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What is the tissue response to stress or injury?
- Inflammation
- Immune response
- Repair or atrophy, necrosis, scarring
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What are the cellular adaptations to stress or injury?
- Atrophy: lack of growth
- Dystrophy: abnormal growth
- Hypertrophy: increased (cell) size
- Hyperplasia: increased cell number
- Dysplasia: abnormal appearance due to abnormal development
- Metaplasia: varied cell differentiation
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What are injurious chemical agents?
- Hypoxia
- Free radicals e.g. reactive oxygen species (ROS)
- Other chemical factors e.g. acidosis
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What are injurious physical agents?
- Heat (temperature extremes)
- Changes in ambient pressure
- Ionizing radiation
- Illumination
- Mechanical stresses
- Noise
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What are injurious physiological agents?
- Infections
- Immunological and inflammatory injury
- Genetic miscoding
- Nutritional imbalances
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What cellular damage is caused by ionizing radiation?
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What are local manifestations of stress or injury?
- Inflammation
- Immunity
- Cellular accumulation of
- •Water
- •Lipids and carbohydrates
- •Glycogen
- •Proteins
- •Pigments
- •Calcium
- •Uric acid (Urate)
- Cellular Death
- •Apoptosis (programmed cell death)
- •Necrosis
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What are systemic manifestations of stress or injury?
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What are the two types of body defenses?
- Innate defenses:
- -Surface barriers (1st line of defense)
- -Internal mechanisms (2nd line of defense)
- Adapaptive defenses: (3rd line of defense)
- -Humoral immunity
- -Cellular immunity
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Describe the innate defenses mechanical protection:
- Skin (epidermis) - closely packed, keratinized cells
- presents a physical barrier to most microorganisms
- »resistant to weak acids and bases, bacterial enzymes, and toxins
- Mucous membrane - secretes viscous mucus
- »cilia & mucus trap then move microbes toward throat
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Describe the innate defenses chemical protection:
- Skin – slightly acidic pH 3-5
- Saliva - lysozymes breakdown bacterial cells
- Stomach mucosae - secrete concentrated HCl and protein-digesting enzymes
- Other secretions (tears, sebum, milk) are antimicrobial
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Describe the innate defenses internal protection:
- •The body uses nonspecific cellular and chemical devices to protect
- itself:
- •Harmful substances are identified by surface
- carbohydrates unique to infectious organisms
• The inflammatory response
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What are the internal cellular and chemical defenses?
- Inflammatory response enlists macrophages, mast cells, WBC's, and cytokines (chemicals)
- Phagocytes and NK cells
- Cellular secretions
- Chemotaxis
- Antimicrobial proteins in blood and tissue fluid
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Describe the function of cytokines:
•Cellular secretions, generally glycoproteins
•Paracrine (local) and autocrine (feedback on secretory cell) effects
•Exhibit pleiotropy (multiple effects) and redundancy (overlapping effects)
- •Interleukins
- –Lymphokines from lymphocytes
- –Monokines from monocytes and macrophages
- •Interferon
- –IFN-α and IFN-β are anti-inflammatory
- –IFN –γ is pro-inflammatory
- •Typical effects:
- –Chemotaxis
- –Enhanced immune response
- –Protein synthesis to generate surface receptors
- -Cell proliferation and differentiation
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Describe the function of mast cells:
- –Degranulation and release of cytokines (acute effect)
- •Vasoactive amines e.g. Histamine
- •Chemotactic factors
- –Cytokine synthesis (chronic effect)
- •Leukotrienes
- •Prostaglandins
- •Platelet-activating factors
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Describe the effects of histamine through H1 and H2 receptors:
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Describe the inflammatory tissue response to injury:
- The 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
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What are the four cardinal signs of acute inflammation?
