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Biological Sciences
Bebhinn Treanor

IMMUNOLOGY – PRINCIPLES OF ADAPTIVE IMMUNITY – LECTURES 6, 7 Some background knowledge: - in bone marrow, pluripotent HSC give rise to common lymphoid progenitor cells - can produce either TC or BC  those CLPC that develop into precursor cells that’re commited to become BC  what distinguishes 1 precursor from another is cell-surface markers - ex. CD34 – present on all human HSC pro-B cells: earliest identifiable cells in BC lineage - type of progenitor cell - retain limited capacity for self-renewal - divide to produce both more pro-B BC and cells that will go onto develop further - main event in pro-BC stage: reararngement of HC genes, which always comes before LC gene rearrangement - early pro-B cell stage: joining of D_H and J_H gene segments - late pro-B cell stage: joining of V_H segment to rearranged DJ_H - rearranged gene is transcribed through to mu C-region gene, the nearest C gene to rearranged V region; RNA transcript is spliced to produce mRNA for the mu heavy chain  first type of Ig chain made by developing BC - after BC expresses mu chain, its called pre-B cell - pre-BC - represent 2 stages in B-C development: - 1. Large-pre BC: less mature; have successfully rearranged HC gene and make mu chain; stopped rearrangements of HC genes but haven’t started rearrangement for LC genes - after it has rearranged HC successfully and made mu chain, it matures into small-pre BC. - 2. Small-pre BC: more mature; LC gene rearrangement occurs in them IMMUNOLOGY – PRINCIPLES OF ADAPTIVE IMMUNITY – LECTURES 6, 7 - kappa LC genes first to rearrange; if these rearrangements fail to make viable kappa chian then lambda LC genes rearranged - when successful joining of LC V and J segment achieved, LC protein synthesized & assembled in ER with mu chains to form membrane-bound IgM - IgM furhter associates with Ig-alpha and Ig-beta for form functonal BCR complex – then transported to cell surface; - rearrangement of light-chain genes stops and small-preBC becomes IMMATURE B-CELL Adaptive immune response: response of antigen-specific B and T lymphocytes to antigen, including the development of immunological memory Adaptive immunity: state of resistance to infection that is produced by adaptive immune response rd - body’s 3 line of defence - iniitated only after physical barriers have been breached and innate immune reponse failed to get rid of invading pathogen - two types of lymphocyte: B cell and T cell - unique featue: able to distinguish from one specific pathogen to another - enables body to make more focused and forceful reponse to any pathogen than is possible with innate immune response alone 3-1 Innate and Adaptive immunity differ in their strategies for pathogen recognition - innate immune receptors recognize either structures shared by many different pathogens or alterations to human cells that’re commonly induced by presence of pathogens IMMUNOLOGY – PRINCIPLES OF ADAPTIVE IMMUNITY – LECTURES 6, 7 adaptive immune response - BC and TC recognize pathogens by using cell surface receptors of just one molecular type: B-cell receptors: antigen receptor on B cells, which is a membrane-bound immunoglobulin molecule. Each BC programmed to make a single immunoglobulin type. The cell-surface form of immunoglobuin serves as BCR for specific antigen. Associated in the membrane with the immunoglobulin are the signal transduction molecules Ig-alpha and Ig-beta - can bind to vast variety of different chemical structures T-cell receptors: highly variable antigen receptor of TC’s; on most TC’s it is composed of variable alpha chain and variable beta chain and is known as alpha:beta TCR; recognizes peptide antigens derived from breakdown of proteins. On minority of TC’s. variable chains are GAMMA and DELTA chains – gamma-delta TCR; - recognize more limited range of antigens than BCR - only expressed as cell-surfaced, and never as soluble proteins (Contrast: antibody for BCR) - type of antigen it reocgnizes is less well-defined - both types of receptors present at cell surface in association with the complex of invariant CD3 chains and X chains, which have a signalling function - can be in an almost infinite number of different versions, each with binding site for different ligand - on infection with pathogen, only those lymphoctes with receptors that can bind to components of particular pathogen are selected to divide, proliferate and differentiate into effector lymphocytes (FIGURE 1.10) - evolved only in vertebrates - suggests that its evolution became feasible or advantageous only with degree of cellualr and anatomical complexity attained by vertebrates - advantages 1. strong immune respones can be precisely targetted aagainst particular pathogen 2. some of the pathogen specific BC’s and TC’s that prolfierate during first infection are retained long afte rinfection terminated; enables subseqeuent infectiosn by same pathogen to be countered and terminated promptly with less disease – immunological memory - what vaccinations seak to induce 3. gives the slowly evolving vertebrates a response that can keep up with multiplicity of rapidly evolving