Bio #3 Immune System

G

#1 characteristic of adaptive immune system: Generation of B and T cell diversity: -by combining variable elements, the immune system assembles a diverse variety of antigen receptors -immunoglobulin (Ig) gene encodes one chain of the B cell receptor, but we can produce many different chains from this one gene by rearranging components of the DNA that is encoded by that gene -each person makes more than 1 million different B cell antigen receptors, and more than 10 million different T cell antigen receptors, even though there are only about 20,000 protein-coding genes in the human genome

#2 characteristic of adaptive immune system:

#3 characteristic of adaptive immune system: Proliferation of B cells and T cells -for any particular epitope, there are only a few cells in the entire body that can recognize it -in the lymph nodes, an antigen (held on the surface of a macrophage) is presented to a steady stream of lymphocytes (B and T cells) until a match is made -the binding of a mature lymphocyte to an antigen initiates events that activate the lymphocyte -once activated, a B or T cell undergoes multiple cell divisions, called clonal selection, to produce a population of identical cells to the mother cell -some of this clone become effector cells, which act immediately on the antigen -B cell effector cells are plasma cells that make and secrete antibodies that have the exact same sequence and binding specificity, but not the transmembrane domain, so they can float out all over the body; they accomplish the immediate immune response -T cell effector cells are helper T cells and cytotoxic T cells -the remaining cloned cells become long-lived Memory Cells, that can give rise to effector cells if the same antigen is encountered again, mounting a quick and deadly response

Ce

Cellular Innate Defenses: -pathogens entering the mammalian body are subject to phagocytosis -phagocytic cells recognize groups of pathogens using TLRs: Toll-like receptors -each TLR binds to fragments of molecules that are seen in big classes of pathogens Types: -TLR3: on the inner surface of endocytic vesicles. Senses for double-stranded RNA, which are a characteristic of viruses. (Never seen in human bodies) -TLR4: on immune cell plasma membranes and recognize lipopolysaccharides, a molecule found on the surface of many bacteria -TLR5: recognizes flagella, a protein of bacterial flagella -TRL9: recognizes unmethylated CpG dinucleotide sites. These sites are very rare on vertebrate genomes, but can found in bacterial genomes and viral DNA -all of these mechanisms can recognize a specific class of pathogen, and then active downstream innate signaling cascades accordingly

Ev

Evasion of Innate immunity by pathogens: -its an arms race! Pathogens avoid destruction by modifying their surface proteins to prevent recognition or by resisting breakdown following phagocytosis -ex: Tuberculosis (TB) gets inside our lysosomes and live there. TB is so deadly because our innate immune responses are insuffifcent to kill it off. -Luckily, we have the stuff to build lots of variation to make the right adaptive immune response to these new evolved pathogens

H

Helper T Cells function in both humoral and cell-mediated immunity: -couple different types of T cells (matured in the thymus): natural killer t-cells, cytotoxic t-cells, and helper t cells -Helper T cells trigger both the humoral and cell-mediated immune responses, although they themselves do not carry out those responses -They need to agree with the B or cytotoxic T cell in order to allow a large response (2nd guy for the nuclear missile key) -with B cells, that means the production of antibodies that neutralize pathogens -with T cells, that means kill infected cells -all nucleated cells have class 1 MHC molecules on their surface (thats all cells except RBCs-erythrocytes) (that MHC molecule is either presenting fragments of a pathogen, or one of the body's natural proteins) -Antigen-presenting cells have class 1 and class 2 MHC molecules on their surface -great diversity of these MHC molecules: each person has a different set of 50 MHC molecules on the surface of each one of their cells. This is the basis of self-recogniton, because T-cells are able to recognize all of these MHC molecules Two requirements for a helper T cell to activate adaptive immune response: 1) a foreign molecule must be presented that can bind to the antigen receptor of a T cell 2) this antigen must be displayed on the surface of an antigen-presenting cell (has both class 1 and class 2 MHC) -not found in every cell, only the phagocytic cells that eat pathogens and display them: dendritic cells (in our tissues), macrophages (circulating blood and lymph), and B-cells. -the class 2 MHC provide a molecular signature by which an antigen-presenting cell is recognized -they once connected, cytokines are released -then a clone of activated helper T cells is made, and then go out to activate either B cells for a humoral immunity response (secretion of antibodies by plasma cells) or cytotoxic T cells for cell-mediated immunity (attack on infected cells)

Immu

Immunoglobulin gene rearrangement -A receptor light chain is encoded by 3 gene segments: a variable (V) segment, a joining (J) segment, and a constant (C) segment -the V and J segments encode for the variable region of the receptor chain, and the C segment encodes for the constant region -The light-chain gene contains a single C segment, 40 different V segments, and 5 different J segments -the alternative copies of the V and J segments are arranged within the gene in a series -Because the functional gene is build from one copy of each type of segment, the pieces can be combined in 200 different ways ( 40 V x 5 J x 1 C) -the number of different heavy-chain genes is even greater, resulting in more diversity (3.5 million different possible combinations of light chain and heavy chain combinations)

T

The process: 1) Starting with DNA of an undifferentiated B-cell: Recombinase enzyme deletes DNA between randomly selected V segment and J segment -it links a single V gene segment (1 of the 40) to a single J gene segment (1 of the 5) 2) Now DNA of a differentiated B cell: Transcription of this permanently rearranged, functional gene (1 V, 1 J, 1 C) 3) RNA processing -the intron that was inbetween the J and C segments is sliced 4) Translation 5) Protein product: This light-chain polypeptide that goes onto the tip of that cell's Y-shaped antigen receptor 6) a light chain and heavy chain assemble together, forming an antigen receptor. Each pair of randomly rearranged H and L chains results in a different antigen-binding surface -furthermore, mutations during the VJ recombination and from Somatic Hypermutation make the number of possible antigen-binding specificities even greater

C

This is how we get specificity of the downstream cellular responses. Class 1 MHC proteins: -cell is infected and its class 1 MHC molecule presents the foreign antigen -the cytotoxic T cell recognizes the MHC molecule and the antigen, binds, and gets activated -the class 1 just activates the cytotoxic t cells, which are designed to kill the infected cell Class 2 MH2 Proteins: -these cells aren't infected, they have simply eaten the pathogen by phagocytosis, and now have some of the antigen remains -the antigens from the ingested microbe are displayed on the class 2 MHC molecule -this allows a different type of T cell, the helper T cell, to recognize this antigen -class 2 activates the helper T cells, which specifically enhances a global response to the pathogen that is being presented and recognized -the helper T cell proliferates, forms clone helper T cells, which then activate the appropriate B cells -different types of antigen-presenting cells interact with helper T cells in distinct contexts -Antigen presentation by a dendritic cell or macrophage activates the helper T cell, which then proliferates, forming clone activated helper T cells -B cells presents antigens to already activated helper T cell, which in turn activate the B cells themselves -Activated helper T cells also help stimulate cytotoxic T cells