Immune System

·         Immune system provides resistance to disease

o   Innate

§  First and second line of defense

·         First: external membrane (mucosae and skin)

·         Second: antimicrobial proteins, phagocytes, etc

o   Adaptive

§  Third line of defense

·         Adapts to it once you’ve already have had it

·         Innates first/second line of defense is to stop pathogens

o   Skin and mucous membranes are physical barriers

§  Physical barrier to most microorganisms

§  Keratin is resistant to weak acids and bases, bacterial enzymes, and toxins

§  Mucosae does the same thing

§  Acid: Acidity of skin and some mucous secretions inhibits growth (aka acid mantle)

§  Enzymes: Lysozyme of saliva, respiratory mucus, and lacrimal fluid kills microorganisms; enzymes in stomach also do the same thing

§  Mucin: Sticky mucus that lines digestive and respiratory tracks traps microorgs.

§  Defensins: antimicrobial peptides that inhibit microbial growth

o   Respiratory system has mods to stop pathogens

§  Nose: mucous lined hair trap particles

§  Cilia of upper respiratory tract sweep mucous toward the mouth

o   Surface barriers breached by cuts trigger second line of defense

·         Innate system (second line of defense) triggered when necessary (when they invaded deeper tissues; includes

o   Phagocytes

o   Natural Killer (NK) cells

o   Inflammatory response (macrophages, mast cells, WBCs, and inflammatory chemicals)

o   Antimicrobial Proteins (Interferons and complement proteins)

o   Fever

·         Many second line defenses have pattern recognition receptors

o   Toll class receptors = trigger immune responses

o   Neutrophils: most abundant, become phagocytic when exposed to infectious material

o   Macrophages: chief phagocytic cells, most abundant

§  Free: wander through tissue space

§  Fixed: stay permanently in organs

·         Phagocytes

o   Process starts when phagocytes recognize and adheres to pathogen’s carbohydrate signature

o   Cytoplasmic extensions bind to particles in a vesicle called phagosome

o   Phagosome fuse with lysosome = phagolysosomes

o   Phagolysosome acidifies and lysosomal enzymes digest particles

o   Indigestible stuff gets thrown out of cell

·         Some pathogens can’t be killed by the lysosomal enzymes

o   T cells get triggered and produced respiratory burst (performed by neutrophils) which kills resistant pathogens

o   Denfensins (in neutrophils) also help by piercing the membrane of pathogen

·         Nonphagocytic cells don’t eat

o   They kill cells that don’t have name tags saying they are from your body

o   Kill by apoptosis (programmed cell death, basically ctrl alt delete)

o   Secrete chemicals that enhance inflammatory response

·         Inflammation lets our body know our tissues are injured

o   Benefits

§  Quarantines the area so it doesn’t go anywhere else

§  Disposes cell debris and pathogens

§  Alerts adaptive immune system

§  Starts repair process

o   Stages of Inflammation

§  Chemical release

·         Chemical released into ECF by injured tissue and/or immune system

o   Ex: Histamine, Kinins, prostaglandins, or cytokines is released

·         These make the capillaries leaky, attract phagocytes to area, cause vasodilation

§  Vasodilation and increased vascular permeability

·         Vasodilation causes hyperemia (congestion with blood), causes redness and heat

·         Increased permeability causes exudate – fluid containing clotting factors

o   Causes local swelling edema

§  Benefits: Surge of fluid helps flush out lymphatic vessels

§  Delivers clotting proteins and complement to area.

o   Swelling push on nerve endings = pain

§  Phagocyte mobilization

·         Neutrophils come first then macrophages

·         If inflammation caused by pathogens = complement is activated, adaptive immunity elements arrive

o   Stage for phagocyte mobilization

§  Leukocytosis – release of neutrophils from bone marrow in response to injured cells

§  Margination – endothelial cells of capillaries in inflamed area project cell adhesion molecules (CAMs) into vessel lumen that grab onto passing neutrophils, causing them to slow and roll along, clinging to vessel wall

§  Diapedesis – neutrophils flatten and squeeze between endothelial cells, moving into interstitial spaces

§  Chemotaxis – inflammatory chemicals act as chemotactic agents that promote positive chemotaxis of neutrophils toward injured area

·         Antimicrobial proteins = enhance innate defense by

o   Direct: Attack directly

o   Indirect: Prevent by preventing them to reproduce

·         Most important antimicrobial proteins

o   Interferons (IFN)

§  A signal to healthy cells saying that we are being attacked, please send in help

§  Secreted by lymphocytes

§  Has widened immune mobilizing effects

§  Activates macrophages and NK cells so they indirectly fight cancer

o   Complement

§  Destroy unknown substances and bacteria

§  Enhance both innate and adaptive defenses

§  3 pathways

·         Classical – antibodies bind to invading organisms and then bind to complement components, once complement proteins activate, they activate everything else

·         Lectin – produced to recognize foreign invaders, when lectin is bound to specific sugars on foreign invaders, it can also bind and activate complement

·         Alternative – complement cascade is activated spontaneously when certain complement factors bind directly to foreign invader

o   Lack of inhibitors on micororgs’ surface allows process to proceed.

