Immunology - Gene Expression and Natural Defense Systems

18 http://microbiology.otago.ac.nz/dept/staff/buchan_glenn/images/Macrophage.jpg Immunology: Gene Expression and Natural Defense Systems 18 Immunology: Gene Expression and Natural Defense Systems • 18.1 What Are the Major Defense Systems of Animals? • 18.2 What Are the Characteristics of the Nonspecific Defenses? • 18.3 How Does Specific Immunity Develop? • 18.4 What Is the Humoral Immune Response? • 18.5 What Is the Cellular Immune Response? • 18.6 How Do Animals Make So Many Different Antibodies? • 18.7 What Happens When the Immune System Malfunctions? www.nyscience.org/whataboutaids/whatis/immune/assets 18.1 What Are the Major Defense Systems of Animals? Animals have various means of defense against pathogens — agents that cause disease  Defense systems are based on recognition of self (one‘s own) and nonself (foreign) molecules www.nyscience.org/whataboutaids/whatis/immune/assets 18.1 What Are the Major Defense Systems of Animals? Two general types of defense mechanisms:  Nonspecific defenses, or innate  act rapidly  include skin, phagocytic cells, and molecules toxic to invaders  Specific defenses, or adaptive  aimed at specific pathogens  Include antibody production  Slow to develop and long-lasting 18.1 What Are the Major Defense Systems of Animals? In animals that have both kinds of defense systems, they work together as coordinated system Nonspecific defenses are first line of defense, and are tremendously important 18.1 What Are the Major Defense Systems of Animals? Parts of the immune system  Lymphoid tissues include thymus, bone marrow, spleen, and lymph nodes — essential parts of defense system Figure 18.1 The Human Lymphatic System 18.1 What Are the Major Defense Systems of Animals?  Blood plasma  contains ions, small molecular solutes, soluble proteins  Red blood cells stay in closed circulatory system  White blood cells and platelets are also found in lymph http://www.med-ed.virginia.edu/courses/path/innes/images/nhjpeg/nh%20blood.jpeg 18.1 What Are the Major Defense Systems of Animals?  Lymph  fluid derived from blood and other tissues  From tissues, lymph moves into lymph system vessels  Lymph vessels join and eventually form thoracic duct, which joins circulatory system at a vein near heart 18.1 What Are the Major Defense Systems of Animals?  Lymph nodes are small, round structures at many sites along lymph vessels  contain white blood cells  As lymph passes through nodes, it is filtered and ―inspected‖ for nonself molecules http://www.medicalook.com/systems _images/Lymph_nodes.gif http://www.lymphoma.org/atf/cf/%7B0363CDD6-51B5-427B-BE48E6AF871ACEC9%7D/The%20Immune%20system%20450.jpg 18.1 What Are the Major Defense Systems of Animals?  Red and white blood cells originate from pluripotent stem cells in bone marrow  These cells constantly divide and can differentiate into variety of blood cells Figure 18.2 Blood Cells (Part 1) 18.1 What Are the Major Defense Systems of Animals? SEM shows leukocytes and red blood cells  White blood cells, leukocytes  Nucleated  can leave closed circulatory system and enter extracellular spaces if nonself molecules or cells are present  number of white blood cells may increase in response to pathogens, providing a clue for detecting infections www.cdc.gov/ncidod/EID/vol8no4/images/ 18.1 What Are the Major Defense Systems of Animals?  Two major types of white blood cells: 1. Granular  includes histamineproducing signaling cells (e.g. mast cells, basophils) and…  phagocytes that engulf foreign cells and debris.  Phagocytes include dendritic cells and macrophages Figure 18.2 Blood Cells (Part 2) 18.1 What Are the Major Defense Systems of Animals? http://diverge.hunter.cuny.edu/~weigang/Images 2. Lymphocytes participate in specific defenses — T cells and B cells  T cells  immature cells migrate from bone marrow to thymus where they mature  B cells  mature in bone marrow and circulate in blood and lymph  make antibodies Figure 18.2 Blood Cells (Part 3) http://oes.digiton.com/cytokine/images 18.1 What Are the Major Defense Systems of Animals? On Your Own Many proteins are involved in cell–cell interactions of defense system:  Antibodies  bind to substances identified as nonself  Secreted by B cells  T cell receptors  integral membrane proteins  recognize and bind nonself molecules on other cells www.immunogen.com/images www.designanduniverse.com/articles/images/army_inside_man/ 18.1 What Are the Major Defense Systems of Animals? www.designanduniverse.com/articles/images/army_inside_man/  Major histocompatibility complex (MHC)  on surface of most mammalian cells  self-identifying labels  