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Transcript
SPECIFIC ACQUIRED IMMUNITY Microbes evade, hosts respond • Recall that innate immunity is based on recognition of molecular patterns in microbial cell walls, which sets off • Phagocytic cells • Complement • Killer cells • Microbes evolved to evade this primitive level of detection • Higher organisms evolved “adaptor” molecules, to connect specific microbial structures to these defense mechanisms The adaptor molecules: Ig and TCR • One end is specific to the invading microbe • The other end mediates cellular function • Alternative way to set off the immune responses T-cell Receptor has structure similar to Ig and mediates a cytotoxic response The Antibody molecule • B cells undergo rearrangement of DNA in the Ig genes – all possible combinations of V, D and J segments into Heavy (VHDHJH) and light (VLJL) chain • These create the CDRs that form the antigen binding site • Millions of different combinations are possible many (nearly all?) are made by different B cell “lines” • B cells with rearranged Ig genes make just that one Ig molecule, and initially put it out on the surface as a membrane bound Ig molecule Clonal Expansion and 1°Response • When antigen interacts with an Ig on a B-cell surface, that B-cell is stimulated to – Proliferate (clonal expansion) – Differentiate into “plasma cells”, that make tons of secreted immunoglobulin of that exact antigenic specificity, and then die. • This is the primary immune response. It is relatively slow because there are very few of each version of naïve B-cell sitting around Memory, and Adaptive response • When B-cells are stimulated to proliferate, some do not differentiate into plasma cells. They “withdraw from the cell cycle” • This is a larger number of cells than were present before the clonal expansion .. if the same microbe/antigen comes again, there will be more cells that are able to “see” it • When memory cells bind antigen, they are stimulated to proliferate and differentiate – and because there are more of them around, the response is much quicker. Memory, and Adaptive response • When B-cells are stimulated to proliferate, some do not differentiate into plasma cells. They “withdraw from the cell cycle” • This is a larger number of cells than were present before the clonal expansion .. if the same microbe/antigen comes again, there will be more cells that are able to “see” it • When memory cells bind antigen, they are stimulated to proliferate and differentiate – and because there are more of them around, the response is much quicker. • The host has “adapted” to the microbe, making a faster response the second time • The secondary response is often also “better” because the cells displaying the highest affinity antibody are the ones that are most likely to bind Ag the second time, and be stimulated Vaccination is based on this more rapid secondary response • Challenge host with antigen that is similar to something “dangerous”: toxin or pathogen – Altered toxin (toxoid, such as Tetanus toxoid) – Related but non-pathogenic virus (Vaccinia for smallpox) – Killed Virus (Salk polio) – Attenuated virus (Sabin polio, egg-passaged influenza) – Recombinant pathogenic marker (Hep B protein expressed in yeast, Strep “M” protein?) • Immune response will give protection because Abs will recognize epitopes on these similar antigens • Immune response can remove antigen or pathogen before it does damage to the host. The T-cell Receptor (TCR) • T-cells are lymphocytes that develop in the thymus. Do not make soluble Ig, but they do make a membrane protein (the TCR) with similar structure and recognition capabilities • T-cells are part of an adaptive and specific response – Specific: Recognition site involves two polypeptide chains that result from gene rearrangement to provide many possible combinations in the variable region (sound familiar?) – Adaptive: Clonal expansion of T-cells occurs • There are different kinds of T-cells with particular functions. The two best studied are Helper Tcells and Cytotoxic cells Adaptor molecules trigger some of the same kinds of responses seen in innate immunity: • Antibodies – Phagocytosis – Complement-mediated killing • T-cell receptor – Cytotoxic lymphocytes Phagocytosis • Antibodies can directly activate macrophages by their Fc regions • Polyvalent binding can enhance this dramatically Complement – “alternative” pathway • “Alternative pathway” ( innate immunity) is set off by repetetive patterns on microbes • C3bBb (C3 convertase) is stabilized by microbes, and catalyzes: – C3 C3b + C3a* – C5 C5b + C5a* C6789 and MAC: * C3a and C5a – Chemotactic for Mf (phagocytosis) – Activate mast cells (inflammation) The “Classical Pathway has a molecule that responds to Antibody recognition of microbes C1r and C1 s have enzymatic activity, cleaving C4 to C4b, and C4b2 to C4b2a Ig activates the “classical” “pathway” of complement • “Classical pathway” is set off by Antibody interacting with C1, a large molecule with subunits q, r and s: • C1qrs catalyzes C4 to C4b, and then C4b2 to C4b2a • C4b2a is a C3 convertase, and catalyzes: – C3 C3b + C3a* – C5 C5b + C5a* C6789 and MAC * C3a and C5a – Chemotactic for Mf (phagocytosis) – Activate mast cells (inflammation) Cell-mediated adaptive immunity: Cytotoxic lymphocytes • Don’t have antibodies … but T-cell receptors, which are similar to antibodies: • Paired polypeptide chains, a and b ; domain structure with C and V regions • Gene rearrangements that provide many versions of the V regions that have exquisite specificity • Non-specific end of molecules mediates the host response • TCRs are membrane-bound molecules – when engaged, cell responds to try to eliminate the foreign entity Cytotoxic Lymphocytes (CTLs) • Some pathogens live inside host cells and thus are difficult for the immune system to detect (viruses are obligate, some parasites are facultative) • CTLs are T-cells lymphocytes that – to recognize foreign things – “see” them really only when they are in normal cells. Cell surface proteins seen in the same cells that contain normal cell proteins eg virally infected cells or tumor cells) – Respond to “foreign in the context of normal” by killing the cell. Cytotoxic Tcells (CTLs kill cells they recognize as bearing foreign antigens (such as virally infected cells, or tumor cells) What CTLs recognize • Normal host cells have a set of proteins that are present on the surface of nearly all cells of that organism – These are “Class 1 Antigens” (from the major histocompatiblity complex, or MHC) • T cells have T Cell receptors that are similar in structure (and function) to Ig molecules • T cell receptors “see” (bind to) Class 1 antigens that look strange because they have foreign molecules lose by. What we say is that they recognize “foreign proteins in the context of class 1 molecules” (more on that later) • T cells undergo clonal expansion when they recognize foreign antigens together in the context of Class 1 MHC proteins – this recognition triggers proliferation of this particular line of cells (sound familiar??) Summary • Antibodies (and T-cell receptors) serve as specific adaptors to recognize invaders and make them subject to the hosts defense system, consisting of phagocytic cells, complement and killer cells • Acquired immunity is specific because the the adaptor molecules are highly variable in structure • It is adaptive because clonal selection and proliferation enhance the response over time and multiple challenges.