in the mammalian genome and , more specifically , in the human genome the most variable region known forms the major histocompatibility complex ( mhc ) that carries a great number of different loci coding for functional genes . some of these genes also exhibit many variants ( alleles ) , characterizing an extremely polymorphic region . these genes belong to the human leukocyte antigen ( hla ) system and code for the major molecules in charge of antigen presentation on the cell surface . the hla system was described by j. dausset , in 1958 , in a work which earned him the nobel prize , in 1980 . up to april 2014 , a total of 11,225 sequenced alleles were known throughout the world , all found in the 30 hla genes located in the mhc genomic region ( http://www.ebi.ac.uk/ipd/imgt/hla/stats.html ) . of note , though the genes are called hla , many authors use mhc to designate the molecules resulting from the expression of these genes , and both names will be used throughout this text . in humans , the mhc region is approximately 4,000-kb - long , located on the short arm of chromosome 6 ( 6p 21.3 ) . these genes , whether or not expressed , are arranged in three genomic regions or classes . the more distal region corresponds to mhc class i , which carries the genes that code for the classic ( 1a ) class i hla- a , -b , and -c heavy chains . an extraordinary degree of polymorphism characterizes these genes ( 2,735 alleles at hla - a , 3,455 alleles at hla - b and 2,259 alleles at hla - c loci ) , and the vast majority of these alleles are functional . there are also so - called non - classic hla loci coding for the expressed , though less variable , genes hla- e , -f , -g , hfe , and the mhc class i chain - related mica and micb . with the notable exception of the mic genes , all class i hla ( hlai ) molecules form heterodimers with the invariant 2-microglobulin chain , coded by a gene on chromosome 15 . all nucleated cells express class i molecules on their cell surface . on the other hand , class ii mhc genes , coding for both chains that will form the functional heterodimer , hla - dr , hla - dq , hla - dp , hla - dm , and hla - do ( 2,649 known alleles ) are located in the more centromeric portion of the mhc region . initially denominated ir ( from immune response ) , from early on these genes were recognized for their control of the immune response . they exhibit restricted expression , being predominantly expressed on antigen - presenting cells ( apc ) , such as macrophages , dendritic cells , langerhans and kupffer cells , as well as b lymphocytes . this is the case for thyrocytes 


  and intestinal epithelial cells 


  where the expression is induced during inflammatory processes . a third genomic region , located between the two , carries numerous genes unrelated to mhc , some of which have important immunological functions . well - known examples are cbf , c2 , and c4a complement genes , a group of tumor necrosis factor ( tnf ) , and heat shock protein 70 ( hsp70 ) chaperoning genes . the list of the many additional genes includes peptide transporter proteins tap1 and tap2 , and psmb8 and psmb9 genes that code for components of the -immunoproteasome , to which we will return later in this text . the genomic organization of the mhc region is an essential feature to understand how the expression and forming of the hla molecules are regulated and coupled to their antigen presenting function . both class i and class ii genes present different regulatory sequences located in their upstream ( 5 ) portion that guarantee constitutive transcription and cytokine - induced regulation of expression , but some are also shared by hla genes of the same class , and therefore , allow parallel transcription . hla genes are also regulated by class - specific trans - activators , respectively cita 


