What did the Chinese do in the eleventh century?
Introduced small pox to infants to protect them later in life, the technique is known as variolation
The word immunity means what?
Means "exempt" from charges. For nearly a Century it has meant resistance to possible attack by an infectious agent. Resistance to certain diseases have been observed even in ancient times
Who performed the first effective immunization? Explain?
Edward Jenner, an English physician in 1798. He observed milk maids infected with cow pox were resistance to small pox.
What is formol used for?
Used for the detoxification of toxins and venoms. Serpa Pinto reported this from his travels though central Africa.
What term replaced variolation?
How did Louis Pasteur influence immunology?
He investigated the possibility of protection against infection by vaccinations with attenuated strains of microorganisms 1st observation was Pasturella aviseptica (chicken cholera) Pasteur concluded that this culture contained attenuated microbes and he extended the term vaccination to mean conferring immunity by injection.
Using attenuated strains of microorganisms as a vaccine was confirmed by ____________ when he applied it to anthrax. How were these strains rendered avirulent?
Pasteur He rendered the organism avirulent by growing them at an unusually high temperature.
How did Elie Metchnikoff study the role of motile cells of a transparent starfish larva?
He introduced a rose thorn into the larva and noticed a few hours later the thorn was surrounded by motile cells.
How did the rabies vaccine come to be?
Pasteur allowed spinal cords taken from rabies infected rabbits to dry, and then used the dry cords as his vaccine material, since the drying process rendered the rabies virus avirulent.
What did Metchnikoff prove?
That Leukocytes will engulf microorganisms. He called this phagocytosis Phagocytosis was greatly enhanced in animals recovering from an infection or after a vaccine against those particular microorganisms
What are the 2 circulating types of cells shown by Metchnikoff to be capable of phagocytosis? What are these cells termed??
Polymorphonuclear Leukocytes (neutrophils) and the macrophages as well as certain fixed cells capable of phagocytosis The cells are termed phagocytes.
What did Wright and Douglas do?
They used washed cells to prove the immune a system used an active enzyme known as opsonin. They proposed a term opsonization.
What did Wright and Douglas do?
They used washed cells to prove the immune a system used an active enzyme known as opsonin. They proposed a term opsonization. (resolution for the humoral and cellular theories)
What is an Antigen?
Any substance capable of inducing a reaction against itself.
Lymphocyte is responsible for both ______ and ________.
Cellular and humoral immunity
What is in Antibody?
Factor present in the serum possessing this activity (inducing a reaction against itself)
What is the instructional theory?
1930-1940 suggest a particular antigen would serve as a template around which antibody would fold. The antibody molecule would therefore assume a configuration complementary to that of the antigen template This theory was discredited as knowledge of DNA RNA and proteins were accumulated.
What is the Selective theory?
In 1900 Paul Ehhrlich proposed that cells expressed a variety of "side-chain" receptors that could react with infectious agents. This binding resulted from a complementary lock and key type interaction. (he further suggested that binding of an infectious agent to the side chain receptor released the side chain and inured production and release of more side-chain receptors from the cell with the same specificity -- antigen selected the appropriate side chain and side chain specificity was determined prior to antigen exposure)
Where did the Clonal selection theory come from?
in 1950 the selection theory was refined into the clonal selection theory by Sir F. Macfarlane Burnet.
What did Sir F. Macfarlane do?
Refined the selection theory to the Clonal Selection theory. he proposed that individual lymphocytes express membrane receptors that are specific for particular antigens. The receptor specificity is determined prior to antigen exposure.
Binding of antigen to a specific receptor activates the cell, resulting in?
its proliferation into a clone of cells, each with the same immunologic specificity as the original parent cell.
What is now accepted as the underlying paradigm of modern immunology?
The Clonal Selection Theory.
What is the Immune system in host defense described as?
A criminal invades a town, threatening its safety; but before he can do any damage, he is surrounded by police and then hauled off and confined in the local jail.
What are the 2 types of immunity?
