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IMM250 - Test NOTES Lecture 6.doc

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University of Toronto St. George

“Growing an adaptive immune system” Severe Combined Immunodeficiency Syndrome (SCID) • “Bubble Boy” • David Vetter poses inside of his bubble in his Houston home in this Dec. 17, 1976 file photo. Vetter was born with a genetic disorder leaving him no natural immunity against disease. He died at age 12. • had no adaptive immunity Innate and adaptive immunity • Immune system has two lines of defense: o Innate immunity:  first to respond to foreign antigen  phagocytic cells are key components of innate response  very limited scope of antigen recognition o Adaptive immunity:  T cells and B cells  B cells produce antibodies  T cells help B cells to produce antibodies and can also directly kill pathogens  Adaptive Immunity confers lifelong protective immunity to re-infection with the same pathogen  B cells and T cells comprise a pool of lymphocytes with a large number of specificities for “antigen” • Both innate and adaptive immune responses are dependent on the activities of leukocytes (white blood cells). • dosnt remember pathogens • lymphocytes compose adaptive immune system Cells of the Immune System • all leukocytes (white blood cells) • all of these cells come from stem cell, a cell that resides in the bone marrow and has capacity to give rise to all of these different cell type lineages • bone marrow transplants transplant stem cells which has the capacity to repopulate the host immune system • in theory you can transplant a signle stem cell to a host and repopulate their entire immune system • adaptive immune system - lymphocytes either B cells or T cells once B cells mature they can take on dif types of memory cells they can be plasma cells which are effectors that make lots of antibodies or be memory cells and have long term memory to infection Critical Concepts that shape the adaptive immune system • Antigens • Diversity • Tolerance • how immune system diverifies itself to recognize lost of antigens • how the immune system knows its experienceing an infection and attacks a microbe and not itself Antigens Other types of Antigens: • Protein antigens: “self” antigen, “tumour” antigen, transplanted tissue, “neo” antigen • bacteria is decorated with proteins that the immune system recognizes as forign, it dosnt recognize the whole bacteria, it recognizes a conponent of the bacteria and that component is called an antigen and the same is true for other microorganisms • protein antigien - proteins are made from our genetic code and they dont divide. • toxins produced by bacteria are proteins and the immune system sees them as dangerous and neutralizes them • multiple sclerosis - self antigen in the brain and patient mount an immune responce to the self protein • tumors express proteins differently than normal proteins • transplants can be a sorce of P antigen • sometimes when you have a lot of inflamation the tissue is trashed in some ways and the new proteins are revealed that would otherwise not be revealed to the host and even though they are self proteins they are now visible to host • antigens are components of something that the immune system recognizes and mounts an immune responce against B cells and T cells “see” antigens differently • B cells have antibody molecules, T cells have T cell receptors o BCR • express antibody molecules on their cell surface • B cell receptor (BCR) has 2 places where it can recognize antigens. They are identical BCR expresses a pair of antigen binding sites that are both identical o TCR • t cells have dif type of receptor, it has 1 antigen binding site, T cell receptor expressed on the surface • the b cell can shed its b cell receptor in the form of an antibody molecule thats released into the blood whereas the T cell receptor does not do that • T cell antigens need not be on the pathogen surface • B cell antigens must be on the pathogen surface • B cells see exposed particles (antigens) on the surface of a pathogen or exposed parts of soluble proteins • T cells see antigens that are “buried” within the pathogen. These are processed by “antigen presenting cells”. Antigen presenting cells may be virally infected • MHC • 2 dif types of lymphocytes B and T cells • b cells see an antigen that sticking out of the surface of the pathogen • on the surface of the influenza virus are proteins, the H and N are two proteins expressed on the surface of the influenza, b cells can see these types of antigens that are sticking out of the surface of the virus • influenza mutates its proteins on the cell surface, but there are also proteins inside the virus that are