HMX Immunology Final Exam 2025

Inflammation - -Delivery of cells/proteins into infected Tissue Leukocytes or White Blood Cells example - -Neutrophil, macrophage, lymphocytes Most abundant cell in Blood - -RBC Neutrophil, or polymorph nuclear leukocyte's action - -A type of phagocyte, Equipped with innate immune receptors; when microbes bind to that receptor, neutrophil engulfs, digest the microbe, undergoes apoptosis Monocyte — macrophage's action - -Have innate receptor, that can phagocytose microbes, kill the microbes; also eat dead neutrophils Tissue sentinel Cells examples - -Cells that are ready and waiting, before infection; Dendritic Cells, resident macrophages, mast cells; all have innate receptors Dendritic Cells' innate response - -After bound by microbes, produce Cytokines, which are pro-inflammatory Macrophage's innate response - -After bound by microbes, eat it, chew it up, release cytokines Mast Cells - -Have granules in cytoplasm, which have inflammatory mediators, when microbe binds, granules release, cytokines made; famous granule = histamine Phagocytes - -Neutrophils and macrophages; neutrophils only chew up microbes, macrophage ingest dead neutrophils as well Cytokines - -Released by tissue sentinel cells, mast cells, resident macrophage, dendritic cells; act on blood vessel endothelial cells; result in migration of more blood cells into tissue Blood Vessels/ venules' role in innate response - -Phagocytes- monocytes, neutrophils are present within blood vessels; after cytokines bind to the receptors, they increase adhesion molecules' expression on the blood vessels Adhesion molecules's role in innate response - -Neutrophils have some adhesion molecules, selectin Ligand, which has low affinity to one of the adhesion molecules, E-Selectin; neutrophils will roll down the blood vessel and constantly bind and unbind to e-selectin; until it reaches another molecule, ICAM-1, where its integrin, IFN-1 will bind to, resulting in a stable arrest; neutrophils flatten out, crawl through endothelial gaps, enter tissues E-selectin - -An adhesion molecule critical for slowing down the neutrophils, present when endothelial wal bound by cytokines, bind with selectin ligand on neutrophils with low affinity ICAM-1 - -surface-expressed adhesion molecule found on endothelial cells, will reach a stable arrest state with neutrophils with IFN-1 on neutrophils Innate response summary - -Microbes enter tissues; sentinel cells secrete cytokines; cytokines act on blood vessels receptors; adhesion molecules result in the entrance of leukocytes, macrophage/neutrophils; neutrophils and macrophage clear the microbes; macrophage clear dead neutrophils Pus formation - -Bacteria multiplies, engage with mast cells, resident macrophages; release cytokines, increase adhesion molecules, neutrophils enter, eat up the microbes; neutrophils die; neutrophils and Microbes are the pus Innate Immunity aspects - -Inflammation and anti-viral state Anti-viral state - -Microbe activates Plasmacytoid dendritic cell, as well as the infected cell to secrete Type 1 Interfreron; which activate anti-viral state by binding to cell receptors, synthesizing proteins that protect the cells from further infection; only work on double stranded RNA virus Type 1 Interferon - -Release by the infected cells and plasmacytoid dendritic cell, act on infected cells' neighbor cells, producing protein, which are only activated when the cells are infected, and only act on double stranded RNA infected cells, lead to apoptosis of the infected cell PAMPs of Bacteria - -Gram-negative, LPS, flagellin; gram-positive, Teichoic acids and Peptide glycan PAMPs of viruses - -Single stranded RNA, Double stranded RNA, double stranded DNA Toll-like receptor - -Pattern recognition receptors that are present on cell surface, recognize microbe parts, result in inflammation; the ones in endosomes trigger anti-viral state Where do Pathogen recognition receptors perform their job? - -On cell surface, signals the producing cytokines, inducing the presentation of endothelial adhesion molecules, resulting in inflammation; in endosomes, signals the production of type 1 interferon, inducing anti-viral state What can PRR recognize? - -SS RNA, DSRNA, DSDNA from virus; LPS, flagellin, teichoic acids, peptidoglycan from bacteria What does cell membrane located PRR activate? - -IL-1, TNF alpha, initiating inflammatory response What does endosomal located PRR activate? - -Type 1 interferon, inducing anti-viral state How are microbes going to initiate immune response, through Toll-like receptors? - -TLR receives PAMP, dimerize, send signals into cell, transcription factors enters nucleus, bind to promoters of TNF, IL-1, lead to the expression of TNF and IL-1 NK-Kappa B - -Normally inhibited; when TLR releases signals after microbes binding, the inhibitory molecule is broken down, and NF-kappa B flows to nucleus, bind to the required genes, induce transcription; messenger RNA translate the proteins, secrete pro-inflammatory cytokines How do Endosomal TLR work, and initiate an anti-viral state? - -TLR sitting within the endosome, identifies dsRNA, induce the phosphorylation of transcription factor, leading the TF entering nucleus, transcribes interferons, create Type 1 interferon, initiating anti-viral state Inflammatory molecules - -TNF alpha and IL-1 Antiviral molecules - -Type I Interferons Complement introduction - -Starts with the cleavage of C3, resulting in C3a, which initiate inflammation, and C3b, which works in opsonization; C3b cleavage C5 to C5a, which initiate inflammation, and C5b, which develops into C9 Pore, which forms pores in bacteria membrane Inflammatory Complement molecules - -C3a, C5a; Opsonization complement Molecules - -C3b, also cleaves C5 C9 pore - -Form pore on bacteria membrane, developed from C5b Agglutinins introduction - -Lectins, recognize carbohydrate PAMP, can clump microbes; activate complement, arms of agglutinins can be bound by complement proteins, destroy microbe Natural antibody on microbes - -The IgM, which has ten binding sites can bind to microbe; the shape changes so the complement proteins can bind to microbes; C1q is the first complement protein bound to IgM How do IgG antibodies work on microbes? - -IgG bind to microbes, complement proteins come along and poke holes on microbes. Opsonization introduction - -C3b, microbes that are originally not attracted to phagocytes can be bound by C3b, after binding, they can attract phagocytes and chew up the microbes Complement activation pathways - -Alternative - C3b cleaved spontaneously; Classical pathway - C3b can be cleaved when antigens bind; Lectin - agglutinins bind to pathogen; these first steps always lead to cleavage of C3 to C3a and C3b; followed by common pathway, where C5 is cleaved to C5a and C5b; C5b develops to pore forming C9 Pore Spontaneous/Alternative Complement activation pathway - -Microbial surface activates pathway directly, lead to C3 cleavage classical pathway of complement activation - -C1q binds to the antibody, after antibody IgM binds to the microbe lectin pathway of complement activation - -Lectin/Agglutinin binds to the microbe, leading to cleavage of C3 to C3a and C3b Results of Complement activation - -Lysis, by C9 Pore [develop from C5b]; inflammation by C3a and C5a; Opsonization by C3b RAG-type SCID, sever combined immunodeficiencies - -RAG1 and RAG2 are required for V, D and J to be combined, lack of them we result in the failure to develop antigen receptors, and hence low number of B AND T cells Pre B receptor - -Present right after V bind to DJ, and in 1/3 chance, a successful B cell is created; only with substitute light chain, for cell to be identified to carry on the heavy chain protein synthesis DiGeorge Syndrome - -Defect of generation of Thymus, No T cells Pro B lymphocyte - -DJ segments X-Linked SCID - -Lymphoid progenitor presents IL-7 on the surface, signaled by the thymus, and resulting in the differentiation into T cell, X-Linked; No T cell, no B cell activation; yes B cells can develop correctly X-Linked Agammaglobulinemia - -D bind to J segments first; V binds to DJ segments with a lot of junction and entropy going on, leading to a 1/3 possibility of success rearrangement when multiple of 3 happens; when that is the case, V-DJ presents a pre-B receptor, which signals BTK to expand the amount of the successful B cells; IF BTK are not present, no B cells can ever be made, Where do VDJ gene diversity come from? - -Two Chains of TCR, alpha and beta; Two chains of BCR, heave and light; genetic recombination; junctional diversity, between segments joining point, there are some bases added or removed Clonal Deletion - -T cells are tested if they are self effective, signals of death are sent to those that are self-reactive Central tolerance - -Happens in Thymus, self-reactive cells are sent a signal and die; results from Clonal Deletion Peripheral Tolerance - -Mediated by Regulatory T cell; self reactive cells can identify self-antigen, and turns into effective T cells; Regulatory T cell dampens the effectors Receptor Editing - -Faul self reactive B Cells are allowed to under another round of gene recombination, resulting in no longer self reactive B cells Autoimmune Diseases caused by antibodies - -Myasthenia Gravis, Lupus; dysfunction of acetylcholine receptor leading to loss of muscle cell contraction, deposit of antibodies and DNA deposit in various parts of the body Autoimmune Diseases caused by T cells - -Type 1 diabetes, inflammation of pancreatic Beta cells leading to loss of function, Psoriasis, Th17 cell recognize self antigen, enters, release IL-17 which calls in neutrophils and damage skin cells, leading to lesions Polymorphisms - -Proteins coded by distant genes present slightly different sets of amino acids, leading to transplantation rejections Allogeneic Response - -Two people with almost identical pieces of genes have slightly difference in proteins due to polymorphisms, result in response from antibodies and T cells activation, resulting in more production of protein; Antibodies and T cells enter and cause inflammation, result in transplant rejection The most polymorphic Genes - -MHC=HLA genes, mainly related to T cells; thousands of different alleles; the major problem in transplantation RBC transfusion rejection - -RBC present carbohydrate antigens, and person has natural IgM antibodies against those one does not have; for example, a type A patient has anti-B antibodies U3 - -U3 Adaptive Immunity is comprised of - -Humoral Immunity, mediated by antibodies produced by B cells, target mostly microbes out of host cells; cell-mediated immunity Four Antibody Functions - -Opsonization, Neutralization Neutralization - -Antibodies bind to virus, prevent virus from binding to any host cell receptors Opsonization - -Antibody coats a microbe, the antibody tail is recognized by phagocyte, phagocyte eats microbe Complement Fixation - -Antibody coats a microbe, recognized by complement proteins, proteins make pores on the microbe, microbe dies Antibody Dependent Cellular Cytotoxicity - -Antibody binds to the spike proteins presented by virus on the infected cells, NK cells bind to the antibodies, release perforin and granzyme, induces death of infected cells Antibodies Structures - -Arms, or the antigen recognizing parts are the Fab portion; tail is the Fc portion, which is bound to the complement proteins, recognized by Phagocytes and NK cells Variable domains on antibodies - -Exists on both heavy and light chain, makes up part of the antigen binding site IgA - -A dimer, or two units, bound by J chains; response in gut, due to its protection from proteases IgM - -10 chains, by J chains; IgE - -Allergies, worms IgG - -Protection against many microbes IgD - -Only in lungs How do antibody capture microbes? - -Stick out three binding sites between the variable regions that fix the antigen, forming the antigen binding site; 3 loops in the light chain, 3 loops in the heavy chain In which situations antibodies can cause disease? - -Ig antibodies may be reactive to self antigens, leading to disease; Ig Antibodies and antigens found complex, and deposit within the basement membrane, mostly vessel walls How do Ig antibodies cause tissue damage - -Complement fixation - antibodies can bind to self antigens, complement system activated, some of which are lyse cells; Opsonization - antibodies bind to self antigens, phagocyte, macrophage comes by, binds to the Fc receptor, internalizing own cells; Inflammation Lymphocytes response to microbial antigens initiate by - -Clonal selection and clonal expansion Specificities of lymphocytes - -Each antigen receptor has some sort of different antigen receptors Clonal Selection - -Antigen binds to lymphocyte, initiating adaptive immune response; there may only be one or two clone of T cells that are working; microbe must first find that antigen receptor, bind to it, then clonal expansion can happen Clonal expansion - -Microbe binds to antigen receptor, send down signals of proliferation of the cell, lead to increase of lymphocytes Where do Lymphocytes come from? - -Monocytes/macrophages, dendritic Cells are part of the lineage; neutrophils, eosinophils, basophils are from another lineage; Common lymphoid progenitor gives rise to B cells and T cells, and also natural killer cells How do HSC divide? - -HSC copies itself, then differentiate into a new cell Development of B cells - -HSC — CLP — Pro-B cell — production of heavy chain, pre-B cell — [if good IG is made in pre-B cells] — immature B cells == Mature B cells in lymph node or spleen Development of T cells - -HSC — CLP - pro-T cell — pro—T cell enters Thymus, where all T cells maturate — T cell beta chain made, pre T Cell made — T cell alpha chain made as well, in its two chains form, express both CD4 and CD8 — CD4 or CD8 mature T cells — travels to lymph node or spleen What makes T cells better than B cells? - -I. Antibodies see everything, so they will bind to unhosted virus asap, but not those which are already infected. T Cells cannot see anything directly, they need signals on cell surface, MHC, so they can directly bind to the source of viral infection. What's so special about B cells? - -Antibodies can work in neutralization, opsonization, CDCC and complement response; antibodies see a wideeeee range of molecules; they protect in multiple ways Variable and Constant Domains - -Only in T cell receptors, only in part of the antigen recognizing molecule, remaining is light chain; diversity guaranteed by combinatorial diversity, junctional diversity when putting in genes between segments U4 - -U4 Dendritic Cells can - -Initiate inflammation and adaptive immune responses, by T cell mediated Response Lymph nodes' role in T cell mediate response - -Provide a place for T cell to meet B cells, and as infection can occur anywhere After DC meets microbes? - -Microbes enter dendritic cells, turned into peptides. Microbes also bind onto the toll-like