Cytokines  signal proteins released by T cells, macrophages, and other cells  Bind to target cells and alter their activity www.cco.caltech.edu/~phplab 18.2 What Are the Characteristics of the Nonspecific Defenses? Nonspecific defenses are general mechanisms  first line of defense  In humans, they include physical barriers, cellular, and chemical defenses http://www.bact.wisc.edu/Microtextbook/images/book_4/chapter_15/15-7.gif Table 18.1 (Part 1) Table 18.1 (Part 2) 18.2 What Are the Characteristics of the Nonspecific Defenses? Skin is a primary nonspecific defense  Bacteria, fungi, and viruses can rarely penetrate healthy unbroken skin  Normal flora  bacteria and fungi that live on body surfaces without causing disease.  Part of defense system  they compete with pathogens for nutrients and space http://www.fungal-infections.info/objekte/inf_fi_sk_sf_en.gif 18.2 What Are the Characteristics of the Nonspecific Defenses? http://www-cellbio.med.unc.edu/grad/depttest/images/piccarson.gif Tears, nasal mucus, and saliva have an enzyme, lysozyme, that attacks bacterial cell walls Mucus in nose and respiratory tract traps microorganisms  Cilia continuously move mucus plus debris up towards nose and mouth http://www-cellbio.med.unc.edu/grad/depttest/images/piccarson.gif 18.2 What Are the Characteristics of the Nonspecific Defenses? Mucus membranes produce defensins, peptides with hydrophobic domains that are toxic to many pathogens http://www.nature.com/nri/journal/v6/n6/imag es/nri1860-f3.jpg http://www.nature.com/nrmicro/journal/v2/n9/images/nrmicro976-f5.gif 18.2 What Are the Characteristics of the Nonspecific Defenses? If pathogens reach digestive tract:  May be killed by gastric juices (hydrochloric acid and proteases), or by bile salts in small intestine  Small intestine lining is not normally penetrated by pathogens http://www.bact.wisc.edu/Microtextbook/images/book_4/chapter_15/15-7.gif 18.2 What Are the Characteristics of the Nonspecific Defenses? Vertebrate blood has antimicrobial proteins that make up complement system  proteins act in a characteristic sequence or cascade — each protein activates the next http://diverge.hunter.cuny.edu/~weigang/Images/16-10_complement_1.jpg 18.2 What Are the Characteristics of the Nonspecific Defenses? Complement proteins provide three types of defense:  Attach to microbes and mark them for phagocytes to engulf  Activate inflammation response and attract phagocytes to site of infection  Lyse invading cells http://diverge.hunter.cuny.edu/~weigang/Images/16-10_complement_1.jpg 18.2 What Are the Characteristics of the Nonspecific Defenses? Interferons are antimicrobial glycoproteins produced by cells when infected by virus  Increase resistance of neighboring cells to same or other viruses  Bind to receptors on noninfected cell membranes  stimulate signaling pathway that blocks viral reproduction http://academic.pgcc.edu/~aimholtz/AandP/206_ONLINE/Immune 18.2 What Are the Characteristics of the Nonspecific Defenses? Phagocytes  travel freely in lymph and circulatory systems, and also move into tissues  Foreign cells, viruses, and fragments become attached to phagocyte membrane, and engulfed  Defensins inside phagocyte digest foreign material Neutrophils engulf WGP 3-6, a yeast beta 1,3/1,6 glucan, which initiates a cascade of immune responses www.biotherapharma.com/images Figure 18.3 A Phagocyte and Its Bacterial Prey 18.2 What Are the Characteristics of the Nonspecific Defenses? Phagocytes (neutrophils and macrophages)  engulf invaders and dead cells  produce cytokines which signal brain to produce fever  Increased temperature inhibits growth of pathogens Macrophage extends a pseudopodium towards some bacteria in foreground www.brookline-design.com www.aids-info.ch/bilder/schule_aids/jpg_bilder 18.2 What Are the Characteristics of the Nonspecific Defenses? Natural killer cells  type of lymphocyte detect virus-infected cells, and some cancer cells  initiate lysis An "NK" cell (N) attached to a "target" cell "T". The NK cell will kill the now helpless target cell quickly, by the injection of deadly perforin. (Courtesy of Dr. G. Arancia and K. Malorni, Rome) www.healingcancernaturally.com 18.2 What Are the Characteristics of the Nonspecific Defenses? Inflammation is a response to injury  Mast cells  Cells adhering to skin and organ linings  release histamine, a chemical signal  Basophils also release histamine Histamines released by mast cell Figure 18.4 Interactions of Cells and Chemical Signals Result in Inflammation (Part 1) 18.2 What Are the Characteristics of the Nonspecific Defenses? Symptoms of inflammation are redness, swelling, heat, pain  Blood vessels in area are dilated, induced by histamine  Capillaries become ―leaky‖  plasma moves into tissues (causes swelling), along with complement proteins and phagocytes 18.2 What Are the Characteristics of the Nonspecific Defenses?  Neutrophils arrive first, then monocytes (which become macrophages)  Engulf invaders, dead cells and debris  responsible for most of healing  Produce several cytokines   may signal brain to produce fever Figure 18.4 Interactions of Cells and Chemical Signals Result in Inflammation (Part 2) 18.2 What Are the Characteristics of the Nonspecific Defenses? Cytokines may also stimulate endothelial cells to make adhesion molecules  phagocytes bind to these and then pass through vessel to tissue http://www.bio.davidson.edu/courses/immunology/Students/spring2006/Latting/Picture%20004.jpg 18.2 What Are the Characteristics of the Nonspecific Defenses? Pus  collection of dead cells and leaked fluids  gradually consumed by macrophages High-magnification of pus in appendix lumen. Pus consists of living and degenerate neutrophil polymorphs together with liquefied tissue debris http://medweb.bham.ac.uk/http/mod/3/1/a 18.2 What Are the Characteristics of the Nonspecific Defenses? Inflammation response may not remain local  Can spread throughout bloodstream — a condition called sepsis, which can be lethal Necrotizing soft tissue infection of the lower abdominal wall causing sepsis. Removal of necrotic tissue to save living tissue was required for infectious source control. http://sitemaker.umich.edu/umpire/files/llq_necrotizing_infection.jpg 18.2 What Are the Characteristics of the Nonspecific Defenses? Fragment of bacterium binds to Invading pathogen is signal CD14 receptor, that stimulates Toll, initiates cascade  A signal transduction pathway links signal and response  Receptor is membrane protein called toll  Toll is part of protein kinase cascade  results in transcription factors for 40 genes involved in specific and nonspecific defenses Figure 18.5 Cell Signaling and Defense 18.3 How Does Specific Immunity Develop? Specific immune system has four key traits: Specificity  Diversity—response to a wide variety of pathogens  Ability to distinguish self from nonself  Memory 18.3 How Does Specific Immunity Develop? Specificity  Lymphocytes are crucial  T cell receptors and antibodies bind to specific nonself (invading) molecules (antigens)  Specific sites on antigens are called antigenic determinants or epitopes Antibodies Figure 18.6 Each Antibody Matches an Antigenic Determinant Antigenic determinants (or epitopes) are small part of antigen Antibodies specific to certain epitopes 18.3 How Does Specific Immunity Develop? Large antigen, such as a whole cell or virus, may have many different antigenic determinants  Some epitopes evoke a more powerful response — called immunodominant  Each T cell and antibody is specific for single antigenic determinant Antigenic determinants (or epitopes) are small part of antigen 18.3 How Does Specific Immunity Develop? Distinguishing self from nonself  Immune system must be able to recognize all body‘s own antigenic determinants, and not attack them 18.3 How Does Specific Immunity Develop? Diversity  Must respond to wide variety of pathogens  Each pathogen may exist in many different varieties or strains Humans can respond specifically to about 10 million different antigenic determinants Once recognized, lymphocytes activated 18.3 How Does Specific Immunity Develop? Immunological Memory  After one response to pathogen, immune system ―remembers‖ pathogen  Responds more quickly and powerfully if that pathogen re-invades  Vaccination introduces an antigenic determinant, and immune system remembers it www.biology.arizona.edu/immunology/tutorials/immunology/graphics 18.3 How Does Specific Immunity Develop? Specific immune system has two types of responses that interact:  Humoral immune response – acts in ―humors‖ (blood & lymph)  Cellular immune response – acts after antigen enters cell http://www.influenzareport.com/ir/images/image27.jpg 18.3 How Does Specific Immunity Develop? Humoral immune response:  Antibodies react with antigenic determinants in blood, lymph, and tissue fluids  Animals produce huge diversity of antibodies  Some antibodies are soluble in blood and lymph  others are integral membrane proteins on B cells Antibodies attached to epitopes on antigen http://digitalartmuseum.com/october/billingsley/artwork/ 18.3 How Does Specific Immunity Develop? When pathogen first invades,  a B cell‘ membrane antibody may recognize one of pathogen‘s antigenic determinants, and bind with it  This stimulates B cell to make multiple copies of antibody 