Innate Immunity (natural, Native, or Nonspecific immunity) Adaptive immunity ( Acquired or Specific immunity)
What is Innate immunity??
it is present in all individuals or animals at all times, hence it is the initial response to microbial invasion.
True or False- innate immunity improves on repeated exposure to a given pathogen and does not discriminate between pathogens.
FALSE BITCHES! Innate immunity does NOT improve on repeated exposure to a given pathogen (i.e no memory) and does not discriminate between pathogens.
Innate immunity constitutes which line of host defenses?
The first and second lines of host defenses.
What mediates adaptive immunity?
T and B lymphocytes
Adaptive immunity is highly specific for a particular _______
How long does it take for adaptive immunity to become fully functional?
it takes several days after a pathogen invades the body
What is the difference between innate immunity and adaptive immunity?
Unlike innate immune response, the adaptive response improves with each successive encounter with the same pathogen (i.e. immunologic memory)
What line of defense is adaptive immunity?
third line of defense
What happens when a microbe eludes innate immune responses?
Adaptive immune response is then enlisted. However, acquired immunity does not operate independently of innate immunity; rather, it supplements and augments the nonspecific defense mechanisms, producing a more effective total response.
What is the first line of defense against microoorganisms?
the first line of defense against mircroorganisms is the intact skin and mucous membranes lining the gastrointestinal, respiratory, and genitourinary tracts.
If a microorganism does breach the skin and mucous membranes and enters the body what other components help destroy the invader?
Neutorphils and macrophages, etc
Name the first lines of defenses... there are 3
1.) intact skin 2.)mucous membranes and their secretions, eg, mucus 3,) Normal flora
Name the second lines of defenses... there are 3
1.) phagocytosis 2.)Inflammation and fever 3.) Antimicrobial substances
Who are much more susceptible to infectious agents because of their immune responses?
The very young and the Very old because their immune responses are Suboptimal
What is a result of loss of taste or smell with age?
As individuals age, they sometimes lose sense of smell and taste. as a result, appetites may decrease and vitamin deficiencies increase. Dietary components such as protein and vitamin A, D, C and B complex are necessary for healthy immune responses.
The skin is a mechanical barrier than helps protect from entry of microorganisms and the epithelia also produce _____ that helps with this. How?
Peptides. Peptides that are produced have a natural antibiotic function (defensins and phagocytosis)
What is the epithelial turnover in humans?
Where the epidermis is completely renewed every 15-30 days
How does sebum help with innate immunity in the first line of defense?
Sebum is produced by sebaceous glands. Sebum forms a protective film over the surface of the skin. Contains lactic and fatty acids that inhibit the growth of many microorganisms (pH 3-5)
How does perspiration help protect the body?
It flushes microorganisms from the surface of the skin. Sweat also contains lysozyme.
How does the oral cavity help keep microorganisms out?
Saliva washes microorganisms from teeth and gums. It also contains antibacterial agents, (lysozymes)
what are the 4 main properties of the gastrointestinal tract?
1.) Low pH of the stomach 2.) Normal Flora 3.) Peristaltic movement, (vomiting and diarrhea) 4.)(Antimicrobial Substances) Proteolytic enzymes, Bile acids, and pancreatic secretions.
What are examples of Antimicrobial substances of the second line of defense?
Complement proteins, lysozymes, bacteriocins, digestive enzymes, low pH (stomach), Defensins
What can pH do to proteins and enzymes?
protein denaturation. High or Low pH can change the shape of an enzyme
Acidophiles grow best at what pH? Neutrophiles grow best at what pH? Alkalophiles grow best at what pH?
Acidophiles- 3.0-4.0 Neutrophiles- 6.5-7.5 Alkalophiles- pH> 8.0
3 main properties of the Respiratory tract in relation to immunity and protection?
1.) mucociliary escalator 2.) Coughing and sneezing (speeds up the escalator) 3.) Alveolar macrophages
How do eyes help keep out microorganisms?
Flushing action of tears. Tears also contain lysozyme
How does the genitourinary tract help keep out microorganisms?
