医学免疫学课件：The Significant MHC

1、The Significant MHCIntroduction to MHC moleculesGeneStructureFunctionsClinical significanceOrgan transplantationOutlineShort arm of chromosome 62 microglobulin on chromosome 15Genomic OrganizationChoo, Sung Yoon. The HLA system: genetics, immunology, clinical testing, and clinical implications. Yons

2、ei medical journal 48.1 (2007): 11-23.Closely linked genesMendelian(孟德尔) inheritance，codominantLinkage disequilibrium HLA HaplotypesChoo, Sung Yoon. The HLA system: genetics, immunology, clinical testing, and clinical implications. Yonsei medical journal 48.1 (2007): 11-23.Class I: all nucleated cel

3、ls; recognized by CD8+ T cellsNK cells recognize MHC class I lossClass II: mainly dendritic cells, macrophages and B lymphocytes; recognized by CD4+ T cellsExpression of MHCStructureAbbas, Abul K., Andrew HH Lichtman, and Shiv Pillai. Basic immunology: functions and disorders of the immune system. E

4、lsevier Health Sciences, 2012.1. Endogenous MHC class I presenting2. Exogenous MHC class II presenting3. Exogenous MHC class I presenting4. Endogenous MHC class II presentingAntigen PresentationProteasome1. endogenous MHC class I processingRuebush, Mary, and Louise Hawley. USMLE step 1 lecture notes

5、: Immunology and microbiology. (2009).Lysosomal proteases2. exogenous MHC class II processingRuebush, Mary, and Louise Hawley. USMLE step 1 lecture notes: Immunology and microbiology. (2009).3. exogenous MHC class I processingHeath, William R., and Francis R. Carbone. Cross-presentation in viral imm

6、unity and self-tolerance. Nature Reviews Immunology 1.2 (2001): 126-134.antigenexported to cytosol degraded by proteasomephagosome fuse with ER recruiting MHC class I and peptide loading machinery antigen translocated into phagosome by TAP MHC class I peptide loading in phagosomesEpstein-Barr virus(

7、EBV), also called human herpesvirus-4Invade B cells through CD21EBNA-1 antigen Exp finding 1: Autophagy blocker decreases antigen presentation to CD4+ T cellsExp finding 2: On inhibition of lysosomal acidification, EBNA-1 accumulate in autophagosomes. Autophagy-lysosomal proteases-MHC class II4. end

8、ogenous MHC class II processingWHYAutophagy target long-lived proteins(EBNA-1 is long-lived); proteasome target short-lived proteins.Then mutate EBNA-1 to make it short-lived, and it shifts into endogenous MHC class I pathway.Understanding of the 3rd pathwayShould we re-interpret the two classical p

9、athways?Defense Against PathogensOrgan Rejection Suppose a patient need an organ transplantation, e.g. kidney. What tests need to be done to ensure the donor kidney is a good match?HLA and Organ TransplantThe uniform first stepNatural antibodies(expressed under natural conditions, without previous e

10、xposure to infection or vaccines.)Hyper-acute graft rejectionBlood TypingHLA typing of donors and recipientsHLA antibody screening of recipientsLymphocyte cross-matchingHLA TestingSerologic typing of HLA antigens HLA-A, B, DR are major transplantation antigens.Molecular typing of HLA alleles 1. HLA

11、typing of donors and recipientsLymphocytes from the donor or recipient are mixed with different antisera(抗血清).1.1 serologic HLA Typing for class IMicro-cytotoxicity testRuebush, Mary, and Louise Hawley. USMLE step 1 lecture notes: Immunology and microbiology. (2009).1.2 serologic HLA typing for clas

12、s IIMixed lymphocyte reactionRuebush, Mary, and Louise Hawley. USMLE step 1 lecture notes: Immunology and microbiology. (2009).to determine if there are any antibodies present that would target the donated organ or tissueExposure to non-self HLA: pregnancy, transfusion, previous organ transplantWill

13、 potentially attack donor tissues that have corresponding HLA type.2. HLA Ab screening of recipientsRecipients serum mixed with donors lymphocytesHelps determine if the intended recipient has any antibodies against antigens present on the donors lymphocytesAny reaction detected would indicate likely

14、 incompatibility3. lymphocyte cross-matchingHyper-acute rejection natural antibodiesAcute rejection donors antigen presenting cellsChronic rejection recipients antigen presenting cellsOrgan RejectionTypical in bone marrow transplantGrafted T cells against hostTo clear mature T cells before transplan

15、tationGraft-versus-host-disease(GVHD)Choo, Sung Yoon. The HLA system: genetics, immunology, clinical testing, and clinical implications. Yonsei medical journal 48.1 (2007): 11-23.Abbas, Abul K., Andrew HH Lichtman, and Shiv Pillai. Basic immunology: functions and disorders of the immune system. Else

16、vier Health Sciences, 2012.Ruebush, Mary, and Louise Hawley. USMLE step 1 lecture notes: Immunology and microbiology. (2009).Heath, William R., and Francis R. Carbone. Cross-presentation in viral immunity and self-tolerance. Nature Reviews Immunology 1.2 (2001): 126-134.Turley, Shannon J., et al. Tr

17、ansport of peptide-MHC class II complexes in developing dendritic cells. Science 288.5465 (2000): 522-527.References Guermonprez, Pierre, et al. ERphagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells. Nature 425.6956 (2003): 397-402.Houde, Mathieu, et al. Phagosomes are competent organelles for antigen cross-presentation. Nature 425.6956 (2003): 402-406.Strominger, Jack L. Major Histocompatibility Complex. Advances in Human Genetics 15 15 (2012): 197.Adams, Jarrett J., et al. T cell receptor signaling is limited by docking geomet