18.3 How Does Specific Immunity Develop? Cellular immune response  Detects and destroys virusinfected cells and mutated cells  Carried out by T cells in blood, lymph, and extracellular spaces in tissues  T cell receptors bind to specific antigenic determinants from virus, which initiates an immune response that results in destruction of foreign cell T cell (blue) identifies molecular signature of a dendritic cell (brown) at a contact point called the immunological synapse. If the immunological synapse signals the presence of a foe, the T cell will attack. www.lbl.gov/Publications/Currents/Archive/view-assets/Oct-03-2003 18.3 How Does Specific Immunity Develop? Clonal selection:  Diversity is generated by DNA changes just after B and T cells are formed  Each B cell is able to produce only one kind of antibody  Antigen binding selects a B or T cell for proliferation — divides to form clone of cells Figure 18.6 Clonal Selection in B Cells 18.3 How Does Specific Immunity Develop? Activated lymphocytes produce two kinds of daughter cells:  Effector cells carry out the attack.  Effector B cells (plasma cells) secrete antibodies  Effector T cells secrete cytokines  Memory cells (both B and T) are long-lived cells that can divide on short notice to produce effector cells 18.3 How Does Specific Immunity Develop? Immunological Memory  Primary immune response  When antigen is first encountered, ―naïve‖ lymphocytes proliferate to produce clones of effector and memory cells  Secondary immune response  When antigen is encountered again, memory cells quickly proliferate and launch army of plasma cells and effector T cells Immunological Memory 18.3 How Does Specific Immunity Develop? Natural immunity  Due to immunological memory, can occur after one exposure to diseases such as chicken pox Artificial immunity is conferred by inoculation with an antigen  Initiate primary immune response, generating memory cells  Two types  Immunization  Vaccination http://ldt.stanford.edu/~aim2004/img 18.3 How Does Specific Immunity Develop?  Immunization — inoculation with antigenic proteins, pathogen fragments, or other molecular antigens  Vaccination — inoculation with whole pathogens that have been modified so they will not cause disease http://ldt.stanford.edu/~aim2004/img Table 18.2 (Part 1) Table 18.2 (Part 2) 18.3 How Does Specific Immunity Develop? Pathogens used for vaccination may be altered by:  Inactivation — treat with heat or chemicals to kill pathogen  Attenuation — reduce virulence of virus by repeatedly infecting cells with it http://www.newscientist.com/data/images/archive/1807/18077404.jpg 18.3 How Does Specific Immunity Develop?  Recombinant DNA technology — produce peptide fragments that bind to lymphocytes, but lack toxic portion of protein  DNA vaccines — under development, inserting gene that encodes antigen http://www.mogam.re.kr/eng/images/img/010.jpg 18.3 How Does Specific Immunity Develop? Immunological tolerance  Normally, body is tolerant of its own molecules  Two mechanisms for tolerance  Clonal deletion  Clonal anergy 18.3 How Does Specific Immunity Develop? Clonal deletion  Removes certain immature B and T cells early in differentiation  Those that show potential to mount immune response by binding to self antigens undergo apoptosis www.cs.unm.edu/~immsec/html-imm/ 18.3 How Does Specific Immunity Develop? Clonal anergy  suppression of immune response if mature lymphocyte Note: CD28 glycoprotein is recognizes self antigens on T cell membrane, not the  Before T cell sends out APC as stated in text cytokines (signaling response) when it binds to antigen, it must also detect second molecule (B7) with its CD28 receptor  CD28 receptor/ligand system is co-stimulatory signal, that binds to B7 (Antigen) protein expressed only on certain antigen-presenting cells (APC)  Most body cells lack this signal  suppresses cytokine release http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/Costimulation.gif Figure 18.7 Immunological Tolerance 18.4 What Is the Humoral Immune Response? B cells are basis of humoral response  First make antibody that is expressed as receptor protein on B cell surface  If antigen binds to receptor, B cell engulfs, digests and presents antigen to Helper T cell (TH)  TH with same specificity must bind to antigen to activate B cell  When stimulated  B cell becomes plasma cell Antigen being presented by Bcell, acting as an APC http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T 18.4 What Is the Humoral Immune Response?  