Urine. Flushing action of urine; acidity of urine. Urine contains lysozyme. Vaginal lactic acid
What is normal flora?
These are microorganisms (mostly bacteria, fungi, protozoa) that colonize a host without causing disease. However, under certain circumstances, some flora can cause disease. They contribute to host defense by preventing potential pathogens from colonizing the host.
What is the role of the normal flora? (i.e. how does normal flora contribute to host defense)
1.) Competition for attachment sites and nutrients (competitive exclusion) 2.) Produces substances that are harmful to pathogens, eg. bacteriocins (antimicrobial peptides produced by bacteria that kill or inhibit other bacteria) In the large intestines, E. Coli producins colicins that inhibit the growth of Salmonella spp. and Shigella spp. 3.) Altering conditions that affect the survival of pathogens, eg, pH and O2 availability. Lactobacillus acidophilus in the vagina alters its pH to prevent over population by Candida albicans.
What are iron- binding proteins?
These are proteins that sequester iron thereby reducing iron available to a pathogen, Eg, transferrin, lactoferrin, and haptoglobin.
What critical role does iron play in bacterial respiration?
as a component of the cytochromes and the iron-sulfide proteins involved in electron transport chain.
What are siderophores?
Iron-chelating compounds produced by various pathogenic bacteria that facilitate the uptake of iron by the bacterial cell.
What is oxygen tension or oxygen concentration?
toxic derivatives of oxygen such as H2O2, superoxide anion, etc, inhibit the growth of obligate anaerobic bacteria, especially in the lungs.
What is complement in terms of a component of innate immunity?
Plasma and cell surface proteins associate with lysis of Gram negative bacteria, chemotaxis of pahgocytes, and opsonization ( the coating of an antigen or particle that facilitates its uptake into a phagocytic cell).
What are interferons?
Low molecular weight glycoproteins produced by certain cells in response to viral infections. IFNs have antiviral and immune regulatory activity.
How does temperature effect microbial growth?
Body temperature inhibits replication of some pathogens, fever enhances phagocytosis. Also antibody production and T cell proliferation are more efficient at higher body temperatures than at normal levels
What can induce fever?
Fever can be induced by bacterial endotoxin (lipopolysaccharide (LPS)) and interleukin-1
What is inflammation?
This is a process which begins following sublethal injury to tissue and ends with complete healing. Cause may be microbiological, physical, or chemical. Inflammation results in the bringing of blood components and cells of the immune system to the site of tissue damage.
2 Main components of Specific immunity?
1.) Antibody- mediated (humoral) immunity 2.) Cell- mediated immunity
What is Antibody- mediated (humoral) immunity?
Antibodies are soluble proteins produced as a result of interaction between a B lymphocyte and an antigen. The antibody has the ability to combine with the antigen that stimulated its production.
Where are Antibodies found?
they are found in plasma, lymph and tissue fluids of the body. They are most effective in eliminating extracellular antigens and bacterial toxins.
What is Cell-mediated immunity?
An adaptive immune response in which antigen specific T cells play the main role. Macrophages and natural killer cells (although non specific cells) are included with T cells in cell-mediated immune responses.
Cell Mediated responses are most important against______________?
Most important against intracellular parasites, in allograft rejection, and in delayed hypersensitivity reactions.
The adaptive immune response is divided into what 3 phases? 1.) ____2.)_____3.)_______
1.) the recognition of antigen by antigen-specific lymphocytes 2.) the activation of the lymphocytes 3.) the effector phase which results in destruction of the antigen.
What does Activation of Lymphocytes result in?`
What is clonal expansion?
The proliferation of antigen specific T and B lymphocytes in response to antigenic stimulation and precedes their differentiation into effector cells and memory cells. ( this is important b/c it allows increases in numbers of T and B cells so they can effectively fight)
What happens after the elimination of the antigen?
The immune response subsides and homeostasis is restored.
Fill in the gaps on this chart
A - Antigen recognition
B- Lymphocyte activation
B2- Clonal expansion
C - Antigen elimination
C3- elimination of antigens
D- Contraction (homeostasis)
E - Memory
What are the two main lines of differentiation of pluripotent stem cells?