receptor, activating it; Chemokine receptor CCR7 bind to endothelial ling cells on lymphatic vessels; DC enter Lymph, flow all the way to lymph nodes Adaptive immune responses in Lymph nodes - -Begins when naive T/B cells see antigens for the first time; How do naive T cells end up in lymph nodes? - -Lymph nodes will be passing through lymph nodes once a while in blood vessels; High endothelial venule within the lymph cells present CCR7, which allow Naive T cells to bind to, leading to the entrance of Naive T cells to lymph nodes T cell zones - -CCR7 molecules happen to be attrative to T cells and Dendritic Cells, so those cells will bind to the CCR7 and meet in the T cell zones, or mid follicular zones Clonal expansion in action - -If T cell's receptor is capable of binding to the peptide-MHC complex, they can bind, and T cell undergoes clonal expansion T cell activation foreplay - -Antigen presenting Cells, Dendritic cells, the cells that degrade proteins to peptide, present on MHC molecules are critical for the very first step; T cell interaction with Dendritic Cells - -CD4 and T cell receptor will be bound by the MHC peptide complex, generating signal number 1; also, microbe presents PAMPs, that are picked up by toll-like receptors on Dendritic Cells, lead to the up-regulation of costimulatory receptors; through binding, signal number 2 is there, lead to T cell activation, to effector T cells Costimulatory Receptor/molecule names - -CD80 or B7-1, B7-2 or CD 86 are the molecules; bind to CD28 expressed on naive T cells Effector T cells - -The activated naive T cells, through signal 1 and signal 2 How to prevent self-reactive T cells? - -If Dendritic picks up a self antigen, which presents self peptides, but there are no costimulatory molecules that bind to CD28 receptor What happens when no costimulatory molecule is present, but MHC has already bound to T cell receptors? - -T cell undergoes apoptosis to be get rid of, anergy, turning unresponsive T cells Antigen Presentation mechanisms in T cells - -Cytosol is separated from the outside of cell; lysosome can bind to MHC Class II, where it is located in a vesicle in cytosol;or it can bind to MHC Class I, CD8, protein is marked by ubiquitin and picked up by proteasome, broke down into the peptide, transferred to ER, shows MHC Class II pathway - -Recognized on dendritic, B cells, Macrophages, bu CD4, lysosome breakdown MHC Class I pathway - -Present on every nucleated cells, by CD8, proteasome breakdown, goes through ER before vesicles and Golgi Inhibitory Signaling of T cells - -In Lymphocytes induce CTLA4 after a while, disabling the B7 costimulatory molecules to bind, stopping the T cells from proliferation; In tissues, T cells present PD 1 receptor on the surface, PD1 can exhaust T cells CTLA-4 - -Presented on T cells after a while of proliferation in lymph nodes, bind to the B7 costimulator/CD28 signaling and stops the proliferation from furthering. PD-1 - -In tissues where T cells are on a rampage, PD-L1 ligand shows and bind to PD-1 receptors on T cells, causing T cells to be exhausted; also used by Tumor signaling to terminate PD-1, and thus T cells action T cells boink B Cells, inducing B cell activation - -Some protein has both T and B cells etitope and is chewed up by Dendritic cells, transferred to Lymph nodes; B cells recognize the protein, later antigen present on MHC II receptor; T cell recognize the MHC complex by DC; T cells express CXCR5 which are originally on B cells; B cells express CCR7 which is found on T cells; they migrate towards the central region and bind by CD40 expressed on B, CD40L expressed on T; only on CD4+, result in B cells proliferation, producing IgM antibodies CXCR5 - -In lymph nodes Expressed by T cells after activation, migrate towards B Cells as they present CXCR5 as well CCR7 - -Expressed in B cells when antigen is recognized. Causes the B cell to move to T cells CD40 - -Expressed by B cells, bound by CD40L expressed by T cells; causing B cells to expand Germinal Centers Formation - -Occurs only with Protein Antigens, require both B cells and T cells; mainly used to change IgM to other antibodies; with help from Follicular Dendritic Cells; produce extra B cells like long lived plasma cell and B memory Cells T helper cells after activating B cells - -Change to T follicular cells, express CXCR5, allowing entrance of follicles; B cells undergo clonal expansion, T cells also proliferate in a smaller extent Follicular dendritic Cell - -Presence in germinal center formation, shows antigen to B cells, in germinal center only; Follicular dendritic cells show an antigen to the B cell, testing their affinity to the antigen Isotype switching - -IgM switched to high affinity antibodies Long live memory B cells - -Second infection induce quicker response Germinal centers reaction on B cells - -B cells normally express antibodies with certain V,D, and J combination; T follicular cell can induce mutation in V segment, result in change of antigen binding sites