Division and differentiation of B cell is stimulated by cytokines from TH cell  As plasma cell develops, ER and ribosomes increase to synthesize antibody proteins  Plasma cell secretes antigen-specific antibodies into blood stream  Also gives rise to a clone of plasma and memory cells http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T http://upload.wikimedia.org/wikipedia/ commons/thumb/f/f7/B_cell_activation. png/300px-B_cell_activation.png Figure 18.8 A Plasma Cell Humoral response Cellular response http://academic.brooklyn.cuny.edu/bi ology/bio4fv/page/aviruses 18.4 What Is the Humoral Immune Response? Antibodies belong to protein group called immunoglobulins  All contain tetramer of four polypeptides  two light chains and two heavy chains  held together with disulfide bridges  Each chain has variable (v) region and constant (c) region 18.4 What Is the Humoral Immune Response?  Constant region determines class of antibody —function and destination  Variable regions are specific for each immunoglobulin — responsible for antibody specificity  Two antigen-binding sites are identical — bivalent Figure 18.9 The Structure of Immunoglobulins (Part 1) Figure 18.9 The Structure of Immunoglobulins (Part 2) Table 18.3 (Part 1) Table 18.3 (Part 2) 18.4 What Is the Humoral Immune Response? Five classes of antibodies:  IgG  most abundant  greatest amounts made during secondary immune response  Soluble  Some IgG bind to antigens and then to macrophages (at base of ‗Y‘), which engulfs antigen Figure 18.10 IgG Antibodies Promote Phagocytosis 18.4 What Is the Humoral Immune Response? Monoclonal antibodies  From clone of B cells  Have specificity for only one antigenic determinant Polyclonal antibodies  from different types of B cells  have specificity for many antigenic determinants 18.4 What Is the Humoral Immune Response? Clone of B cells can be made by fusing a B cell with a tumor cell — resulting cell is hybridoma hybridoma makes monoclonal antibodies and grows indefinitely in culture Figure 18.11 Creating Hybridomas for the Production of Monoclonal Antibodies 18.4 What Is the Humoral Immune Response? Monoclonal antibodies are used for:  Immunoassays — detecting small amounts of molecules in tissue or fluids  Immunotherapy  monoclonal antibodies for antigenic determinants on cancer cells  Can be coupled with radioactive, toxic drug, virus, etc. (multi-step targeting) http://content.answers.com/main/content/wp/en/1/1e/MonoclonalAb.jpg 18.4 What Is the Humoral Immune Response?  Passive immunization  short-lived monoclonal antibodies are injected into life threatening situations  when there is not enough time to allow immune system to mount its own defense http://energycommerce.house.gov/108/Hearings/05072003hearing917/ 18.5 What Is the Cellular Immune Response? Cellular immune response  mediated by T cells  directed against any factor that changes normal cell into an abnormal cell  T cell receptors are glycoproteins, with two polypeptide chains  two chains have different amino acid sequences Figure 18.12 A T Cell Receptor 18.5 What Is the Cellular Immune Response?  Major difference between antibodies and T cell receptors:  T cell receptors (TCR) bind only to an antigenic determinant (Ag) that is displayed on surface by major histocompatibilty complex (MHC) of an antigen-presenting cell (APC) http://users.path.ox.ac.uk/~scobbold/tig 18.5 What Is the Cellular Immune Response?  When T cell is activated, it forms clone and descendents differentiate into two types of effectors:  Cytotoxic T cells (TC) recognize abnormal cells and kill them by lysis.  Helper T cells (TH) assist both humoral and cellular responses. Cytotoxic T cell engulfing virus-infected cell Humoral response Cellular response http://academic.brooklyn.cuny.edu/bi ology/bio4fv/page/aviruses 18.5 What Is the Cellular Immune Response? Major histocompatibility complex (MHC) proteins  Plasma membrane glycoproteins  Main role is to present antigens (on APC) to T cell receptors (TCR) so that T cell can distinguish between self and nonself http://users.path.ox.ac.uk/~scobbold/tig 18.5 What Is the Cellular Immune Response? Two classes of MHC proteins:  Class I is on surface of every nucleated cell  Bind to polypeptide fragments, travel to membrane and ―present‖ fragments to TC cells  TC cells have CD8 surface protein that binds to MHC I Figure 18.14 The Interaction between T Cells and Antigen-Presenting Cells (Part 1) Figure 18.14 The Interaction between T Cells and Antigen-Presenting Cells (Part 2) 18.5 What Is the Cellular Immune Response? http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/ClassII_CD4.gif  Class II is on surfaces of B cells, macrophages, and other antigen-presenting cells  When nonself antigen is ingested, fragments bind to MHC II  Antigen is carried to membrane and presented to TH cells  TH cells have a surface protein CD4 that binds to MHC II Figure 18.13 Macrophages Are Antigen-Presenting Cells 18.5 What Is the Cellular Immune Response?  