Chapter 21 - The Immune System
- Innate (nonspecific) system responds quickly and consists of:
- First line of defense - intact skin and mucosae prevent entry of microorganisms
- Second line of defense - antimicrobial proteins, phagocytes, and other cells
- Inhibit spread of invaders throughout the body
- Inflammation is its hallmark and most important mechanism
- Adaptive (specific) defense system
- Third line of defense - mounts attack against particular foreign substances
- Takes longer to react than the innate system
- Works in conjunction with the innate system
INNATE (NONSPECIFIC) SYSTEM
- Surface Barriers
- Keratin in the skin:
- Presents a formidable physical barrier to most microorganisms
- Resistant to weak acids and bases, bacterial enzymes & toxins
- Epithelial membranes produce protective chemicals that destroy microorganisms
- Skin acidity (pH of 3 to 5) inhibits bacterial growth
- Sebum contains chemicals toxic to bacteria
- Stomach mucosa secrete concentrated HCl and protein-digesting enzymes
- Saliva and lacrimal fluid contain lysozyme
- Mucus traps microorganisms that enter the digestive and respiratory systems
- Mucus-coated hairs in the nose trap inhaled particles
- Mucosa of the upper respiratory tract is ciliated
- Cilia sweep dust- and bacteria-laden mucus away from lower respiratory passages
- Phagocytes and Natural Killer Cells
- Macrophages are the chief phagocytic cells
- Free macrophages wander throughout in search of cellular debris
- Kupffer cells (liver) and microglia (brain) are fixed macrophages
- Neutrophils become phagocytic when encountering infectious material
- Eosinophils are weakly phagocytic against parasitic worms
- Mast cells bind and ingest a wide range of bacteria
- Mechanism of Phagocytosis
- Microbes adhere to the phagocyte
- Pseudopods engulf the particle (antigen) into a phagosome
- Phagosomes fuse with a lysosome to form a phagolysosome
- Invaders in phagolysosome are digested by proteolytic enzymes
- Indigestible and residual material is removed by exocytosis
- Natural killer cells (NK): Small, distinct group of large granular lymphocytes
- React nonspecifically & eliminate cancerous and virus-infected cells
- Kill their target cells by releasing perforins; other cytolytic chemicals
- Secrete potent chemicals that enhance the inflammatory response
- INFLAMATION: Tissue Response to Injury
- Inflammatory response is triggered whenever body tissues are injured
- Prevents the spread of damaging agents to nearby tissues
- Disposes of cell debris and pathogens
- Sets the stage for repair processes
- The four cardinal signs of acute inflammation are redness, heat, swelling, and pain
Inflammatory Response
- Begins with a flood of inflammatory chemicals released into the extracellular fluid
- Inflammatory mediators:
- Include kinins, prostaglandins (PGs), complement, and cytokines
- Are released by injured tissue, phagocytes, lymphocytes, and mast cells
- Cause local small blood vessels to dilate, resulting in hyperemia
- Chemicals liberated by the inflammatory response increase the permeability of local capillaries
- Exudate (fluid containing proteins, clotting factors, and antibodies):
- Seeps into tissue spaces causing local edema (swelling), which contributes to the sensation of pain
- Edema - The surge of protein-rich fluids into tissue spaces
- Helps to dilute harmful substances
- Brings in large quantities of oxygen and nutrients needed for repair
- Allows entry of clotting proteins, which prevents the spread of bacteria
- Phagocytic Mobilization (extavasation) - Occurs in four main phases:
- Leukocytosis - neutrophils are released from the bone marrow in response to leukocytosis-inducing factors released by injured cells
- Margination - neutrophils cling to the walls of capillaries in the injured area
- Diapedesis - neutrophils squeeze through capillary walls and begin phagocytosis
- Chemotaxis - inflammatory chemicals attract neutrophils to the injury site
- Fever - Abnormally high body temperature in response to invading microorganisms
- The body's thermostat is reset upwards in response to pyrogens, chemicals secreted by leukocytes and macrophages exposed to bacteria and other foreign substances
- High fevers are dangerous as they can denature enzymes
- Moderate fever can be beneficial, as it causes:
- The liver and spleen to sequester iron and zinc (needed by microorganisms)
- An increase in the metabolic rate, which speeds up tissue repair
- CRP
- Produced by the liver in response to inflammatory molecules
