PM Page 164 mac100 mac 100: 1268_tm:8536d:Goldsby et al. / Immunology 5e-:
8536d_cho7 161-184 8/16/02 12: 09 PM Page 165 mac100 mac 100: 1?/8_tm: 8536d: Goldsby et al./Immunology Se Major Histocompatibility Complex CHAPTER 7 URE 7-3 Production of congenic mouse Cross AB, which has the genetic background of arental strain a but the H-2 complex of strain B Crossing inbred strain A(H-2)with strain B(H-2) generates Fi progeny that are heterozygous(a/b) at all H-2 loci. The Fi progeny are interbred to pro interbreeding duce an F2 generation, which includes a/a, a/b, and b/b individuals. The F2 progeny homozygous r the B-strain H-2 complex are selected by their ability to reject a skin graft from strain A; any prog from future breeding. The selected b/b homozy Strain-A skin grafts gous mice are then backcrossed to strain A; the re- nd selection for ability reject an A-strain graft is repeated for at least 12 backcross restored at all loci except the H-2 locus, which for the b strain Interbreed. select and Strain a. B except at a single genetic locus or region. Any pheno- typic differences that can be detected between congenic strains are related to the genetic region that distinguishes ABA邱 the strains. Congenic strains that are identical with each Parental other except at the mHc can be produced by a series of crosses, backcrosses, and selections. Figure 7-3 outlines the Congenic B10.A steps by which the H-2 complex of homozygous strain B B10.A(2R) b2 an be introduced into the background genes of homozy- gous strain a to generate a congenic strain, denoted A B B10.A(4R)b4 The first letter in a congenic strain designation refers to the B10.A(18R)i8 strain providing the genetic background and the second letter to the strain providing the genetically different MHC FIGURE 7.4 Examples of recombinant congenic mouse strains region. Thus, strain A.B will be genetically identical to generated during production of the B10. A strain from parental strain 10(H-2)and parental strain A(H-2).Crossover events within the strain A except for the MHC locus or loci contributed by H-2 complex produce recombinant strains, which have a-haplotype strain B During production of congenic mouse strains, a crossover alleles(blue)at some H-2 loci and b-haplotype alleles (orange)at event sometimes occurs within the H-2 complex, yielding a other loci recombinant strain that differs from the parental strains or the congenic strain at one or a few loci within the H-2 duction of a B10. A congenic strain. Such recombinant complex Figure 7-4 depicts haplotypes present in several re- strains have been extremely useful in analyzing the MHC be- binant congenic strains that were obtained during pro- cause they permit comparisons of functional differences
except at a single genetic locus or region. Any phenotypic differences that can be detected between congenic strains are related to the genetic region that distinguishes the strains. Congenic strains that are identical with each other except at the MHC can be produced by a series of crosses, backcrosses, and selections. Figure 7-3 outlines the steps by which the H-2 complex of homozygous strain B can be introduced into the background genes of homozygous strain A to generate a congenic strain, denoted A.B. The first letter in a congenic strain designation refers to the strain providing the genetic background and the second letter to the strain providing the genetically different MHC region. Thus, strain A.B will be genetically identical to strain A except for the MHC locus or loci contributed by strain B. During production of congenic mouse strains, a crossover event sometimes occurs within the H-2 complex, yielding a recombinant strain that differs from the parental strains or the congenic strain at one or a few loci within the H-2 complex. Figure 7-4 depicts haplotypes present in several recombinant congenic strains that were obtained during production of a B10.A congenic strain. Such recombinant strains have been extremely useful in analyzing the MHC because they permit comparisons of functional differences Major Histocompatibility Complex CHAPTER 7 165 F2 a/a b/b × a/b a /b × Strain-A skin grafts Cross Interbreeding Select for b/b at H-2 complex F1 a/a a/b a/b b/b Strain A × a/b a/b × Backcross Interbreed, select, and backcross for ≤ 10 cycles ≤ Strain A•B a/a FIGURE 7-3 Production of congenic mouse strain A.B, which has the genetic background of parental strain A but the H-2 complex of strain B. Crossing inbred strain A (H-2a ) with strain B (H-2b ) generates F1 progeny that are heterozygous (a/b) at all H-2 loci. The F1 progeny are interbred to produce an F2 generation, which includes a/a, a/b, and b/b individuals. The F2 progeny homozygous for the B-strain H-2 complex are selected by their ability to reject a skin graft from strain A; any progeny that accept an A-strain graft are eliminated from future breeding. The selected b/b homozygous mice are then backcrossed to strain A; the resulting progeny are again interbred and their offspring are again selected for b/b homozygosity at the H-2 complex. This process of backcrossing to strain A, intercrossing, and selection for ability to reject an A-strain graft is repeated for at least 12 generations. In this way A-strain homozygosity is restored at all loci except the H-2 locus, which is homozygous for the B strain. Strain Parental Congenic Recombinant congenic A B10 B10.A B10.A (3R) B10.A (2R) B10.A (4R) B10.A (18R) H-2 haplotype a b a i3 h2 h4 i18 KA A E E S D H-2 loci β β α α FIGURE 7-4 Examples of recombinant congenic mouse strains generated during production of the B10.A strain from parental strain B10 (H-2b ) and parental strain A (H-2a ). Crossover events within the H-2 complex produce recombinant strains, which have a-haplotype alleles (blue) at some H-2 loci and b-haplotype alleles (orange) at other loci. 8536d_ch07_161-184 8/16/02 12:09 PM Page 165 mac100 mac 100: 1268_tm:8536d:Goldsby et al. / Immunology 5e-: