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Body Defenses & Immunity
immunity = resistance to disease
the immune system provides defense against all the microorganisms and toxic cells to which we are exposed without it we would not survive till adulthood
our body has many ways to prevent or to slow infections
Many factors affect an individual’s overall ability to resist infections: Genetics: human diseases, zoonoses, etc Age: mainly an immune response Health: eg. protein deficiency less phagocytic activity eg. stress lower resistance to disease Hormones: eg. cortisone (a glucocorticoid) reduces inflammatory response
the immune system is a functional system rather than a system with discrete organs parts of many organs contribute to body defense almost all organs in body play some role in immunity dispersed chemicals, cells and tissues dispersal and transport via circulatory and lymphatic systems
two major mechanisms that protect the body:
- Innate, nonspecific system of a. physical and chemical barriers b. internal cells and chemicals
- Adaptive system that fights specific pathogens
or, can view the immune system as a three tiered system of defense a. physical and chemical barriers b. chemical and cellular barriers c. specific defense mechanisms
Innate, Nonspecific Resistance
Physical Barriers
1 st^ major level of protection from invasion and infection
nonspecific – treats all potential pathogens the same way
attempt to prevent entry of pathogens into body
1. Intact Skin
tightly packed cells filled with waxy keratin
thick, multiple layers of dead keratinized cells
shed regularly
rarely, if ever, penetrated while intact only a few parasitic worms (cercariae) can do this
if skin is broken: staphs and streps are most likely to get in
sebaceous glands provides protective film over skin
acidity of skin secretions ('acid mantle') inhibit bacterial & fungal growth;
also contains bacteriocidal chemicals
but if skin is moist, not cleaned frequently enough may permit yeasts and fungi already present to become a problem
- Mucous Membranes
line all systems that open to outside of body nasal hairs trap pathogens
mucous thick, sticky, traps pathogens
Internal Cellular and Chemical Defenses
1. blood has nonspecific, antimicrobial chemicals that help to fight invaders:
eg. transferrins – bind to Fe to inhibit bacterial growth
2. Simple Phagocytosis many WBC’s travel through blood and tissues and gobble up bacteria and foreign material
mostly neutrophils and macrophages (formed from monocytes) migrate to area of infection monocytes enlarge on way to become macrophages engulf and destroy circulating pathogens especially bacteria
some macrophages are “fixed macrophages” that screen blood as it passes by esp in liver, bronchial tubes of lungs, nervous system, spleen, lymph nodes, bone marrow peritoneal cavity [referred to as the reticuloendothelial system]
eosinophils can produce toxins and are most active against parasitic worms
mechanism of phagocytosis:
1. Chemotaxis chemical attraction to invaders, microbial products, components of WBC’s or damaged cells 2. Adherence attachment to surface of foreign material may be hampered by capsules (eg. S. pneumonia, H. Influenza) or M proteins (eg. S. pyogenes) must trap them against rough surface (eg. blood vessel wall, clot, etc) also can be more readily phagocytized if 1 st^ coated with certain plasma proteins that promote attachment (=opsonization) 3. Ingestion plasma membrane of phagocyte extends around microorganism or cell 4. Digestion
forms food vacuole inside WBC fuses with lysozomes takes 10-30 minutes to kill most bacteria enzymes: lysozyme hydrolyzes peptidoglycan of cell wall lipases, proteases, ribonucleases hydrolyzes other cellular components some enzymes also produce toxic oxygen products: eg. O2 -^ , H2O2, OH -
residual body discharges wastes
not all microorganisms are killed once phagocytized eg. Staph and Actinobacillus actually produce toxins that kill phagocytes eg. Chlamydia , Shigella , Mycobacterium , Leishmania (protozoan), and Plasmodium can survive inside phagocyte they can prevent fusion of lysozome eg. other microbes can remain dormant for months
phagocytosis also plays a role in specific immunity
3. Natural Killer Cells the “pit bulls” of the defense system another kind of WBC police the body in blood and lymph promote cell lysis of virus infected cells or cancer cells not phagocytic 4. Inflammatory Response larger response that prevents spread of infection from localized area
damage to body’s tissues causes: redness, pain, heat and swelling sometimes loss of function
overall, has beneficial effect: a. destroys injuring agent b. removes it and its byproducts or limits its effects c. repairs or replaces damaged tissues
occurs in three major stages: a. vasodilation
6. Complement Reactions: foreign substance may trigger cascade which activates complement proteins = complement fixation ~5% of all blood proteins (20 different ones) are complement proteins they can operate nonspecifically or specifically complement proteins formed from liver cells, lymphocytes, monocytes trigger a cascade reaction (inactive active) initiation amplification effects
complement fixation can cause any of the following effects: a. cell lysis (cytolysis) membrane attack complex forms “transmembrane channels” digests a hole in bacterial cell, killing it
