Your Active Immune Defenses

INDUCTION OF AN IMMUNE RESPONSE Foreign invaders - viruses, bacteria, allergens, toxins and parasites- constantly bombard our body. 1 YOUR ACTIVE IMMUNE DEFENSES 2 ADAPTIVE IMMUNE RESPONSE • a specific response - invariant (generalized) - early, limited specificity - the first line of defense ! ! Innate Immunity • results in acquired immunity Adaptive Immunity - variable (custom) - later, highly specific - ‘‘remembers’’ infection • long term immunity - “memory” • involves two types of lymphocytes: – T cells – B cells 1. Barriers - skin, tears 2. Phagocytes - neutrophils, macrophages 3. NK cells and mast cells 4. Complement and other proteins ADAPTIVE IMMUNE RESPONSE • the specific response is customized for each pathogen • responsible for acquired immunity • involves antigen-presenting cells and two types of lymphocytes • turns on when needed - inducible • “remembers” the pathogens it has “seen” and goes into action faster the second time • may confer lifelong immunity 3 White Blood Cells (WBCs) 4 There are two main types of WBCs involved in the adaptive immune response: • antigen-presenting cells (APCs) - not pathogen-specific - ingest foreign substances and break them down -macrophage (MØ) -dendritic cells (DC) -B cells • B and T lymphocytes (B or T cells) - pathogen-specific - different types recognize different invaders and lead to their destruction 1 5 Human red and white blood cells Types of lymphocytes 6 There are two types of lymphocytes. Both form from bone marrow stem cells: Human red blood cells (red), activated platelets (purple) and white blood cells monocyte (green) and T lymphocyte (orange). Colorized-SEM (scanning electron micrograph) T cells mature in the thymus Magnification:-1200x-(Based on an image size of 1 inch in the narrow dimension) B cells mature in the bone marrow Both cell types enter the lymph nodes and spleen after they are mature. From there they can look for foreign invaders in the bloodstream. T cells 7 T cell training 8 • T cell precursors arrive in the thymus from the bone marrow • there are millions of different T cells – the difference is in their receptors (surface markers) • each T cell has a unique receptor that will recognize a different foreign substance • mature in the thymus, where they learn to tell the difference between self and “non-self” - critical, because if they did attack “self”, autoimmune disease could result • there, they express specific T cell receptors and meet cells that “wear” bits of self proteins, called MHC (major histocompatibility complex), that are markers for the body’s own cells • there are two steps - first, T cells must recognize self-MHC, or they are destroyed - in a second step, T cells that bind too tightly to self-MHC are also destroyed • remaining T cells go to the spleen and lymph nodes, and wait for antigens. • If they recognize an antigen, some will “go into battle” and others become memory cells 2 9 Steps in T cell development 10 Steps in T cell development (cont’d) Step 1. Positive selection occurs in the thymic cortex Step 2. Negative selection occurs in the thymic medulla. MHC selfrecognition molecules 11 Types of T cells 12 T Lymphocytes • • Based on function, there are different types including: • helper T cells (CD4+ or Th) – start the immune response • cytotoxic T cells (CD8+ CTL or Tc) – kill the body’s abnormal cells, like virus-infected cells and cancer cells • Formed in bone marrow; migrate to and mature in Thymus gland Exhibit unique T-cell Antigen receptors (TCR’s) on surface TCR’s can only recognize Ag with associated with MHC glycoproteins – MHC I – found on nearly all nucleated cells – MHC II – found only on APC’s Once T cell binds to Ag, it triggers cell division to form both memory T cells and effector T cells There are 2 populations of T cells characterized by the type of CD glycoprotein found on surface: TH – exhibits CD4 TC – exhibits CD8 3 13 14 The Antigen presentation scenario: Fig 1-8 Kuby, 4e Different patterns of cytokines determines types of Immune Response: -if TC cell recognizes an Ag/MHC I complex, it divides and differentiates to become CTL if TH cell recognizes Ag/MHC II complex, it divides and stimulates B cells, TC cells, and MØ 15 B cells • produced and mature in bone marrow • each B cell produces and wears a unique antibody on its surface 16 B Lymphocytes: • • • – Plasma cells (effector B cells) – Memory cells • clonal selection - when a B cell encounters a matching antigen, it begins to divide rapidly. – Some then become plasma cells that all produce the same antibody, and then die. – Others become memory cells. • the specific antibody produced by a plasma cell is also secreted in soluble form and circulates in the blood Form and mature in bone marrow Exhibit antibody receptors on membrane Once naïve B cells bind Ag, they divide rapidly to produce: Humoral Immunity Plasma cells are secretory; live only a few days (produce > 2,000 molecules of Ig/sec) Memory cells have longer life span than naïve B cells 4 Selection of B cells by antigen (clonal selection) 17 B cells make Antibodies 18 • specific – react with only one antigen Different types of B cells have different receptor molecules. ! • Are Y-shaped proteins called immunoglobulins (Ig) • each is made of two heavy and two light chains of amino acids, held together by disulfide bonds When a pathogen (germ) “locks on” to a receptor, that type of B cell is selected. ! • Must be associated with Ig " (B29) and Ig # (mb-1) to form the functional B Cell Receptor molecule (BCR) The selected B cell divides rapidly to make lots of copies of itself. The copies make lots of antibodies against the pathogen. Antibody structure 19 Each is made of two identical heavy and two identical light amino acid chains, held together by disulfide bonds - parts of the antibody (Ab) are constant, i.e., the same for every antibody - parts are variable - the arms of the “Y” have different amino acid sequences that cause specific binding to antigen • the fact that there are many different variable regions results in antibodies that react with almost any antigen you could possibly encounter! 