Definitions• Immunity = protection against infections• Immune system = collection of cells and moleculesthat defend us against microbes• Immune deficiencies → infections• Immune excesses → autoimmune diseases
Innate (Natural) Immunity• Always present (innate); doesn’t change over time• First line of defense when bugs come• Major components:• Epithelial barriers (skin, GI, respiratory)• NK cells• Complement
Adaptive (Acquired) Immunity• Second line of defense• More specific (adaptive) and powerful than innate• Major components:• Lymphocytes• Lymphocyte products• Two types of adaptive immunity:• Humoral immunity (mediated by antibodies)• Cellular immunity (mediated by T cells)
Lymphocytes• Present in lymphoid organs and in blood• Groups• T-lymphocytes (grow up in thymus)• B-lymphocytes (grow up in bone marrow)• Each one has receptors for a specific antigen• Recognize millions of different antigens!• Diversity generated by:• rearrangement of antigen receptor genes• different joining of the gene segments• Gene rearrangement studies
Lymphoid tissues• Lymphocytes grow up in primary organs, thentravel to secondary organs, searching forantigens.• Primary organs• thymus• bone marrow• Secondary organs• lymph nodes• spleen• mucosal and cutaneous lymphoid tissues
Lymph nodeInterfollicular area (brown)Follicle
T-Lymphocytes• Live in blood, bone marrow, lymphoid tissues• Two basic functions:• kill stuff• help other cells do their jobs• T-cell receptor (TCR) complex recognizes antigens• binds antigen• sends signals to the T cell• Antigens must be:• displayed by other cells…• …AND bound to an MHC receptor
MHC• Collection of genes on chromosome 6• Three regions: class I, class II, class III• Highly polymorphic!• Gene products:• class I molecules• class II molecules• class III molecules (and other stuff)Major histocompatibility (MHC) complex
class I MHC moleculeclass II MHC moleculeclass II MHC genes class I MHC genesclass III MHC genes
MHC• Encoded by three loci: HLA-A, HLA-B, HLA-C• Display antigens from within the cell(e.g., viral antigens) to CD8+ T cells.• Present on all nucleated cells! (Good idea.)Class I MHC molecules
MHC• Encoded by three loci: HLA-DP, HLA-DQ, HLA-DR• Display extracellular antigens (e.g., bacterialantigens the cell has eaten) to CD4+ T cells• Present mainly on antigen presenting cells, likemacrophages! (Makes sense.)Class II MHC molecules
B-Lymphocytes• Live in blood, bone marrow, lymphoid tissues• Basic function: make antibodies (immunoglobulins)• B-cell receptor complex recognizes antigens• binds antigen• sends signals to T cells• Antigens can be free and circulating (don’t have tobe bound to MHCs or displayed by other cells to berecognized!)
Natural Killer Cells• Belong to innate immunity arm• No highly variable receptors like T and B cells• Main job: recognize and kill damaged or infected cells• Antigens can be free and circulating (don’t have to bebound to MHCs or displayed by other cells to berecognized!)
Antigen-presenting cells• Main job: catch antigens and display them to lymphocytes• Dendritic cells• Have fine cytoplasmic projections• Present all over body: skin, lymph nodes, organs• Capture bug antigens, display to B and T cells• Other APCs• Macrophages eat bugs and present antigens toT cells, which tell macrophages to kill bugs• B cells present antigens to helper T cells, which tellB cells to make antibodies
Effector cells• These guys carry out the ultimate immunesystem task: eliminate infection• Types of effector cells• NK cells• Plasma cells• T cells (both CD4+ and CD8+)• Macrophages• Other leukocytes (e.g., neutrophils)
The Innate Immune Response• Main bug barriers: skin, mucosa• If bugs make it through epithelium, theyencounter innate immune system• What happens in the innate immune system?• Phagocytes eat bugs, kill them• Cytokines are released• Complement is activated• The adaptive immune system is activated
Immunology Overview• Definitions• Cells• Lymphocytes• Antigen-presenting cells• Effector cells• Responses• The innate immune response• Capturing and displaying antigens
Capturing and displaying antigens• Dendritic cells in epithelium capture bug antigens,transport them to lymph nodes• APCs in lymph nodes eat antigens, display them(using their MHC receptors) to T cells• B cells in lymph nodes also recognize antigens• Antigens and molecules produced during innateimmune response trigger proliferation anddifferentiation of B and T cells
Cell-mediated immunity• Naïve T cells are activated by antigen andcostimulators in lymph nodes…• …then they proliferate and differentiate intoeffector cells that go find the antigen.• CD4+ T cells help macrophages eat bugs• CD8+ T cells kill infected cells directly• All these steps are dependent upon cytokinesHow does the process work?