b. opsonization makes pathogens stickier and easier for the leukocytes to phagocytize
c. enhances infllammatory response helps trigger release of histamine and chemical attractants for WBC’s
the effects of complement activation are short lived they are quickly destroyed
malfunctions of system may result in some hypersensitivity disorders
7. Interferon antiviral chemical secreted by infected cells they are host cell specific, not virus specific different tissues in same host produce different interferons all interferons are small proteins stable at low pH heat resistant produced by infected cells and spread to uninfected cells stimulate synthesis of antiviral proteins that disrupt various stages of viral multiplication effective for only short periods good for acute, short term infections eg. colds, influenza
interferon is now produced in quantity by recombinant DNA
technology has only very limited effects on cancer cells high doses have side effects: fatigue, fever, chills, joint pain, seizures experimentally used to treat HIV, Hepatitis, genital herpes, influenza, common cold might work better with other agents in combination
but these same proteins may be strongly immunogenic to others eg. transfusions, transplants
microorganisms and pollen grains are immunogenic because their surface membranes have many such foreign molecules on them
examples of antigen containing structures: bacterial capsules cell wall lipopolysaccharides of G- bacteria glycoproteins in cell membranes attachment sites for viruses bacterial toxins and extracellular enzymes
small molecules such as peptides, nucleotides, and many hormones are NOT immunogenic but may become so by attaching to the body’s own proteins (=Haptens)
eg. chemicals in poison ivy, animal dander, some detergents, cosmetics, etc
actually, only certain parts of an entire antigen are immunogenic usually a small sequence of amino acids (~10) that triggers an immune reactions = antigenic determinants (=epitopes)
most naturally occurring antigens have a variety of antigenic determinants eg. large proteins have 100’s
specific immunity involves two different kinds of lymphocytes: T cells and B cells: both originate in bone marrow T cells move to thymus for further maturation B cells develop further in bone marrow after development both are dispersed to lymph nodes and spleen until needed
The immune response (specific immunity) involves the interaction of two major processes in the body, directed by two different kinds of lymphocytes (WBC’s): A. Antibody Mediated Immunity (AMI; Humoral Immunity)
B. Cell Mediated Immunity (CMI)
Antibody Mediated Immunity
=AMI; =Humoral Immunity
involves the release of proteins called antibodies
Mediated by B lymphocytes (B-cells)
B-Cell Development & Activation
- by the time an infant is a few months old B lymphocytes (B cells) have completed the 1st^ stage of their development: manufactured in fetal liver they synthesize up to 100,000 antibody molecules that they hold in the cell membrane
- The next stage of development occurs in lymph nodes and spleen only occurs if B cell encounters an antigen it recognizes:
a. specific B cells activated by exposure to an antigen antigen binds to antibodies on cell membrane of B cell b. triggers clonal selection and multiplication produces numerous copies of identical cells with identical antibodies on cell membranes c. differentiation into plasma cells and memory cells d. plasma cells secrete antibodies 2,000 Ab/sec over few (4-5) days, then dies e. memory cells do not secrete antibodies but if later exposed to same antibody they can develop into plasma cells and secrete antibodies ie. they “remember” an earlier encounter with the antigen
Antibodies
antibodies are proteins called immunoglobins eg. gamma globulin of plasma proteins
each of us has ~ a billion different kinds of antibodies and each of these has a unique shape
each immunoglobin molecule consists of 4 polypeptide chains joined together to form a “Y” shaped molecule
each antibody has 2 or more combining sites
Ig E associated with allergies causes certain WBC’s to release histamine dilates capillaries constricts bronchi
Ig D very low concentrations in serum levels increase during chronic infections
formation of the antigen/antibody complex by B-cell activity does not generally destroy the invader it prepares it for destruction by non-specific phagocytosis (WBC’s) triggering complement fixation CMI (T-cell activity)
antibodies bind to antigens to cause a variety of possible effects:
1. Agglutination bind to antigens on cells to cause them to clump together makes it easier for WBC’s to remove 2. Precipitation binds soluble antigens together causing them to precipitate out of solution makes it easier for WBC’s to remove them 3. Neutralization binds to bacterial toxins (esp. exotoxins) and causes them to be nontoxic 4. Prevents viral attachment binds to viral receptor sites to prevent viral invasion of cells (doesn’t work for latent viruses) 5. Stimulates Natural Killer Cells antibodies coat and mark a cell for destruction by the NK cells =antibody dependent cell mediated cytotoxicity 6. Complement Fixation triggers complement reactions especially against cellular antigens cascade reactions can cause: -cell lysis
