MHC & HLA

Departemen MikrobiologiFK USU

DefinitionsHistocompatibility Antigen adalah Antigen yang terdapat pada sel / jaringan yang berperan pada reaksi penolakan terhadap organ transplant

DefinitionsMajor Histocompatibility Antigen adalah Histocompatibility Antigen yang memberikan respon imun yang sangat kuat & berperan penting pada peristiwa penolakan organ transplant

DefinitionsMajor Histocompatibility Complex : group of genes on a single chromosome encoding the MHC antigensSekelompok atau kompleks gen pada satu kromosom yang memberi kode pd MHC antigen

Kelompok gen tersebut dikenal sebagai lokus awal menentukan ekspresi molekul-molekul permukaan sel tubuhSel-sel tubuh yang bernukleus memiliki epitop permukaan yang ekspresinya sudah ditentukan secara genetikContoh : Sel darah merah yang memiliki Antigen A, B dan Rh (rhesus)

DefinitionsHuman Leucocyte Antigen = HLA adalah MHC Antigen pada manusiaAntigen permukaan tersebut pertama kali digambarkan pada leukositPada penderita yang telah mendapat transfusi darah berulangkali ditemukan Ab yang dapat menggumpalkan lekosit human leucocyte antigen

Kompleks HLA HLA-AHLA-BHLA-CHLA-D (dipecah menjadi HLA-DR, HLA-DQ, dan terakhir ditemukan HLA-DP)Setiap lokus polimorf & masih terdiri atas beberapa haplotypeSetiap haplotype menentukan pembentukan molekul permukaan sel ciri Ag tersebut

MHC gen pada manusia

Pembagian MHCMolekul MHC kelas I dan kelas II berperan pada pengenalan imun yaitu pada presentasi fragmen Antigen kepada sel TBerdasarkan rumus bangunnya, MHC dapat dibagi menjadi 3 golongan

Terdiri dari : kompleks HLA-A, HLA-B dan HLA-CMenetapkan ekspresi atau Ag permukaan kelas I beupa protein pada membran permukaan semua sel tubuh yang memiliki nukleus dan trombositMengikat peptida molekul lain yg diproduksi dlm selContoh : protein virus ditranspor ke permukaan sel bersama MHC kelas I sehingga kompleks MHC kelas I & peptida dikenal oleh sel T CD8+ (sitotoksik)Molekul MHC kelas I

Molekul MHC kelas IITerdiri dari : kompleks HLA-D (DR dan DQ) dan HLA-DP

Menetapkan ekspresi atau Ag permukaan sel kelas II imuno-kompeten seperti sel B, monosit, makrofag, APC (antigen presenting cells) dan sel T (yg diaktifkan)

Mengikat peptida sesudah diproses sel APC dibawa ke permukaan sel dikenali oleh sel CD4+ permulaan respon imun

Molekul MHC kelas III

Sejumlah protein yg ekspresinya ditentukan oleh MHC kelas III : komponen komplemen (C2,C4), faktor B properdin, TNF (Tumor Necrosis Factor) dan Lymphotoxin (LT), bbp jenis enzim, heat shock protein tertentu & molekul pengangkut yg diperlukan dlm proses antigenAntigen MHC kelas III tidak mempunyai peranan pada respon imun yang menentukan bertahannya suatu organ transplan

JaringanMHC Kelas IMHC Kelas IISel sistem imunSel B++++++Sel susunan saraf Perifer+++-Sel saluran napasTrakhea++++++HatiSel sinusoid++++++EndotelKapiler(kec otak& plasenta++++++

MHC locus-allele-haplotype Lokus MHC sangat polimorfikTerdapat banyak alternatif pasangan allele pada 1 lokusLokus berhubungan erat satu dengan yang lainPasangan allele disebut HAPLOTYPESeseorang mendapatkan haplotype (pasangan allele) dari ibu dan dari ayahnya Pasangan allele diekspresikan scr codominan

