Immunology Chapter 10: Cell-Mediated Cytotoxicity PDF

‫‪Immunology‬‬ ‫ﺗﻔرﯾﻎ ‪ :‬ﻣﺎﻟك اﻟﻌﺑوﺷﻲ‪ ،‬اﺣﻣد ﻧوري‪ ،‬ﻋﺑد اﻟﺣﻛﯾم أﺑو رﺟﺎ‬ ‫ﺗدﻗﯾق ‪ :‬ﻓﺗﺣﻲ ﻣﻠﺣم‪ ،‬اﻣﯾر ﻋواﺷرة‬  Chapter 10 Cell-mediated Cytotoxicity 2 Immunology 7105306 Summary (‫ )ﺑﺷﻛل ﻋﺎم اﻟﻔﯾروﺳﺎت و ﺷوﯾﺔ ﺑﻛﺗﯾرﯾﺎ‬intracellular ‫ ﺑﺗ...

‫‪Immunology‬‬ ‫ﺗﻔرﯾﻎ ‪ :‬ﻣﺎﻟك اﻟﻌﺑوﺷﻲ‪ ،‬اﺣﻣد ﻧوري‪ ،‬ﻋﺑد اﻟﺣﻛﯾم أﺑو رﺟﺎ‬ ‫ﺗدﻗﯾق ‪ :‬ﻓﺗﺣﻲ ﻣﻠﺣم‪ ،‬اﻣﯾر ﻋواﺷرة‬  Chapter 10 Cell-mediated Cytotoxicity 2 Immunology 7105306 Summary (‫ )ﺑﺷﻛل ﻋﺎم اﻟﻔﯾروﺳﺎت و ﺷوﯾﺔ ﺑﻛﺗﯾرﯾﺎ‬intracellular ‫ ﺑﺗﻛون ﺑﺷﻛل أﺳﺎﺳﻲ ﻓﻲ‬cell mediated cytotoxicity ‫طﺑﻌﺎ ال‬ Cell-mediated cytoxicity is an essential defence against intracellular pathogens, including viruses, some bacteria and some parasites. cytotoxicity ‫ﻋﻧﺎ ﻧوﻋﯾن ﻣن اﻟﺧﻼﯾﺎ اﻟﻣﺳؤوﻟﺔ ﻋن‬ (innate ‫ ھﻲ‬NK ‫( )ﻧﺗذﻛر اﻧو‬Tc) T cytotoxic ‫ او‬nk ‫ ﻣﺛل‬lymphoid.1 myeloid ‫ ﻻﻧو اﺻﻠﮭم‬non-lymphoid ‫ ﺑﻛوﻧوا‬myeloid.2 ‫ و‬self MHC ‫ ﯾﻌﻧﻲ ﻻزم ﯾﺗﻌرف ﻋﺎل‬MHC Restriction ‫ ﺑﺗﻣﺷﻲ ﻋﺎل‬T cell ‫ )ﺑﻧﻌرف اﻧو ال‬Tc ‫ﺑدﻧﺎ ﻧﺣﻛﻲ ﻋن ﺷﻐل ال‬ ( activation ‫ ﻋﺷﺎن ﯾﺻﯾرﻟﮭﺎ‬foreign antigen ‫ﻋﻠﻰ‬ (activation ‫ ﻋﺎﻟﺧﻠﯾﺔ ﺑﺗﻌرف اﻧو ﻓﻲ ﺧﻠل و ﺑﺻﯾرﻟﮭﺎ‬self MHC ‫ ﻣﺎ ﻟﻘت ال‬NK ‫ ﯾﻌﻧﻲ ﻟو ال‬: ‫ ﺑﺗﺷﺗﻐل اﻟﻌﻛس‬NK ‫ھﺳﺎ ال‬ ‫ ﻋﺎل‬loading ‫ ﺑﺎﻟﺧﻠﯾﺔ و ﺻﺎر‬fragmentation ‫ دﺧل ﺻﺎرﻟو‬virus ‫ ھﺳﺎ ﻟو اﺟﺎ ﻋﻧﺎ‬.. ‫طب ﻟﯾش ھﯾك؟ ﺷوف ﯾﺎ ﺳﯾدي‬ (MHC Restriction ‫ )ﺑﺗﻣﺷﻲ ﻋﺎل‬T cytotoxic ‫ ھون ﺑﺗﺗﻧﺷط ال‬presenting ‫ و ﺻﺎر‬MHCI ‫ ﯾﻌﻧﻲ ﻣش ﺣﯾﺗم ال‬loading ‫ ﺑﺗﻛون ﻗﺎدرة ﺗﺧرب ﺧطوة ﻣن ﺧطوات ال‬intracellular microbes ‫ھﺳﺎ اﻟﻠﻲ ﺑﺻﯾر اﻧو ﻓﻲ‬ ‫ ﺑﺗﺗﻧﺷط ﻻﻧﮭﺎ ﻋرﻓت اﻧو ﺻﺎر‬MHC ‫ ﻟﻣﺎ ﻣﺎ ﺗﺷوف‬NK ‫ ﻋﺎﻟﺳطﺢ )ﻋﺷﺎن ھﯾك ال‬MHC ‫ و ﻓش‬antigen presenting (‫ﺧﻠل‬ T ‫ ف ﻻ ﺑﺗﺗﻧﺷط ال‬non-self antigen ‫ ﺑﻧﺳب ﻗﻠﯾﻠﯾﺔ ﻋﺎﻟﺳطﺢ و ﻣﺎ ﻓﻲ ﻋﻠﯾﮭﺎ‬MHC ‫اﻣﺎ ﺑﺎﻟﺣﺎﻟﺔ اﻟطﺑﯾﻌﯾﺔ ﯾﻛون ﻓﻲ‬ ‫ ﻋﺎﻟﺳطﺢ‬MHC ‫ ﻋﺷﺎن ﻓﻲ‬NK ‫( وﻻ ﺑﺗﺗﻧﺷط ال‬MHC Restriction ‫ )ﻋﺷﺎن‬cytotoxic CTLs and NK cells are the lymphoid effectors of cytotoxicity. Most CTLs are CD8+ and respond to non-self antigens presented on MHC class I molecules. Some virally infected and cancerous cells try to evade the CTL response by downregulating MHC class I. NK cells recognize these MHC class I negative targets.  ‫ و ھﻲ‬NK ‫ ﻋﺎل‬receptors ‫ﻓﻲ ﻋﻧﺎ‬.. ‫ او ﻋدﻣﮭﺎ‬MHC ‫ اﻋﻘد ﻣن وﺟود‬NK ‫ﻣوﺿوع ال‬ ‫ )ﯾﻌﻧﻲ ﻋدم اﻻرﺗﺑﺎط ﺑﻧﺷط ال‬NK ‫ ﺑﺛﺑط ال‬MHC ‫ ﻣﺣددات ﺑﺎﻻﺣﻣر و ھدول ارﺗﺑﺎطﮭم ﺑﺎل‬:inhibitory receptors ‫( و ﻟو ﻧﻼﺣظ اﻧو ﻛل رﯾﺳﯾﺑﺗور ﺧﺎص ﺑﺎﺷﻲ‬NK ‫ ل‬upregulation ‫( ﺑﺗﻌﻣل‬infected cell) target cell ‫ ﺑﺎﻻﺧﺿر و اﻟﻠﻲ ﺑﺻﯾر اﻧو ال‬: activating receptors NK ‫ ﻟل‬activation ‫ و ھﺎد ﺑﺎدي ل‬activating receptors‫ اﻟﻠﻲ ﺑﺗرﺑط ﻋﻠﻰ ال‬ligands ‫ ﺗﺎﻋﺗﮫ اﻗوى ھو اﻟﻠﻲ ﺑﺻﯾر‬signal ‫ و اﻟﻠﻲ ﺑﺗﻛون ال‬receptors ‫ ﺑﯾن ال‬balance ‫ﻻزم ﻧﻧﺗﺑﮫ اﻧو ﻓﻲ‬ NK cells recognize cells that fail to express MHC class I. NK cells express a variety of inhibitory receptors that recognize MHC class I molecules. When these receptors are not engaged, the NK cell is activated. Killer Immunoglobulin-like Receptors (KIRs) recognize classical MHC class I molecules. CD94 interacts with HLA-E. LILRB1 recognizes a wide range of class I molecules. Cancerous and virally infected cells express ligands for the activating receptor NKG2D. Stressed cells, including cancerous and virally infected cells, upregulate ULBP1– 3, MICA and MICB, which are ligands for NKG2D. This results in NK cell activation. The balance of inhibitory and activating signals determines NK cell activation. cell mediated ‫ ﺑﻌﻣل ﻋﺎل‬IgG ‫ )ﻣش ﺣﻛﯾﻧﺎ زﻣﺎن اﻧو‬antibody ‫ و ھﻲ ﺑﺎل‬NK ‫ﻓﻲ طرﯾﻘﺔ ﺛﺎﻧﯾﺔ ﻟﺗﻧﺷﯾط ال‬ Fc ‫ ﻣن‬NK ‫ و ﺑرﺑط ﻋﺎل‬Fab ‫ ﻣن ال‬target cell ‫ راﺑط ﻋﺎل‬antibody ‫( ﺑﻛون ال‬cytotoxicity NK cells can also mediate ADCC (antibody dependent cell cytotoxicity )  ‫ طرق ﻟﻧﻌﻣل‬3 ‫ ھﺳﺎ ﻓﻲ‬.. apoptosis ‫ و ﯾﺻﯾر‬cytotoxicity ‫ رح ﺗﺑﻠش ال‬Tc/NK‫ ﻟل‬activation ‫ﺑﻌد ﻣﺎ ﺻﺎر‬ apoptosis Fas ligand & TNF ‫ ﻣﺛل‬ligands & receptors ‫ ﺣﻛﯾﻧﺎ ﻋﻧﮭﺎ ﺑﺎل‬: direct cellular interaction‫ ﺑﺎل‬ ‫ )اﻟﻣﯾﻛﺎﻧزم ﺗﺎﻋﺗﮭم‬perforin & granzymes ‫ ﻣﺟﮭزة ﻣواد ﻣﺛل‬Tc/NK ‫ ﺑﺗﻛون ال‬: granule exocytosis ‫ ﺑﺎل‬ exocytosis ‫ ﺑﺗﻌﻣل ﻟﻠﻣواد‬activation ‫ و ﺑس ﯾﺻﯾرﻟﮭﺎ‬granules ‫ﻣﺣطوط ﺗﺣﺗﮭم ﺧط( ﻓﻲ‬ cytokine production ‫ ال‬ Cytotoxicity is effected by direct cellular interactions, granule exocytosis and cytokine production. Fas ligand and TNF can induce apoptosis in the target cell. Granules containing perforin and granzymes are also released. Perforin forms a pore in the cell membrane, allowing granzymes access to the cytosol. Granzymes trigger the cell’s intrinsic apoptosis pathways. : ‫ ھﻲ‬cytotoxicity ‫ اھم اﻟﺧﻼﯾﺎ اﻟﻠﻲ ﺑﺗﻌﻣل‬myeloid ‫ ھﺳﺎ ال‬.. lymphocytes ‫ﻛل اﻟﻠﻲ ﺣﻛﯾﻧﺎه ﻛﺎن‬ granules exocytosis ‫ و ﻣﻣﻛن ﺗﻌﻣل‬phagocytosis ‫ ھدول ﺑﻌﺗﻣدوا ﻋﺎل‬:Macrophages &neutrophils ‫ )طﺑﻌﺎ‬cytotoxic granules ‫ و ﺑﺗﻔرز‬target cell ‫ اﻟل ﺑﺗرﺑط ﻋﺎل‬antibodies ‫ ﺑﺗﺗﻌرف ﻋﺎل‬: Eosinophils ‫ ﻓﺑﯾﺟﻲ ال‬phagocytosis ‫ ﯾﻌﻧﻲ ﺣﺟﻣﮭم ﻛﺛﯾر ﻛﺑﯾر ﻓﻣﺎ ﺣﺗﻘدر ﺗﻌﻣﻠﮭم‬parasites ‫ ھو ال‬eosinophils ‫اﺧﺗﺻﺎص ال‬ ( Fc ‫ ﺗرﺑط ﻋﺎل‬eosinophil ‫ و ﺑﺗﯾﺟﻲ ال‬parasite ‫ ﺑرﺑط ﻋﺎل‬IgE Macrophages, neutrophils and eosinophils are non-lymphoid cytotoxic effectors. Macrophages and neutrophils usually destroy pathogens by phagocytosis, but can also sometimes release the contents of their granules into the extracellular environment. Eosinophils release cytotoxic granules in response to antibody-coated cells. 5 Immunology 7105306  Cytotoxic lymphocytes ‫ ﺑﻛون‬extracellular ‫ ﻟﯾش؟ ﻻﻧو ال‬intracellular ‫ ﻻزم ﻧدرك اﻧﻧﺎ ﺑﻧﺣﻛﻲ ﻋن‬cell cytotoxicity ‫ﻟﻣﺎ ﺑﻧﺣﻛﻲ ﻋن‬ intracellular pathogen ‫ )ﺣﻛﺎ اﻟدﻛﺗور اﻧو ﻟو طﻠﻊ ال‬humoral mechanism (antibodies) ‫ﻣﺗدﺧل ﻓﯾﮭﺎ ال‬ humoral mechanism ‫ﻣن اﻟﺧﻠﯾﺔ )ﺳواء ﻋﺷﺎن اﻧﺗﻘﺎل ﻟﺧﻠﯾﺔ ﺛﺎﻧﯾﺔ او ﻏﯾرو( ﺳﺎﻋﺗﮭﺎ ﻣﻣﻛن ﺗﺗدﺧل ال‬ parasites ‫ ﺑﺗﺷﻣل ﻓﯾروﺳﺎت ع ﺷوﯾﺔ ﺑﻛﺗﯾرﯾﺎ ع رﺷﺔ‬Intracellular ‫ ﻣﻣﻛن ﺗﺗﺣﻘق ﻣن ﺧﻼل‬cell cytotoxicity ‫ال‬ NK.1 T cytotoxic.2 macrophages, neutrophils & eosinophils ‫ ﻣﺛل‬Myeloid.3 It is an essential defense against intracellular pathogens, including: viruses; some bacteria; and some parasites. Several types of cells have cytotoxic potential, including: cytotoxic T lymphocytes (CTLs); natural killer (NK) cells; and some myeloid cells. 6 Immunology 7105306 ‫‪CTLs and NK cells mediate cytotoxicity‬‬ ‫ﺑدﻧﺎ ﻧﺣﻛﻲ ﻋن ﻛل ﻣن ال ‪ NK‬و ‪ Tcytotoxic‬و وﯾﻧﺗﺎ ﺑﺻﯾرﻟﮭم ‪activation‬‬ ‫‪T cytotoxic‬‬ ‫ﻟﻣﺎ ال ‪ target‬ﺗﻛون ‪ infected‬ﺑﻧﻌرف اﻧو ﺑﺻﯾر ‪ presenting‬ﻟل ‪ viral protein‬ﻋﻠﻰ ‪.. MHC‬ھﺳﺎ ال ‪ TCR‬ﺑرﺑط ﻋﺎل‬ ‫‪ MHC‬و ﺑرﺑط ﻋﺎﻟﺑروﺗﯾن )ﺷو ﺳﻣﯾﻧﺎھﺎ ھﺎي؟ ‪ (dual specificity or MHC restriction‬و ﻛﻣﺎن ﺑرﺑط ال ‪) CD8‬اﯾش‬ ‫وظﯾﻔﺗو؟‪ (*co-receptor* Increase affinity..‬ھﺳﺎ ﺑﻌد ﻣﺎ ﯾﺻﯾر اﻻرﺗﺑﺎط ﺑﺻﯾر ‪ activation‬ﻟل ‪ Tc‬و ﺑﺗﻘﺗل ال‬ ‫‪ target‬ﻣن ﺧﻼل اﻟﻣﯾﻛﺎﻧزﻣز اﻟﻠﻲ ﺣﻛﯾﻧﺎھن ﺑﺎل‪summary‬‬ ‫ﺳﻣﯾﻧﺎھﺎ ‪ non-self recognition‬ﻻﻧو ال‪Tc‬‬ ‫طﺑﻌﺎ ﻣﺎ ﻧﻧﺳﻰ اﻧو ال ‪TCR‬‬ ‫ﺗﻌرﻓت ﻋﻠﻰ ‪non-self peptide‬‬ ‫ﺑﻛون ‪ specific‬ﻟﻠﺑﺑﺗﯾد و ھو‬ ‫اﻟﻠﻲ ﺑﻌﻣل ال ‪first signal‬‬ ‫ﺑﻧﻌرف ﻛﯾف ﺻﺎر ال ‪MHC‬‬ ‫‪)loading‬ﺑﺗﺷﺎﺑﺗر‪(8‬‬ ‫ﻣﻼﺣظﺔ ﺻﻐﯾرة‪ :‬ال ‪ Tc‬ﺑﺎﻟﻌﺎدة ﺑﻛوﻧوا ‪ CD8+‬ﯾﻌﻧﻲ ﺑﺗﻌّرﻓوا ﺑس ﻋﺎل ‪... MHCI‬ﺑس ﻓﻲ ﻧﺳﺑﺔ ﺻﻐﯾرة ﻣن ال ‪ Tc‬ﺑﻛوﻧوا‬ ‫‪ CD4+‬و ﺑﺗﻌرﻓوا ع ‪MHCII‬‬ CTLs and NK cells mediate cytotoxicity Natural Killer activating & inhibitory receptors ‫ ﺑﺗﺣدد ﻣن ﺧﻼل ﻋدة‬NK ‫ ﻟل‬activity ‫ اﻧو ال‬summary ‫ﺣﻛﯾﻧﺎ ﺑﺎل‬ : ‫ رح ﯾﺗﻘﺎﺗﻠوا‬2 receptors ‫ﺑﺎﻟﺣﺎﻟﺔ اﻟطﺑﯾﻌﯾﺔ ﻓﻲ‬ NK ‫ ﻟل‬activation ‫ و ﺑﻌﻣل‬tonic activating ligand ‫ ﺑرﺑط ﻋﺎل‬:NK recptor.1 ‫ اﻷﻗوى ھو ال‬2 receptors ‫ )ﻟﻣﺎ ﯾﺟﺗﻣﻌوا ال‬inhibition ‫ و ﺑﻌﻣل‬MHC ‫ ھﺎد ﺑرﺑط ﻋﺎل‬: Inhibitory receptor.2 (inhibitory MHC ‫ ﻋﻣل ﻋﻠﻰ إﻋﺎﻗﺔ ال‬intracellular pathogen ‫ اﺳﻣﮭﺎ ھﯾك ﻻﻧو اﻟﻠﻲ ﺑﺻﯾر اﻧو ال‬: Missing self recognition target cell ‫ ﻋﺳطﺢ ال‬MHC ‫ و ﻣﺎ ﺻﺎر ﻓﻲ‬loading NK ‫ ﻟل‬activation ‫ و ﺑﺻﯾر‬inhibition ‫ و ﺑﺎﻟﺗﺎﻟﻲ ﻣﺎ ﺣﯾﺻﯾر‬inhibitory ‫ ﻣﺎ ﺣﯾرﺑط ال‬MHC ‫ﻓﻠﻣﺎ ﯾﺧﺗﻔﻲ ال‬ ‫ ﻣوﺟود ﻛﺎن ﺗﺎﺛﯾر‬MHC ‫ﻟو ﻛﺎن‬ ‫ اﻗوى ﺑس ﻻﻧو ﻣش ﻣوﺟود‬inhibitory‫ال‬ inhibition ‫ﻣﺎ ﺻﺎر‬ intracellular ‫ﻣﺛل ﻣﺎ ﻗﻠﻧﺎ اﻧو ال‬ MHC presenting ‫ أﻋﺎق ال‬pathogen ‫‪CTLs and NK cells mediate cytotoxicity‬‬ ‫ﺣﻛﯾﻧﺎ ﺑرﺿو ﺑﺎل ‪ summary‬اﻧو ال ‪ activation‬ﻟل ‪ NK‬ﺑﺗﺣﻛم ﻓﯾﮭﺎ ﻋواﻣل ﺛﺎﻧﯾﺔ ﻣﺛل ‪:‬‬ ‫‪ :Stress induced ligands‬ھﺎد ﺑﺻﯾرﻟو ‪ upregulation‬ﻟﻣﺎ ﺗﻛون اﻟﺧﻠﯾﺔ ‪ infected‬و ﺑرﺑط ﻋﺎل ‪ NKG2D‬اﻟﻣوﺟود ﻋﺎل‬ ‫‪) NK‬طﺑﻌﺎ ھﺎد اﻻرﺗﺑﺎط ﺑﻌﻣل ‪(activation‬‬ ‫‪ :ADCC‬ﺑﻧﻌرف ﻛﻣﺎن اﻧو ﻓﻲ ‪ Fc receptor‬ﻋﺎل ‪) NK‬اﺳﻣﮫ ‪ (CD16‬و ھﺎد ﺑﺷﺗﻐل وﻗت ﻣﺎ ﯾرﺑط ﻋﻠﯾﮫ ‪ Ig‬راﺑط ﺑﺎﻧﺗﺟﯾن )ﺑﻌﻣل‬ ‫‪(activation‬‬ ‫‪ ü‬ﻓﻲ ﺣﺎﻟﺔ ﺣﻛﺎھﺎ د‪.