Chapter+07(1).pdf

genes”;their current designation as histocompatibility-2(H-2)genes was in reference to Gorers group II blood-groupantigens.Although Gorer died before his contributions wererecognized fully,Snell was awarded the Nobel prize in 1980for this work.The MHC Encodes Three Major Classes of MoleculesThe major histocompatibility complex is a collection ofgenes arrayed within a long continuous stretch of DNA onchromosome 6 in humans and on chromosome 17 in mice.The MHC is referred to as the HLA complex in humans andas the H-2 complex in mice.Although the arrangement ofgenes is somewhat different,in both cases the MHC genes areorganized into regions encoding three classes of molecules(Figure 7-1):IClass I MHC genes encode glycoproteins expressed onthe surface of nearly all nucleated cells;the majorfunction of the class I gene products is presentation ofpeptide antigens to TCcells.chapter 7IGeneral Organization and Inheritance of the MHCIMHC Molecules and GenesIDetailed Genomic Map of MHC GenesICellular Distribution of MHC MoleculesIRegulation of MHC ExpressionIMHC and Immune ResponsivenessIMHC and Disease SusceptibilityMajorHistocompatibilityComplexE possesses a tightly linked cluster of genes,the ma-jor histocompatibility complex(MHC),whoseproducts play roles in intercellular recognition and in dis-crimination between self and nonself.The MHC partici-pates in the development of both humoral and cell-mediated immune responses.While antibodies may reactwith antigens alone,most T cells recognize antigen onlywhen it is combined with an MHC molecule.Furthermore,because MHC molecules act as antigen-presenting struc-tures,the particular set of MHC molecules expressed by anindividual influences the repertoire of antigens to which thatindividuals THand TCcells can respond.For this reason,theMHC partly determines the response of an individual toantigens of infectious organisms,and it has therefore beenimplicated in the susceptibility to disease and in the devel-opment of autoimmunity.The recent understanding thatnatural killer cells express receptors for MHC class I antigensand the fact that the receptorMHC interaction may lead toinhibition or activation expands the known role of this genefamily(see Chapter 14).The present chapter examines theorganization and inheritance of MHC genes,the structure ofthe MHC molecules,and the central function that thesemolecules play in producing an immune response.General Organization andInheritance of the MHCThe concept that the rejection of foreign tissue is the resultof an immune response to cell-surface molecules,now calledhistocompatibility antigens,originated from the work ofPeter Gorer in the mid-1930s.Gorer was using inbred strainsof mice to identify blood-group antigens.In the course ofthese studies,he identified four groups of genes,designatedI through IV,that encoded blood-cell antigens.Work carriedout in the 1940s and 1950s by Gorer and George Snell estab-lished that antigens encoded by the genes in the group desig-nated II took part in the rejection of transplanted tumorsand other tissue.Snell called these genes“histocompatibilityPresentation of Vesicular Stomatitis Virus Peptide(top)and Sendai Virus Nucleoprotein Peptide by Mouse MHCClass I Molecule H-2Kb8536d_ch07_161-184 8/15/02 8:41 PM Page 161 mac114 Mac 114:2nd shift:IClass II MHC genes encode glycoproteins expressedprimarily on antigen-presenting cells(macrophages,dendritic cells,and B cells),where they present processedantigenic peptides to THcells.IClass III MHC genes encode,in addition to otherproducts,various secreted proteins that have immunefunctions,including components of the complementsystem and molecules involved in inflammation.Class I MHC molecules encoded by the K and D regions inmice and by the A,B,and C loci in humans were the firstdiscovered,and they are expressed in the widest range ofcell types.These are referred to as classical class I molecules.Additional genes or groups of genes within the H-2 or HLAcomplexes also encode class I molecules;these genes aredesignated nonclassical class I genes.Expression of the non-classical gene products is limited to certain specific celltypes.Although functions are not known for all of thesegene products,some may have highly specialized roles inimmunity.For example,the expression of the class I HLA-G molecules on cytotrophoblasts at the fetal-maternal in-terface has been implicated in protection of the fetus frombeing recognized as foreign(this may occur when paternalantigens begin to appear)and from being rejected by ma-ternal TCcells.The two chains of the class II MHC molecules are en-coded by the IA and IE regions in mice and by the DP,DQ,and DR regions in humans.The terminology is somewhatconfusing,since the D region in mice encodes class I MHCmolecules,whereas the D region(DR,DQ,DP)in humansrefers to genes encoding class II MHC