  and ciita , 


  and the ubiquitous nuclear factor kappa b ( nf - kb ) is a hlai regulator shared with many other genes . these and other factors carry out the fine - tuning of hla molecule production and function in each tissue or cell type . just like the class i heterodimer formed by an  heavy chain and 2-microglobulin , class ii molecules are also heterodimers formed by  and  chains , coded by a and b genes , respectively . in the class ii mhc region , we find only hla - dra1 , but depending on the haplotype ( set of genes found on the same chromosome stretch ) one or more expressed hla - drb genes may be seen . therefore , some haplotypes carry one sole hla - drb1 functional allele whereas others carry additional expressed alleles at the hla - drb3 , 4 , or 5 loci . for example , 1,091 different dr beta chains are known . on the other hand , hla - dqa1 and hla - dqb1 , hla - dpa1 , and hla - dpb1 loci , all polymorphic , form hla - dq and hla - dp heterodimers , both in cis and in trans , with similar but not identical structure and function to hla - dr . non - classic class ii genes form the invariant molecules hla - do and hla - dm , which carry out highly specialized functions in peptide presentation . each of us carries a pair of chromosomes 6 hence will express on the surface of a single antigen - presenting cell 1 or 2 hla - a , 1 or 2 hla - b , 1 or 2 hla - c , several hla 1b , in addition to 1 to 4 hla - dr , 1 to 4 hla - dq , 1 to 4 hla - dp molecules , comprising hundreds of thousands different units . as each of us carries a unique set of hla genes , the array of possible combinations expressed by each individual in a given population is enormous . this hla diversity allied to the multiplicity of alleles leads to the extraordinary potential of antigen presentation not only in one individual , but in a group of individuals , a concept extended to a whole population . in contrast with this variability , the basic design of an hlai or hlaii molecule is quite similar , forming a goblet anchored to the cell membrane by way of one or two chains , as short chain 2-microglobulin confers stability without attaching to the membrane . the external part of the goblet , comprising domains alpha 1 and 2 in the class i molecules and domains alpha 1 and beta 1 in the class ii molecules , exhibits a groove , made up of a floor composed of 8 anti - parallel  sheet strands and an -helical border . the hla grooves have pockets where the antigen - derived peptides ( usually 9 amino acids long ) are lodged for presentation to the t - cell receptor ( tcr ) . the hlai groove formed only by the  chain is closed , but the hlaii groove formed by the juxtaposition of  and  chains is open , which permits the lodging of peptides longer than the groove itself . the original papers referred to above also carry detailed computerized views of these complex molecules . the uniqueness of this molecular design is highlighted when the thousands of sequences from the known alleles are compared . the variability of the proteins , reflected in the corresponding dna sequence , is predominantly clustered in certain portions of the genes . these hypervariable regions , as occurs with immunoglobulin receptors and tcr , are found mainly on the external part of the molecule , inside and in the borders of the groove , that is , precisely at the site where the peptides are lodged , in contrast to the rest of the molecule , the alpha 3 domain in the class i molecules and alpha 2 and beta 2 domains in the class ii molecules , where the sequence is highly conserved . the amino acids that form the floor and sides of the groove create a motif or pattern , specific for each allelic variant , which defines what kind of peptide will fit into the groove and bind to that hla molecule . 


  of note , the peptides need only bind to some of the available residues within the groove leaving the rest of the amino acids in the sequence free . in spite of constraints imposed by the unique motif , this limited anchoring allows an impressive variety of peptides to be presented by each hla groove . 


  the single most important reason ensuring the success of peptide presentation by hla molecules becomes clear when we consider the molecules in charge of recognizing the peptide - hla complex : the tcr . tcrs are produced by gene rearrangements carried out by a unique enzymatic complex called rag ( recombination - activating gene ) where gene segments are joined to form a novel gene coding for alpha , beta , gamma , or delta tcrs whilst eliminating the intervening dna sequences . for example , to form the beta chain of a tcr , 52 v ( variable ) segments , 2 d ( diverse ) segments , and 13 j ( joining ) segments are reshuffled to form a single functional vdj segment , which will be processed together with a c ( constant ) segment to form the final beta chain . this tcr dna rearrangement is quite random and thus , each t - lymphocyte will express a unique tcr . researchers calculate that 10  and 10  tcrs can be generated , each with a highly variable portion specifically placed in the part of the molecule contacting the hla - peptide complex . in the second part of this review we will show how these antigens are prepared for presentation to the t - lymphocyte in order to guarantee a recognition that will lead to activation and clonal expansion of the t - cells in charge of the adaptive immune response . finally , the unique design and variability of hla class i molecules serves also to regulate natural killer ( nk ) cells by way of a specific group of receptors , the killer - cell immunoglobulin - like receptors ( kirs ) . though peptides have been shown to interfere in the recognition by kirs , 


  antigen presentation is not involved in the basic functions of these ligand - receptor pairs and is beyond the scope of this article . for more information no genoma de mamferos e , mais especificamente , no genoma humano , a regio mais varivel conhecida forma o complexo principal de histocompatibilidade ( mhc - major histocompatibility complex ) , que carrega um grande nmero de diferentes loci , que codificam genes funcionais . alguns desses genes tambm exibem muitas variantes ( alelos ) , caracterizando uma regio extremamente polimrfica . 