Human Leucocyte AntigenHuman MHC/HLA terletak pada kromosom 6Nomenklatur : spesifisitas HLA diidentifikasikan dengan Huruf & nomor (A1,B5,dll).Haplotype diidentifikasi dengan spesifisitas individu (cth A1,B7,Cw4,DP5,DQ10,DR8)

Lokus HLA ILokus HLA IIHLA-AHLA-BHLA-CHLA-DPHLA-DQHLA-DRA1A2A3AIIA24(9)A25(10)A29 (w19)Aw68 (28)B7B8B13B14B38(16)B39(16)Bw41Bw52 (5)Bw47Cw1Cw2Cw3Cw5Cw6Cw7Cw11DPw1DPw2DPw3DPw4DPw5DPw6DPCp63DQw5(w1)DQw6(w1)DQw7(w3)DQw9(w3)DR1DRw15(2)DRw16(2)DRw17(3)DRw18(3)

Inheritance of MHC allelesA/C A/D B/C B/D A/R1 R2/C R2/R1R1=C-D recombinationR2=A-B recombinationPossible children of parents with HLA haplotype A/B and C/D

MHC products expressed on cellsIf Jack and Jill have four children; Bo, Kim, Mo and LeeTheyll all inherit antigens of the parental MHCOf their haplotypes will be of the father or motherUnless during meiosis, a crossover should occur

The inheritance of MHC genes

MHC products expressed on cells

Crossing overresults in new haplotypes

Fungsi MHC Molekul MHC kelas I meliputi antigen HLA-A,HLA-B,HLA-C dapat dikenali sel Tc yang berperan pada penolakan organ transplantMolekul MHC kelas I disebut pula Antigen Transplantasi

Cytotoxic T cells (Tc)Menghancurkan sel yang terinfeksi oleh pathogen intraselular dan sel kankerMolekul MHC kelas I (pada sel tubuh bernukleus) mengekspresikan protein asingAktivitas diperbesar oleh protein permukaan CD8 yang dipresentasikan oleh kebanyakan sel T cytotoxic (Tc) mirip dengan CD4 & MHC kelas II Sel Tc melepaskan perforin : protein yang membentuk pori2 pada membran sel target sehingga sel menjadi lysis dan pathogen akan terekspos pada Anibodi yg bersirkulasi

Fungsi MHCPeranan fisiologis HLA kelas II untuk memberikan sinyal respon imun terhadap Th yang berinteraksi dengan sel APC (antigen presenting cell) di satu pihak, dengan sel B di pihak lain.Distribusi HLA kelas II bersifat terbatas supaya aktivasi sel Th juga hanya pada keadaan tertentu sajaMHC kelas II : mengawasi interaksi antara sel-sel imunokompeten

Helper T lymphocytes (Th)Berfungsi pada Imunitas Humoral & Imunitas SelulerDistimulasi oleh antigen presenting cells (APC)Permukaan T cell (protein CD4) mendorong aktivasiCytokines disekresi (stimulasi lymphocyte lainnya):a) interleukin-2 (IL-2): mengaktivasi sel B dan sel T cytotoxic (Tc)b) interleukin-1 (IL-1): mengaktivasi sel T helper (Th) T untuk menghasilkan IL-2

Fungsi MHCOleh karena aktivasi sel Th merupakan respon imun, molekul MHC kelas II disebut pula Antigen Ia (Immune respons associated)

*The MHC GENE COMPLEX:

The MHC complex contains a number of genes that control several antigens, most of which influence allograft rejection. These antigens (and their genes) can be divided into three major classes: class I, classII and classIII. The classI and classII antigens are expressed on cells and tissues whereas as classIII antigens are represented on proteins in serum and other body fluids (e.g.C4, C2, factor B, TNF). Antigens of classIII gene products have no role in graft rejection.