·         Fever

o   Abnormally high body temp as a response to invading micro orgs

o   Leukocytes and macrophages exposed foreign substances secrete pyrogens

§  Pyrogens = respond to hypothalamus, and raise body’s temperature

o   Benefits: causes liver and spleen to sequester iron and zinc (needed by microorgs), increase metabolic rate, which increases rate of repair

·         Adaptive Defense

o   Adaptive immune system is a specific defense system, that eliminates almost all pathogen in body (it needs to be primed bc its specific)

o   Activities

§  Amplifies inflammatory response

§  Activates compliment

o   Shortcoming: must be primed by initial exposure to specific foreign substance

§  Priming takes time

o   Characteristics

§  Specific – recognizing and targets specific antigens

§  Systemic – not restricted to initial site

§  Memory – mounts an even stronger attack to antigens its already met

o   Two main branches

§  Humoral (antibody-mediated)

§  Cellular (cell-mediated)

o   Humoral immunity

§  Antibodies, produced by lymphocytes circulate freely throughout the body

§  Bind temporarily to target cell

·         Temporarily inactivate

·         Mark for destruction by phagocytes and complement

§  Has extracellular targets

o   Cellular immunity – lymphocytes act against target cells

§  Direct: kills infected cells

§  Indirectly: releasing chemicals that enhance inflammatory response; or activating other lymphocytes

§  Has intracellular targets

o   Antigens

§  Substances that mobilize adaptive defenses

·         Can be complete antigen or hapten (incomplete) (hap=half)

·         Contain antigenic determinants

·         Can be a self-antigen

§  Complete antigens

·         Immunogenicity: Ability to stimulate proliferation of specific lymphocytes

·         Reactivity: can react with activated lymphocytes and antibodies released by immunogenic reactions

§  Incomplete antigens (aka haptens)

·         Involve molecules so small to be seen so they aren’t immunogenic by themselves

·         May be immunogenic if hapten attaches to body’s own proteins (Ex: poison ivy reactions)

§  Antigenic determinants: parts of antigen that antibodies and lymphocytes bond to (these are very specific and only certain parts can bond to certain antibodies)

o   Self-antigens: all cells are covered with a variety of proteins located on surface that are not antigenic to self, but may be antigenic to others in transfusions (look at slide for MHC)

·         Three crucial cells in adaptive immune system

o   B cells = humoral immunity

o   T cell = cellular immunity

o   Antigen presenting cells (don’t respond to specific antigens)

·         Lymphocyte development, maturation, and activation

o   Origin – both t and b originate in red bone marrow

o   Maturation – educated lymphocytes and mature in primary lymphoid organs (thymus and red bone marrow

§  Immunocompetence: teach them to be competent and recognize 1 specific antigen

§  Self-tolerance: must be unresponsive to its own antigen

o   Seeding secondary lymphoid organs and circulation

§  Sent to them and awaits encounter with antigen to be activated

o   Antigen encounter and activation

§  Encounters antigen and bonds to it which triggered more lymphocytes and develop further

o   Proliferation and differentiation

§  Once activated, lymphocyte proliferates and created exact copies of its self, most clones become effector cells, some become memory cells

o   Antigen receptors

§  Huge variety of receptors and multiple genetic combinations creates a lot of variety

o   Lymphocyte education during maturation (look at slides for these)

§  Positive selection

§  Negative selection

·         Antigen presenting cells – engulf antigens and present fragments of antigens to T cells for recognition

·         Major types

o   Dendritic cells

§  Found in connective tissues and epidermis

·         Act as mobile sentinels of boundary tissues (they are guards basically)

·         They phagocytize pathogens

·         Most effective

o   Macrophages

§  Widely distributed in lymphoid organs and connective tissues

§  Present antigens to T cells and activates them. They also go eat them

§  They are very hungry

o   B cells

§  Don’t activate T cells

§  Present cells so T cells can help themselves activate

·         B cells are activated when antigens bind to surface receptors

o   Triggers endocytosis which leads to proliferation and differentiation B cells into effector cells