-opsonization -inflammatory enhancement
primary vs secondary response
primary persons initial exposure to an antigen lag of several days before antibodies begin being produced peak production in ~10 days secondary reexposure to same pathogen triggers memory cell response memory cells can persist for 20 years or more much quicker response much stronger response
natural vs artificial immunity
natural immune response is triggered due to natural exposure to a pathogen
artificial (=acquired) immune response is triggered by a medical procedure, eg vaccination
active vs passive immunity
active exposure triggers body’s own immune response including memory cells
passive subject receives antibodies from another person or animal, rather than making them himself offers immediate protection, short term no active antibody production is stimulated no memory develops
eg. fetus gets antibodies from mom eg. gamma globulin to treat hepatitis, botulism, snake bites, etc
help B cells recognize antigens
there can be no immune response without them
ii. Cytotoxic T- cells (CD8 cells) directly kill specific target cells by lysis especially effective against foreign cells, cancer cells, fungi , some protozoa and helminths recognizes virally infected cells by viral antigens on cells surface
iii. Suppressor T-cells (CD8 cells) restricts rampant uncontrolled immune response dampens activity of T and B cells brings immune response to an end
iv. Delayed Hypersensitivity Cells chronic infections cell mediated allergies
v. Memory Cells
Lymphokines: various T-cells secrete immunoactive chemicals = lymphokines = cytokines
soluble chemical messengers by which cells of the immune system communicate with each other
1. chemotactic factor attracts macrophages to invaders 2. macrophage activating factor tells macrophages to destroy antigen gives them enhanced antibacterial activity: increased metabolic activity more lysosomes increased phagocytosis 3. lymphotoxin poison which kills any cell it contacts requires direct cell contact 4. migration inhibition factor halts macrophage migration
5. Miscellaneous other immunoactive chemicals
a. Interleukin 1 stimulates helper T-cells in presence of antigen attracts macrophages in inflammatory resonse
b. Interleukin 2 proliferation of TH cells proliferation and differentiation of B-cells activation of Tc and NK cells
c. alpha interferon inhibits intracellular viral replication increases activity of macrophages against microbes and tumor cells
d. Tumor Necrosis Factor toxic to tumor cells enhances activity of phagocytic cells
e. GM-CSF (Granulocyte Macrophage-Colony Stimulating Factor) stimulates the formation of RBC’s and WBC’s from stem cells
Interactions of AMI and CMI Systems:
both systems work together to increase the immune response against specific foreign antigens
eg. production of antibodies by B-cells often requires helper T-cells esp. “T-dependent antigens” – proteins such as viruses, bacteria, foreign RBC’s, hapten–carrier combinations
eg. stimulate B-cells to differentiate into plasma cells and produce antibodies
Clinical Applications of Immunity
1. Vaccinations
based on primary vs secondary response primary persons initial exposure to an antigen lag of several days before antibodies begin being produced peak production in ~10 days
secondary reexposure to same pathogen triggers memory cell response memory cells can persist for 20 years or more much quicker response much stronger response
natural vs acquired immunity natural immune response is triggered due to natural exposure to a pathogen acquired (=artificial) immune response is triggered by a medical procedure, eg vaccination
active vs passive immunity active exposure triggers body’s own immune response including memory cells passive subject receives antibodies from another person or animal, rather than making them himself offers immediate protection, short term no active antibody production is stimulated no memory develops
eg. fetus gets antibodies from mom eg. gamma globulin to treat hepatitis, botulism, snake bites, etc
2. Monoclonal Antibodies specific B cell (with desired antibodies) is fused to cancer cell rapid production of large numbers of the same antibody
3. Organ Transplants and Rejections same principle as blood transfusions usually need immunosuppressive drug therapy 4. Allergies immediate (acute) hypersensitivity mediated by B cells IGE mast cells histamine anaphylactic shock
delayed hypersensitivities mediated by T cells antihistamines don’t work use corticosteroids
5. Immunodeficiencies congenital eg. SCID
acquired eg. AIDS
6. Autoimmune Diseases
5% of adults in North America 2/3 rd^ of victims are women
normal state of self tolerance breaks down due to: self reactive lymphocytes are normally silenced during development in this case some escape and attack body new self antigens (?antibodies) appear due to gene mutation or hapten binding foreign antigens resembling self antigens trigger antibodies that not only attack foreign antigens but self antigens as well
autoantibodies & sensitized T-cells
some of most common autoimmune diseases:
eg. Multiple Sclerosis destruction of myelin sheath of brain and spinal cord especially in young adults nerve fibers are severed neurons short circuit