1.) The myeloid lineage 2.) the lymphoid lineage
What does the myeloid lineage produce?
it produces monocytes neutrophils, basophils, eosinophils, and other cells.
What does the Lymphoid Lineage produce?
Plasma proteins represent a mix of what two types of properties?
What are the major plasma proteins?
structural and functional
Albumin, Fibrinogen, and Globulin.
Where are the major plasma proteins produced?
virtually all the albumin and fibrinogen, and 50% to 80% of globulins are produced in the LIVER!! the remaining globulin proteins are produced in the lymphoid organs and tissues.
What are Globulins?
They are principally responsible for the body's innate and adaptive immune responses against invading pathogens. They are comprised of complement proteins and antibodies.
What can Hosts immune responses result in (related to immunopathology)?
1.) Autoimmunity: Response is directed against self- antigens 2.) Immunodeficiency: Ineffective immune response. 3.) Hypersensitivity: overactive immune response resulting in allergies. 4.) Transplantation reaction: Rejection allograft.
How are CD molecules identified?
By using monoclonal antibody. They may be used as markers to differentiate different tcell populations, such as CD 4+ T cell ( T Helper cell) or CD8+ T cell ( Cytolytic T lymphocyte)
What is an Antigen?
What must it be capable of?
Any substance that can induce humoral and/ or cell - mediated immune responses when introduced into an individual or animal.
The antigen must be capable of reacting with specific receptors on T and B cells and with the antibodies produced against it.
What are microbial antigens?
Bacteria, fungi, viruses, protozoa and helminth parasites.
What are non microbial antigens?
Foreign proteins, food antigens, plant antigens ( eg. Pollen), cell surface proteins ( eg red blood cells antigens) etc.
What influences the degree of antigenicity of a molecule?
1.) Foreignness 2.) Chemical Complexity 3.) Molecular size 4.) Stability 5.) Degradability 6.) Genetic makeup of the host. 7.) method of administration.
What is foreigness?
How does it relate to antigenicity?
What are the four types?
Self vs Non self. The macromolecule must come from a foreign source.
The more foreign the antigen, the more vigorous the immune response.
autologous, syngeneic (isogeneic), allogeneic, xenogeneic
What are autologous antigens?
Antigens found within the same individual
What are Synegenic (isogeneic) antigens?
Antigens found in genetically identical indiciduals, (Twins or inbred mice)
What are allogeneic antigens?
Antigens found in genetically dissimilar members of the same species, Eg, blood- group antigens.
What are Xenogeneic antigens?
Antigens found in different species.
What does chemical complexity mean (relative to antigenicity?)
The more complex a molecule, the more varied the epitope (antigenic determinant) composition, Hence the more likely different (individual) immune responses will be induced.
What are the most complex organic compounds therefore they are the most antigenic?
Proteins - They are often composed of 18 or more amino acids. -This diversity imparts epitopes of differeing specificities to the protein.
Simple polysaccharides are _______ antigens. Why?
Weak antigens, because they do not possess sufficient chemical complexity, additionally, they are rapidly degraded before the immune system has had time to respond to them.
More complex polysaccharides are ________. (compared to simple polysaccharides in terms of antigenicity requirements)
Antigenic (capsular polysaccharides and lipopolysaccharides.)
How is antigenicity of polysaccharides enhanced?
IF they are coupled to proteins as glycoproteins.
Why are Lipids weak antigens?
Due to their structural simplicity and rapid metabolism. However, immune responses to lipids may be enhaced when they are conjugated to proteins (lipoproteins) or polysaccharides (glycolipids)
The most potent antigens are proteins with high____________.
Molecular weights ( above 100,000)
In general molecules with weights below _______ are weak antigenic
10,000 and very small ones, ex amino acids are non antigenic.
What is an example of an non antigenic molecules?
The number and variety of epitopes increase proportionately with_______
the size of the protein.
With carbohydrate antigens, the number if epitopes may increase with size but__________ does not.