- Erythema - redness
- Increased perfusion - heat
- Edema – swelling
- Nociceptive hypersensitivity - pain
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Describe the inflammatory chemical response to injury:
Begins with a flood of inflammatory chemicals released into the extracellular fluid
- Inflammatory mediators:
- –Kinins, prostaglandins (PGs), complement, and cytokines
- –Released by injured tissue, phagocytes, lymphocytes, and mast cells
- –Cause local small blood vessels to dilate, resulting in hyperemia (increased perfusion)
- –Chemotaxis attracts more inflammatory cells (+ve feedback cascade)
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Describe the inflammatory vascular response to injury:
Allows entry of clotting proteins, which prevents the spread of bacteria
- Exudate
- –fluid containing proteins, clotting factors, and antibodies
- –seeps into tissue spaces - local edema (swelling) - contributes to the sensation of pain & immobilises body part
- –Helps dilute harmful substances
- –Brings oxygen and nutrients needed for repair
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What is the sequence of events in the process of inflammation?
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Describe macrophages:
- Are the chief phagocytic cells
- Undergo diapedesis to leave the circulation
- Free macrophages wander throughout a region in search of
- cellular debris
- Fixed macrophages such as Kupffer cells (liver) and microglia (brain) become ‘resident’
- in the tissue
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Describe phagocytes:
- Neutrophils become phagocytic when encountering infectious material
- Eosinophils are weakly phagocytic against parasitic worms
- Mast cells bind and ingest a wide range of bacteria (and release histamine)
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Describe the mechanism of phagocytosis:
1. Microbes adhere to the phagocyte
2. Phagocyte forms pseudopods that eventually engulf the particle.
3. Phagocytic vesicle containing antigen (phagosome).
4. Phagocytic vesicle is fused with a lysosome.
5. Microbe in fused vesicle is killed and digested by lysosomal enzymes within the phagolysosome, leaving a residual body
6. Indigestible and residual material is removed by exocytosis.
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Describe the four main stages of phagocytic mobilisation:
1. Leukocytosis - neutrophils released from bone marrow in response to factors released by injured cells
2. Margination – neutrophils cling to the walls of capillaries in the injured area
3. Diapedesis – neutrophils squeeze through capillary walls and begin phagocytosis
4. Chemotaxis – inflammatory chemicals attract neutrophils to the injury site
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Describe the effects of degranulation and synthesis by mast cells:
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Describe NK cells:
A small, distinct group of large granular lymphocytes
React nonspecifically and eliminate cancerous and virus-infected cells
Kill their target cells by releasing perforins and other cytolytic chemicals
Secrete potent chemicals that enhance the inflammatory response
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Describe the antimicrobial proteins:
- Enhance the innate defenses by:
- –Attacking microorganisms directly
- –Hindering microorganisms’ ability to reproduce
- •The most important antimicrobial proteins are:
- –Interferon
- –Complement proteins
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Describe interferon:
Genes that synthesize Interferon 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
a, b and g interferons
•Interferons also activate macrophages and mobilize NK cells
- •FDA-approved αIFN is used:
- –As an antiviral drug against hepatitis C virus
- –To treat genital warts caused by the herpes virus
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Describe complement:
20 or so proteins that circulate in the blood in an inactive form
Proteins include C1 through C9, factors B, D, and P, and regulatory proteins
Provides a major mechanism for destroying foreign substances in the body
Amplifies all aspects of the inflammatory response
Produce a membrane attack complex (‘mac attack’)
Kills bacteria and certain other cell types (our cells are resistant to complement)
Enhances the effectiveness of both nonspecific and specific defenses
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Describe the mechanism of 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
- (Note that in fever, the body thermostat is normally reset for homeostasis at a higher temperature not let out of control)
•High fevers are dangerous because they can denature enzymes
- •Moderate fever can be beneficial, as it causes:
- –The liver and spleen to sequester (hold on to) iron and zinc (needed by microorganisms)
- –An increase in the metabolic rate, which speeds up tissue repair
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Describe the adaptive immune responses:
The adaptive immune system is antigen-specific, systemic, and has memory
- Two separate but overlapping arms:
- –Humoral (antibody-mediated) immunity
- –Cellular (cell-mediated) immunity
The ultimate targets of all immune responses are mostly large, complex molecules (antigens) not normally found in the body (i.e. nonself)
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What are antigens?