Human MHC:Class I MHC:

The classI gene complex contains three major loci, B, C and A and other undefined minor loci (Figure 1). Each major locus codes for a polypeptide, "-chain that contains antigenic determinants, is polymorphic (has many alleles) and associates with $-2 microglobulin ($-chain) and expressed the cell surface.

Class II MHC:

The classII gene complex also contains at least three loci, DP, DQ and DR; each of these loci codes for "- and one chain polypeptides which associate together to form the classII antigens. Like the classI antigens, the classII antigens are also polymorphic. DR locus may contain more than one (up to 4) functional $-chain genes.

Mouse MHC:

The mouse MHC is located on chromosome 17.

Class I MHC:

It consists of two major loci, K and D. Unlike the human MHC, the mouse classI gene complex loci are not together but they are separated by classII and classIII genes.

Class II MHC:

The classII gene complex contains two loci, A and E each of which code for one " and one chain polypeptide, which form one classII molecule. The mouse classII gene complex is also known as the I region and the genes in this complex are referred to as Ir (immune response) genes since they control the magnitude of immune responsiveness of different mouse strains to certain antigens. Products of A and E loci are also termed IA and IE antigens, collectively known as Ia antigens.*Inheritance:

MHC genes are inherited as a group (haplotype), one from each parent. Thus, a heterozygous human inherits one paternal and one maternal haplotype, each containing three class-I (B, C and A) and three classII (DP, DQ and DR) loci. Therefore, a heterozygous individual can inherit a maximum of 6 class I specificities (Figure 2). Since the class II MHC molecule consists of two chains, with some antigenic determinants (specificities) on each chain, and they can associate in cis (along the DNA strand) or trans (across two DNA strands) combination, each individual can have four specificities for each of the three class II loci. Likewise, a heterozygous mouse inherits one haplotype from each parent containing two class-I loci (K and D) and two classII loci (A and E), each in two allelic forms. It, can therefore, express on its cells a total of 8 MHC antigens (2classI antigens and 2 classII antigens from each parent). *Inheritance:

MHC genes are inherited as a group (haplotype), one from each parent. Thus, a heterozygous human inherits one paternal and one maternal haplotype, each containing three class-I (B, C and A) and three classII (DP, DQ and DR) loci. Therefore, a heterozygous individual can inherit a maximum of 6 class I specificities (Figure 2). Since the class II MHC molecule consists of two chains, with some antigenic determinants (specificities) on each chain, and they can associate in cis (along the DNA strand) or trans (across two DNA strands) combination, each individual can have four specificities for each of the three class II loci. Likewise, a heterozygous mouse inherits one haplotype from each parent containing two class-I loci (K and D) and two classII loci (A and E), each in two allelic forms. It, can therefore, express on its cells a total of 8 MHC antigens (2classI antigens and 2 classII antigens from each parent). *Inheritance:

MHC genes are inherited as a group (haplotype), one from each parent. Thus, a heterozygous human inherits one paternal and one maternal haplotype, each containing three class-I (B, C and A) and three classII (DP, DQ and DR) loci. Therefore, a heterozygous individual can inherit a maximum of 6 class I specificities (Figure 2). Since the class II MHC molecule consists of two chains, with some antigenic determinants (specificities) on each chain, and they can associate in cis (along the DNA strand) or trans (across two DNA strands) combination, each individual can have four specificities for each of the three class II loci. Likewise, a heterozygous mouse inherits one haplotype from each parent containing two class-I loci (K and D) and two classII loci (A and E), each in two allelic forms. It, can therefore, express on its cells a total of 8 MHC antigens (2classI antigens and 2 classII antigens from each parent). *Crossover:

Haplotypes, normally, are inherited intact and hence antigens encoded by different loci are inherited together (e.g., A2; B27; Cw2; DPw6; DQw9; DRw2). However, on occasions, there is crossing over between two parental chromosomes, thereby resulting in new recombinant haplotypes. Thus, any one specificity encoded by one locus may combine with specificities from other loci. This results in vast heterogeneity in the MHC make-up in a given population.