‬وﻟﯾد اﻧو ﻟو ﻛﺎن ﻓﻲ ‪) MHC‬ﯾﻌﻧﻲ ال ‪ inhibitory‬ﺷﻐﺎل( ﺑس ﺑرﺿو ال ‪ NKG2D‬راﺑط ﺑﺎل ‪stress‬‬ ‫‪) induced‬طﺑﻌﺎ و ﻛﻣﺎن ال ‪ NK receptor‬راﺑط ﺑﺎل ‪ (tonic‬ﺑﮭﺎي اﻟﺣﺎﻟﺔ ﺑﺻﯾر ‪) activation‬ذاﻛرﯾن ﻟﻣﺎ ﺣﻛﯾﻧﺎ اﻧو‬ ‫اﻟﻣوﺿوع زي ‪balance‬‬ CTLs and NK cells mediate cytotoxicity CTLs recognize processed antigen presented on the target cell by MHC molecules, using their T cell receptor (TCR). Most CTLs are CD8+ and recognize antigen presented by MHC class I molecules, but a minority are CD4 + and recognize antigen presented on MHC class II molecules. In contrast, NK cells have receptors that recognize MHC class I on the target and inhibit cytotoxicity. NK cells also express a number of activating receptors to identify their targets positively, including NKG2D and their Fc receptor (CD16). 1 Immunology 7105306 0 Effector CTLs home to peripheral organs and sites of inflammation Activated CTLs downregulate sphingosine phosphate receptor to exit the lymph node. L-selectin and CCR7, upregulate CD44 and LFA-1. ‫ ﻣﺛﻼ ھون ﺑدھﺎ‬lymph node ‫ زي ﻓﻲ ال‬secondary lymphoid organ ‫ﻓﻲ ال‬T cytotoxic ‫ ﻟل‬activation ‫ﻟﻣﺎ ﯾﺻﯾر‬ ‫ ﻣﻌﯾﻧﺔ ﻣﺛﻼ‬receptors ‫؟ ﻓﯾﮫ‬lymph node ‫ طﯾب أﺻﻼ ﺷو اﻟﻲ ﻣﻘﻌدھﺎ ﺑﺎل‬lymph node ‫ھﺎي اﻟﺧﻠﯾﺔ ﺗطﻠﻊ ﻣن ال‬ ‫ ﻋﻠﻰ‬recruitment ‫ او‬targeting ‫ او‬homing ‫ ﻣﻌﯾﻧﺔ اﻟﻲ ﺑﺗﻌﻣﻠﮭﺎ زي‬cytokines ‫ ﺑﺗرﺑط ﻋﻠﯾﮭﺎ‬chemokine receptors lymph node ‫ال‬ surface ‫ ﻋﻠﻰ ال‬receptors ‫ ﻟﮭﺎي ال‬concentration ‫ ﯾﻌﻧﻲ ﺑﻘﻠﻠو ال‬down regulation ‫ﻓﻠﻣﺎ ﻧطﻠﻌﮭﺎ ﻣن ھﻧﺎك ﺑﻌﻣﻠو‬ ‫ ﻓﮭون ﺑﺻﯾر ﻋﻧﺎ‬lymphnode ‫ اﻟﻲ ﺑﺗﻛون راﺑطﺗﮭﺎ ﺑﺎل‬l-selectin ‫ ﻟل‬down regulation ‫ وﻛﻣﺎن ﺑﻌﻣﻠو‬t cell ‫ﺗﺑﻌت ال‬ ‫ وﺑﺻﯾر‬lymphnode ‫ اﻟﮭﺎ ﻓﻲ ال‬attachment ‫ ﻟﻠﺑروﺗﯾﻧﺎت اﻟﻲ ﺑﺗﺳﺎﻋد ﻓﻲ ﺑﻘﺎءھﺎ ووﺟودھﺎ وال‬down regulation interaction ‫ وﺗﻌﻣل‬target tissue ‫ اﻟﻲ ﺑﺗﺳﺎﻋدھﺎ ﺗروح ﻋﻠﻰ ال‬other ligands and receptors ‫ ل‬upregulation killing ‫ اﻟﻲ ﻻزم ﺗﺗﻌﺎﻣل ﻣﻌﮭم وﺗﻌﻣﻠﮭم‬infected ‫ﻣﻊ اﻟﺧﻼﯾﺎ اﻟﻲ ھﻣﻲ‬ Effector T cells may also express adhesion molecules that allow them to home to specific tissues. ‫ اﻟﻲ ﺑﺣرك‬3 step modelling system ‫ ﻟﻣﺎ ﺣﻛﯾﻧﺎ ﻋن ال‬inflammation‫زي ﻟﻣﺎ ﻛﻧﺎ ﻧﺷرح ﺑﺎل‬ ‫ او اﻟﻲ‬virally infected cell ‫ اﻟﻲ ﻓﯾﮭﺎ ال‬target ‫ ﻟل‬T cell ‫ ﻧﻔس اﻟﻣﺑدا ﺑس ھون ﺑﺣرك ال‬،neutrophil‫ال‬ t cytotoxic ‫ ﻟل‬activation ‫ اﻟﻲ ﻛﺎن اﻟﺳﺑب ﻓﻲ ال‬damage‫ﻓﯾﮭﺎ ال‬ CTLs recognize antigen presented on MHC class I molecules The TCR and CD8 localize to the signaling domain in the center of the synapse (cSMAC); degranulation occurs in the secretory domain. Adhesion molecules that stabilize the cell–cell interactions are located at the periphery of the supramolecular activation complex (pSMAC). CTLs recognize antigen presented on MHC class I molecules cell to cell ‫ ل‬stablize ‫ اﻟﻲ ﺑﺗﺛﺑت او ﺑﺗﻌﻣل‬molecules ‫ ھون ﺑورﺟﯾﻧﺎ ال‬t cytotoxic ‫ وال‬target cell ‫ اﻟﻲ ﺑﯾن ال‬synapse ‫ھون ﺑورﺟﯾﻧﺎ ال‬ target cell ‫ وال‬t cell ‫ ﺑﯾن ال‬interaction secretory ‫ وال‬signaling domain ‫ ال‬-5 ‫ ﻟل‬release ‫ ﺑﺻﯾر‬activation ‫ وﻓﯾﮫ ﻛﻣﺎن ﺑﻌد ﻣﺎ ﯾﺻﯾر‬-4 ‫ اﻟﻲ ھﻣﻲ‬PSMAC ‫ ﺑﻧﺳﻣﯾﮭم ال‬domains ‫ او اﻟﺑروﺗﯾﻧﺎت اﻟﻲ رح ﺗﻌﻣل‬enzymes ‫ او ﻟل‬toxic product supramolecular activation complex secretory domains ‫ ﻟﻠﺧﻠﯾﺔ اﻟﻲ ﺑﺗﻛون ﻣوﺟودة ﺑﺎل‬targeting ‫ ھون ﺑﺻﯾر‬-3 ‫ ھﺎي اﻟﺑﯾرﻓورﯾن ﻣن‬-6 ‫ ﻣن ﺧﻼل‬activation ‫اﻟﺑروﺗﯾﻧﺎت اﻟﻲ ﺑﺻرﻟﮭﺎ‬ signaling domain ‫ اﻟﻲ ﺑﻌﻣل‬release ‫ ﻓﻲ اﻟﺧﻠﯾﺔ‬pore specific ‫ ھﻲ ال‬-2 t cell receptor t cell ‫ﻋﻠﻰ ال‬ ‫ اﻟﻲ‬granzyme ‫ ال‬-7 ‫ﯾدﺧل ﻣن ﺧﻼل ھﺎي ال‬ ‫ اﻟﻲ اﻧﻔﺗﺣت وﯾﻌﻣل‬pore MHC ‫ ھﻲ‬-1 ‫ ﻣن‬apoptosis‫ﺗﺣﻔﯾز ﻟل‬ ‫ ﻋﺎرض‬molecule ‫ ﻟل‬activation ‫ﺧﻼل ال‬ foreign antigen caspase pathway ‫وﻣن ﺧﻼل طرق اﺧرى‬ ‫‪CTLs and NK cells are complementary in the defense‬‬ ‫‪against virally infected and cancerous cells‬‬ ‫ﻛﯾف ﺑﻛﻣﻠو ﺑﻌض؟ ﺑﻛﻣﻠو ﺑﻌض ﻣن ﺣﯾث اﻧو واﺣد ﺑﺗﻌﺎﻣل ﺑﺣﺎﻟﺔ وﺟود ال ‪ MHC‬اﻟﻲ ﻣﺣﻣل ب ‪foreign‬‬ ‫‪ protein‬واﻷﺧر ﺑﺗﻌﺎﻣل ﻓﻲ اﻟﺣﺎﻟﺔ اﻻﺧرى اﻟﻲ ﻣﻣﻛن اﻋﺗﺑرھﺎ ﺑﺳﺑب وﺟود اﻟﻔﺎﯾروﺳﺎت ﺻﺎر‬ ‫‪ downregulaion‬او ﺻﺎر ﻋﻧﺎ ‪ effect‬او ‪ targeting‬ﻟل ‪ MHC‬ﻋﻠﻰ أي وﺣدة ﻣن ال ‪ steps‬ﺗﺑﻌت ال‬ ‫‪ loading‬او ﻋﻣﻠﯾﺔ ال‪ trasnportation‬ﻟل ‪ MHC molecule‬اﻟﻲ ‪ loaded‬ﻣﺷﺎن ﯾﻧﻌرض ﻋﻠﻰ اﻟﺧﻠﯾﺔ‬ ‫ﻓوﻗﺗﮭﺎ ﺑﺗﯾﺟﻲ ال ‪ NK‬زي ﻛﺎﻧﮭﺎ اﻟﺷرطﻲ اﻟﻲ ﻗﺎﻋد ﺑﻠف‪ ،‬أي ﺧﻠﯾﺔ ﻣﻌﮭﺎش ھوﯾﺗﮭﺎ )ھوﯾﺗﮭﺎ ھو ال ‪(MHC1‬‬ ‫ﺑﺗﯾﺟﻲ ال ‪ NK‬ﺑﺗﻘﺗﻠﮭﺎ‬ ‫‪NK cells check that cells of the body are carrying their identity‬‬ ‫;)‪card (MHC class I‬‬ ‫‪CTLs check the specific identity (antigen specificity) on the card.‬‬ ‫دور ال ‪ CTL‬ﺑﯾﺟﻲ ﻟﻣﺎ ﻣوﺟود ال ‪ MHC molecule‬ﻓﺑﺗطﻠﻊ ﻋﻠﻰ ال ‪ MHC‬وﻋﻠﻰ اﯾش ﺣﺎﻣل او ﻋﺎرض‬ ‫ﻋﻠﯾﮫ ﻓﺎذا ﺣﺎﻣل ‪ non self antigen‬ﺑدھﺎ ﺗﻌﻣل ‪ activation‬وﺑﺗﻌﻣﻠﮭﺎ ‪ killing‬ﻻﻧو ﻓﯾﮫ ﻋﻧدھﺎ ﺑروﺗﯾن‬ ‫ﻏرﯾب ﺣﺎﻣﻠﺗﮫ وﻋﻧدھﺎ ﻣﺷﻛﻠﺔ‬ Not all NK cells mediate cytotoxicity In humans, most NK cells are CD56+CD3− cells. However, not all cells with this phenotype are effective killers: 90% of blood NK cells are CD56low (i.e. they have low expression of CD56). These cells contain cytotoxic granules and are effective killers; 10% of blood NK cells are CD56hi (i.e. they express high levels of CD56). These cells do not contain cytotoxic granules, but can respond to target cells by producing the TH1 cytokine IFNγ; NK cells present in the lymph nodes, liver, and lungs are also less cytotoxic than CD56low blood NK cells; NK cells found in the uterus do contain cytotoxic granules, but do not degranulate in response to target cells. Their function is likely to be the production of angiogenic factors and mediation of placental implantation; a recently described subset of NK-like cells found in MALT are not cytotoxic but do produce IL-22, which is important for mucosal integrity.  ‫ ﻓﻲ ھﺎي ال‬development ‫ ﻣن ال‬steps ‫ اﻟﻲ ﺑﺗﻣر ب‬NK‫ھون ﺑﺷرﺣﻠﻧﺎ ﻋن ال‬ ‫ ﻟﺑروﺗﯾﻧﺎت‬expression ‫ و‬down regulation ‫ و‬up regulation ‫ ﺑﺻﯾر ﻋﻧﺎ‬steps Not all NK cells mediate cytotoxicity ‫ ھدول ال‬surface ‫ ﻣﺧﺗﻠﻔﺔ اﻟﻲ ﻓﯾﮫ ﻣﻧﮭم ﺑﺗﻛون ﻣوﺟودة ﻋﻠﻰ ال‬receptors ‫و‬ activity ‫ ﻻﻟﮭﺎ وﻣﻣﻛن ﯾﻛون اﻟﮭم دور ﺑﺎل‬activity ‫ ﻣﻣﻛن ﯾﻌﻛﺳو ال‬receptors ‫واﻟوظﯾﻔﺔ اﻟﻲ رح ﺗﻘوم ﻓﯾﮭﺎ ﺑﺷﻛل ﻣﺑﺎﺷر‬ In humans, most NK cells (Which are activated) are CD56+CD3− cells. (Any NK cell with these receptors will be a fully mature NK cell which is ready to do its main function –killing the cells that have problems-) However, not all cells with this phenotype are effective killers: 90% of blood NK cells are CD56low (i.e. they have low expression of CD56) (CD56 positive but with low expression). These cells contain cytotoxic granules and are effective killers; 10% of blood NK cells are CD56hi (i.e. they express high levels of CD56) (These cells are not fully developed). These cells do not contain cytotoxic granules, but can respond to target cells by producing the TH1 cytokine IFNγ; NK cells present in the lymph nodes, liver, and lungs are also less cytotoxic than CD56low blood NK cells; NK cells found in the uterus do contain cytotoxic granules, but do not degranulate in response to target cells. Their function is likely to be the production of angiogenic factors and mediation of placental implantation; (They have different functions) a recently described subset of NK-like cells found in MALT (A secondary lymphoid organs) are not cytotoxic but do produce IL-22, which is important