·         Most clone cells become plasma cells, antibody-secreting effector cells

·         Clone cells that do not become plasma cells become memory cells

o   Provide immunological memory

·         Primary immune response

o   First time virus enters cell, cell proliferation and differentiation happens upon exposure

o   Peak level of antibodies are reached in 10 days, they decrease afterwards

·         Secondary Immune response

o   Re-exposure to same virus gives faster, more prolonged, more effective response

§  Sensitized memory cells provide immunological memory

§  Which shortens the time you are sick

·         Active humoral immunity: occurs when B cells encounter antigens and produce specific antibodies against them

·         Two types of active humoral immunity (look at slides)

o   Naturally acquired – formed in response to actual bacterial or viral infection

o   Artificially acquired – formed in response to vaccine of dead or attenuated pathogens

·         Passive humoral immunity: occurs when ready-made antibodies are introduced into body

o   B cells aren’t challenged by antigens, immunological memory does not occur

o   Protection ends when antibodies degrade

o   Two types of Passive:

§  Naturally acquired: antibodies delivered to fetus via placenta to infant through milk

§  Artificially acquired: injection of serum

·         Antibodies – also called immunoglobulins are proteins secreted by plasma cells

o   Four chains of antibodies consist of: Two Heavy (H) chains and two light (L) chains

o   Stems make up constant (C) regions

·         Antibodies are grouped into 5 Ig classes

o   IgM

§  Pentamer (bigger than others); first antibody release

§  Potent agglutinating agent

§  Ready fixes and activates complement

o   IgA

§  Monomer or dimer; found in mucus and other secretions

§  Helps prevent entry of pathogens

o   IgD

§  Monomer attached to surface of B cells

§  Functions as B cell receptor

o   IgG

§  Monomer, 75%-85% of antibodies in plasma ‘From secondary and late primary responses

§  Crosses placental barrier

o   IgE

§  Monomer active in some allergies and parasitic infections

§  Causes mast cells and basophils to release histamine.

·         Questions he’ll ask: which of these is receptors, which activates a compliment, which is pentamer

·         Almost all secondary responses are IgG

·         IgM turning into IgA or IgE can occur

·         Antibody targets and functions (look at slides)

o   Neutralization – simple, but most important defensive mechanisms, antibodies block specific sites on viruses or bacterial exotoxins, prevent antigens from binding to receptors on tissue cells, antigen-antibody complexes undergo phagocytosis

o   Agglutination – antibodies can bind same determinant on two different antigens at the same time, allows for antigen

o   Precipitation

o   Complement fixation

·         T cells provide defense against intracellular antigens; some directly kill others trigger chemicals

o   CD4 – become helper t cells usually, they activate b cells

o   Some become either regulatory or memory t cells

o   CD8 cells become cytotoxic that destroy cells harboring foreign antigens

·         Activation is a two step process (both occur on surface of same APC, both are required for clonal selection of t cell) (look at slides)

o   Antigen binding

o   Co-stimulation

o   Proliferation and differentiation (look at slides)

·         Cytokines – chemical messenger of immune system

o   It mediates how a cell becomes before it becomes it

§  It mediates cell development, differentiation, and response in immune system

§  Include interferons and interleukin

·         Interleukin-1 is released by macrophages which stimulate T cells

·         Interleukin-2 is a key growth factor, this encourages t cells to divide rapidly

·         Helper T cells (aka CD4)

o   Activate B cells which release antibodies and activate T cells

o   Help ready the attack against a certain antibody

o   It incre

·         Activation of B cells

o   Helper t cells interact directly with B cells (it needs a helper t in order to be activated

o   Stimulate B cells to divide rapidly and increase antibody release (look at cells)

·         CD8 activation

o   Needs a helper t cell that has become activated and destructive cytotoxic cells

·         Amplification of innate defenses (look at slide

·         Cytotoxic T cells

o   Directly attack and kill cells

o   They are in the blood and lymph/lymphoid organs

o   Activated T cells target

§  Virus-infected cells

o   Special move: lethal hit

§  It releases perforins which cause holes and release granzymes

§  or it can bind to membrane receptor

o   Natural killer cells and cytotoxic cells survey the body looking for foreign cells

·         Regulatory T cells

o   They regulate the cells that are doing the killing, so they don’t kill too much

·         Most common type of organ transplant is an allograft, which is the transplant from the same species (human kidney to human kidney)

o   Success depends on similarity of tissues

§  Blood type, other blood antigens, MHC antigens need to match as closely as possible