MHC I and MHC II proteins have an antigen binding site, which holds a polypeptide fragment  T cell receptor recognizes not just the antigenic fragment, but the fragment bound to MHC I or II www.designanduniverse.com/articles/images/army_inside_man/ Figure 18.14 The Interaction between T Cells and Antigen-Presenting Cells (Part 3) http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/ 18.5 What Is the Cellular Immune Response? Humans have three gene loci each for MHC I and II, all six loci have hundreds of alleles  Different people have very different genotypes for these proteins  Genes for MHC, antibodies, and T cell receptors may have descended from one ancestor, and represent a gene ―superfamily‖ Chromosome 6 http://imgt.cines.fr/textes/IMGTrepertoireMHC/LocusGenes/chromosomes/human/Hu_MHCchrom6.jpg 18.5 What Is the Cellular Immune Response? Humoral immune response:  Activation phase occurs in lymphoid tissue  TH cell binds to antigenpresenting macrophage with Class II MHC  produces a clone  Effector phase  TH cells activate B cells with same antigen specificity  produce antibodies Figure 18.15 Phases of the Humoral and Cellular Immune Responses (Part 1) Figure 18.15 Phases of the Humoral and Cellular Immune Responses (Part 2) http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/U Class II MHC protein Electron micrograph (courtesy of J. W. Uhr) shows a B cell and T cell bound to each other. The bar = 1 μm. 18.5 What Is the Cellular Immune Response? B cells are also antigenpresenting cells  Take up antigens bound to surface receptors by endocytosis, then display fragments on MHC II proteins  TH cell binds to displayed complex, releases cytokines that cause B cell to produce a clone of plasma cells http://upload.wikimedia.org/wikipedia/commons/thumb/f /f7/B_cell_activation.png/300px-B_cell_activation.png 18.5 What Is the Cellular Immune Response? Cellular immune response:  Activation phase  virus-infected or altered cell displays peptide fragments bound to MHC I  TC cell binds and is activated to form a clone  Effector phase  TC clones recognize other infected cells  bind to them and initiate lysis Figure 18.15 Phases of the Humoral and Cellular Immune Responses (Part 3) Figure 18.15 Phases of the Humoral and Cellular Immune Responses (Part 4) 18.5 What Is the Cellular Immune Response? TC cells produce perforin, which lyses cells  TC cells also bind to receptor (Fas) on target cells that initiates apoptosis  TC cells recognize self MHC proteins complexed with foreign or altered fragments www.cat.cc.md.us/courses/bio141/lecguide/unit3/cellular/cmidefense/ctls/images 18.5 What Is the Cellular Immune Response? TC cells require costimulatory signal  second signal for activation  when TC first binds to infected cell, there is additional interactions of TC CD28 and its ligand on APC  Also starts production of inhibitor to ensure that response will end  Afterwards, TC surface protein CTLA4 binds preferentially with CD28 ligand (CD86), blocking activation of TC cells Note: CD28 glycoprotein is on cytotoxic T cell membrane, not the APC as stated in text http://kugi.kribb.re.kr/KUGI/Pathways/mBioCarta/ m_ctla4Pathway/m_ctla4Pathway.gif 18.5 What Is the Cellular Immune Response? MHC proteins are important in self-tolerance  Developing T cells are ―tested‖ in thymus  T cells unable to recognize self MHC proteins die quickly  If T cell binds to self MHC proteins and body‘s own antigens, it dies http://www.nature.com/ni/journal/v8/n4/images/ni0407-333-F1.jpg 18.5 What Is the Cellular Immune Response? For organ transplants to be successful, MHC proteins must match  tissue from another person has different MHC proteins and is recognized as nonself — it is destroyed or ―rejected‖ by immune system  Drugs are used to overcome rejection — cyclosporin blocks transcription factor necessary for T cell development Cyclosporine (CsA) binds to cyclophylin (CpN), forming a complex that eventually blocks CaN, which controls transcription of interleukin 2 gene, thus blocking T cell development http://www-ermm.cbcu.cam.ac.uk/nfig002ssh.gif 18.6 How Do Animals Make So Many Different Antibodies? As B cells develop, their genomes become modified so that each mature B cell can produce only one specific antibody  Each gene encoding an immunoglobulin is actually a supergene assembled from cluster of smaller genes  Every cell has hundreds of genes that could participate in synthesis of antibodies Figure 18.16 Heavy-Chain Genes 18.6 How Do Animals Make So Many Different Antibodies?  