Why are highly flexible molecules that have no fixed shape poor antigens??
Because the Lymphocyte antigen receptor recognizes an antigen by its shape.
T Cells respond only to _______ antigens.
What must APCs do to an antigen before it can be expressed?
they must first degrade the antigen before they can express antigenic peptides noncovalently bound to MHC molecules on their cell surface
Macromolecules that cannot be degraded and presented with MHC molecules are _________ antigens.
The genetic constitution of the host determines whether a given molecule will stimulate an ______ _______.
low does of an antigen may not stimulate an immune response either because the amount given fails to activate enough lymphocytes or renders the lymphocytes unresponsive. On the other hand a very high dose of antigen may lead to _______ _______
What does the route of antigen administration determine?
Which organs and cell populations will initiate the immune response.
Antigens administered _________, usually elicit the strongest response.
Subcutaneously. The antigens are taken up by Langerhans cells present in the skin, Carried to local lymph nodes, where they are processed and presented to T cells.
What are Epitopes?
The sites on or within the antigen that stimulate the immune response and against which that response is directed. Thus, epitopes determine the specificity of the antigen molecule.
When are internal epitopes expressed?
Only after the antigen has been partially degraded in vivo by antigen- presenting cells.
What does it mean that many antigens are polyvalent or multivalent?
What does polyvalent mean?
What does multivalent mean?
Simultaneous immune responses may be mounted against the various epitopes on theses antigens.
polyvalent - many epitopes of different specificities
multivalent - many epitopes of the same specificities
Why can antibodies produced to one antigen cross react with an unrelated antigen?
does the antibody have the same affinity for both antigens?
it is possible because the two unrelated antigens share on or more identical or very similar epitope(s)
No, the affinit of the antibody will be higher for the original epitope
What does Cross reactivity (heterophile antigens) provide the basis for?
- Some autoimmune diseases, -heterologous vaccines (measles distemper) -false positive diagnosis.
What is a B cell receptor?
This is the cell surface receptor of B cells that recognizes a specific antigen. It consists of a membrane immunoglobulin molecule in association with the signal transduction molecules IgA and IgB
What is a T cell receptor?
Cell surface receptor of T cells that binds to antigenic peptide presented in association with major histocompatibility complex molecule. It is made up of Alpha and Beta protein chains that associate with the signal transduction molecules CD3 plus zeta
What is the Major histocompatibility complex? MHC
These are proteins encoded by MHC genes. They are classified as class 1 , class 2 and class 3 MHC molecules. Class 1 and class 2 MHC molecules are cell surface molecules that present antigenic peptides to T cells.
What is a hapten?
a non antigenic molecule, usually of low- molecular weight, that by itself, cannot induce an immune response, but can react with the products of that response.
What do Haptens include?
Some antibiotics, analgesics, poison ivy, etc.
To induce an immune response, a hapten must always be coupled to a ______
carrier substance, preferably protein antigen ( called carrier protein) The hapten acts as a new epitope of the carrier protein and an immune response is generated to both the hapten and the native epitopes of the protein
What are some carrier proteins for a hapten?
Serum albumin, globulins, and synthetic polypeptides.
Antibody specific for a given hapten can recognize and bind the hapten, where the hapten is _______ or ______ to a carrier substance.
Free or bound to a carrier substance.
Who is credited for most of the work with haptens?
What did Karl Landsteiners work illustrate?
The diversity of the immune response and specificity of antigen-antibody and antigen -T cell reactions, (ex, Paul Ehrlichs lock and key phenomenon)
What are Autocoupling Haptens?
These are a unique class of haptens which possess the ability to form spontaneous covanelnt bonds with self proteins to create neoantigens (new antigens) in vivo. -these conjugates represent novel antigens to the animal or individual, and the animal or individual responds with an immune response.
Unlike the usual response to antigen-hapten complexes, the response to autocoupling haptens can have _____ ______ _____ _______ ________.
Can have serious consequences in the body.
What is the resin of poison ivy called?