Cell-mediated immunity• Polypeptides that do lots of different things:• help leukocytes grow and differentiate• activate T cells, B cells and macrophages• help leukocytes communicate• recruit neutrophils• Made by lymphocytes and macrophages• Examples: TNF, the interleukins, interferon γWhat are cytokines?
Cell-mediated immunity• CD4+ T cells differentiate into two kinds of effector cells:• TH1 cells (activate macrophages, cause B cells to secrete Ab)• TH2 cells (activate eosinophils, cause B cells to secrete IgE)• These guys go to the site of infection, and with thehelp of macrophages and cytokines, do their thing.• CD8+ T cells differentiate into cytotoxic T cells• These guys kill cells that have microbes in their cytoplasm.• They are like little assassins.What kinds of effector T cells are there?
• B cells get activated by exposure to antigens(sometimes with the help of CD4+ T cells)• B cells differentiate into plasma cells (that makeantibodies)• The antibodies do nasty things to bugsHow does the process work?Humoral immunity
• Y-shaped glycoprotein• 2 light chains (κ or λ)• 2 heavy chains (α, γ, δ, ε, or μ)• Constant regions of heavy chain form the Fc fragment• binds to APCs• defines isotype (immunoglobulin class: IgA, IgE, etc.)• Variable regions of both chains form the Fab fragments• binds to antigen• defines idiotypeWhat is an antibody again?Humoral immunity
• Bind to – and “neutralize” – bugs, so they can’tinfect cells.• Coat (“opsonize”) bugs, making them yummy tomacrophages and neutrophils (which havereceptors for the Fc portion of IgG! Howhandy!).• Activate complement.What do antibodies do?Humoral immunity
What is complement?Just give me the bottom line.Humoral immunity• It’s a bunch of proteins that poke holes in cells.
Okay, give me a little more information.Humoral immunity• Consists of about 20 plasma proteins (C1, C2, etc.)• Can be activated in a few different ways• by antigen-antibody complexes• by bacterial LPS• by bugs that have mannan on their surfaces• Activation proceeds in a cascade fashion• End results:• cell lysis• chemotaxis• opsonization
Immunologic memory• Most effector lymphocytes die after killing the bug.• A few memory cells live on for years.• expanded pool of antigen-specific lymphocytes• respond faster, better than naïve cells• vaccines depend on these guys
Innate immunity1. Dendritic cell eats bugs• Displays antigen to naïve T cells (which MHC?)
Innate immunity1. Dendritic cell eats bugs• Displays antigen to naïve T cells (which MHC?)• T cells mature (put on costumes, and getready to do their jobs)
Innate immunity1. Dendritic cell eats bugs• Displays antigen to naïve T cells (which MHC?)• T cells mature (put on costumes, and getready to do their jobs)2. Neutrophil eats bugs; kills with toxic chemicals
Innate immunity1. Dendritic cell eats bugs• Displays antigen to naïve T cells (which MHC?)• T cells mature (put on costumes, and getready to do their jobs)2. Neutrophil eats bugs; kills with toxic chemicals3. NK cell kills bugs
Adaptive immunity: Cell-mediated1. Helper T cell does stuff
Adaptive immunity: Cell-mediated1. Helper T cell does stuff• Tells macrophage to eat bugs
Adaptive immunity: Cell-mediated1. Helper T cell does stuff• Tells macrophage to eat bugs• Tells B cell to make antibodies
Adaptive immunity: Cell-mediated1. Helper T cell does stuff• Tells macrophage to eat bugs• Tells B cell to make antibodies2. Cytotoxic T cell does stuff
Adaptive immunity: Cell-mediated1. Helper T cell does stuff• Tells macrophage to eat bugs• Tells B cell to make antibodies2. Cytotoxic T cell does stuff• Finds and kills infected cell (how?)
Adaptive immunity: Humoral1. B cell makes antibodies, which coat bugs• “Neutralizes” bugs• Opsonizes bugs (yummy for who?)
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