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CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Immunological Bioinformatics Introduction to the immune system Department of Systems Biology Technical University of Denmark Vaccination Vaccination • Administration of a substance to a person with the purpose of preventing a disease • Traditionally composed of a killed or weakened micro organism • Vaccination works by creating a type of immune response that enables the memory cells to later respond to a similar organism before it can cause disease Department of Systems Biology Technical University of Denmark CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS • Figure 1-20 CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Effectiveness of vaccines CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS 1958 start of small pox eradication program Department of Systems Biology Technical University of Denmark The Immune System CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS The innate immune system The adaptive immune system Department of Systems Biology Technical University of Denmark The innate immune system Unspecific Antigen independent Immediate response No training/selection hence no memory Pathogen independent (but response might be pathogen type dependent) Department of Systems Biology Technical University of Denmark CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS • • • • • The adaptive immune system – Humoral Parasite – Cellular http://tpeeaupotable.ifrance.com/ma%20photo/bilharzoze.jpg Virus http://en.wikipedia.org/wiki/Image:Aids_virus.jpg Bacteria Department of Systems Biology http://www.uni-heidelberg.de/zentral/ztl/grafiken_bilder/bilder/e-coli.jpg Technical University of Denmark CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Pathogen specific Adaptive immune response CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Signal induced – Pathogens • Antigens – Epitopes B Cell T Cell Department of Systems Biology Technical University of Denmark Antibody - Antigen interaction The antibody recognizes structural properties of the surface of the antigen Fab Epitope Paratope Antibody Department of Systems Biology Technical University of Denmark CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Antigen CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Humoral immunity Department of Systems Biology Cartoon by Eric Reits Technical University of Denmark The Humoral Response - Activation Phase The immune response starts with an antigen approaching a cell of the immune system, here a macrophage. macrophage http://www.pfizerlearninglab.co.uk/ Department of Systems Biology Technical University of Denmark CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS antigen CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Antigen engulfed in vesicle The macrophage engulfs the antigen by phagocytosis. Lysosome containing enzymes http://www.pfizerlearninglab.co.uk/ Department of Systems Biology Technical University of Denmark CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS The vesicle containing an antigen fuses with a lysosome. The enzymes in the lysozome break down the antigen into fragments. This is antigen processing. antigen processing http://www.pfizerlearninglab.co.uk/ Department of Systems Biology Technical University of Denmark Inside the macrophage, the processed antigens combine with special class II MHC proteins. These proteins can move to the cell surface membrane. Class II MHC proteins http://www.pfizerlearninglab.co.uk/ Department of Systems Biology Technical University of Denmark CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS enzymes and proteins combining The antigen/MHC protein complex is displayed on the immune cell surface membrane. The macrophage is now known as an antigen presenting cell. Antigen-presenting cell http://www.pfizerlearninglab.co.uk/ Department of Systems Biology Technical University of Denmark CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Processed antigen/ MHC protein complex The next stage involves a helper T cell (also know as a T-helper cell) as well as the macrophage T helper cell (TH) http://www.pfizerlearninglab.co.uk/ Department of Systems Biology macrophage (antigen-presenting cell) Technical University of Denmark CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS receptors which bind to specific antigen/MHC protein complex The receptors on the helper T cell enable it to bind to the specific antigenMHC complex of the antigen presenting cell. CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS helper T cell macrophage (antigen-presenting cell) Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ Cytokines from macrophage Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS The binding of the helper T cell with the antigen - MHC protein complex triggers the macrophage to release proteins (cytokines) that activate the helper T cell. The activated helper T cell now releases its own cytokines Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Cytokines from helper T cell cell, so they are specific for the original antigen. Clone of helper T cells Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS The released cytokines stimulate the helper T cell to reproduce and form a clone of cells. Each new cell has the same receptors as the original helper T The Humoral Response - Effector Phase IgM). Some of these are specific for the same antigen presented earlier by the antigen presenting cell. IgM receptor antigen B cell Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Another phase of the immune response begins with a B cell. The B cell has membrane bound globular receptor proteins (called IgM bound to antigen engulfed by cell lysosome Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS The B cell’s receptor protein (an IgM) binds to the antigen, and the cell engulfs the antigen by endocytosis. B cell Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS The vesicle formed inside the B cell fuses with a lysosome. This contains digestive enzymes which break down the antigen. Fused vesicles containing antigen and enzymes from lysosome CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Fragments of the digested antigen remain after processing within the vesicle. Processed antigen Class II MHC protein Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS The processed antigen is attached to Class II MHC receptors within the B cell, and is transported to the membrane. Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ The MHC proteins form a complex with the antigen which is displayed on the surface of the B cell. It has become another type of antigen presenting cell B cell (antigen presenting cell) Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Antigen/MHC protein complex A helper T cell from the clone of cells produced earlier specifically recognises the antigen presented by the B cell. CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Helper T cell clone Antigen-presenting B cell Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ This triggers the release of cytokines from the T cell. Once the cytokines are released the helper T cell no longer binds to the B cell. helper T cell binds to antigen complex on B cell Cytokines released by helper T cell http://www.pfizerlearninglab.co.uk/ Department of Systems Biology Technical University of Denmark CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS The helper T cell cell binds to the antigen/MHC protein complex displayed by the B cell. B cell clones Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS The cytokines released by the helper T cell stimulate the B cell to divide and form a clone of identical cells The B cells continue to divide and form two groups of clones. Some are long – lived MEMORY cells. Most are antibody-secreting PLASMA cells. Plasma cells have extensive endoplasmic reticulum and many ribosomes. Plasma cells Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Memory cell antibodies Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Plasma cells are essentially antibody factories. They produce and secrete antibodies identical to those of the surface receptors of the original parent B cell an antibody-antigen complex. This complex makes it easier for other white blood cells to engulf the antigen (phagocytosis). Antibody-antigen complex Department of Systems Biology Technical University of Denmark http://www.pfizerlearninglab.co.uk/ CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Like the IgM surface receptors on the parent B cell, the antibodies can bind to and inactivate the antigens, forming Cellular Immunity CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Diversity is a hallmark of the (adaptive) immune system – Huge diversity within a host – At least 108 different T & B cell clones Receptors made by recombination & Nadditions Somatic mutation during immune response Repertoires are (partly) random – Randomness requires self tolerance Department of Systems Biology Technical University of Denmark CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Diversity of lymphocytes MHC-I molecules present peptides on the surface of most cells CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark CTL response CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Healthy cell MHC-I Virusinfected cell Department of Systems Biology Technical University of Denmark MHC class I with peptide CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Anchor positions Department of Systems Biology Technical University of Denmark