第六章 MHC生理学

E-A
Y-F A-V
Silent
A-D A-E
I-L
DPB1*01011 TAC GCG CGC TTC GAC AGC GAC GTG GGG GAG TTC CGG GCG GTG ACG GAG CTG GGG CGG CCT GCT GCG GAG TAC TGG AAC AGC CAG AAG GAC ATC CTG GAG GAG DPB1*01012 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --DPB1*02012 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --DPB1*02013 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AC -A- --- --- --- --- --- --- --- --- --- --- --- --DPB1*0202 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --DPB1*0301 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --DPB1*0401 -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --DPB1*0402 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --DPB1*0501 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --DPB1*0601 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --DPB1*0801 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --DPB1*0901 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- --- --- --- --DPB1*1001 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --DPB1*11011 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- C-- --- --- --DPB1*11012 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- C-- --- --- --DPB1*1301 --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --DPB1*1401 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --DPB1*1501 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- C-- --- --- --DPB1*1601 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --DPB1*1701 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- --- --- --- --DPB1*1801 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- --- --- --- --DPB1*1901 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --DPB1*20011 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --DPB1*20012 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --C --- --- --- --- --- --- --- C-- --- --- --DPB1*2101 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --DPB1*2201 CT- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --DPB1*2301 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --DPB1*2401 -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -AG --- --- --- --- --- --- --- --- --- --- --- --- --DPB1*2501 -T- -T- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- -A- -A- --- --- --- --- --- --- --- --- C-- --- --- --DPB1*26011 --- --- --- --- --- --- --- --- --A --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --DPB1*26012 --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- --- ---
No of polymorphisms
198 8 2 15
A B C EFG
Data from /HIG/index.html September 2005
MHC Class II 基因的多态性
人类有超过700个MHC class II 复等位基因
No of polymorphisms
and Its Relevance to Alloreactivity (Baruj Benacerraf )
(Baruj Benacerraf held his Nobel Lecture on 8 December 1980, at Karolinska Institutet, Stockholm)
Jean Dausset鉴定出人MHC基因（称为HLA）
HLA ( Human leukocyte antigen)
HLA was discovered by searching for cell surface molecules in one individual that would be recognized as foreign by another individual
(Figure hasn’t changed since October 2003)
62
28 10
A BC
25 96
DR DQ DP
Data from /HIG/index.html September 2005
绝大多数的MHC多态性都是点突变，发生在抗原结合部位
Jean Dausset
leukocyte because the antibodies were tested by binding to the leukocytes of other individuals, and antigens because the molecules were recognized by antibodies
• 各种哺乳动物都拥有主要组织相容性复合体（major histocompatibility complex, MHC)，人的MHC统称为HLA。
• MHC在启动特异性免疫应答中起重要作用。
IMMUNE GRAFT REJECTION
Snell 制备了小鼠近交系，率先开展了免疫排斥机制的研究
1940s
结论： 移植排斥反应是由于抗原依赖的免疫反应，而且这种免疫反应具有记忆性
Parental strains
F1 hybrid (one set of alleles from each parent)
X A
AxB
A
B
AxB
父代移植到子代 ACCEPTED
子代移植到父代 REJECTED
B
Байду номын сангаас
A single genetic region is identified by Snell‘s group, which is primarily responsible for rapid rejection of tissue grafts, and this region was named the major histocompatibility-2, or simply H-2
MHC I基因: 经典的HLA-B, HLA-C, HLA-A，非经典的HLA-E, -F, -G, -H, J , -X。这些基因编码MHC I类分子的链（β2链由非HLA基因编码）。
III类基因区主要编码补体蛋白和炎症因子等，如C4, C2, B因子基因；某些 细胞因子基因，如TNF基因，LT基因；分子伴侣基因，如HSP70基因等。
mhc基因的多态性人类mhc基因的突变率大于1整个人类有1318个mhci的等位基因包括无意突变同义突变和编码区外突变733个mhcii复等位基因datafromwwwanthonynolanorgukhigindexhtmlseptember20056993961981318alleles998october2003657july200015classmhcclassii基因的多态性人类有超过700个mhcclassii复等位基因494231192866datafromwwwanthonynolanorgukhigindexhtmlseptember2005733alleles668october2003492july2000drdpdqdmdoclassiib1a1b1a1b1100antigensclassii40antigensfigurehasntchangedsinceoctober200328622510dqdpmhcclassii抗原的血清型mhc分子的多样性可以用mhc特异性的抗体来鉴定称为血清型seratype血清型的数量远远低于dna序列的多样性datafromwwwanthonynolanorgukhigindexhtmlseptember2005dpb101011tacgcgcgcttcgacagcgacgtgggggagttccgggcggtgacggagctggggcggcctgctgcggagtactggaacagccagaaggacatcctggaggagdpb101012dpb10202ctdpb10501ctdpb12101ctdpb12201ct30hladpallelesequencesbetweennucleotides204290aminoacids3568绝大多数的mhc多态性都是点突变发生在抗原结合部位yfavsilentadaeeailpolymorphicnucleotidesencodeaminoacidsassociatedpeptidebindingsitemhcallelemhcallelemhc的多态性影响抗原肽的结合mhc的口袋形状抗原结合沟槽的壁沟槽底部的改变都会影响抗原肽与mhc的结合和抗原肽的呈递