- CRP is a clinical marker used to assess for:
- The presence of an acute infection
- An inflammatory condition and its response to treatment
- Functions of CRP
- Binds to PC receptor of pathogens and exposed self-antigens
- Plays a surveillance role in targeting damaged cells for disposal
- Activates complement
- Antimicrobial Proteins -Enhance the innate defenses by:
- Attacking microorganisms directly
Hindering microorganisms' ability to reproduce
The most important antimicrobial proteins are Interferon and Complement proteins
- Interferon
- Genes that synthesize IFN are activated when a host cell is invaded by a virus
- Interferon molecules leave the infected cell and enter neighboring cells
- Interferon stimulates the neighboring cells to activate genes for PKR (an antiviral protein)
- PKR nonspecifically blocks viral reproduction in the neighboring cell
- Interferons are a family of related proteins each with slightly different physiological effects
- Lymphocytes secrete gamma interferon, but most other WBCs secrete alpha interferon
- Fibroblasts secrete beta interferon
- Interferons also activate macrophages and mobilize NKs
- FDA-approved alpha IFN is used:
- As an antiviral drug against hepatitis C virus
- To treat genital warts caused by the herpes virus
- Complement
- 20 or so proteins that circulate in the blood in an inactive form
- Provides a major mechanism for destroying foreign substances in the body
- Amplifies all aspects of the inflammatory response
- Kills bacteria and certain other cell types by lysis and opsonization
- Enhances the effectiveness of both nonspecific and specific defenses
- Complement can be activated by two pathways:
- Classical pathway is linked to the immune system - depends on binding of antibodies to invading organisms (complement fixation)
- Alternative pathway is triggered by interaction of complement factors and polysaccharide molecules
- present on microorganisms
- Each pathway involves a cascade in which complement proteins are activated in an orderly sequence and where each step catalyzes the next
Adaptive (Specific) Defenses
- The adaptive immune system is a functional system that:
- Recognizes specific foreign substances
- Acts to immobilize, neutralize, or destroy foreign substances
- Amplifies inflammatory response and activates complement
- The adaptive immune system is antigen-specific, and has memory
- Complete Antigens
- The ultimate targets of all immune responses are mostly large, complex molecules not normally found in the body (nonself)
- Haptens (Incomplete Antigens)
- Small molecules found in poison ivy, dander, some detergents, and cosmetics, penicillin etc.
- If they link up with the body's proteins, immune system may recognize them as foreign and mount a harmful attack (allergy)
- It has two separate but overlapping arms
- Humoral, or antibody-mediated immunity
- Cellular, or cell-mediated immunity
- Self-Antigens: MHC Proteins
- Our cells are dotted with protein molecules (self-antigens) that are not antigenic to us but are strongly antigenic to others
- One type of these, MHC proteins, mark a cell as self
- The two classes of MHC proteins are:
- Class I MHC proteins - found on virtually all body cells
- Class II MHC proteins - found on certain cells in the immune response
- Are coded for by genes of the major histocompatibility complex (MHC) and are unique to an individual
- Each MHC molecule has a deep groove that displays a peptide, which is a normal cellular product of protein recycling
- In infected cells, MHC proteins bind to fragments of foreign antigens, which play a crucial role in mobilizing the immune system
- Cells of the Adaptive Immune System
- Lymphocytes
- Immature lymphocytes are released from bone marrow
- Whether a lymphocyte matures into a B cell or a T cell depends on where in the body it becomes immunocompetent
- B cells mature in the bone marrow
- T cells mature in the thymus
- Antigen-presenting cells (APCs):
- Major rolls in immunity are:
- To engulf foreign particles
- To present fragments of antigens on their own surfaces, to be recognized by T cells
- Major APCs are dendritic cells (DCs), macrophages, and activated B cells
- The major initiators of adaptive immunity are DCs, which actively migrate to the lymph nodes and secondary lymphoid organs and present antigens to T and B cells
- Specific Immunity -Antigen Presentation
- A Macrophage ______ digests and ________ a protein antigen (part of the digested pathogen) on a _______ protein on the cell ____________.
