CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Immunological Bioinformatics Introduction to the immune system

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark 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

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Figure 1-20

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Effectiveness of vaccines 1958 start of small pox eradication program

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark The Immune System The innate immune system The adaptive immune system

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS 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)

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark The adaptive immune system Pathogen specific –Humoral –Cellular Bacteria Virus Parasite

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Adaptive immune response Signal induced –Pathogens Antigens –Epitopes B Cell T Cell

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Antibody - Antigen interaction Fab Antigen Epitope Paratope Antibody The antibody recognizes structural properties of the surface of the antigen

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Cartoon by Eric Reits Humoral immunity

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark The immune response starts with an antigen approaching a cell of the immune system, here a macrophage. antigen macrophage The Humoral Response - Activation Phase

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark The macrophage engulfs the antigen by phagocytosis. Lysosome containing enzymes Antigen engulfed in vesicle

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark 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

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS 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. enzymes and proteins combining Class II MHC proteins

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark The antigen/MHC protein complex is displayed on the immune cell surface membrane. The macrophage is now known as an antigen presenting cell. Processed antigen/ MHC protein complex Antigen-presenting cell

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark The next stage involves a helper T cell (also know as a T-helper cell) as well as the macrophage T helper cell (T H ) macrophage (antigen-presenting cell) receptors which bind to specific antigen/MHC protein complex

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark The receptors on the helper T cell enable it to bind to the specific antigen- MHC complex of the antigen presenting cell. macrophage (antigen-presenting cell) helper T cell

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark 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. Cytokines from macrophage

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark The activated helper T cell now releases its own cytokines Cytokines from helper T cell

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark 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 cell, so they are specific for the original antigen. Clone of helper T cells

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Another phase of the immune response begins with a B cell. The B cell has membrane bound globular receptor proteins (called IgM). Some of these are specific for the same antigen presented earlier by the antigen presenting cell. antigen B cell IgM receptor The Humoral Response - Effector Phase

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark The B cell’s receptor protein (an IgM) binds to the antigen, and the cell engulfs the antigen by endocytosis. IgM bound to antigen engulfed by cell lysosome

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark 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 B cell

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Fragments of the digested antigen remain after processing within the vesicle. Processed antigen Class II MHC protein

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark The processed antigen is attached to Class II MHC receptors within the B cell, and is transported to the membrane.

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark 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 Antigen/MHC protein complex B cell (antigen presenting cell)

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark A helper T cell from the clone of cells produced earlier specifically recognises the antigen presented by the B cell. Antigen-presenting B cell Helper T cell clone

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark The helper T cell cell binds to the antigen/MHC protein complex displayed by the B cell. 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. Cytokines released by helper T cell helper T cell binds to antigen complex on B cell

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark The cytokines released by the helper T cell stimulate the B cell to divide and form a clone of identical cells B cell clones

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark 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. Memory cell Plasma cells

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Plasma cells are essentially antibody factories. They produce and secrete antibodies identical to those of the surface receptors of the original parent B cell antibodies

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Like the IgM surface receptors on the parent B cell, the antibodies can bind to and inactivate the antigens, forming an antibody-antigen complex. This complex makes it easier for other white blood cells to engulf the antigen (phagocytosis). Antibody-antigen complex

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Cellular Immunity

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Diversity is a hallmark of the (adaptive) immune system Diversity of lymphocytes –Huge diversity within a host –At least 10 8 different T & B cell clones Receptors made by recombination & N- additions Somatic mutation during immune response Repertoires are (partly) random –Randomness requires self tolerance

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Figure 1-14

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark 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 Healthy cell Virus- infected cell MHC-I

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Department of Systems Biology Technical University of Denmark Anchor positions MHC class I with peptide