Chapter 21The Immune System: Innate and Adaptive Body Defenses

Immunity: Ability to provide resistance to disease

Innate (nonspecific) systemFirst line of defense: external body membranes; like skin and mucosaeSecond line of defense: antimicrobial proteins, phagocytes and other cells

Adaptive (specific) systemThird line of defense: attacks particular foreign substancesTakes much longer

Innate Defenses: Skin and Mucosae

1. Acidity of skin secretions2. Stomach acid3. Saliva and lacrimal fluid contains lysozyme, which destroys bacteria4. Sticky mucus and ciliated cells of the upper respiratory system

Phagocytes:

Macrophages – derived from monocytesFree macrophages – wander through tissue spaces

Alveolar macrophagesDendritic cells (Langerhan’s cells) of epidermis

Fixed macrophages – permanent residents of particular organsKupffer cells Microglia

Neutrophils – Become phagocytic when encounter infectious materialEosinophils – Weakly phagocytic

When they encounter parasitic worms, discharge contents of cytoplasmic granules all over them.

Mast cells – can bind with, ingest and kill a wide range of bacteria

Mechanism of Phagocytosis

1. Adherence2. Opsonization3. Respiratory burst

Internal Defenses: Natural Killer cells

NK cells: can lyse and kill cancer cells and virus infected body cells before adaptive system is activated.

NK cells are part of large group of granular lymphocytes, unlike lymphocytes of adaptive system, are nonspecific

Done by recognizing surface markers as “non-self”.Release cytolytic chemicals called perforinsAlso release chemicals that elicit the inflammatory response

Internal Defenses:Inflammation: Tissue Response to Injury

Inflammatory response: triggered anytime tissues are injured by anything.examples: ___________________

Beneficial effects:1. Prevents spread of damaging agents2. Disposes of cell debris and pathogens3. Sets the stage for repair

Signs of inflammation:redness, heat, swelling and pain.

Vasodilation and Increase Vascular Permeability:

Sources of inflammatory mediators: most important: histamine, prostaglandins, complement

1. Stressed tissue cells, 2. Phagocytes3. Lymphocytes 4. Mast cells 5. Blood proteins

Benefits of swelling

1. Helps dilute harmful substances2. Brings large amounts of oxygen and nutrients3. Entry of clotting proteins

β-defensin is released in larger quantities from mucosal cells to prevent infectionArea is invaded my more phagocytes Complement and adaptive immunity is activated if inflammation was caused by pathogens1. Leukocytosis2. Margination

This forces the injured part to rest, which aids healing.Impairment of function some consider to be the 5th sign of inflammation.

Inflammatory chemicals are released by injured cells

Vasodilation leads to symptoms of inflammation

1. More blood comes to the area 2. fluid leaves the capillaries and enters the tissues 3. macrophages enter the area in great numbers, to engulf foreign matter.

Job: Clean up debris and pathogens

Redness, Swelling, Pain, Heat, Impairment

3. Diapedesis4. Positive Chemotaxis

Homeostatic ImbalancePusAbcessesInfectious granulomas

Antimicrobial Proteins

Interferon – released by some cells infected with viruses 1. Stimulates nearby cells to interfere with viral replication2. Activates macrophages and 3. mobilizes NK cells

Complement – a group of at least 20 plasma proteins that normally circulate in the blood in an inactive state.

Function: 1. If activated, it unleashes chemical mediators which amplify nearly all aspects of inflammatory response.2. Kills bacteria and other cells by lysis (Our own cells can de- activate complement)

How is it activated?1. Classic Pathway: Binding of antibodies to foreign invaders. Complement binds to them (complement fixation)2. Alternate pathway: Interact with polysaccharides on the surface of certain microorganisms.

FeverSystemic response to invading microorganisms (Ch 24)Stimulated by Pyrogens – chemicals secreted by leukocytes and macrophages exposed to foreign substancesHeat denatures enzymes – high fevers are dangerous!

Mild fever 1. Causes liver and spleen to sequester iron and zinc which bacteria require in large amounts to multiply2. Speeds up cellular metabolism to increase regeneration

Adaptive Defenses

Must meet (be primed) by the pathogen – takes time. Meanwhile the nonspecific systems are activated and we feel bad

Both pathways:1. Lead to cell lysis2. Promote

Phagocytosis3. Enhance

inflammation

1. It is specific2. It is systemic3 It has memory

Humoral Immunity (antibody mediated immunity) – provided by antibodies in the body’s “humors”

Cellular Immunity (cell-mediated immunity) – lymphocytes themselves defend the body

Both respond to the same antigens (substances that provoke an immune response – recognized as “nonself”)

Antigens

Complete antigens:1. Immunogenicity – ability to stimulate specific lymphocytes and antibodies2. Reactivity – ability to react with the activated lymphocytes

ex: proteins (strongest), nucleic acids, some lipids large polysaccharides. Also, bacteria, fungi and viruses because of surface macromolecules.