for mucosal integrity. :‫ ﺑﺗﺧﺗﻠف ﺑﻧﺎًء ﻋﻠﻰ ﺷﻐﻠﺗﯾن‬NK cell ‫ ﺗﺎﻋت ال‬function‫ ال‬:‫ﻣﻠﺧص اﻟﺳﻼﯾد‬ low level ‫ وﻻ‬high level ‫ ﯾﻌﻧﻲ‬exprerssion ‫ ﻟل‬level ‫ او ﻗدﯾش ال‬concentration ‫ وﺣﺳب ال‬receptor ‫ ﻟل‬expression ‫ أوﻻ ﺣﺳب ال‬-1 ‫ اﻟﻲ ھﻲ ﻓﯾﮫ‬target site ‫ ﺑﺎﻹﺿﺎﻓﺔ ﻟل‬-2 ‫‪NK cell development‬‬ ‫ھﻸ ﺑدﻧﺎ ﻧﯾﺟﻲ ﻟل ‪ NK development‬وﻧﺷوف ﻋن ﺷو ﻛﻧﺎ ﻧﺣﻛﻲ ﻗﺑل ﺷوي‬ NK cell development CD34 is a marker of stem cells, which is expressed by cells in early stages of NK development, but not by cells that are committed to the NK lineage. CD117 (also called SCF receptor or c-kit) is expressed by cells before they are committed to becoming NK cells, and in immature NK committed cells, but its expression is lost in more mature cells. CD122 is a marker of NK commitment in mice, but in humans it is not detectable until the mature CD56hi stage, which is also characterized by expression of CD94. In the final stage of NK cell development, CD56hi NK cells become CD56low , and also start to express KIRs. ‫‪NK cell development‬‬ ‫‪ 3‬ﺧطوات رﺋﯾﺳﯾﺔ‪:‬‬ ‫اﻷوﻟﻰ‪multipotent progenitor cell :‬‬ ‫اﻟﺛﺎﻧﯾﺔ‪committed NK precursos :‬‬ ‫اﻟﺛﺎﻟﺛﺔ‪mature NK :‬‬ ‫وﺗﺣت اﻟﻲ ﺑﺎﻻﺻﻔر ﺑوﺿﺢ ال ‪markers‬‬ ‫ﻻﺣظ ال ‪ CD34‬ﻋﺑﺎرة ﻋن ‪ marker‬ﻟل ‪stem‬‬ ‫‪ cell‬او ال ‪ precursor cell‬اﻟرﺋﯾﺳﯾﺔ وھﺎي‬ ‫‪expressed in the early stages‬‬ ‫ﺑﻌدﯾن ﺑﯾﺟﻲ ‪ marker‬ال ‪ CD38‬ﺑﺻرﻟﮫ‬ ‫‪ expression‬ﻓﻲ اﻟﺑداﯾﺔ ﺑﻌدﯾن ﺑﺻﯾر ﯾﻘل ال ‪level‬‬ ‫ﺗﺑﻌﮫ ﻓﺑﮭﺎي اﻟﻣرﺣﻠﺔ ﺑﻛون زي ﻛﺎﻧﮫ ‪down‬‬ ‫‪regulated‬‬ ‫ﻧﯾﺟﻲ ﻟﻠﻣﺎرﻛر اﻟﻲ ﺣﻛﯾﻧﺎ ﻋﻧو ﻣن ﻗﺑل اﻟﻲ ھو ال‬ ‫‪ CD56‬ﻻﺣظ اﻧﮫ ﯾﺗم اﻧﺗﺎﺟﮫ ﻋﻠﻰ ‪ low level‬ﻓﻲ‬ ‫اﻟﺑداﯾﺔ ﺑﻌدﯾن ﺑﺻﯾر ﯾﻌﻼ ﺗدرﯾﺟﯾﺎ وﺑوﺻل ﻟﻔل ﻋﺎﻟﻰ‬ ‫وﺷوف ﻋﺎﻟرﺳﻣﺔ زي ﻣﺎ ﺣﻛﯾﻧﺎ اﻟﻲ ﺑﺗﻛون ﻋﻧدھﺎ ال‬ ‫‪ CD56‬ﺑﺎل ‪ high level‬ﯾﻌﻧﻲ ﺑﺗﻌﻣﻠﮫ ‪expression‬‬ ‫ﺑﺷﻛل ﻛﺑﯾر ﺑﺗﻛون ﻧﺳﺑﺗﮭﺎ ﺑﺎﻟدم ‪ %10‬اﻣﺎ اﻟﻲ ﺑﺗﻌﻣل‬ ‫‪expretion‬ﻟل ‪ CD56‬ﺑﻠﻔل اﻗل ﺑﺗﻛون ھﻲ ال‬ ‫‪10%‬‬ ‫‪90%‬‬ ‫‪ major‬وﻧﺳﺑﺗﮭﺎ ‪%90‬‬ ‫وﻓﯾﮫ ﻋﻧﺎ ‪ receptor‬ﻣﮭم اﻟﻲ ھو ال ‪killer‬‬ ‫‪ receptor KIR‬ھﺎد ال‪ receptor‬ﺑﺻرﻟﮫ‬ ‫‪ expression‬ﺑس ﺑﺎﻟﻣراﺣل اﻟﻧﮭﺎﺋﯾﺔ اﻟﻲ ھﻲ ﻟﻣﺎ‬ ‫ﺗﺻﯾر اﻟﺧﻠﯾﺔ ‪ effective killer‬وﻻﺣظ ﻛﻣﺎن ﺑﻧﻘدر‬ ‫ﻧرﺑطﮭﺎ ﻣﻊ ال ‪CD56‬‬ ‫ھدول ال ‪ markers‬ﺑﺻرﻟﮭم ‪ up & down regulation‬ب ‪concentrations‬‬ ‫ﺑرﺿو ﻻﺣظ ﻛﻣﺎن ﻓﻲ ال ‪ CD94‬ﻧﻔس اﻻﺷﻲ‬ ‫ﻣﺧﺗﻠﻔﺔ وھﺎي اﻻﺧﺗﻼﻓﺎت اﻟﻣوﺟودة ھون اﻟﮭﺎ دور اﻧو ھﺎد ال ‪ receptor‬ﻣوﺟود او ﻷ‬ ‫ﺑﺻرﻟﮫ ‪ expression‬ﻋﻠﻰ ‪ low level‬ﺑﻌدﯾن ﺑﺑﻠش‬ ‫او ﻋﺎﻻﻗل ﻧﯾﺟﻲ ﻧﺣﻛﻲ اﻟﻠﻔل ﺗﺑﻌﺗو ﻣوﺟودة او ﻷ وﺑﺄﺛر ﻋﻠﻰ ال ‪ activation‬ﻣﻊ ال‬ ‫ﯾﺧﺗﻔﻲ ال ‪ expression‬ﺗﺑﻌو ﻟﻣﺎ ﺗﺻﯾر اﻟﺧﻠﯾﺔ‬ ‫‪ ligands‬اﻟﻣوﺟودة ﻋﻠﻰ ال ‪target cells‬‬ ‫‪fully developed‬‬ NK cell receptors with well-defined ligands ‫ اﻟﻣوﺟودات‬receptors ‫اﻟﺟدول ﻣﻌطﯾﻧﺎ ﻛل ال‬ ‫ ﻣﺟﻣوﻋﺎت رح‬5 ‫ وﻣﻘﺳﻣﮭن ل‬NK cells ‫ﻋﻠﻰ‬.‫ﻧوﺧذ ﻛل ﻣﺟﻣوﻋﺔ وأﻣﺛﻠﺔ ﻋﻠﯾﮭن‬ (inhibition ‫ ﯾﺎ‬activation ‫)اﻟﻌﻼﻗﺔ ﺑﺗﻛون ﯾﺎ‬ 11 Immunology 7105306 NK cell receptors Killer immunoglobulin-like receptors recognize MHC class I HLA-C They are present on the majority of CD56low NK cells ‫ ﺑﺗﺗﻌرف ﻋﻠﻰ‬killer immunoglobulin-like receptors ‫ﻋﻧﺎ اﻟﻣﺟﻣوﻋﺔ اﻷوﻟﻰ‬ ‫ وزي ﻣﺎ ﺷﺎﯾﻔﯾن اﻧﮫ ﺗﻘرﯾﺑﺎ ً ﻛﻠﮭن ﺑﻌﻣﻠن‬،HLA-C, B, A ‫ ﻣن ﻧوع‬MCH class 1 ،NK ‫ ﻟل‬activation ‫ ﺑﻌﻣل‬KIR2DS1 ‫ ﻣﻊ‬HLA-C2 ‫ ﻣﺎﻋدا ﻟﻣﺎ ﯾرﺑط‬inhibition ‫ وﻟﮭﯾك ﻣﻧﺳﻣﯾﮭن‬CD56 low NK cells ‫وطﺑﻌﺎ ً ﺑﻛوﻧن ﻣوﺟودات ﺑﻛﺛرة ﻋﻠﻰ‬.effective killers ‫ ﻻﻧﮫ ھو‬S ‫ ھو اﻟوﺣﯾد ﺑﮭﺎي اﻟﻣﺟﻣوﻋﺔ ﻣن ﻧوع‬KIR2DS1 receptor -:‫ﻣﻼﺣظﺔ‬ ‫ زي ﻣﺎ ﺷﺎﯾﻔﯾن‬activation ‫ وﻟﮭﯾك ﺑﻌﻣل‬ITIM ‫اﻟوﺣﯾد اﻟﻲ ﻣﺎ ﻓﻲ ﻋﻧده ﺳﻠﺳﻠﺔ‬.