- Part of the humoral immune system:
- Are substances that can mobilize the immune system and provoke an immune response
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Describe the antigenic determinants:
- Only certain parts ofan entire antigen are immunogenic
- Antibodies andactivated lymphocytes bind to these antigenic determinants–Most naturallyoccurring antigens have numerous antigenic determinants that:
- -Mobilize severaldifferent lymphocyte populations
- -Form different kindsof antibodies against it–Large, chemicallysimple molecules (e.g., plastics) have little or no immunogenicity
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Describe MHC proteins:
Our cells are dotted with protein molecules (self-antigens) that are not normally antigenic to us but are strongly antigenic to others
One type, the Major Histocompatibility Complex (MHC) proteins, mark a cell as self
- The two classes of MHC proteins are:
- –Class I MHC proteins – found on virtually all body cells
- >always recognised by CD8 T cells
- >display peptides from endogenous antigens
- –Class II MHC proteins – found only on mature B cells, some T cells, and antigen presenting cells
- >loaded class II MHC molecules then migrate to cell mambrane and display antigenic peptide for recognition by CD4 cells
- MHC proteins are unique to an individual
- Each MHC molecule has a deep groove that displays a peptide
- In infected cells, MHC proteins bind to fragments of foreign antigens to form antigen-antibody complexes and present them to T and B lymphocytes.
- Both types of MHC proteins are important to T cell activation
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What are the cells of the adaptive immune system?
- Two types of lymphocytes
- –B lymphocytes – involved in humoral immunity
- –T lymphocytes – involved in cell-mediated arm of immunity
- Antigen-presenting cells (APCs):
- –Do not respond to specific antigens
- –Play essential auxiliary roles in immunity
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Describe antigen presenting cells:
- •Major roles 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 macrophages, activated B cells, and dendritic cells (DCs).
•DCs migrate to the lymph nodes and secondary lymphoid organs, and present antigens to T and B cells
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Describe lymphocytes:
•Immature lymphocytes released from bone marrow are essentially identical
•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
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Describe inmmunocompetent B and T cells:
•Display a unique type of receptor that responds to a distinct antigen
•Become immunocompetent before they encounter antigens they may later attack
•Are exported to secondary lymphoid tissue where encounters with antigens occur
•Mature into fully functional antigen-activated cells upon binding with their recognized antigen
•It is genes, not antigens, that determine which foreign substances our immune system will recognize and resist
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Describe the humoral immunity response:
•Antigen challenge – first encounter between an antigen and a naive immunocompetent cell
•Takes place in the spleen or other lymphoid organ
- •If the lymphocyte is a B cell:
- –The challenging antigen provokes a humoral immune response
•Stimulated B cell forms clones bearing the same antigen-specific receptors
•Antibodies are produced against the challenger (antigen)
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Explain immunological memory:
- •Primary immune response – cellular differentiation and proliferation, which occurs on the first exposure to a specific antigen
- –Lag period: 3 to 6 days after antigen challenge
- –Peak levels of plasma antibody are achieved in 10 days
- –Antibody levels then decline
- •Secondary immune response – re-exposure to the same antigen
- –Sensitised 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
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What are the types of acquired immunity:
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Describe antibodies
•Also called immunoglobulins
- –Constitute the gamma globulin portion of blood proteins
- –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
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What are the classes of antiobodies?
•IgA – helps prevent attachment of pathogens to epithelial cell surfaces, found in milk.
•IgE –binds to mast cells and basophils, causing histamine release when activated. -Involved in allergic reactions.
•IgD –attached to the surface of B cells, important in B cell activation
•IgM –released by plasma cells during the primary immune response
•IgG –the most abundant and diverse antibody in primary and secondary response; crosses the placenta and confers passive immunity to the foetus
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What are the mechanisms of the antibody action?
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What is the importance of cellular response?
•T cells recognize and respond only to processed fragments of antigen displayed on the surface of body cells
- •T cells are best suited for cell-to-cell interactions, and target:
- –Cells infected with viruses, bacteria, or intracellular parasites
- –Abnormal or cancerous cells
- –Cells of infused or transplanted foreign tissue
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Define cytotoxic T cells (Tc):
TC cells, or killer T cells, are the only T cells that can directly attack and kill other cells
They circulate throughout the body in search of body cells that display the antigen to which they have been sensitized
- Their targets include:
- –Virus-infected cells
- –Cells with intracellular bacteria or parasites
- –Cancer cells
- –Foreign cells from blood transfusions or transplants
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