Incomplete antigens: Haptenssmall molecules (peptides, nucleotides, hormones) by themselves do not stimulate an immune response, but do if they combine with a body protein. (Allergies)

1. Have only reactivityex: penicillin, poison ivy, animal dander, detergents, cosmetics …

Antigenic Determinants

Places on the antigen where antibodies and lymphocytes may bindMany different types on one antigenSo one antigen may activate many different types of lymphocytes and antibodies

Self-Antigens: MHC Proteins

Major Histocompatibility Proteins: Surface glycoproteins recognized as “self” by our immune system, (but not others’)

Class I MHC proteins – found on nearly all body cellsClass II MHC proteins – found on only certain body cells that act in immunity

Cells of the Adaptive Immune System: An Overview

1. B-lymphocytes: produce antibodies - (humoral immunity)2. T-lympocytes: do not produce antibodies - (cell mediated immunity)

3. Antigen presenting cells – present antigens to other cells

T-cells

1. T-cells become immunocompetent in the thymus and mature under the direction of thymic hormones. 2. Only those with the sharpest MHC survive (only about 2%)

Positive Selection: T-cells able to recognize self MHC (Major Histocompatibility Complex Proteins) survive, the rest undergo apoptosis.

Negative Selection: Those passing positive selection do thisThose that bind too strongly to MHC are eliminatedPurpose: ensures that T-cells exhibit self tolerance.

B-cells

Become immunocompetent and self tolerant in the bone marrow.Little is known about the factors that control B-cell maturation in humans. Self reactive B-cells are inactivated – anergy, others are killed or undergo apoptosis (clonal deletion)

Primary Lymphoid Organs: thymus and bone marrowSecondary Lymphoid Organs: all other lymphoid organs

Lymphocytes become immunocompetent before meeting antigens – so it is in our genes not antigens that determine what foreign substances our immune system will be able to recognize.

Naïve immunocompetent T & B cells are exported to secondary lymph organs (lymph nodes, spleen…) where they encounter antigens and thus become fully functional (antigen activated cells).

Antigen Presenting Cells

Purpose – engulf antigens and present fragments on their surfaces to T- cells for destructionTypes of APCs:

1. Dendritic cells (in CT)2. Langerhans cells (epidermis)3. Macrophages (lymphoid organs)4. Activated B-cells5. Reticular cells

Immature lymphocytes are essentially identical. Whether they become B-cells or T-cells depends on where in the body they become immunocompetentImmunocometence: ability to recognize foreign antigens by binding to it.

When B or T cells become immunocompetent, the display a unique type of receptor on their surface enable the cell to recognize and bind to a specific antigen.

Located where they would more likely encounter antigens

APCs and lymphocytes are found throughout lymphoid tissues, but some tend to be more numerous in certain areas.

Humoral Immune Response

Antigen Challenge: First encounter with an antigenB-cell: provokes humoral immune response – produces antibodies

Clonal Selection and Differentiation of B-cells

B-cells is activated (completes differentiation) during antigen challenge: until they meet their first antigen, they are not yet fully mature.

The antigen “selects” the B cell with the receptors complementary to the antigen. This B cell makes many clones of itself. Many of these clones differentiate into plasma cells, which produce antibodies. Other B cells become memory B cells. These remain in the body in case the antigen invades again.

Immunological Memory – provide memory cells

Primary Immune response – Cellular proliferation and differentiation (to plasma cells which produce antibodies) on first exposure to antigenLag time is 3-6 daysPeak levels within 10 days – then decline

Secondary Immune response – occurs upon re-exposure to same antigen

Much fasterMore prolongedMore effective

Antibodies bond much tighter to antibodies in secondary responseAntibody titer much higherTiters remain high for weeks or monthsPlasma cells keep functioning much longer than the 4-5 days as in primary response

Vaccines do not provide the life long immunity that naturally acquired immunity does!Why? Cellular memory is only poorly established. Why? Explained later.

Passive Humoral Immunity

Memory cells provide immunological memory

Memory cells are already there and produce plasma cells within hours. Peak antibody levels occur within 2-3 days and antibody titers much higher than in primary response and remains high for weeks or months.

You see the same general response in cellular immunity

Active and Passive Humoral Immunity

Active: B-cells produce antibodies1. Naturally acquired – by getting the disease2. Artificially acquired – vaccines

Active Humoral Immunity: B-cells are actively producing antibodies

B-cells not challenged so:No immunological memoryBorrowed antibodies degrade in 2-3 weeks.

Natural – through the placentaArtificial – IgG shots or antivenom

All antibodies have: 2 identical heavy chains (H)2 identical light chains (L)

Chains make:A. Make a T or Y shapeB. Have a V (variable) region – antigen binding siteC. Have a C (constant) region – same (or nearly) in all antibodies

1. Forms the stem2. Determines the class of antibody 3. Common functions of all antibodies in that class

a. Effector regions here dictate1. what cells and regions it can bind to2. how this class of antibody functions in antigen

elimination.