  esses genes pertencem ao sistema de antgenos leucocitrios humanos ( hla , human leukocyte antigen ) e codificam as principais molculas encarregadas da apresentao do antgeno na superfcie celular . o sistema hla foi descrito por j. dausset , em 1958 , em um trabalho que lhe rendeu o prmio nobel , em 1980 . at abril de 2014 , um total de 11.225 alelos sequenciados j era conhecido em todo o mundo , todos encontrados nos 30 genes hla localizados na regio genmica do mhc ( http://www.ebi.ac.uk/ipd/imgt/hla/stats.html ) . importante notar que , embora esses genes sejam conhecidos como hla , muitos autores usam mhc para designar as molculas resultantes da expresso desses genes , e ambos os nomes so usados no decorrer deste texto . em humanos , a regio do mhc , com aproximadamente 4.000 kb de comprimento , localiza - se no brao curto do cromossomo 6 ( 6p 21.3 ) . esses genes , expressos ou no , a regio mais distante corresponde ao mhc de classe i , que contm os genes que codificam as cadeias pesadas clssicas ( 1a ) hla- a , -b , e -c . um grau extraordinrio de polimorfismo caracteriza esses genes ( 2.735 alelos nos lcus em hla - a , 3.455 alelos em hla - b e 2.259 alelos em hla - c ) e a maioria desses alelos  funcional . tambm existem os chamados loci no clssicos de hla de classe i , que codificam os genes hla- e , -f , -g , hfe , e mica e micb ( relacionado a mhc de classe i a e b ) , que so expressos , mas so menos variveis . com a notvel exceo dos genes mic , todas molculas hla de classe i ( hlai ) formam heterodmeros com a cadeia invariante 2-microglobulina , codificada por um gene no cromossomo 15 . por outro lado , os genes mhc de classe ii que codificam as duas cadeias que formam os heterodmeros funcionais hla - dr , hla - dq , hla - dp , hla - dm e hla - do ( 2.649 alelos conhecidos ) se localizam na poro mais centromrica da regio do mhc . inicialmente chamada de ir ( do ingls , immune response ) , desde cedo esses genes tm sido reconhecidos por seu controle da resposta imunolgica . eles exibem expresso restrita , sendo predominantemente expressos em clulas apresentadoras de antgenos ( apc , do ingls antigen - presenting cells ) , como macrfagos , clulas dendrticas , clulas de langerhans e de kupffer , assim como linfcitos b. algumas clulas exibem hla classe ii ( hlaii ) sob certas condies anmalas . este  o caso de tirecitos 


  e de clulas epiteliais intestinais , 


  onde a expresso  induzida durante processos inflamatrios locais . uma terceira regio genmica , localizada entre os dois , carrega numerosos genes no relacionados ao mhc , alguns dos quais tm importantes funes imunolgicas . exemplos bem conhecidos so os genes cbf , c2 e c4a do complemento , o grupo de genes de fatores de necrose tumoral ( tnf ) , e genes que codificam chaperonas , as protenas de choque trmico 70 ( hsp70 ) . 




  a lista dos muitos genes adicionais inclui as protenas transportadoras de peptdeos tap1 e tap2 , e psmb8 e psmb9 , genes que codificam componentes do -imunoproteassomo , ao qual retornaremos mais adiante neste texto . a organizao genmica da regio mhc  um aspecto essencial para a compreenso de como a expresso e a formao das molculas de hla so reguladas e acopladas  sua funo de apresentao de antgeno . tanto genes de classe i como os de classe ii apresentam diferentes sequncias regulatrias localizadas em sua poro  montante ( upstream ) ( 5 ) , que garantem a transcrio constitutiva e a regulao de expresso induzida por citocinas , mas algumas tambm so compartilhadas por genes hla da mesma classe e , portanto , permitem a transcrio em paralelo . os genes hla so tambm regulados por transativadores especficos de classe ( class - specific trans - activators ) , respectivamente cita 


  e ciita , 


  e o fator nuclear kappa b ( nf - kb ) ubquo  um regulador de hlai compartilhado com muitos outros genes . estes e outros fatores so responsveis pelo ajuste fino da produo e funo das molculas hla em cada tecido ou tipo celular . as protenas assim , como o heterodmero de classe i  formado por uma cadeia  pesada e a 2-microglobulina , as molculas de classe ii so tambm heterodmeros formados por cadeias  e  , codificadas pelos genes a e b , respectivamente . na regio mhc de classe ii , encontramos apenas hla - dra1 , mas , dependendo do hapltipo ( conjunto de genes encontrados no mesmo trecho de cromossomos ) , um ou mais genes hla - drb expressos podero ser encontrados . assim , alguns hapltipos carregam um nico alelo funcional hla - drb1 , enquanto outros carregam alelos adicionais expressos nos loci hla - drb3 , 4 ou 5 . por outro lado , os loci hla - dqa1 e hla - dqb1 , hla - dpa1 e hla - dpb1 , todos polimrficos , formam heterodmeros hla - dq e hla - dp , tanto em cis como em trans , com estrutura e funo similar , mas no idntica a de hla - dr . genes no clssicos de classe ii formam as molculas invariantes hla - do e hla - dm , que desempenham funes altamente especializadas na apresentao de peptdeos . cada um de ns carrega um par de cromossomos 6 e , portanto , expressar na superfcie de uma nica clula apresentadora de antgeno 1 ou 2 hla - a , 1 ou 2 hla - b , 1 ou 2 hla - c , vrios hla 1b , alm de 1 a 4 molculas hla - dr , 1 a 4 hla - dq , 1 a 4 hla - dp , perfazendo centenas de milhares de diferentes unidades na superfcie de cada clula . medida que cada um de ns carrega um conjunto singular de genes hla , a diversidade das combinaes possveis presentes em cada indivduo em uma dada populao  imensa . leva ao extraordinrio potencial de apresentao de antgeno no apenas em um indivduo , mas em um grupo de indivduos  um conceito que pode ser estendido para uma populao inteira . em contraste com essa variabilidade , o desenho bsico de uma molcula hlai ou hlaii  muito similar , formando uma taa ancorada  membrana celular , por meio de uma ou duas cadeias , sendo que a cadeia curta 2-microglobulina confere estabilidade sem se fixar na membrana . a parte externa da taa , que inclui os domnios alfa 1 e alfa 2 , nas molculas de classe i , e domnios alfa 1 e beta 1 , nas molculas da classe ii , exibe uma fenda , constituda de um piso composto de 8 fitas antiparalelas , tipo folheto  e uma borda em -hlice . 