molecules!Fortu-nately,the designation D for the general chromosomal loca-tion encoding the human class II molecules is seldom usedtoday;the sequence of the entire MHC region is available sothe more imprecise reference to region is seldom necessary.As with the class I loci,additional class II molecules en-coded within this region have specialized functions in theimmune process.The class I and class II MHC molecules have commonstructural features and both have roles in antigen processing.By contrast,the class III MHC region,which is flanked by theclass I and II regions,encodes molecules that are critical toimmune function but have little in common with class I or IImolecules.Class III products include the complement com-ponents C4,C2,BF(see Chapter 13),and inflammatory cy-tokines,including tumor necrosis factor(TNF)andheat-shock proteins(see Chapter 12).162PART IIGeneration of B-Cell and T-Cell ResponsesV I S U A L I Z I N G C O N C E P T SFIGURE 7-1Simplified organization of the major histocompat-ibility complex(MHC)in the mouse and human.The MHC is re-ferred to as the H-2 complex in mice and as the HLA complex inhumans.In both species the MHC is organized into a number ofregions encoding class I(pink),class II(blue),and class III(green)gene products.The class I and class II gene productsshown in this figure are considered to be the classical MHC mol-ecules.The class III gene products include complement(C?)pro-teins and the tumor necrosis factors(TNF-?and TNF-?).IIIIIComplexMHC classRegionGeneproductsIAC proteinsH2KH2LH2DIETNF-TNF-TNF-TNF-H2IIDSIEIAKIIIComplexMHC classRegionGeneproductsDQC proteinsHLA-AHLA-CHLA-BDRHLAIIIACBC4,C2,BFDRDQDPHuman HLA complexMouse H-2 complexDP8536d_ch07_161-184 8/16/02 12:09 PM Page 162 mac100 mac 100:1268_tm:8536d:Goldsby et al./Immunology 5e-:Allelic Forms of MHC Genes Are Inherited in Linked Groups Called HaplotypesAs described in more detail later,the loci constituting theMHC are highly polymorphic;that is,many alternativeforms of the gene,or alleles,exist at each locus among thepopulation.The genes of the MHC loci lie close together;forexample,the recombination frequency within the H-2 com-plex(i.e.,the frequency of chromosome crossover eventsduring mitosis,indicative of the distance between given genesegments)is only 0.5%crossover occurs only once in every200 mitotic cycles.For this reason,most individuals inheritthe alleles encoded by these closely linked loci as two sets,onefrom each parent.Each set of alleles is referred to as a haplo-type.An individual inherits one haplotype from the motherand one haplotype from the father.In outbred populations,the offspring are generally heterozygous at many loci and willexpress both maternal and paternal MHC alleles.The allelesare codominantly expressed;that is,both maternal and pater-nal gene products are expressed in the same cells.If mice areinbred(that is,have identical alleles at all loci),each H-2 lo-cus will be homozygous because the maternal and paternalhaplotypes are identical,and all offspring therefore expressidentical haplotypes.Certain inbred mouse strains have been designated asprototype strains,and the MHC haplotype expressed bythese strains is designated by an arbitrary italic superscript(e.g.,H-2a,H-2b).These designations refer to the entire set ofinherited H-2 alleles within a strain without having to listeach allele individually(Table 7-1).Different inbred strainsmay 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-2complex.If two mice from inbred strains having different MHChaplotypes are bred to one another,the F1generation inher-its haplotypes from both parental strains and therefore ex-presses both parental alleles at each MHC locus.For exam-ple,if an H-2bstrain is crossed with an H-2k,then the F1in-herits both parental sets of alleles and is said to be H-2b/k(Figure 7-2a).Because such an F1expresses the MHC pro-teins of both parental strains on its cells,it is histocompatiblewith both strains and able to accept grafts from eitherparental strain(see example in Figure 7-2b).However,nei-ther of the inbred parental strains can accept a graft from theF1mice because half of the MHC molecules will be foreign tothe parent.The inheritance of HLA haplotypes from heterozygoushuman parents is illustrated in Figure 7-2c.In an outbredpopulation,each individual is generally heterozygous at eachlocus.The human HLA complex is highly polymorphic andmultiple alleles of each class I and class II gene exist.How-ever,as with mice,the human MHC loci are closely linkedand usually inherited as a haplotype.When the father andmother have different haplotypes,as in the example shown(Figure 7-2c)there is a one-in-four chance that siblings willinherit the same paternal and maternal haplotypes andtherefore be histocompatible with each other;none of theoffspring will be histocompatible with the parents.Although the rate