During B cell development, genes are cut out and rearranged  One gene is chosen randomly for joining, others are deleted  A unique supergene is assembled  Result: enormous diversity of specific antibodies http://student.biology.arizona.edu/honors97/group2/assets/images www.thebody.com/nih/images/ Figure 18.17 Heavy-Chain Gene Rearrangement and Splicing (Part 1) Gene rearrangement for heavy chain 18.6 How Do Animals Make So Many Different Antibodies?  Genes for light chains are on separate chromosomes  made in similar way, with an equally large amount of diversity possible  Light and heavy chain diversity together yield about 21 billion possibilities www.som.soton.ac.uk/research/cancersciences/ members/sahota 18.6 How Do Animals Make So Many Different Antibodies? Other mechanisms for diversity:  Imprecise recombination – when DNA is rearranged, errors can occur during recombination creating new codons  Before DNA is rejoined, terminal transferase adds nucleotides, creating insertion mutations (frameshifts and new codons)  High spontaneous mutation rate 18.6 How Do Animals Make So Many Different Antibodies? Class switching:  B cells can make only one type of antibody at a time, but it can change class of antibody it makes  Early B cells produce IgM — receptors that recognize specific antigenic determinants 18.6 How Do Animals Make So Many Different Antibodies?  If B cell becomes plasma cell, a deletion occurs in DNA, resulting in antibody with different constant region of heavy chain  Antibody still has same variable regions, and thus same specificity; but different function determined by constant region  TH cells induce class switching through cytokine signals http://www.nature.com/nrm/journal/v3/n12/images/nrm972-i1.jpg Figure 18.18 Class Switching 18.7 What Happens When the Immune System Malfunctions? Allergic reactions  occur when immune system overreacts or is hypersensitive to an antigen  antigen may not be dangerous, but immune system produces inflammation and other symptoms  Two types  immediate hypersensitivity  delayed hypersensitivity http://www.healthsystem.virginia.edu/internet/medlabs/images/Cutaneous%20allergic%20reaction.gif 18.7 What Happens When the Immune System Malfunctions? Immediate hypersensitivity:  When exposed to allergen, large amounts of IgE (an antibody) are produced  IgE constant end binds to mast cells and basophils  release large amounts of histamine  Histamines produce symptoms such as inflammation, blood vessel dilation, difficulty in breathing Figure 18.19 An Allergic Reaction (Part 1) Figure 18.19 An Allergic Reaction (Part 2) 18.7 What Happens When the Immune System Malfunctions? http://images.healthcentersonline.com/allergy/images/article/AntihistamineAct.jpg  These reactions can be treated with antihistamines  Severe allergic reactions can lead to death  Allergy to pollen can be treated by desensitization — small amounts of allergen are injected under skin, stimulates IgG production, but not IgE production 18.7 What Happens When the Immune System Malfunctions? http://web.indstate.edu/thcme/PSP/04psp/TH1VTH204_files/image002.jpg Delayed or cell-mediated hypersensitivity:  Begins hours after exposure to allergen  Antigen is taken up by antigen-presenting cells and a T cell response is initiated  Example: poison ivy rash http://www.lni.wa.gov/Safety/Research/Dermatitis/EdMat/PhytoSlides/21to25/default.asp 18.7 What Happens When the Immune System Malfunctions? Autoimmunity  clones of B and T cells produced that are directed against self antigens  Possible causes:  Failure of clonal deletion  Viral infection — if virus has antigenic determinant that resembles self antigen  Molecular mimicry — self has antigens that resemble nonself and are recognized by T cells http://www.rndsystems.com/DAM_public/5724.gif 18.7 What Happens When the Immune System Malfunctions? Autoimmune diseases tend to ―run in families‖ indicating a genetic component  Genome scans indicate transcription factor for B cells, RUNX1, may be involved  Some alleles for MHC II are strongly associated with autoimmune diseases http://lythgo.googlepages.com/image005.gif/image005-full.jpg 18.7 What Happens When the Immune System Malfunctions? Some autoimmune diseases:  Systemic lupus erythematosis (SLE)  antibodies to cellular components result in large circulating antibody-antigen complexes that become stuck in tissues  causing widespread inflammation http://www.eorthopod.com/images/ContentImages/arthritis/arthritis_lupus/arthritis_lupus_lupus01.jpg 18.7 What Happens When the Immune System Malfunctions?  