housekeeping of the virus that are there to replicate its genome and so on, and those proteins are invisible to B cells but can be seen by T cells • the antigen binding site is created by virtue of how the antibody molecule is assembled, the antibody molecule is 4 chains 2 heavy chains and 2 light chains • you cell makes 2 copies of teh heavy chain that stick together by disulphide bonds and this causes a stable interaction between the heavy chains • the light chians make a disulphide bond with the heavy chain • the combination of the light chain and the heavy chain make up an antigen binding site • every cell has a major histability complex (MHC) • 2 types of MHC: MHC+1 is expressed in every cell of your body • MHC+1 carrys parts of the virus to reveal it to your t cell • the virus replicates within the cell, the genetic material of the virus is integrated into the infected cell then proteins are made from this template then the proteins get broken down and these degraded proteins get moved to the ER then they get loaded on the suface of the MHC and move to the cell surface so what the t cell sees is a little bit of viral protein carried by host MHC and this is a way of t cell to see inside the pathogen • cells that are infected with the virus make viral DNA or RNA and this gets made into viral proteins, the proteins get broken up and degraded and put inside the ER where there loaded onto the surface of MHC and then carryed out to the surface. the t cell receptor on the surface of the t cell recognizes antigen as a combination of a viral peptide with MHC. so it sees the antigen only in the context of MHC, if you give the peptide on its own the t cell dosnt do anything, needs to see the peptide in the content of MHC. THis is a powerful way for a T cell to survel the host for any infcted cells. this is also true for tumors, so this is a powerful way for t cells to tackle antigens that are invisble to b cells and because these antigens are more involved in the housekeeping of the pathogen they tend to not get mutated Critical Concepts that shape the adaptive immune system • Antigens • Diversity • Tolerance • immune system can see a multiple array of antigens Clonal Selection Theory • colonal selection theory - • have lymphocytes that are made from stem cells, and these lymphocytes have a number of specificities and only some b cells will see foreign antigen, some b cells will see self antigen, • the b cells that see foreign antigen are cells that you want expand and get activated as soon as an infection occurs so as an infection occurs the ones that see a foreign antigen specifically will repidly divide and produce daughter cells and this is clonal expansion and this is called clonal theory • *because a single b cell makes a signle specificity* • you will only expand that b cell with that single specific antibody molecule that recognizes the pathogen Development and Diversification of B cells • Appearance of the BCR on the cell surface is an important developmental checkpoint • 10,530 possible combinations • Humans generate about 10 billion different antibodies, each capable of binding a distinct epitope of an antigen. • during b cell development the aquisition of b cell receptors (aka antibody molecules) happens during development in bone marrow, • antigen receptor expression is the go signal that its time to scearch for antigens. So • b cells are formed by complex genetic mechanisms where they basically pick and choose different genes and glue them together, and combination allows specificity • 2 heavy chains, 2 light chains form an antibody • and the heavy chain can be divided into 4 dif types of gene segments V,D,J,C genes • the antibody recognition site is formed by the combination of VDJ • then theres only one of 5 constant regions that can be chosen • c gene is the one that dictates the class of antibody that has nothing to do with antigen recognition, • the same happens in light chains but they dont have d genes, just V and J and also a constant region • happening in bone marrow when b cells are developing and continues to happen throughout lifetime of host • 2 genes that make b cell receptor, 1st gene is the heavy chain gene, which is comprised of 4 gene segments, the 2nd chain is the light chain gene which is comprised of 3 segments, so make 2 genes, 1 gene = 1 proten, therefore makeing 2 genes, light chain gene and heavy chain gene and making 2 proteins a light chain protein and a heavy cell protein, heavy chain p and light chain p are going to stick together inside the cell and will be displayed on the cell surface Surface immunoglobulin (Ig) • Expressed on the surface of B cells. • Can bind a large variety of chemical structures. • Have specificity for antigens