of recombination by crossover is lowwithin 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),andthe 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 unrelatedindividuals to have identical sets of HLA genes.MHC Congenic Mouse Strains Are Identicalat All Loci Except the MHCDetailed analysis of the H-2 complex in mice was madepossible by the development of congenic mouse strains.In-bred mouse strains are syngeneic or identical at all geneticloci.Two strains are congenicif they are genetically identicalMajor Histocompatibility ComplexCHAPTER7163TABLE 7-1H-2 Haplotypes of some mouse strainsH-2 ALLELESPrototype strainOther strains with the same haplotypeHaplotypeKIAIESDCBAAKR,C3H,B10.BR,C57BRkkkkkkDBA/2BALB/c,NZB,SEA,YBRddddddC57BL/10(B10)C57BL/6,C57L,C3H.SW,LP,129bbbbbbAA/He,A/Sn,A/Wy,B10.AakkkddA.SWB10.S,SJLssssssA.TLt1skkkdDBA/1STOLI,B10.Q,BDPqqqqqq8536d_ch07_161-184 8/16/02 8:28 AM Page 163 mac100 mac 100:1268_tm:8536d:Goldsby et al./Immunology 5e-:(a)Mating of inbred mouse strains with different MHC haplotypesb/bb/bb/bb/bb/kb/kk/kk/kk/kb/kF1 progeny(H-2b/k)H-2k parentH-2b parentHomologous chromosomes with MHC loci(b)Skin transplantation between inbred mouse strains with same or different MHC haplotypesParental recipientSkin graft donorParentProgeny recipientb/bb/kb/kk/kProgenyb/bk/kb/kk/kParent(c)Inheritance of HLA haplotypes in a typical human familyParentsProgenyA/BC/DB/RA/CA/DB/CB/D(d)A new haplotype(R)arises from recombination of maternal haplotypes17w3211ABCHLA AllelesDRDQDP28w2322344w44131135w17343AHaplotypesBCDR44w47345e2FIGURE 7-2(a)Illustration of inheritanceof MHC haplotypes in inbred mouse strains.The letters b/b designate a mouse homozy-gous for the H-2bMHC haplotype,k/k ho-mozygous for the H-2khaplotype,and b/k aheterozygote.Because the MHC loci areclosely linked and inherited as a set,theMHC haplotype of F1 progeny from the mat-ing of two different inbred strains can be pre-dicted easily.(b)Acceptance or rejection ofskin grafts is controlled by the MHC type ofthe inbred mice.The progeny of the cross be-tween two inbred strains with different MHChaplotypes(H-2band H-2k)will express bothhaplotypes(H-2b/k)and will accept graftsfrom either parent and from one another.Neither parent strain will accept grafts fromthe offspring.(c)Inheritance of HLA haplo-types in a hypothetical human family.In hu-mans,the paternal HLA haplotypes arearbitrarily designated A and B,maternal Cand D.Because humans are an outbredspecies and there are many alleles at eachHLA locus,the alleles comprising the haplo-types must be determined by typing parentsand progeny.(d)The genes that make upeach parental haplotype in the hypotheticalfamily in(c)are shown along with a new hap-lotype that arose from recombination(R)ofmaternal haplotypes.8536d_ch07_161-184 8/16/02 12:09 PM Page 164 mac100 mac 100:1268_tm:8536d:Goldsby et al./Immunology 5e-:except at a single genetic locus or region.Any pheno-typic differences that can be detected between congenicstrains are related to the genetic region that distinguishesthe strains.Congenic strains that are identical with eachother except at the MHC can be produced by a series ofcrosses,backcrosses,and selections.Figure 7-3 outlines thesteps by which the H-2 complex of homozygous strain Bcan be introduced into the background genes of homozy-gous strain A to generate a congenic strain,denoted A.B.The first letter in a congenic strain designation refers to thestrain providing the genetic background and the secondletter to the strain providing the genetically different MHCregion.Thus,strain A.B will be genetically identical tostrain A except for the MHC locus or loci contributed bystrain B.During production of congenic mouse strains,a crossoverevent sometimes occurs within the H-2 complex,yielding arecombinant strain that differs from the parental strains orthe congenic strain at one or a few loci within the H-2 complex.Figure 7-4 depicts haplotypes present in several re-combinant congenic strains that were obtained during pro-duction of a B10.A congenic strain.Such recombinantstrains have been extremely useful in analyzing the MHC be-cause they permit comparisons of functional differences Major Histocompatibility ComplexCHAPTER7165F2a/ab/ba/ba/bStrain-A skin graftsCrossInterbreedingSelect for b/bat H-2 complexF1a/aa/ba/bb/bStrain Aa/ba/bBackcrossInterbreed,select,andbackcross for 10 cycles Strain ABa/aFIGURE 7-3Production of congenic mousestrain A.B,which has the genetic background ofparental strain A but the H-2 complex of strain B.Crossing inbred strain A(H-2a)with strain B(H-2b)generates F1progeny that are heterozygous(a/b)at all H-2 loci.The F1progeny are interbred to pro-duce an F2generation,which includes a/a,a/b,and b/b individuals.The F2progeny homozygousfor the B-strain H-2 complex are selected by theirability to reject a skin graft from strain A;any prog-eny t