microbes, ebcause it has capacity and versatility to recognize and attack any new target 3-2 Immunoglobulins and TCR’s are highly variable recognition molecules of adaptive immunity IMMUNOLOGY – PRINCIPLES OF ADAPTIVE IMMUNITY – LECTURES 6, 7 immunoglobulin: antigen binding molecule of BC’; aka BCR - expressed on BC surface; BC’s pathogen-recognition receptors antibodies: secreted form of immunoglobuin made by BC’s - secreted by effector B cells (aka plasma cells); soluble form of immunoglobulin - acts as molecular adaptor/bridge; with one site it binds to pathogens and with another it binds to effector cells and molecules that can destroy pathogen - immunoglobulins have several different types of constant region (CONTRAST: TCR does not); confers different effector functions on the secreted antibodies and can also target them to various bodily sites. antigen: originally defined as any molecule that binds specifically to an antibody; also refers to any molecule or molecular fragment that can be bound by an MHC molecule and presented to TCR antigen receptors: cell-surface receptor on lymphocytes that recognizes antigen. For BC, its cell-surfaceimmunoglobun, for TC, its TCR; all those present on individual lymphocyte are identical and recognize same epitope - epitope: portion of antigenic molecule that is bound by antibody or gives rise to MHC-binding peptide that is recognized by TCR; aka antigen determinant. specific: describes property of antibodies and other antigen-binding molecules and immune system receptors that interact selectively with ONLY 1 type or few types of molecule or cell; aka specificity variable region (V region): part of immunoglobulin or TCR or of its constituent polypeptide chains, that varies in amino acid sequence between isoforms having different antigenic specificities; responsible for determining antigen specificity. - at N-terminal; varies from one immunoglobulin vs. another - contain sites that bind antigens constant region (C region): part of immunoglobulin or TCR (or of its consistuent polypeptide chains) that is of identical amino acid sequence in moelcules of the same isotype but different antigen-binding specificites. - very similar in amino-acid sequence between immunoglobulins - contain binding sites for cell-surface repceotrs on phagocytes, and other inflammatory cells , complement protein IMMUNOLOGY – PRINCIPLES OF ADAPTIVE IMMUNITY – LECTURES 6, 7 FIGURE 3.1 - immunoglobulins and TCR are structurally related molecules with shared ancestry immunoglobulins – 2 different polypeptides (heavy chains, liht chains) - each consists of two identical heavy chains and two identical light chains transmembrane regions – used to anchor surface immunoglobulin unto cell membrane - C-terminal of each heavy chain - antibodies secreted from immunoglobulin lack these transmembrane regions but otherwise identical to surface immunoglobulins - TCR - 1 alpha chain, one beta chain which’re both anchored on TC membrane - each has variable region and constant region - variable regions form antigen-binding site 3-3 diversity of immunoglobulins and TCRs is generated by gene arrangement IMMUNOLOGY – PRINCIPLES OF ADAPTIVE IMMUNITY – LECTURES 6, 7 - diversity in antigen receptors of BC’s and TC’s generated by genetic mechanisms unique to Ig and TCR genes - different parts of variable regions of Ig and TC receptor chains encoded by separate gene segments V, D, and J - each present in genome as tandem array of variant forms - genes for Ig heavy chain and TCR beta chain: arrays of V,D, and J segments - genes for Ig light chain and TCR alpha chain: V and J segments only FIGURE 3.3 Gene rearrangement: in context of immunology, refers to somatic recombination process that occurs at immunoglobuin and TCR loci in developing BC’s and TC’s and assembles the sequence encoding a functional variable region of an immunoglobuin or TCR chain - makes variable-region sequence that can be transcribed and translated - process: for functional gene to be made, one of each of the different gene segments must be brought into register by breakping and splicing the DNA with elimination of intervening regions Rearranging genes: in context of immunology, Ig and TCR loci in developing BC’s and TC’s, in which somatic recombination brights together the V(D) and J gene segments and assembles the sequence encoding a functional variable region for an Ig or TCR chain. Further rearrangement of Ig heavy- chain gene is used to switch the isotope from mu to gamma, alpha or epsilion. - rearranging genes refers to TCR and Ig genes; these two are the only human genes requriing rearrangement in order to be functional IMMUNOLOGY – PRINCIPLES OF ADAPTIVE IMMUNITY – LECTURES 6, 7 Germline configuration (germline form): original unrearranged organization of the immunoglobulin and TCR genes in the DNA of germ cells and in somatic cells other than TC’s and BC’s - this is configuration they (ie.Ig and TCR genes) are in before gene rearrangement Somatic recombination: DNA recombination that occurs between gene segments in the Ig genes and TCR genes in developing BC’s and TC’s, respectively; generates complete exon composed of V gene segment and J gene segment (and