20 Antibody – another view - variable regions of the light chain (grey) and the heavy chain (yellow) form the antigen binding site - light chain constant region is blue while heavy chain constant region is red. The two chains are joined by carbohydrate (purple). 5 Four classes of secreted antibodies Antigens 21 22 Antigen (Ag) – the molecule an antibody (Ab) binds to • IgM – a pentamer – five Y-shaped immunoglobulins joined together – • usually a foreign substance • each antigen has different sites that antibodies can bind to, so that one antigen can be bound by several different antibodies – the “early” Ab, it is produced before any of the other types – – it activates complement • IgG – the most common form, and the major one for secondary responses • IgA – mostly a dimer – two Y-shaped immunoglobulins secreted in saliva, colostrum, milk, semen, mucus • IgE – binds to receptors found on mast cells – involved in allergy and parasitic infections How Antibody Binds to Antigen • examples in the case of allergy could be pollen, cat dander, or a chemical in soap 23 24 How an Antibody Works When an Ab finds its Ag on an invader, it will bind there and act as a “trash tag”, marking it for destruction by “killer” cells, macrophages or complement Antibody binds to target antigen Receptor for constant region of antibody on NK cell - recognizes a bound antibody After binding, the NK cell is signaled to kill the target cell The target cell dies by apoptosis and/or membrane damage The top part of this figure shows how different shaped antigens can fit into the binding site of antibodies: left, pocket; center, groove; right, extended surface. The panels below show space-filling or computer-generated models indicating where contact between the peptide antigen and antibody occurs. 6 25 Antibody Variability The Number Dilemma 26 • You have about a trillion different antibodies able to react with millions of different types of Ag There are several reasons why there are an enormous number of different antibodies: • but you only have about 30,000-60,000 genes which code for all the proteins you need in your entire body, most of which are not Ab • different combinations of heavy and light chains which are encoded by different genes • so there cannot be one gene for one antibody to code for these – we wouldn’t have enough antibodies! • recombination So how can your body produce Ab to so many antigens, even those it’s never seen? Antibody Genes • others 27 Genes for antibodies aren’t like most other genes - they come in pieces that are assembled by cutting and pasting the DNA (this only happens in Ab and TCR genes) 28 A unique recombination occurs in each B cell • • variable segments (V) – many different versions each B cell combines these gene segments to make an Ab chain like shuffling a deck of cards Unique combination of segments becomes joined by somatic gene rearrangement - V, D, and J for the heavy chain, V and J for the light chain • diversity segments (D) – several different versions • • joining segments (J) – a few different versions • constant segments (C) – a few different versions that are nearly identical since there are multiple types of each gene segment, there are many thousands of possible V-D-J combinations so that each B cell gets a unique combination of segments! 7 29 A unique recombination occurs in each B cell 30 •Since there are multiple types of each gene segment, there are many thousands of possible V-D-J combinations so that each B cell gets a unique combination of segments! Additional diversity occurs because there are two types of light chains. • each B cell combines these gene segments to make an Ab chain like shuffling a deck of cards - V, D, and J are joined to C for the heavy chain, -V and J are joined to C for the light chain 31 Humoral vs Cell-mediated Immune Response: 32 Other sources of variability Humoral: • when V, D, and J pieces are joined, they may not always be joined perfectly – if some base-pairs are lost or added, the Ab will end up with a different amino acid sequence • variable region genes mutate at a higher rate than other genes in your body occurs when Ag becomes coated with Ab which brings about the elimination of the foreign body (B cell mediated) -cross-link several Ag’s to form clumps -> more easily phago’d -bind complement proteins -neutralize toxins, viruses, and bacteria from binding target cells Cell-Mediated: occurs when effector T cells are activated (T cell mediated) -activated TH cells ! activate phagocytic cells activate B cells to produce Ab -activated TC cells ! kill altered self cells (viral infected and tumor cells) 8 INDUCTION OF AN IMMUNE RESPONSE Foreign invaders - viruses, bacteria, allergens, toxins and parasites- constantly bombard our body. 33 ! Innate Immunity - invariant (generalized) - early, limited specificity - the first line of defense 1. Barriers - skin, tears 2. Phagocytes - neutrophils, macrophages 3. NK cells and mast cells 4. Complement and other proteins ! YOUR ACTIVE IMMUNE DEFENSES Adaptive Immunity - variable (custom) - later, highly specific - ‘‘remembers’’ infection 1. APCs present Ag to T cells 2. Activated T cells provide help to B cells and kill abnormal and infected cells 3. B cells - produce antibody specific for antigen 9