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62 Cards in this Set
- Front
- Back
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Adaptive Immune system |
- developed based on RAG (recombinase activating gene) - products of RAG responsible for somatic recombination of gene segments encoding antigen receptors (B-cell and T cell receptors) - diversity - relies on recombination events - clonal distribution and selection - acquisition of memory |
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clonal distribution and selection |
distribution and selection of antigen receptors from a randomly generated and highly diverse repertoire of specificities |
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acquisition of memory |
Memory T or B cells are generated following the resolution of an immune response to a pathogen |
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Memory in vaccines |
1) prime - immune system recognizes organism 2) boost - memory expansion if organism seen later in life, immune system automatically kicks in |
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Adaptive Immune response B cells |
- B cells secrete antibody - specificity of antibody secreted is same as surface bound B cell receptor (BCR) - humoral immunity |
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Adaptive Immune Response T cells |
- express unique T cell receptors (TCR) - function by either direct contact (CD3+CD8+CTL: kiss of death) OR - secretion of cytokines (CD3+helper, cytotoxic and suppressor T cells) - cell mediated immunity |
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characteristics adaptive immunity |
specificity and memory |
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Principle cytokine |
IL-2 growth factor for T cells |
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Suppressor T cells |
CD25 and phosP3 turn immune response off tumors can induce generation of suppressor T cells in cancer |
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Why adaptive response |
- normally innate immunity can handle extracellular - infection outruns innate or intracellular = adaptive |
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clonal proliferation |
- progenitor cells give rise to large numbers of lymphocytes w/ different specificity - infection: lymphocytes with receptors that recognize pathogen are activated - proliferation and differentiation of pathogen-activated lymphocytes give effector cells to terminate infection |
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Diversity of acquired response - benefits adaptive immunity |
- many different pathogens - large repertoire of B and T cells allows response - response can adapt to changes/mutations - B and T cells retained as memory |
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Timing of response for antibodies and T cells |
Primary response: - lag phase: inflammation - lymphocytes and monocytes respond to antigen: 7-10 days Secondary response: - due to memory cells, response is immediate This is how prime and boost works in vaccines |
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Things to consider in Immune response |
- Pathogen type: intra vs. extra cellular; humoral vs. CMI - antigen presentation - normal vs. infected: Major histocompatibility complex (MHC) - effector cells to clear pathogen: cytokines; cytotoxic mechanisms |
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TLR receptors |
Immunity: innate and acquired Pathogens: intra and extra cellular Diversity: limited Expression: constituitive Where: all cells (antigen presenting cells) Type: pathogens Effector mechanism: cytokine release and inflammation |
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BCR |
Immunity: innate and acquired Pathogens: extra cellular Diversity: very diverse Expression: constituitive Where: B cells Type: soluble antigens and pathogens Effector mech: antibody production |
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TCR |
Immunity: acquired
Pathogens: intra and extra cellular Diversity: very diverse Expression: constituitive Where: T cells Type: virus, bacteria, tumor, transplant Effector mech: helper, cytotoxic, suppressor T |
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MHC |
Immunity: acquired Pathogens: extra and intra cellular Diversity: very Expression: constituitive, up-regulated by cytokines Where: Class I: all nucleated, Class II: APC Type: virus, bacteria, tumor, transplant Effector mech: helper, cytotoxic, suppressor T cells |
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Activation T cell |
1) Dendritic cell takes up infectious virus particles/remnants of virus 2) cross-presentation of antigen by dendritic cell (spleen or lymph node) - APC 3) Activates helper T cell via binding of CD40/CD40L and MHC-II/TCR on CD4 cell 4) activates cytotoxic T cell via binding CD80/86/CD28 and MHC-I/TCR 5) differentiation CD8 T cell 6) CD8 T cell attacks virally infected cell displaying matching MHC-I via binding TCR/MHCI - CD8 unit attaches to cells 7) CD8 T cell releases perforins/granzymes and cytokines |
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MHC |
major histocompatibility complex |
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HLA |
human leukocyte antigen |
