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The Immune System Chapter 51 Introduction Vertebrates have three levels of defenses -1. The Integumentary System -Skin and mucous membranes provide first line of defense -2. Nonspecific (innate) Immune System -Acts very rapidly after onset of infection -3. Specific Immune System -Eliminates microbes that escaped the 2 second line of defense Skin The skin is the largest organ of the body -Provides a nearly impenetrable barrier, reinforced with chemical weapons -Oil & sweat glands give skin a pH of 3-5 -Lysozyme breaks bacterial cell walls -Also contains many normal flora -Non-pathogenic microorganisms that out-compete pathogenic ones 3 Skin The skin is composed of three layers: epidermis, dermis, hypodermis -Epidermis = 10-30 cells thick -Stratum corneum – Outermost layer; cells shed continuously -Stratum spinosum – Middle layer -Stratum basale – Innermost layer cells actively dividing -Contains keratin, which makes skin tough and water-resistant 4 Mucosal Epithelial Surfaces The digestive, respiratory and urogenital tracts are lined by mucous membranes -Cells secrete mucus which traps microbes Digestive tract -Salivary lysozyme; acidic stomach Respiratory tract -Ciliary action Urogenital tract -Acidic urine 5 Nonspecific Immunity The nonspecific or innate immune system consists of cellular and chemical devices that respond to any microbial infection -The response is quite rapid Among the most important defenses are 3 types of LEUKOCYTES (WHITE BLOOD CELLS) 6 Leukocyte 1 of 3 Macrophages -Large, irregularly shaped cells -Kill microbes by phagocytosis -Mature from monocytes that enter tissues from the blood 7 Leukocytes 2 and 3 Neutrophils -The most abundant circulating leukocytes -First to appear at site of damage/infection -Kill microbes by phagocytosis Natural killer (NK) cells -Destroy pathogen-infected and cancer cells by programmed cell death or apoptosis -Produce perforins and granzymes 8 NK Cells and Macrophages Working Together 9 The Inflammatory Response -Injured cells release chemical alarms, including histamine and prostaglandins (seen in allergies) -Cause nearby blood vessels to dilate and increase in permeability -Promote phagocyte accumulation -Hallmark signs = Redness, warmth, swelling, pain, and 10 potential loss of function The Inflammatory Response Inflammation is accompanied by an acute phase response, manifested by fever -Macrophages release interleukin-1 -Causes hypothalamus to raise body temperature -Promotes activity of phagocytes, while impeding microbial growth -However, very high fevers are hazardous as they may denature critical enzymes 11 Complement The complement system consists of about 30 different proteins that circulate in the blood in an inactive form -Upon pathogen encounter, a cascade of activation occurs -Some proteins aggregate to form a membrane attack complex (MAC) on surface of pathogen 12 Complement Other functions of complement proteins -C3b coats surface of invading pathogens, thereby enhancing their phagocytosis -Some stimulate the release of histamine from mast cells and basophils -Some attract more phagocytes to the area of infection 13 Interferon Interferons (IFN) are proteins that play a key role in body defense...they are secreted ligands -Three major types: IFN-a, IFN-b, IFN-g -IFN-a and IFN-b are produced by almost all body cells in response to viral infection -Induce degradation of viral RNA -IFN-g is produced only by T-lymphocytes and natural killer cells -Protects from infection and cancer 14 The Specific Immune System 15 The Specific Immune System The scientific study of immunity began with Edward Jenner in 1796 -Observed that milkmaids who had cowpox rarely experienced smallpox -Inoculated individuals with fluid from cowpox vesicles to protect them from smallpox -Vaccination 16 The Specific Immune System Two important concepts Has cellular memory (an ability to remember antigens) Does not harm the body’s own cells (when all is working well). 