Urushiol (type IV Hypersensitivity)
Urushiol binds to any protein it comes in contact with, including skin proteins. The modified skin proteins are regarded as _______ and attacked by ______ and ______ results.
the modified skin proteins are regarded as foreign and attacked by lymphocytes, and an allergic contact dermatitis results.
What are cytokines?
Soluble proteins secreted by the cells of innate and adaptive immunity that stimulate ( and occasionally suppress) the growth, maturation, and functioning of the cells of the immune system.
Cytokines usually act _______.
Locally, however on occasion, they may exhibit endocrine action.
Cytokines act by binding to___________________
Specific cytokine receptors on the cells that they affect.
What are Lymphokines?
Cytokines primarily produced by lymphocytes.
What are Monokines?
Cytokines primarily produced by monocytes and macrophages.
What are interleukins (IL)?
Cytokines produced by leukocytes that act on other leukocytes.
When are cytokines usually produced? At what concentration are they active?
During the activation and effector phases of innate and adaptive immune responses. They are active in very low concentrations.
Cytokine secretion is a ____,_______ event.
a brief, self limited event ( they are not stored as preformed molecules)
Cytokines often influence the synthesis of ________
How do cytokines exert their effects?
Cytokines exert their biological effects by binding to specific high affinity cytokine receptors ( a cell may express up to 1000 receptors), triggering a series of biochemical events that influence the activities of immune cells and organs.
The expression of many cytokine receptors is regulated by?
Specific signals. The signals may be another cytokine or antigen binding to the cell.
Some cytokine receptors can have Circulating forms that do what?
Block the cytokine before it reaches its cellular target (regulated the activity of the cytokines)
what are the sources of individual cytokines?
They may be produced by multiple cell types.
What are proinflammatory cytokines?
These cytokines contribute to the initiation of a wide spectrum of activities during the inflammatory response, such as fever, acute phase response, etc
What does proinflammatory cytokines include?
IL-1, IL-6 and tumor necrosis factor Alpha
Proinflammatory cytokines act in concert with _______ and _______ to ensure the development of physiologic responses to a wide variety of stimuli, such as microbial infections and tissue injury.
Chemokines and hematopoietic cytokines
What are the sources of IL-1?
Macrophages, Endothelial cells, Langerhans cells, B cells, Epithelial cells (keratinocytes, dendritic cells. etc.)
What are the two principal forms of IL-1?
IL-1 Alpha and IL-1 Beta
What does IL-1 ALPHA bind to?
Binds to the macrophage membrane, enabling macrophages to activate lymphocytes that come in contact with them.
Why is IL-1 Beta the most found in circulation?
Because IL-1 Beta is secreted by cells, thus, most of the IL_1 found in the circulation is IL-1 Beta. Both forms (alpha and Beta) bind to the same receptors and mediate the same biological activities.
What is IL-1 receptor antagonist (IL-ra)?
This is a third form of IL-1 that binds to IL-1 receptors but is biologically inactive so that it functions as a competitive inhibitor of IL-1. It is an endogenous regulator that serves to prevent excessive IL-1 driven inflammatory response.
What are some principal activities of Interleukin-1 (IL-1)?
* Lymphocyte actvation- major co stimulator of Th2 cells ( Th1 cells lack IL-1 receptors and do not respond to IL-1)
* Acts on endothelial cells to increase expression of adhesion molecules that mediate leukocyte extravasation and secrete chemokines that activate leukocytes.
* Stimulates the production of neutrophils and platelets by the bone marrow
* (Actute-phase reaction-) stimulates heaptocytes to synthesize increased levels of acute-phase proteins in response to inflammation.
* (Nervous system) acts on the brain to cause fever, lethary and lack of appetite (acts on ant hypthal = PGE2 induced fever)
* Initiates metabolic wasting
How does IL-1 induce fever?
IL-1 acts on the thermoregulatory center in the anterior hypothalamus, resulting in prostaglandin- induced (PGE2) fever.
What are the sources of IL-6?
Macrophages, endothelial cells, Th2 cells, etc.