Rheumatoid arthritis  T cell response can not be shut down, possibly due to low CTLA4 activity  Results in joint inflammation because of influx of white blood cells http://www.nature.com/nri/journal/v7/n1/images/nri1984-f1.jpg 18.7 What Happens When the Immune System Malfunctions?  Hashimoto’s thyroiditis — immune cells attack thyroid secretions Struma lymphomatosa in Hashimoto thyroiditis (Right). Note: diffuse, pale yellow infiltrate affecting the entire thyroid. The yellow infiltrate is caused by an influx of lymphocytes, which may form follicles. Normal thyroid (Left) http://www.pharmacology2000.com/Thyroid/c21_s40.gif 18.7 What Happens When the Immune System Malfunctions?  Insulin-dependent diabetes mellitus (type I)  Occurs most often in children  Caused by an immune reaction against pancreatic cells that make insulin http://medicalimages.allrefer.com/large/type-i-diabetes.jpg 18.7 What Happens When the Immune System Malfunctions? Immune deficiency disorders can be inherited or acquired  T or B cells never form, or B cells lose their ability to become plasma cells  Severe combined immunodeficiency (SCID), or Bubble Boy Syndrome where both T and B cells are defective http://www.dana.org/uploadedImages/Images/Content_Images/pub_immunologysrcbk_img_17.jpg 18.7 What Happens When the Immune System Malfunctions?  TH cells (crucial to both humoral and cellular responses), are targets of HIV retrovirus that results in AIDS — acquired immune deficiency syndrome A doctor examines an emaciated AIDS patient in Lusikisiki, South Africa. Ninetyfour out of every hundred HIV-infected people live in developing nations, where currently available drug therapies are largely unaffordable. http://science.nationalgeographic.com/staticfiles/NGS/Shared/StaticFiles/Science/Images/Content/aids-patient-984747-ga.jpg 18.7 What Happens When the Immune System Malfunctions? HIV can be transmitted by:  Blood — e.g., needle contamination  Exposure through broken skin, wounds, mucus membranes  Through blood of infected mother to baby during birth http://static.howstuffworks.com/gif/ http://abbott.com/static/content/image/hivAccess_map1.gif 18.7 What Happens When the Immune System Malfunctions? HIV initially infects TH cells, macrophages, and dendritic cells  These cells carry virus to lymph nodes and spleen  HIV preferentially infects activated TH cells in lymph nodes and spleen  Up to 10 billion viruses are made per day in initial phase of infection http://www.nature.com/nri/journal/v6/n11/images/nri1960-f1.jpg 18.7 What Happens When the Immune System Malfunctions? Symptoms abate as T cells mount an immune response But antibody-complexed viruses can still infect TH cells — secondary infection  Rate of secondary infection reaches a low, steady state level — set point  Set point level varies in individuals, and determines rate of disease‘s progress Figure 18.20 The Course of an HIV Infection 18.7 What Happens When the Immune System Malfunctions? Gradually, TH cells are destroyed, and person is susceptible to many infections Opportunistic infections:  Kaposi‘s sarcoma, a rare skin cancer caused by a herpesvirus  Pneumonia caused by fungus Pneumocystis carinii  Lymphoma tumors caused by Epstein-Barr virus Figure 18.21 Relationship between TH Cell Count and Opportunistic Infections 18.7 What Happens When the Immune System Malfunctions? HIV is an enveloped RNA retrovirus Virally encoded proteins necessary for infection and replication:  Membrane glycoproteins gp120 and gp41 attach to host cell proteins CD4 and a co-receptor Figure 18.22 Two Receptors for HIV 18.7 What Happens When the Immune System Malfunctions?  Reverse transcriptase  catalyzes synthesis of complementary DNA (cDNA) from viral RNA  Lacks proofreading function, which leads to high mutation rate and a pool of mutant viruses http://webs.wichita.edu/mschneegurt/biol103/lecture15/ 18.7 What Happens When the Immune System Malfunctions? http://webs.wichita.edu/mschneegurt/biol103/lecture15/  Integrase — catalyzes insertion of cDNA into host chromosome Protease —completes viral proteins 18.7 What Happens When the Immune System Malfunctions? Treating HIV  develop agents that block steps in viral life cycle without harming host cells  Highly active antiretroviral therapy (HAART)  combination of drugs — protease inhibitor and two reverse transcriptase inhibitors  Many people on HAART develop mutant strains of HIV 18.7 What Happens When the Immune System Malfunctions? New drug combinations are constantly being developed to combat mutating strains of HIV Researchers are developing vaccines Countries with ongoing or completed HIV vaccine trials http://www.hivvaccineenterprise.org/ _img/vaccinetrials.gif