17 ANTIGENS An antigen is a molecule that provokes a specific immune response. A single protein may have many different antigenic determinants or epitopes -Each can stimulate a distinct immune response 18 19 Lymphocytes Lymphocytes are leukocytes (FROM BONE MARROW--via hematopoiesis) with surface receptors for antigenic determinants -Direct an immune response against either the antigen or the cell that carries it When a naïve lymphocyte binds a specific antigen for the first time, it gets activated by a process called clonal selection -Produces a clone of cells: some respond immediately, others are memory cells 20 Examples of 2 Lymphocytes Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Lymphocyte Receptor Proteins B Cell T Cell Antigen-binding Antigen-binding site site Antigen B-cell receptor Antigen Plasma membraneT-cell receptor 21 Examples of 2 Lymphocytes B lymphocytes (B cells) -Respond to antigens by secreting antibodies or immunoglobulins (Ig) -Participate in HUMORAL IMMUNITY T lymphocytes (T cells) -Regulate other immune cells or directly attack cells that carry specific antigens -Participate in CELL-MEDIATED IMMUNITY 22 Organs of the Immune System -Primary lymphoid organs -Bone marrow and thymus -Secondary lymphoid organs -Lymph nodes, spleen, and mucosal-associated lymphoid tissue (MALT) 23 B cells come from the Bone Marrow The bone marrow is site of B cell maturation -Each B cell has about 105 Ig molecules on its surface, all with the same specificity -However, different B cells will have different specificities -B cells recognize epitopes directly -Any lymphocytes that are likely to bind to self-antigens undergo apoptosis 24 T cells come from the Bone Marrow The thymus is the site of T cell maturation -Each T cell has about 105 identical T-cell receptors on its surface -Recognize epitopes only if they are combined with major histocompatibility complex (MHC) peptides -Lymphocytes that cannot bind MHCs, or that bind self-MHC/self-peptide too 25 Not All B cells leave the Bone Marrow Not all T cells leave the Thymus Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Bone marrow stromal cell Ig on B cell surface binds, inducing apoptosis Igs Ig does not bind; B cell leaves bone marrow MHC– peptide complex Dendritic cell TCR binds TCRs tightly, inducing apoptosis TCR binds weakly; T cell leaves thymus Cells that cannot bind MHC are also eliminated 26 Secondary Lymphoid Organs The locations of these organs promote the filtering of antigens that enter any part of an individual’s body -Mature but naïve B and T cells become activated in the lymph nodes -The spleen is site of immune responses to antigens found mainly in the blood -Mucosal-associated lymphoid tissue (MALT) include the tonsils and appendix 27 2 types of T Cells -Cytotoxic T cells (Tc) -CD8+ cells, recognize MHC class I (found on all nucleated cells) -Helper T cells (TH) -CD4+ cells, recognize MHC class II (found only on antigen-presenting cells) 28 Cytotoxic T cells -Naïve TC cells are activated upon TCR recognition of foreign peptide displayed on self-MHC class I protein on dendritic cells -Clonal expansion and differentiation into activated cells and memory cells -Activated cells induce apoptosis in cells with same specificity as first cell -Likely a viral-infected or cancer cell 29 Helper T cells Working with B cells and Macrophages 30 Helper T cells Working with B cells and Macrophages...CONTINUED -TH cells respond to exogenous antigen that is taken up by an antigen presenting cell -Antigen is partially digested, then complexed with MHC class II proteins -Complex is transported to and displayed on the cell surface 31 Helper T cells Working with B cells and Macrophages...CONTINUED -Activated TH cell gives rise to a clone of TH cells including both effector cells and memory cells -Most effector TH cells leave the lymphoid organs and circulate around the body -Secrete proteins called cytokines -Promote humoral and cell-mediated immune responses 32 Helper T cells Working with B cells and Macrophages...CONTINUED -Humoral immunity begins when naïve B cells in secondary lymph organs meet antigens -B cells are activated when their surface Igs bind to a specific epitope on an antigen -TH cytokines may also be required -Activation results in clonal expansion and differentiation into plasma and memory cells -Plasma cells produce soluble antibodies against the same epitope 33 Helper T cells Working with B cells and Macrophages...CONTINUED Plasma cells produce soluble antibodies against the same epitope Macrophage or Neutrophil binds the antibody epitope 34 Immunoglobulins An immunoglobulin consists of two identical short polypeptides, light chains, and two identical longer polypeptides, heavy chains -Four chains are held by disulfide bonds, forming a Y-shaped molecule -Fab regions = Two “arms” -Fc region = “Stem” 35 Immunoglobulins Each chain has a variable region (amino acid sequence differs between Igs) and a constant region -The variable regions fold together to form a cleft, the antigen-binding site Each Ig can bind two identical epitopes -Allows formation of antigen-antibody complexes -Indeed, Igs can agglutinate, precipitate