What are the main activities of IL-6?
* T cells- promotes IL-2 and IL-2R production and T cell differentiation. * B cells- differentiation of B cells into plasma cells and antibody production. * Stimulates synthesis of acute- phase proteins, endogenous pyrogen. * Bone marrow. Stimulation of hematopoiesis, in concert with colony stimulating factors, it promotes the production of neutrophils and platelets.
What are the sources of TNF-Alpha?
Macrophages; T cells, NK cells, Mast cells, etc. It occurs in cell membrane-bound forms and secreted forms.
What are the principle activities of TNF-Alpha ( tumor necrosis factor- alpha)?
* Vascular endothelium- expression of adhesions molecules and synthesis of chemokines (CXCL8) * Activates neutrophils and macrophages, enhancing their microbicidal activities. * Stimulates synthesis of acute-phase proteins; potent endogenous pyrogen. * Pathologic abnormalities ( prolonged production or high concentration)
What are some pathologic abnormalities caused by TNF-Alpha?
1.) Intravascular thrombosis- TNF stimulates endothelial cell expression of tissue factor, a potent activator of coagulation. Thrombosis of tumor blood vessels account for its tumor killing activity. 2.) Cachexia- Characterized by wasting of muscles and fat cells (TNF referred to as cachetin) 3.) Principal mediator of septic shock in Gram negative septicemia. Very large amounts of TNF result in inhibition of muscle tone and cardiac contractility, resulting in decreased blood pressure and shock.
What are chemokines (chemotactic cytokines)?
They comprise a large family of small proteins that are involved in the migration of leukocytes from the blood to tissues and activation of leukocytes.
What do chemokines play a central role in?
Chemokines are produced by?
Leukocytes and various tissue cells such as fibroblasts, endothelial cells and epithelial cells.
Secretion of chemokines Is induced by?
Pathogens and by proinflammatory cytokines, principally TNF alpha and IL-1. However some chemokines are produced constitutively in lymphatic organs, where they aid in the traffic of lymphocytes through the organs in the absence of inflammation.
What are chemokine receptors?
They consist of seven-transmembrane polypeptide chains and belong to the large family of G-protein- coupled receptors. They are classified according to the type of chemokines they bind.
How are chemokines classified?
into subfamilies based on the position of two of the four highly conserved NH2 terminal cysteine residues they possess.
Describe CXC chemokines. What do they mostly attract and activate? what is the most important one?
they have their first two cyseines separated by one amino acid. They mostly attract and activate neutrophils. The most important is CXCL8 (IL-8)
Describe CC chemokines (beta chemokines)
What do they mostly recruit and activate?
[What do they include?]
They have two adjacent cysteine residues. They mostly recruit and activate monocytes, lymphocytes, basophils, NK cells, and eosinophils.
[include: CCL3/CCL4 (macrophage inflammatory proteins [MIP-1alpha and MIP-1Beta]), CCL2 (monocyte chemoattractant protein-1 MCP-1), CCL11 (eotaxin), CCL5 (RANTES - regulated upon activation normal T cell expressed and secreted, etc)]
What are Hematopoietic cytokines?
Various cytokines produced in the immune response stimulate the growth and differentiation of bone marrow precursor cells.
What are some examples of Hematopoietic cytokines?
* IL-3 * IL-7 *Stem cell factor *GM-CSF, M-CSF, G-CSF
What are sources of IL-3 and what does it do?
T cells, macrophages, mast cells etc. *Promotes the growth and differentiation of stem cells into all known mature cell types (multilineage colony-stimulating factor, multi-CSF)
What are some sources of IL-7 and what does it do?
Bone marrow and Thymic stromal cells * Growth of T- and B cell progenitors (lymphopoietic cytokine)
What are the sources of Stem cell factor, when is it active and what does it do?
SCF is constitutively produced by bone marrow stromal cells. Active as membrane bound form or secreted form. * Required for the earliest stages of leukocyte development in the bone marrow. It may also play a role in sustaining the viability and proliferation of immature T cells in the thymus and of mast cells in mucosal tissues.