a D gene segment at Ig and TCR heavy chain loci) that encodes variable region of Ig or TCR polypeptide chain - process of gene arrangement in BC’s and TC’s called this, because it occurs in somatic cells; those bodily cells that aren’t germ cells FIGURE 3.4 - numerous combinations of V, D and J (or V and J only) can be brought together by gene rearrangement - principle source of variable region diversity - further diversity arises from imprecision in enzymatic machinery used to cut and paste DNA during gene rearrangement - introduces additional nucleotides into joints between gene segments - these 2 processes together creates seqeuence diversity in variable regions of individual chains of Ig and TCR polypeptides - additional diversity in ABS’s arise from combinatorial association of different heavy and light chains in Ig and of different alpha and beta chains in TCR’s FIGURE 3.5 IMMUNOLOGY – PRINCIPLES OF ADAPTIVE IMMUNITY – LECTURES 6, 7 - because of these gene rearrangement mechanisms going on in Ig, TCR, consequence is that you get each lymphocyte expressing Ig or TCR (depending on whether BC or TC) of single specificity - adaptive IS can be targeted toward any particular pathogen by selecting only those lymphocytes with appropriate receptors - when infection occurs, only very small proportion of lymphoctes have receptors that recognize particular pathogen - to increase their numbers, each lymphocte stimualted by pathogen first proliferates to give rise to clone of cells all expressing an identical Ig or TCR; as they proliferate, the pathoen-seleted BC’s and TC’s differentiate into effector cells that work together to eliminate pathogen (FIG 3.5) Clonal selection: central principle of adaptive immunity; mechanism by which adaptive immune responses derive only from individual antigen-specific lymphocytes, which are stimulatedby the antigen to proliferate and differentiate into antigen- specific effector cells - process by which pathogens select particular lymphocytes Clonal expansion: proliferation of selected cloens Primary immune response: adaptive immune response that follows a person’s first exposure to an antigen. - takes several days to produce sufficient numbers of antigen-specific TC’s and BC’s to be effective, and during this period the pathogen is least restrained and most able to cause disease 3-5 Adaptive immune repsonses are initiated in secondary lymphoid tisuses by antigen-bearing DC’s and TC’s - compare innate immune response: initated at site of infectio nand later involves liver, where acute-phase response proteins synthesized; - to adaptive immune response: initiated in specialized lymphoid tissues and organs dedicated to this purpose and are found throughout body - include lymph nodes, spleen’s white pulp, and gut’s Peyer’s patches - all these tissue have similar microanaomy and ciruclation that promote boht meeting of pathogen-derived antigens with rare pathogen-specific TC’s and BC’s and subsequent activation and differentiation of antigen-activated lymphocytes into effector cells FIGURE 3.6 - first step in adaptive immune response: pathogen to be carried by DC’s from infected site to nearest secondary lymphoid tissue. Dendritic cells: professional APC’s with branched, dendritic morphology; most potent stimulators of T-cell responses; aka interdigitating reticualr cells; derived from bone marrow and distinct from follicular dendritic cell that presents antigen to BC’s; - immature dendritic cells take up and process antigens but cannot yet stimulate TC’d IMMUNOLOGY – PRINCIPLES OF ADAPTIVE IMMUNITY – LECTURES 6, 7 - mature (Activated) dendritic cells present in secondary lymphoid tissue & are able to stimulate TC’s - type of phagocytic leukocyte developmentally related to macrophages - similarity to macropahges in that they are resident in tissues and are specializedi n uptake and breakdown of pathogens - different from macropahges in that presence of infectionc auses them to differentiate into mobiel cells that transport bacteria and their antigens through the lymph to the secondary lymphodi tissue that drains the infected site - comprise the essential connecting link between innate immunity and actiavtion of adaptive immune reponse - their cell differentiation and movement occur if innate immune response unable to contain the infection  this situation is assessed by means of interactions between DC’s, NKC’s and other innate immunity cells Naïve: - ex. naïve T cells: mature TC that has left thymus but has not yet encoutnered its specific antigen - ex. naïve B cells: mature BC that has left bone marrow but has not yet encountered its specific antigen - receptors of nearly all naïve T cells will not recognize bacterial antigens displayed by dendritic cell, and those T-cells will continue their circulation, leaving the node in the efferent lymph - the minute fraction of TC’s with receptors specific for bacterial Ag will bind their Ag’s on the dendritic cell surface and stay in contact with DC’s, where they are activated to divide and differentiate into efefctor T-cells Effector: Effector cells: lymphocytes that can act to remove pathogens from
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