·         Immunodeficiencies

o   Something that impairs the function and/or production of immune cells

o   Severe Combined immunodeficiency (SCID) syndrome: genetic defect with marked deficit in B and T cells

§  Defective enzyme (ADA) allows accumulation of metabolites which is lethal to T cells; fatal if not treated

§  Treatment: bone marrow transplant

o   Hodgkins disease: cancer of B cells; which depresses lymph nodes

o   Acquired immune deficiency syndrome (AIDS

§  Human immune deficiency virus (HIV): cripples immune system by interfering with activity of helper T cells

§  Cause severe weight loss, night sweats, and swollen lymph nodes

§  Opportunistic infections occur

o   HIV: transmitted through body fluids, blood, semen, and vaginal secretion

§  Can enter through blood transfusion, contaminated needles, sex and oral sex, and mother to fetus

§  HIV depresses cellular immunity

§  Multiplies in lymph nodes during asymptomatic period

§  Symptoms begin when immune system collapses

§  Virus can invade brain, leading to dementia

§  HIV-coated glycoprotein attached to CD4 receptors

§  No cure yet

·         Autoimmune disease: when immune system loses ability to distinguish self from foreign

·         Autoimmunity: production of autoantibodies and sensitized T_c cells that destroy body tissues

o   Examples: Myasthenia gravis, Graves’ disease, Rheumatoid arthritis (BONUS QUESTION)

·         Treatment of autoimmune diseases

o   Suppress entire immune system (use anti-inflammatory drugs (corticosteroids), block cytokine action, block co-stimulatory molecules

·         Research

o   Activating regulatory T cells; inducing self-tolerance using vaccines; directing antibodies against self-reactive immune cells.

·         Failure of self-tolerance

o   Autoimmunity may be caused by weak self-reactive lymphocytes that are activated by:

§  Foreign antigens that resemble self-antigens

·         Hypersensitivities

o   An immune response perceived (otherwise harmless) threat that can cause tissue damage

o   Different types are distinguished by

§  Their time course

§  Whether antibodies or T cells are involved

o   Antibodies cause immediate and subacute hypersensitivities

o   T cells cause delayed hypersensitivity

·         Immediate hypersensitivity

o   Also called acute I hypersensitivity, also known as allergies

o   Reaction begins seconds after contact with allergen

o   Initial contact is asymptomatic, once the body produces memory cells toward the allergen is when the reaction happens

o   IgE is activated against antigen and binds to mast cells and basophils (release histamine)

o   The histamine causes an inflammatory response

o   Histamine causes vasodilation and leakiness in vessels; symptoms: runny nose, itchy hives, watery eyes

§  Asthma can occur if allergen is inhaled

§  Antihistamines are needed to control

o   Allergic reactions can be local or systemic

o   Local reaction involves mast cells of skin, or respiratory and gastrointestinal mucosa

·         Systemic response: anaphylactic shock

o   Treatment: epinephrine

·         Subacute hypersensitivities

o   Caused by IgM and IgG transferred via blood plasma or seru,

o   Slow onset but long duration

o   Cytotoxic (type II) reactions

§  Antibodies bind to antigens on specific body cells, stimulate phagocytosis and complement-mediated lysis of cellular antigens

§  Example: mismatched blood transfusion reaction

o   Immune complex (type III) hypersensitivity

§  Antigens widely distributed in body or blood

§  Insoluble antigen-antibody complexes form

§  Complexes cannot be cleared from area of body

§  Intense inflammation, local cell lysis, and cell killing by neutrophils

§  Ex: systemic lupus erythematosus

o   Delayed hypersensitivity (type IV)

§  Slow onset

§  Depends on helper T cells

§  Macrophages and cytotoxic T cells cause damage

§  Ex: allergic contact dermatitis

§  Agents act as haptens

§  TB skin test depends on this reaction

·         Developmental Aspects of Immune System

o   Immune system stem cells develop in liver and spleen in weeks 1-9

o   Bone marrow becomes primary source of stem cells later through adult life (True or false question (know this))

o   Lymphocyte development continues in bone marrow and thymus

o   T_H2 lymphocytes predominate in newborn;  T_H1

·         Influences on immune system function

o   Nervous system: depression, emotional stress, and grief impair immune response

o   Diet: vitamin D is required for activation of CD8 cells à TC cells

·         With age, immunity system gets worse

o   More likely to get autoimmune diseases

o   Cancer happens more frequently

o   Why immune system fails is unknown, but they speculate that its because the atrophy of the thymus causes less T and B cells to be produced.