- This action cause the secretion of interleukin-1 which attracts additional ______________ and __________________ to the infected area.
- A specific CD4 which is a _________ lymphocyte reacts with the presented _________ on the ________ molecule.
- Both the macrophage and Helper T will produce a variety of stimulatory molecules (lymphokines) which will cause cloning and activation of specific lymphocytes to combat the pathogen that contains the presented antigen.
- Now the activated _____________ lymphocyte has a crucial role in both _______________immunity and __________________ immunity.
- Specific Immunity - Cellular-mediated(1st animation)
- Activation of Cell-Mediated Immnunity by CD8's (Cytotoxic T lymphocytes) (CTL).
- A viral infected _____ presents a processed _______ from the virus on a ______ molecule on its cell __________.
- A specific CTL reacts with the presented ________ on the ______ molecule and releases ____________ to cause a type of cytoskeleton destruction known as ___________.
- Apoptosis kills host cells without damaging ____________.
- The remains of the cells are than engulfed by a ___________.
- The specifically activated CD8's now are cloned and activated by ___________________ cells releasing _____________________.
- Also in this process of activation a ___________________ cell for this antigen is produced in case of a secondary infection. (____________established)
- Specific Immunity - Humoral (Antibody Mediated)
- Specific B-cell receptor (Igd) recognizes a ________ antigen takes it in digests and presents a peptide/MHC-II complexes on cell membrane.
- Activation of the B Cell (2nd animation) by _________
- After stimulations the activated B will be cloned by __________.
- The cloned B cells than convert to ________ ______ that produce __________.
- Also ___________ cells are produced which will react quickly to produce plasma cells to produce ___________if reinfected by the same antigen.
- Immunological Memory
- Primary immune response - occurs on first exposure to specific antigen
- Lag period: 3 to 6 days after antigen challenge
- Peak levels of plasma antibody are achieved in 10 days
- Secondary immune response - re-exposure to the same antigen
- Sensitized memory cells respond within hours
- Antibody levels peak in 2 to 3 days at much higher levels than in the primary response
- Antibodies bind with greater affinity, and their levels in the blood can remain high for weeks to months
- Antibodies
- Also called immunoglobulins
- Structure of
- Antigen Binding Site - Specific for foreign antigen protein
- Complement Binding Site - causes release of complement when activated by a antigen (not all antibodies have this site)
- Macrophage Binding Site - activates macrophages
- Plasma cells make over a billion different types of antibodies
- Are soluble proteins secreted by activated B cells and plasma cells in response to an antigen
- Are capable of binding specifically with that antigen
- There are five classes of antibodies: IgD, IgM, IgG, IgA, and IgE
- IgD - attached to surface of B cells, important in B cell activation
- IgM - released by plasma cells during the primary immune response; activates complement
- IgG - monomer that is the most abundant and diverse antibody in primary and secondary response; crosses the placenta and confers passive immunity; activates complement
- IgA - helps prevent attachment of pathogens to epithelial cell surfaces: in secretions (tears, saliva, milk); levels decrease during stress; defends against bacteria and viruses
- IgE - binds to mast cells and basophils, causing histamine release
- Antibody Targets
- Antibodies themselves do not destroy antigen; they inactivate and tag it for distruction (phagocytosis)
- All antibodies form an antigen-antibody (immune) complex
- Defensive mechanisms used by antibodies are
- Neutralization - antibodies bind to and block specific sites on viruses or exotoxins, thus preventing these antigens from binding to receptors on tissue cells
- Agglutination - antibodies bind the same determinant on more than one antigen
- Makes antigen-antibody complexes that are cross-linked into large lattices
- Cell-bound antigens are cross-linked, causing agglutination
- Precipitation - soluble molecules are cross-linked into large insoluble complexes