  as fendas hla tm bolses em que os peptdeos derivados dos antgenos ( geralmente com comprimento de 9 aminocidos ) esto alojados para apresentao ao receptor de clula - t ( tcr , t - cell receptor ) . a fenda hlai formada apenas pela cadeia   fechada , mas a fenda hlaii formada pela justaposio de cadeias  e   aberta , o que permite o alojamento de peptdeos mais longos que a prpria fenda . a singularidade desse desenho molecular  ainda mais evidente quando as milhares de sequncias dos alelos conhecidos so comparadas . a variabilidade das protenas , refletidas na sequncia correspondente de dna ,  predominantemente agrupada em certas pores dos genes . essas regies hipervariveis , como ocorre com receptores de imunoglobulina e tcr , so encontradas principalmente na parte externa da molcula , dentro e nas bordas da fenda , isto  , bem no local onde os peptdeos esto alojados , em contraste com o resto da molcula , ou seja , o domnio alfa 3 nas molculas classe i , e domnios alfa 2 e beta 3 nas molculas de classe ii , onde a sequncia  muito preservada . os aminocidos que formam o piso e os lados da fenda criam um motivo ou padro , especfico para cada alelo , que define o tipo de peptdeo que se encaixar na fenda , ligando - se quela molcula hla . importante salientar que os peptdeos necessitam apenas se fixar a alguns dos resduos disponveis dentro da fenda , deixando o restante dos aminocidos na sequncia livre . a despeito das limitaes impostas por um padro nico , esse ancoramento limitado permite que uma variedade impressionante de peptdeos seja apresentada por cada fenda hla . a principal razo de garantia do sucesso de apresentao de peptdeos por molculas hla se torna clara quando consideramos as molculas responsveis por reconhecer o complexo peptdeo - hla : o tcr . os tcrs so produzidos por rearranjos de genes desenvolvidos por um complexo enzimtico singular , chamado rag ( recombination - activating gene ) , em que segmentos de genes so ajuntados para formar um novo gene que codifica tcrs alfa e beta , ou gama e delta , enquanto elimina as sequncias de dna intervenientes . por exemplo , para formar a cadeia beta de um tcr , 52 segmentos v ( variveis ) , 2 segmentos d ( diversos ) e 13 segmentos j ( juncionais ) so redistribudos de maneira a formar um nico segmento funcional vdj , que ser processado juntamente de um segmento c ( constante ) , para formar a cadeia beta final . esse rearranjo do dna dos genes de tcr  bem aleatrio e , assim , cada linfcito - t expressar um tcr singular . pesquisadores calculam que 10  e 10  tcrs podem ser gerados , cada qual com uma poro altamente varivel especificamente posicionada na parte da molcula de contato com o complexo hla - peptdeo . na segunda parte desta reviso , mostraremos como esses antgenos so preparados para apresentao ao linfcito t a fim de garantir um reconhecimento , que levar  ativao e  expanso clonal das clulas - t encarregadas da resposta imune de adaptao . finalmente , o desenho nico e a variabilidade das molculas hla classe i servem tambm para regular as clulas natural killer ( nk ) por meio de um grupo especfico de receptores similares a imunoglobulinas , chamados killer - cell immunoglobulin - like receptors ( kirs ) . embora tenha sido demonstrado que peptdeos interferem no reconhecimento por kirs , 


  a apresentao de antgenos no est envolvida nas funes bsicas desses pares de ligante - receptor e est alm do escopo deste artigo .
the setting for the occurrence of an immune response is that of the need to cope with a vast array of different antigens from both pathogenic and non - pathogenic sources . 
 when the first barriers against infection and innate defense fail , adaptive immune response enters the stage for recognition of the antigens by means of extremely variable molecules , namely immunoglobulins and t - cell receptors . 
 the latter recognize the antigen exposed on cell surfaces , in the form of peptides presented by the hla molecule . 
 the first part of this review details the central role played by these molecules , establishing the close connection existing between their structure and their antigen presenting function .