‫ﺑﺎﻟرﺳﻣﺔ اﻟﻣﺟﺎورة‬ Killer Immunoglobulin-like Receptors ‫ اﺧﺗﺻﺎر ل‬KIR 12 Immunology 7105306 ‫‪The lectin-like receptor CD94 recognizes HLA-E‬‬ ‫‪ HLA-E‬و ‪HLA-‬‬ ‫‪ G‬ھن ﻋﺑﺎرة ﻋن‬ ‫‪non-classical‬‬ ‫‪MHC‬‬ ‫‪molecules‬‬ ‫ﻣﺟﻣوﻋﺔ ‪ lectin-like receptors‬ﺑﺗﺗﻌرف ﻋﻠﻰ ‪ HLA-E‬وﻣﻧﻼﺣظ اﻧﮫ ﻛﻠﮭن ﺑﻌﻣﻠن‬ ‫‪ ،activation‬وإذا ذاﻛرﯾن ﻟﻣﺎ اﻟدﻛﺗور ﺷرح ‪ HLA‬ﺣﻛﯾﻧﺎ وظﯾﻔﺗﮭم ﻣﻊ ال ‪NK cells‬‬ ‫إﻧﮫ ﺑﻣﺟرد ﻣﺎ ﺷﺎﻓت ال ‪ NK‬ال ‪ MHC molecule‬ﻋﻠﻰ ﺳطﺢ اﻟﺧﻠﯾﺔ ﻣﺎ رح ﯾﺻﯾر إﻟﮭﺎ‬ ‫‪ activation‬وﺑﺑﻠش دور ﺧﻼﯾﺎ ﺛﺎﻧﯾﺔ زي ‪.T-cell‬‬ ‫وﻟﻛن ﻓﻲ ﺣﺎﻟﺔ ‪ HLA-E‬ﻣﻧﻌﺗﺑره ‪ exception‬ﻟﮭﺎي اﻟﻘﺎﻋدة ﻷﻧﮫ ﺷﻐﻠﮫ ﺑﺧﺗﻠف وال‬ ‫‪ loading‬ﺗﺑﻌﮫ ﻣﺧﺗﻠف وال ‪ peptide‬إﻟﻲ ﺑﺣﻣﻠﮭﺎ ﺑﺗﻛون ﻏﯾر وﺣﺗﻰ ﺗﻌﺎﻣﻠﮫ ﺑﻛون‬ ‫ﻣﺗﻣم ﻟل ‪.MHC class 1 molecules‬‬ ‫وھﯾك ﺑﻛون دوره ‪ mainly activation‬وﻟﻛن اﺋﺎ ارﺗﺑط ﻣﻊ ‪ CD94-NKG2A‬رح‬ ‫ﯾﻌﻣل ‪.inhibition‬‬ ‫واﻟرﺳﻣﺔ ﻣوﺿﺣﺔ اﻟﻔرق ﺑﯾن ‪.inhibitory and non-inhibitory receptors‬‬ ‫‪13‬‬ ‫‪Immunology 7105306‬‬ The lectin-like receptor CD94 recognizes HLA-E CD94 associates with members of the NKG2 family via a disulphide bond. NKG2A contains intracellular ITIMs (immunoreceptor tyrosine inhibitory motifs) and so forms an inhibitory receptor. NKG2C lacks ITIMs but has a charged lysine residue (K) in its transmembrane segment, which allows it to interact with ITAM (immunoreceptor tyrosine activatory motif) – containing adaptor molecules. 13 Immunology 7105306 HLA-E presents peptides of other MHC class I molecules MHC ‫ ﻣن‬leader peptide ‫ھﺳﺎ ﺑﯾﺟﻲ ﻋﻧﺎ اﺷﻲ اﺳﻣﮫ‬ ‫ ﻓﻲ‬HLA-E molecules ‫ وﺑﺗرﺑط ﺑﺎل‬class 1 functional ‫ وﻣﺷﺎن ﯾﻧﺗﺞ ﻋﻧﺎ‬endoplasmic reticulem ‫ و‬TAP transporters ‫ ﺑﻠزﻣﻧﺎ‬HLA-E molecules.‫ ﻣﺷﺎن ﻧﻘوم ﺑرﺑطﮭن ﻣﻊ ﺑﻌض‬Tapasin ‫ رح ﯾﺧرج ﻋﻠﻰ ﺳطﺢ‬functional ‫ ﺑس ﯾﻛون‬HLA-E ‫وال‬.‫ ﯾﺗﻌرف ﻋﻠﯾﮫ‬NK ‫ ﻋﻠﻰ‬CD94 receptor ‫اﻟﺧﻠﯾﺔ ﻣﺷﺎن‬ ‫ ﺑﺗﻘوم‬MHC class 1 molecules ‫وﺧﻼل ھﺎي اﻟﻔﺗرة ال‬ cytoplasmic ‫ ﻣن‬antigenic peptides ‫ﺑﻌرض‬.endoplasmic reticulem ‫ إﻟﻲ ﺗم إدﺧﺎﻟﮭﺎ ل‬protiens 14 Immunology 7105306 HLA-E presents peptides of other MHC class I molecules Leader peptides from MHC class I molecules are loaded onto HLA-E molecules in the endoplasmic reticulum, a process that requires TAP transporters and tapasin to assemble functional HLA-E molecules. These are presented at the cell surface for review by CD94 receptors on NK cells. The MHC class I molecules meanwhile present antigenic peptides from cytoplasmic proteins that have been transported into the endoplasmic reticulum. These complexes are presented to the TCR on CD8+ CTLs. 14 Immunology 7105306 LILRB1 recognizes all MHC class I molecules including HLA-G ‫ ﺗﺑﻌﮭم‬function ‫ وال‬HLA-G ‫ وﺣﺗﻰ ﺑﺗﺗﻌرف ﻋﻠﻰ‬MHC class 1 molecules ‫ ﺑﺗﺗﻌرف ﻋﻠﻰ ﻛل أﻧواع‬LILRB1 ‫ﻋﻧﺎ ﻣﺟﻣوﻋﺔ‬.Inhibtion ‫ ﻣﺎ رح ﺗﻛون‬Self MHC class 1 molecules ‫ ﺑﺗﻌرف ﻋﻠﻰ‬inhibitory receptor ‫ ﻣﺎ ﻓﻲ ﻋﻧدھﺎ‬NK cell ‫وﻓﻲ ﺣﺎل ﻛﺎن ﻋﻧﺎ‬.target cells ‫ ﻛﺎﺳﺗﺟﺎﺑﺔ ل‬cytokines ‫ أو ﻣﺎ رح ﺗﻘدر ﺗﻔرز‬Cytotoxicity ‫ﻗﺎدرة ﻋﻠﻰ اﻟﻘﯾﺎم ب‬ effector ‫ ﻣﺎ رح ﺗﻌﻣل‬self MHC class 1 molecules ‫ ﺑﺗﻌرف ﻋﻠﻰ‬activating receptor ‫ ﻋﻧدھﺎ‬NK ‫وﻓﻲ ﺣﺎﻟﺔ ﻛﺎﻧت ﺧﻠﯾﺔ‬.Hyporesponsive ‫ وھذول اﻟﺧﻼﯾﺎ ﻣﻧﺳﻣﯾﮭن‬functions ‫ ﺗﺑﻌﺎﺗﮭﺎ زي ﻟﻣﺎ ﻣﺎ ﯾﺻﯾر إﻟﮭﺎ‬effectors functions ‫ ﺗﻘوم ﺑﺎل‬hyporesponsive NK cells ‫وﻟﻛن ﻓﻲ ﺑﻌض اﻟﺣﺎﻻت ﺑﺗﻘدر‬.IL-2 ‫ ﻣن ﻗﺑل‬activation -:‫ﻣﻼﺣظﺔ‬ receptors ‫ وﺑﯾن ال‬target cells ‫ ﻣن ﻗﺑل ال‬expression ‫ اﻟﻲ ﺑﺻﯾر اﻟﮭم‬ligands ‫ ﺑﯾن ال‬balance ‫ﺑﻛون ﻋﻧﺎ‬.NK cells ‫إﻟﻲ ﺑﺗﻌﻣﻠﮭم ال‬ 15 Immunology 7105306 LILRB1 recognizes all MHC class I molecules including HLA-G NK cells are self-tolerant An NK cell lacking an inhibitory receptor that recognizes a self MHC class I molecule cannot carry out cytotoxicity or cytokine production in response to target cells; An NK receptor that has an activating receptor that recognizes a self MHC class I molecule is also unable to carry out effector functions. Such NK cells are referred to as ‘hyporesponsive’; Hyporesponsive NK cells may still be able to carry out effector functions in some situations, such as when activated by IL-2. 