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MHC Class I genetics |
- 3 genes on human chromosome 6 important for presenting Ag to T cells - heavy chain genes: HLA-A, HLA-B, HLA-C - beta 2 microglobulin gene (chr 15) required - gene expression co-dominant: 6 different class I molecules per cell - HLA gene has many allelic variants in population: each allele binds different spectrum of antigenic peptides |
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MHC class II genetics |
- 3 genes on chr. 6 for presenting Ag to T cells - HLA-DR, HLA-DQ, HLA-DP (each gene for 2 distinct protein chains) - co-dominant expression: up to 16 different class II molecules, each binding unique spectrum antigenic peptides - highly polymorphic in population |
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Pathogen effect on MHC genes |
- virus can down regulate HLA-A or HLA-B genes to prevent Class I expression - tumor cells can also do this - Class II genes are important for transplants to match |
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Organization MHC gene complex |
HLA halotype: HLA genes are inherited on single chromosome (chr 6) Class I: HLA-A, HLA-B, HLA-C Class II: HLA-DP, HLA-DQ, HLA-DR Co-expresses alleles cofactor: B2-microglobin on chromosome 15 |
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Class I presenting cells |
- T cells - B cells - Macrophages - Dendritic cells - Neutrophils - Liver hepatocytes - Kidney epithelium - Brain |
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Class II presenting cells |
- T cells - B cells - Macrophages - Dendritic cells |
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High expression both MHC I and II |
professional APC - B cells - Dendritic cells (macrophages also common APC) |
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MHC class I vs. MHC class II presenting cells |
presenting MHC I: display antigenic peptides derived from intracellular pathogens - target CD8 T cells presenting MHC II: display antigenic peptides from extracellular pathogens - present Ag to CD4 helper T cells |
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upregulator Class II expression |
gamma interferon |
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MHC molecules in population |
- highly polymorphic - ensures most individuals are heterozygotes = broader spectrum of peptides that can be bound by any individual |
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MHC class I structure |
- Three regions: alpha 1, alpha 2, alpha 3 - alpha1 and 2 most important for presenting peptide - alpha 3 inserts on cell membrane - infariat chain: separate molecule that stabilizes alphas - bind small peptides (8-9 aa) - 6 different MHC class I per cell |
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MHC class II structure |
- alpha 1 and alpha 2 - beta 1 and beta 2 - no need stabilization - peptide binding groove: beta 1 and alpha 1 - holds larger peptides (8-25 aa) |
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Promiscuous binding specificity |
- anchor residues must be specific - other residues in between can be different MHC I: L at carboxyl end, different two aa away MHC II: carboxyl end and one away from amino end |
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TCR |
T cell receptor - recognizes peptides - goes through education in thymus and only let out ones that bind to MHC I and MHC II (not too strongly) and none that bind to self - made of alpha and beta chains (main variability is in alpha) and zeta chains - zeta chains send signal to make IL-2 to differentiate into effector cell and kill Complex: TCR with one CD3 on each side |
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CD3 |
in TCR complex one combo per side: - epsilon with gamma - epsilon with delta When TCR bound to MHC and peptide, signals nucleus to begin activation of T cell proliferation |
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Two classes of TCR |
Gamma delta - found in mucosa in gut - not much polymorphism Alpha beta - recognize millions of different peptides Both have variable region, constant region and transmembrane region |
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How do you get different TCRs |
RAG gene recombinase - clips gene segments so they can be built into different alpha and beta chains alpha chain locus: chr. 14 gamma chain locus: chr. 7 delta chain locus: chr. 14 |
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What contributes to TCR diversity and immunoglobulin diversity |
Diversity: TCR alpha > TCR beta > immunoglobulin - variable segments (V) - diversity segments (D) - TCR has many joining segments |
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MHC restriction |
TCR binds to both peptide and MHC molecule restricted to single class I and single peptide |
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antigen processing |
intracellular degradation of protein antigens into peptides, which are then bound to MHC molecules |
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Antigen presentation |
placement of antigenic peptide on surface of an APC bound to MHC molecules so that antigen can be presented to a TCR on T cell |
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Mechanism of antigen processing |