they bind. • Consists of two identical heavy and light chains. • Anchored to the membrane of the cell by transmembrane regions of the heavy chains. B cell with antigen specific BCR on it’s surface Secreted antibodies of the same specificity as the membranebound • antigen binding site displays the most diversity • TM is charged to stick into the b cell (cells are normally charged) Clonal selection of Antigen-specific B cells • b cell has to neutralize the pathogen, the b cell divides and makes many dughter cells, all of which have the original b cell receptor specificity, and then the b cells go through a kind of genetic programe where they relize they made enough copies of themselves and now need to make tons of antibodies, then b cells become plasma cells which stop expressing the b cell receptor on its surface but makes a version of the b cell receptor thats spit outside the plasma cell so that it can roam the body and look for pathogens by passive diffusion. so the b cell make antibody products in large quantities which is important for neutralizing the pathogen Secreted immunoglobulin (Ig) • Expressed on the surface of B cells. • Can bind a large variety of chemical structures. • Have specificity for antigens they bind. • Consists of two identical heavy and light chains. • Anchored to the membrane of the cell by transmembrane regions of the heavy chains. • the antibody molecule thats secreted by the b cell looks identical to the surrface b cell antibody but it lost its TM region and its secreted immunoglobulin (aka antibody) Antibody secreting cells: plasma cells • Mature B cells express membrane bound antigen-specific immunoglobulin. • Each B cell is committed to express immunoglobulin with one specificity. • Encounter with a pathogen stimulates the proliferation and differentiation of B cells into plasma cells. • Plasma cells secrete antibodies of the same specificity as membrane bound immunoglobulin expressed by the B cell precursor. • resting b cells that express membrane bound Ig aka b cell receptor recognize antigen on the surface of the patthogen, the b cells divide and become plasma cells that secrete antibodies Immunoglobulin isotypes • Membrane-bound immunoglobulins are expressed as monomers. • majority of serum Ig is IgG and IgM • IgM is the first antibody that sees that pathogen but as the infection goes on the IgM molecules sometimes switch thier c regions for one that looks like IgG Antibody: IgG • Most abundant in humans (80% of serum Ig). • 4 human subclasses: IgG1, IgG2, IgG3, IgG4 o cross placenta: IgG1, IgG3, IgG4 o complement activation:  IgG3 > IgG1 > IgG2 (IgG4 does not) o binding to Fc receptors:  IgG1, IgG3 >> IgG4 > IgG2 • good at activating complement • a way to team up with Ig to destroy a pathogen • so it will stick to IgG and will neutralize the pathogen • IgG can bind to Fc receptors which are proteins that stick out of phagocytic cells that recognize that c terminal head chain constant region of IgG and then the antibody in colaberation with the phagocyte can then destroy the pathogen Antibody: IgM • 5-10% of serum Ig • First isotype made during a primary immune response • secreted form: pentamer o includes J chain which joins o Ig at Fc region through disulphide bonds o high valency  best at binding antigens with repeating epitopes  best at activating complement o does not diffuse well • has a pentomeric structure • through serum Antibody: IgA • 10-15% of serum Ig • main isotype in external secretions, e.g. breast milk, saliva, tears, mucus • Dimerization required for transport across epithelium • secretory IgA (dimer or trimer) o J chain o secretory component (polypeptide) • sees antigens that are in mucosal secretions • main antibody seeing natural flora • bc it has a component to it that allows it to pass through barriers that lead to secretions Antibody: IgE • very low concentration in serum • mediates immediate hypersensitivity o symptoms of asthma, allergy o binds to Fc receptors on:  basophils (blood)  mast cells (tissue)  crosslinking of receptor-bound IgE by antigen (allergen) leads to release of granules, e.g. histamine • only need it when infected with paracytes, Antibody: IgD • Low levels in blood. • IgD and IgM are co-expressed and are the main membrane-bound Igs on mature B cells. • Effector function unknown. How antibodies function: Antibodies can act directly on pathogens • your antibody may see bacteria toxins • or components of the bacterial cell and all it does is bind to the bacteria and dosnt kill it, the way it kills the bacteria is that phagocytes will see the constant region of the antibody via Fc receptors, the constant region of the antibody stic
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