15 Immunology 7105306 Cancerous and virally-infected cells are recognized by NKG2D Forming a disulphide-linked homodimer 16 Immunology 7105306  NK cells can also recognize antibody on target cells using Fc receptors ‫ ﺣﯾث إﻧﮫ ال‬AbDCC ‫ إﻟﻲ ﺣﻛﯾﻧﺎ ﻋﻧﮫ‬CD16 ‫ زي ال‬،FC receptors ‫ ﻣن ﺧﻼل ال‬recognetion ‫ ﺑﺗﻌﻣل‬NK ‫ھون ﺑﺣﻛﻲ اﻧﮫ ال‬ ‫ وﺑﺗﯾﺟﻲ ال‬antigen receptor site ‫ ﺗﺑﻌﮫ وﺑﻛون ﻋﻠﯾﮫ ال‬FAB ‫ ﻣن ﺧﻼل ال‬target cell ‫ ﺑرﺑط ﻋﻠﻰ ال‬IgG ‫ زي‬antibody.NK cell ‫ ﻟل‬activation ‫ وﺑﻌﻣل‬Antigen receptor site ‫ ﺑﺎل‬FC receptor ‫ وﺑرﺑط ال‬NK 17 Immunology 7105306 Signaling through activating and inhibitory receptors adaptor molecules ‫ ل‬recruitment ‫ رح ﯾﺻﯾر ﻋﻧﺎ‬activation receptors ‫ ﻣن ﺧﻼل‬signaling ‫ھﺳﺎ ﻟﻣﺎ ﯾﺻﯾر ﻋﻧﺎ‬ intracellular ‫ ل‬recruit and phoshorulate ‫ وھﺋول ﺑﻌﻣﻠوا‬،ITAM-like motif ‫ أو‬ITAM ‫وھﺋول ﺑﻛون ﻋﻧدھم‬ ‫ رح‬inhibitory receptors ‫ ﻣن ﺧﻼل‬signaling ‫ وﻟﻣﺎ ﯾﺻﯾر ﻋﻧﺎ‬،NK ‫ ل‬activation ‫ وھذا ﺑﺄدي ﻟل‬signaling molecules activation ‫ ﻟل‬phosphorylation ‫ ﻟل‬inhibition ‫ وال ﺑﺗﻌﻣل‬inhibitory phosphatases ‫ ﻟل‬recruitment ‫ﯾﺻﯾر‬.signaling molecules 18 Immunology 7105306 Signaling through activating and inhibitory receptors Signaling through activating receptors leads to the recruitment of adaptor molecules that contain either an ITAM or ITAM-like motif. These recruit and phosphorylate intracellular signalling molecules, leading to NK cell activation. Signaling through inhibitory receptors recruits inhibitory phosphatases, which inhibit the phosphorylation of activating signalling molecules. 18 Immunology 7105306 Cytotoxicity Cytotoxicity is effected by direct cellular interactions, granule exocytosis, and cytokines Direct cell–cell signaling via TNF family molecules; Pore formation, which allows apoptosis-inducing proteins to access the target cell cytoplasm; Indirect signaling via cytokines. -:Cytotoxicity ‫ھون ﻋﻧﺎ طرﯾﻘﺗﯾن ﻟل‬ membrane ‫ ﺑﺎل‬pores ‫ وﺑﻌﻣل‬perforin ‫ ﺑﯾﺟﻲ ﻋﻧﺎ‬-1 2 ‫ ﻟداﺧل اﻟﺧﻠﯾﺔ‬apoptosis- inducing proteins ‫وﺑﺗدﺧل ال‬ 1 ‫( أو ﺑﺗﻔﻌل‬X) ‫ وﺑﺻﯾر ﻋﻧﺎ‬granzyme A ‫واﻣﺎ ﺑﺗﻔﻌل‬ ‫ أو‬ROS ‫ وﺑﻛون ﻋﻧده ﺧﯾﺎرﯾن ﯾﺎ ﺑزﯾد ﺗرﻛﯾز‬granzyme B.Caspase 3,7,8 ‫ وﺑﻔﻌل‬caspase pathway ‫ﺑروح ﻋﻠﻰ‬ TNFR family ‫ ﺑرﺑﺗطن ﺑﺎل‬cytokines ‫ ﻣن ﺧﻼل‬-2 ‫ وﺑﺻﯾر ﻋﻧﺎ‬Caspase 10 ‫ وإﻣﺎ ﺑﻧﺷطن ال‬receptors ‫ وﺑﺗﻔﻌل ﻣﻌﮫ‬extrinsic pathway ‫ أو ﺑﺗﻔﻌل ال‬apoptosis.apoptosis ‫ وﺑﺄدي ﻟل‬Caspase 3,7,8 19 Immunology 7105306 20 Immunology 7105306 CTL and NK cell granules contain perforin and granzymes Granzyme B cleaves pro-caspases 3, 7, and 8, triggering apoptosis in the target cell. Granzyme b-deficient mice show delayed but not ablated cytotoxicity, illustrating the importance of other pathways; Granzyme A triggers apoptosis via a caspase-independent pathway. It targets the er- associated protein complex SET, activating dnase, which nicks the target cell DNA. It also cleaves nuclear laminins, leading to loss of nuclear structure, and acts in the mitochondria to increase ROI production. ‫ ﺑﺎل‬Pores ‫ واﻟﻲ ﺑﻌﻣﻠن‬Perforins ‫ ﺑﺗﻘوم ﺑﺈﻓراز‬target cell ‫ ﺑﻌد ﻣﺎ ﺗﺗﻌرف ﻋﻠﻰ ال‬،‫ ﺑﺗﻘل اﻟﺧﻼﯾﺎ‬NK ‫ھون ﺑﺷرح ﻛﯾف ال‬ ‫ وﺑﻌد ﻣﺎ ﺗﻣوت اﻟﺧﻠﯾﺔ‬apoptosis ‫ وﺑدﺧﻠن ﻟداﺧل اﻟﺧﻠﯾﺔ وﺑﻌﻣﻠن‬granzymes ‫ وﺑﻌدﯾن ﺑﯾﺟﻲ ﻋﻧﺎ‬target cell ‫ ﻟل‬membrane.apoptosis ‫ وﺑﺗﻘﺿﻲ ﻋﻛل اﺷﻲ ﺗم ﻣن ال‬phagocytosis ‫ وﺑﺗﻌﻣل‬big eater ‫ اﻟﻲ ﺳﻣﯾﻧﮭﺎ ال‬macrophage ‫ﺑﯾﺟﻲ دور ال‬ 21 Immunology 7105306 Some cell types are resistant to cell-mediated cytotoxicity During degranulation, a membrane-bound form of cathepsin B lines the granule membrane and cleaves perforin on the CTL or NK side of the synapse; CTL and NK express cflip, a protein that inhibits the cleavage of caspase 8 and prevents apoptosis via the caspase 8 pathway; They also express protease inhibitor 8 (PI-8), a serpin that can inhibit granzyme B activity. cell-mediated ‫ ل‬resistant ‫ھﺳﺎ ﻓﻲ ﻋﻧﺎ ﺧﻼﯾﺎ ﺑﺗﻛون ﻋﻧدھﺎ‬ -:‫ ﺑﺳﺑب ﻋدة ﻋواﻣل ﻣﻧﮭن‬cytotoxicity ‫ ﻋﻠﻰ ﺷﻜﻞ‬cathepsin B ‫ ﺑﻛون ﻋﻧﺎ‬degranulation ‫ ﺧﻼل‬-1 ‫ وﺑﻌﻤﻞ‬granule membrane ‫ وﺑﻜﻮن ﻣﻐﻄﻲ ال‬membrane-bound.synapse ‫ ﻣﻦ‬CTL or NK ‫ ﻋﻠﻰ ﺟﮭﺔ‬perforin ‫ ﻟﻞ‬cleavage ‫ وھﺬا ﻋﺒﺎرة ﻋﻦ‬cflip ‫ ل‬expression ‫ ﺑﺘﻌﻤﻞ‬CTL and NK ‫ ال‬-2 ‫ وﺑﻤﻨﻊ ال‬caspase 8 ‫ ﻟﻞ‬cleavage ‫ ﻟﻞ‬inhibition ‫ﺑﺮوﺗﯿﻦ ﺑﻌﻤﻞ‬.caspase 8 pathway ‫ ﻣﻦ ﺧﻼل‬apoptosis ‫ ﺑﻌﻤﻞ‬serpin ‫( وھﻮ ﻋﺒﺎرة ﻋﻦ‬PI-8) ‫ ل‬expression ‫ وﺑﻌﻤﻠﻮا‬-3.granzyme B activiy ‫ ل‬inhibition.more selective ‫ ﺗﻜﻮن‬cytotoxicity ‫وھﺌﻮل اﻟﻌﻮاﻣﻞ ﺑﺨﻠﻦ ال‬ 22 Immunology 7105306  Some cell types are resistant to cell-mediated cytotoxicity Cont …. Neurons, hepatocytes and some placental cell populations MHC I resistant to cell-mediated cytotoxicity ‫ إﻻ اﻧﮭﺎ‬MHC class 1 molecules ‫ ﻟل‬down regulation ‫ھون ﻋﻧﺎ ﺧﻼﯾﺎ ﺑﺎﻟرﻏم اﻧﮭﺎ ﻋﺎﻣﻠﺔ‬ -:‫ﺷﺎرﺣﻠﻧﺎ ﻛل وﺣدة ﻟﯾش‬ ‫ ﻟل‬expression ‫ ﺑﺗﻌﻣل‬cornea and testes ‫ )رح ﻧوﺧذھم ﻟﻘدام( زي ال‬immune privileged sites ‫ واﻟﺧﻼﯾﺎ اﻟﻣوﺟودة ﺑﺎل‬neurons ‫ ﻋﻧﺎ‬-1.tissue ‫ ﻟﻣﺎ ﯾدﺧﻠن ال‬Fas- expressing T & NK cells ‫ ﻓﻲ‬apoptosis ‫ ﻟل‬inducing ‫ وھذا ﺑﻌﻣل‬Fas lignad neurons, hepatocytes and most placental ‫ وﻓﻲ اﻟﺣﻼت اﻟطﺑﯾﻌﯾﺔ‬not efficient killers ‫ ﺑﻛوﻧوا‬tissue-resident NK ‫ﻣﻧﻌرف إﻧﮫ‬-2.Blood NK cells ‫ وﻣﺎ ﺑﺗﺗﻌرض ﻟل‬،‫ ﻓﻘط‬tissue-resident NK ‫ ﺑﺗﺗﻌرض ﻟل‬extravillous trophoblast cells peripheral ‫ وﺑﺗﻛون ﺑﺎﺗﺻﺎل ﻣﺑﺎﺷر ﻣﻊ‬MHC class 1 molecules ‫ ﻷي‬expression ‫ ﻣﺎ ﺑﺗﻌﻣل‬placental villous trophoblast cells -3.‫ ﺑس ﻟﺳﺎ ﻣش ﻣﻌروﻓﺎت‬other mechanisms ‫ وﻓﻲ‬resistance ‫ وھذا ﺑزﯾد ال‬syncytium ‫ وﺑﻘوﻣن ﺑﺗﺷﻛﯾل‬،blood NK cells classical ‫ ﻟل‬experssion ‫ وﺑﺗﻌﻣل‬peripheral blood NK cells ‫ ﺑﺗﻛون ﻋرﺿﺔ ﻟل‬some placental extravillous trophoblast cells -4 NK ‫ ﻟل‬activation ‫ ﻟل‬inhibtion ‫ وھﺋول ﺑﻌﻣﻠن‬non-classical class I molecules HLA-E and –G ‫ و‬MHC class I molecule HLA-C.‫ ﺑﻔﻌﺎﻟﯾﺔ ﻛﺑﯾرة‬cells 23 Immunology 7105306  Some cell types are resistant to cell-mediated cytotoxicity Cont …. Neurons, hepatocytes and some placental cell populations MHC I neurons, as well as cells in other immune privileged sites, such as the cornea and testes, express FasL. This induces apoptosis in Fas-expressing T and NK cells as they enter the tissue; tissue-resident NK cells are generally not efficient killers. In non-pathological situations, neurons, hepatocytes and most placental extravillous trophoblast cells are only exposed to tissue-resident, and not blood NK cells; placental villous trophoblast cells express no MHC class I molecules, and are in direct contact with peripheral blood NK cells. They form a syncytium, and this may confer some resistance to killing, but other mechanisms, as yet undefined, are also likely to be important; some placental extravillous trophoblast cells are exposed to peripheral blood NK cells. These express the classical MHC class I molecule HLA-C, and the non-classical class I molecules HLA-E and -G, which effectively inhibit NK cell activation. 23 Immunology 7105306 ‫‪Macrophages and neutrophils primarily kill target cells by‬‬ ‫‪phagocytosis‬‬ ‫ھﺳﺎ ھون ﺑﺣﻛﻲ اﻧﮫ ﻋﻧد ‪ macrophage and neutrophils‬ﺑﺗﻘﺿﻲ ﻋﻠﻰ ال ‪ target cells‬ﻣن ﺧﻼل طرﯾﻘﺗﯾن إﻣﺎ ﻣن ﺧﻼل ‪ phagocytosis‬أو ﻣن‬ ‫ﺧﻼل إﻓراز ﻣﺟﻣوﻋﺔ ﻣن ال ‪ products‬إﻟﻲ ﺑﺗﺄدي ﻟﻠﻣوت ال ‪ target cell‬زي ‪ Cationic proteins‬و ‪ activation of C3a‬و ‪ hydrolases‬و ‪ROS‬‬ ‫و‪ RNI‬و ‪.tumor necrosis factor‬‬ ‫وﻟﻛن ﺗم اﻛﺗﺷﺎف طرﯾﻘﺔ ﺛﺎﻟﺛﺔ ﺑﺗﺳﺗﺧدﻣﮭﺎ ﺧﻼﯾﺎ ‪ neutrophils‬ﻟﻣﺎ ﻣﺎ ﺗﻘدر ﺗﺗﺧﻠص ﻣن ال ‪ target cell‬ﻣن ﺧﻼل اﻟطرق اﻟﺳﺎﺑﻘﺔ‪ ،‬ﺑﺗﻘرب ﻋﻠﻰ ال ‪target‬‬ ‫‪ cell‬وﺑﺗﻘوم ﺑﺎﻹﻧﺗﺣﺎر ﺣﯾث إﻧﮭﺎ ﺑﺗﻧﻔﺟر وﺑﺗطﻠﻊ اﻟﺷﺑﻛﺔ اﻟﻛروﻣﺎﺗﯾﻧﯾﺔ ﺗﺑﻌﺗﮭﺎ وﺑﺗﻐطﻲ اﻟﻣﻧطﻘﺔ اﻟﻣﺳﺗﮭدﻓﺔ وﻓﻲ ﺑﺟﻣﺳﻧﺎ ‪ antinuclear antibodies‬ﺑﺗﯾﺟﻲ‬ ‫وﺑﺗرﺑط ﺑﺎﻟﺷﺑﻛﺔ وﺑﺗﻌﻣل ‪ activation‬ﻟل ‪ complement system‬وﺑﺻﯾر ﻋﻧﺎ ‪ Lysis‬ﻟﻠﺧﻼﯾﺎ‪.‬‬ ‫‪24‬‬ ‫‪Immunology 7105306‬‬ Macrophages and neutrophils primarily kill target cells by phagocytosis In general, macrophages and neutrophils destroy pathogens by internalizing them and barraging them with toxic molecules and enzymes within the phagolysosome. These include: the production of reactive oxygen species, toxic oxidants, and nitric oxide; the secretion of molecules such as neutrophil defensins, lysosomal enzymes and cytostatic proteins 24 Immunology 7105306