Antibody ClassesMADGE

Named for C regions on heavy chains

IgD Always bound to B-cell surface so acts as B-cell receptorIgG Most abundant in plasma

Only class that can cross the placentaCan fix complement

IgE Almost never found in bloodInvolved in allergies “trouble makers”

IgA Occurs in both diner and monomer formsDimer – secretory IgA: mucus and secretions to body surfacePrevents pathogens from gaining entry

IgM Occurs in both monomer and pentameter formsFirst released to blood from plasma cellsCan fix complement

Antibodies do NOT destroy antigensThey form antigen-antibody complexes andinactivate them and tag them for destruction

Defensive mechanisms used by antibodies

NeutralizationAgglutinationPrecipitationComplement fixation

Artificial Passive Immunity is given for diseases that kill before active immunity can be established – rabies, tetanus, botulism…

Some can fix complement, some circulate in blood, or are found in body secretions or cross the placenta barrier…

Most importantPLAN: Precipitation

Lysis (Complement)AgglutinationNeutralization

Complement FixationWorks against cellular antigens like bacteria, mismatched blood…

1. Antibodies bind to cells2. This causes change in shape exposing complement binding sites3. This triggers complement fixation to antigenic cell surface4. This causes lysis of the cell

Remember chemicals released during complement activation greatly enhance inflammatory response and promote phagocytosis and opsonization – a positive feedback mechanism

NeutralizationAntibody blocks specific sites on viruses or bacterial exotoxins

The toxic effect is lost if the antigen cannot bind to tissue cell receptorsAntibody complex later pahgocytized.

AgglutinationBecause antibodies have more than one antigen binding site, they can bind to the same determinant on more than one antigen at a time. So antigen antibody complexes can form lattices – when they do this it is called agglutination.

PrecipitationSoluble molecules are cross-linked to large complexes that settle out (more easily engulfed now).

Cell Mediated Immune Response(T-cells are much more diverse than B-cells)

Antibodies provide only partial immunity.Useless against things like tuberculosis bacillus (it is inside body cells to multiply)

T-cells: Two major types – CD 4 and CD 8T4 cells (T helper) TH cells T8 cells cytotoxic TC cells destroy body cells that harbor anything foreign

What happens to T cells after Pathogens are destroyed?

Other types that exist are suppressor T cells and memory T cells

Antibodies work in the extra-cellular environment (in humors). Secretions, blood, ECF… and do not enter tissues unless a lesion is present and then it is a race: antibodies are specialized to attach to intact bacteria and soluble molecules. Antibodies do not destroy antigens! They just tag them and make it easier for other cells (phagocytes) to destroy them.

Students read the section about commercially prepared Monoclonal Antibodies

Proliferation peaks within a week after exposure to antigen trigger.Period of apoptosis 7-30 days (activated T cells die off – dangerous to keep them around

since they produce huge amounts of inflammatory cytokines).Some 1000s of T clones become memory T cells that persist for life (for same antigen).

Specific T cell RolesHelper T cells – central role in adaptive immunity

Once activated (by an antigen) function to stimulate proliferation of T and B cells that have already bound to an antigen.

Cytotoxic T cells

Organ Transplants and Prevention of Rejection

1. Autografts: tissue grafts transplanted from one body site to another in the same person2. Isografts: grafts donated to a patient by a genetically identical individual, an identical twin.3. Allografts: grafts transplanted from individuals that are not genetically identical but belong to

the same species.4. Xenografts: grafts taken from another species, such as transplanting a baboon heart into a

human.

Autografts and isografts are always successful and xenografts work only temporarily. Allografts are most commonly used, but finding a perfect match is virtually impossible. At least a 6-antigen match is required. Patient is then treated with immunosuppressant drug, which often have severe side effects.

Homeostatic Imbalances of Immunity

Without T Helper cells, there is no immune response!

See Table: Cells and molecules of the Adaptive immune system TC cells are the only ones that can attack and kill other cells.

Search through blood, lymph and lymphoid tissuesFor cells infected with anything& transplantsAs long as antigen and co-stimulatory signal is present.

See picture: how does it work? Different TC cells use different chemicals, but the result is the same in the end: Lysis. So, also called cytolytic T cells.

Immunodeficiency

1. SCID2. AIDS

Autoimmune diseases1. Multiple Sclerosis2. Myasthenia gravis3. Grave’s disease4. Type I diabetes mellitus5. Systematic lupus erythematosus6. Glomerulonephritis7. Rheumatoid arthritis

Hypersensitivity – allergies

1. Acute or Type I hypersensitivitesa. Anyphylaxisb. Anyphylactic shockc. Atopy

2. Subacute Hypersensitivitiesa. Cytotoxic (type II) reactions

3. Immume complex (type III hyrpersensitivitya. Farmer’s lung

4. Delayed hypersensitivities (Type IV) reactionsa. Transfusions of mismatched bloodb. Allergic dermatitisc. Mantoux and tine tests for tuberculosisd. Cell-mediated hypersensitivity