or neutralize antigens 36 Immunoglobulin Diversity Human B cells can generate antibodies with over 1010 different antigen-binding sites -This diversity is generated through a process called DNA rearrangement An Ig protein is encoded by different segments of DNA -V (variable), D (diversity), J (joining) -Plus a constant region 37 Immunoglobulin Diversity These segments are joined during maturation in the bone marrow in B-cells -First, a D and a J segment are joined -Then, DJ is combined with a V segment -Transcription and RNA processing follow, linking variable region to a constant region -Translation occurs in the rough ER, where heavy and light chains are joined together 38 The regional genes (V, D, J) are flanked by Recombination Signal Sequences (RSSs) that are recognized by a group of enzymes known collectively as the VDJ recombinase. 39 T Cell Receptors The structure of a TCR -Unlike Igs, TCRs are not secreted -TCR diversity is also caused by DNA rearrangements 40 Immune Responses The first encounter with a foreign antigen is called the primary immune response -Only few B or T cells can recognize antigen The second encounter is called the secondary immune response -This time there is a large clone of memory cells that can recognize the antigen -Immune response is more effective 41 42 Autoimmunity The acceptance of self cells is known as immune tolerance Autoimmune diseases are caused by the failure of immune tolerance -Result in activation of autoreactive T cells, and production of autoantibodies by B cells -Cause inflammation and organ damage -Alleviated by corticosteroids and NSAIDs, including aspirin 43 Allergy Allergy refers to a greatly heightened response to a foreign antigen, or allergen -The most common type is known as immediate hypersensitivity -Results from excessive IgE production -Seasonal hay fever -Provoked by ragweed or other pollen 44 Allergy On initial exposure to allergen, B cells are activated to secrete IgE antibodies -Bind to FC receptors on mast cells or basophils On subsequent exposure to allergen, allergen cross-links bound IgEs -Cells are induced to release histamine and other inflammatory mediators -Produce symptoms of allergy 45 Allergy In systemic anaphylaxis, the allergic reaction is severe and potentially life-threatening -Anaphylactic shock = Blood pressure drop, and bronchial constriction -Death within 20-30 minutes Most people, however, experience local anaphylaxis -Hives or mild asthma 46 Allergy -Contact dermatitis -Caused by varied materials, such as poison ivy, nickel in jewelry and cosmetics 47 Antibodies in Medicine A person’s blood type is determined by antigens found on surface of red blood cells -ABO blood types = Types A, B, AB and O -Rh factor = Rh positive and Rh negative The immune system is tolerant of its own RBC antigens, but makes antibodies that bind to those that differ -For example, people with type A blood make antibodies against the B antigen 48 Antibodies in Medicine In blood transfusions, the antigens of the donor can’t trigger the antibodies of the recipient -For instance, a type A person cannot donate to a type B or type O -These would have anti-A antibodies Blood is typed by agglutination reactions, using circulating IgM antibodies 49 Antibodies in Medicine A mismatched blood transfusion may be deadly -Within 5-8 hours, tremendous hemolysis of the transfused RBCs is detected -Due to formation of complement MACs -The released hemoglobin is converted to bilirubin -Can cause severe organ damage, especially to kidneys 50 Evading the Immune System Some pathogens can alter their surface antigens to avoid immune system detection Influenza virus expresses 2 surface proteins: hemaglutinin (HA) and neuraminidase (NA) -Antigenic drift = Point mutations to the HA and NA genes -Antigenic shift = Appearance of a new virus subtype where HA and/or NA proteins are a mix of surface antigens from two original strains 51 Evading the Immune System Salmonella typhimurium -Can alternate between expression of two different flagellar proteins Mycobacterium tuberculosis -Once phagocytosed, inhibits fusion of the phagosome with lysosomes Neisseria gonorrhoeae -Secrete proteases that degrade IgA antibodies 52 Evading the Immune System HIV, human immunodeficiency virus, mounts a direct attack on TH cells -Binds to CD4 proteins, and is endocytosed An individual is considered to have AIDS when their TH cell level has dropped significantly -Immunosuppression results in an increase in opportunistic infections and cancers 53 Evading the Immune System HIV in red TH cells in green 54