- Complement fixation and cell lysis and activation of phagocytosis
- The main mechanism used against cellular antigens
- Enhances the inflammatory response
- Types of Acquired Immunity
- Active Humoral Immunity
- Naturally acquired - response to a bacterial or viral infection
- Artificially acquired - response to a vaccine of dead or attenuated pathogens
- Passive Humoral Immunity
- Differs from active immunity in the antibody source and the degree of protection
- B cells are not challenged by antigens
- Immunological memory does not occur
- Naturally acquired - from the mother to her fetus via the placenta
- Artificially acquired - from the injection of serum, such as gamma globulin
Organ Transplants
- The four major types of grafts are:
- Autografts - graft transplanted from one site on the body to another in the same person
- Isografts - grafts between identical twins
- Allografts - transplants between individuals that are not identical twins, but belong to same species
- Xenografts - grafts taken from another animal species
- Prevention of Rejection
- Prevention of tissue rejection is accomplished by using immunosuppressive drugs
- However, these drugs depress patient's immune system so it cannot fight off foreign agents
- Tissue rejection reaction
- resembles cellular immune response against antigens
- important to match MHC antigens
- immunosuppressive drugs used to prevent rejection
- "Privileged" Immunity
Immunodeficiencies
- Congenital and acquired conditions in which the function or production of immune cells, phagocytes, or complement is abnormal
- SCID - severe combined immunodeficiency (SCID) syndromes; genetic defects that produce:
- A marked deficit in B and T cells
- Abnormalities in interleukin receptors
- Hodgkin's disease - cancer of lymph nodes leads to immunodeficiency by depressing lymph node cells
- Acquired immune deficiency syndrome (AIDS) - cripples the immune system by interfering with the activity of helper T (CD4) cells
- Severe weight loss, night sweats, and swollen lymph nodes
- Opportunistic infections occur, including pneumocystis pneumonia and Kaposi's sarcoma
- Caused by HIV (human immunodeficiency virus)
- HIV mutates quickly
Autoimmune Diseases
- Loss of the immune system's ability to distinguish self from nonself
- The body produces autoantibodies and sensitized TC cells that destroy its own tissues
- Examples include multiple sclerosis, myasthenia gravis, Graves' disease, Type I (juvenile) diabetes mellitus, systemic lupus erythematosus (SLE), glomerulonephritis, and rheumatoid arthritis
- Mechanisms
- Ineffective lymphocyte programming - self-reactive T and B cells that should have been eliminated in the thymus and bone marrow escape into the circulation
- New self-antigens appear, generated by:
- Gene mutations that cause new proteins to appear
- Changes in self-antigens by hapten attachment or as a result of infectious damage
- If the determinants on foreign antigens resemble self-antigens:
- Antibodies made against foreign antigens cross-react with self-antigens
- Antigen called an allergen
- Immunity established the same
- Later exposure causes undesirable side effects
- Type I
- immediate-reaction allergy
- caused by antibodies interacting with allergen and symptoms appear in minutes
- atopy- hives, hay fever, asthma, eczema, gastric disturbances
- anaphylactic shock - systemic IgE-mediated - penicillin, insect stings
- Type II
- antibody-dependent cytotoxic reaction
- takes 1-3 hours to develop
- transfusion reaction
- Type III - immune-complex reaction
- takes 1-3 hours to develop
- antibody complexes cannot be cleared from body
- damage of body tissues
- too much complement released
- small vessels become clogged
- neutrophils release too many lysosomal enzymes
- Type IV - Delayed hypersensitivity - takes about 48 hours to occur
- results from repeated exposure to allergen
- eruptions and inflammation of the skin
- mediated by T cells and symptom take hours to days to develop
- activates killer T cells and lymphokines which attract basophils and macrophages which destroy tissue
- allergy of infection- measles, chicken pox, TB
- contact hypersensitivity - poison ivy, soaps, cosmetics
- allergen is absorbed by epithelial cells /T cells invade (destroy and inflame)
Links
AZT Mechanism of Action
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