Depends on location of pathogen and type of APC - Cytosolic pathogens - Intravesicular pathogens - Extracellular pathogens and toxins |
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cytosolic pathogens |
Any cell Degraded in: cytosol Peptides bind to: MHC class I Presented to: effector CD8 T cells Effect on presenting cell: death |
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Intravesicular pathogens |
Macrophage Degraded in: endolytic vesicles Peptides bind to: MHC class II Presented to: effector CD4 T cells Effect on presenting cell: activation to kill intravesicular bacteria and parasites |
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Extracellular pathogens and toxins |
B cell Degraded in: endocytic vesicles Peptides bind to: MHC class II Presented to: CD4 T cells Effect on presenting cell: activation of B cells to secrete Ig to eliminate extracellular bacteria/toxins |
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Antigen presenting cells expression of MHC |
Express both forms of MHC molecules - MHC class I binds peptides from intracellular pathogens - peptide then presented to CD8 T cell - MHC class II binds peptides from extracellular pathogens - peptide then presented to CD4 T cell |
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MHC and HLA |
Major Histocompatibility Complex Human Leukocyte Antigen (gene - protein) |
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Turnover cytoplasmic proteins in MHC I synthesis pathway |
Turnover is normal cellular process used w cell proteins - this is normal cell 1) Protein antigen in cell 2) antigen processing by proteasome results in breakdown of protein - in cytosol 3) Clipped peptides get picked up by TAP in ER membrane 4) Peptides hook onto MHC I protein being made in ER 5) MHC I with peptide gets transported to cellular membrane 6) MHC I is displayed, turned over, others displayed |
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Antigen processing of intracellular antigens |
Class I molecules bind and present peptides derived from cytoplasmic sources of antigen (intracellular pathogens) - this is infected cell 1) viral proteins synthesized in cytoplasm 2) peptide fragments bound by MHC class I in ER 3) bound peptides transported by MHC I to surface 4) cytotoxic T cell recognizes complex of peptide with MHC I and kills infected cell |
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Cross presentation |
MHC Class I molecules Bacteria proteins is degraded in phagolysosome Some antigen gets out to ER Expressed as MHC class I Cell is not infected this way |
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Antigen processing of extracellular antigens |
Class II molecules bind and present peptides derived from extracellular space 1) macrophage engulfs and degrades bacterium, producing peptides 2) Bacterial peptides bound by MHC class II in vesicles - barring chain prevents MHC II binding to proteins in cytoplasm 3) Bound peptides transported by MHC II to cell surface 4) Helper T cell recognizes complex of peptide antigen with MHC class II and activates macrophage |
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Antigen processing by B cells |
- extracellular antigens via MHC Class II molecules - utilizes surface immunoglobulin to capture antigen 1) Cell surface immunoglobulin of B cell binds bacteria - cell engulfs and degrades - peptides 2) Bacterial peptides bound by MHC class II in endocytic vesicles 3) Bound peptides transported by MHC class II to cell surface 4) Helper T cell recognizes complex with MHC class II and activates B cell |
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TCR recognition |
Recognize peptide antigens produced by degradation of proteins 1) Dendritic cell takes up pathogen for degradation 2) Pathogen taken apart inside dendritic cell 3) Pathogen proteins unfolded and cut into small pieces 4) Peptides bind to MHC molecules and complex goes to surface 5) TCR bind peptide: MHC complexes on dendritic cell surface |
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epitope |
antigenic determinant - peptide antigen |
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TCR response to microbes |
Tailored to lifestyle of pathogen - extracellular pathogens: presented on APC to CD4 T cell - MHC II - intracellular pathogens: presented on APC to CD8 T cell - MHC I Coreceptors of T cell ensure binds to proper MHC - CD4: CD40L - CD8: CD28 |
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CD4 T cell function |
Helper T cells: use cytokines and also - make cytotoxic T cells - provide things to make T cells proliferate - IL-17 for inflammation - Differentiate to get rid of parasites - Turn on B cell responses - TH2 cells - Follicular helper cells - help B cells make antibody, isotype switching |
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Th1 (helper T-cell 1) |
cell mediated immunity |
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Th2 |
helps humoral immunity |
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Th17 |
mediates inflammatory responses |
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Tregs |
suppress immunity |
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MHC class III |
complement proteins TAP |