What are sources of GM-CSF, M-CSF and G-CSF and what does it do?
T cells , macrophages, endothelial cells, mast cells, and bone marrow stromal cells.
* CSF cytokines promote the expansion and differentiation of bone marrow progenitor cells.
Granulocyte- monocyte colony stimulating factor; Monocyte-CSF, CSFs: so called because....?
because these cytokines are assayed, in vitro, by their ability to stimulate the formation of cell colonies in bone marrow cultures.
RELOOK AT PAGE 23-26 He said don't worry about it!
(Lizzie adds - I added cards from the bottom of page 25 and page 26--Charlie went over them in his review...)
RELOOK AT PAGE 23-26 He said don't worry about it!
The complement system consist of Approximately.......?
20 heat- labile serum and cell surface proteins, many of which are enzyme precursors that must be cleaved to form active enzymes.
Complement proteins are normally found in ________
Complement proteins make up about ____% of the total plasma alpha and beta globulins.
Complement proteins also leak out of________ into the tissue spaces.
Complement proteins are synthesized mainly by the ________ and _________
Liver and macrophages.
In 1895, shortly after the discovery of antibodies, ________ demonstrated that _____ were lysed when they were exposed to fresh _______ antiserum. However, if the antiserum was heated to ____ for 30 minutes or ____ for a few weeks, it could no longer cause lysis but would instead ____ the bacteria since _____ ____ _____ ___. When fresh guinea pig serum was added to the ____ or ____ antiserum, the ability to lyse ____ was regained. He concluded that the lytic effect required two factors: 1) _____ and 2) ______ present in normal serum. Later, _____ called the ____ component COMPLEMENT since it was thought to assis or complement the lytic function of antibodies
56 degress Celsius
antibodies are heat-stable
heated or aged
What are the two main pathways for complement activation and what are they initiated by?
1.) classical pathway which is initiated by antigen-antibody (IgM or IgG) complexes
2.)The alternate pathway which is initiated by microbial surfaces.
Both complement activation pathways lead to the production of?
C3b, the central molecule of complement cascade.
C3b can combine with other complement components to generate__________?
C5 convertase, the enzyme that leads to the terminal pathway that produces the membrane attack complex (MAC)
When the complement system is activated, multiple products are formed that perform a variety of biological functions, including_______________.
Cell membrane lysis.
How are complement proteins labeled?
numerically with the prefix C or designated by letters of the alphabet.
What is the most abundant complement protein?
The enzyme cascades are generated by ____________________?
the sequential proteolytic cleavage of enzyme precursors (proenzymes or zymogens) to generate enzymes with proteolytic activity. In the process, an inhibitory fragment (small fragment "a") is removed, exposing the active site on the major fragment ("b").
Regulatory proteins present in serum and on host cell membranes inhibit or minimize _______________.
How does this relate to microorganisms?
Compliment mediated damage. *Since microorganisms lack these regulatory proteins. complement activation is allowed to occur on microbial surfaces.
What are proteins of the classical pathway?
C1, C2, C3 and C4
What are the proteins of the alternative pathway?
C3, Factor B, Factor D, Properdin.
What initiates the classical complement Pathway?
Initiated by binding of C1 to the Fc regions of IgM or IgG molecules that have bound to antigen. C1 is composed of 3 subunits: C1q and two molecules each of C1r and C1s held together by non covalent bonds and stabilized by calcium ions.
What is C1q?
It looks like six globes held on slender shafts that fuse into a common base. The globes serve as the recognition unit. When IgM or IgG binds to its antigen, its active site on the Fc region is exposed to C1q **C1q cannot bind to free or soluble IgM or IgG.
How many C1-q binding sites do each IgM or IgG Fc region possess?
Only ONE. and each C1q molecule must bind to two FC regions to be activated.
TRUE/FALSE IgM is a much more efficient complement binding antibody than IgG.
IgM provides two closely spaced complement-acting sites whereas several molecules of IgG must bind to the target cell so that two IgG molecules are close enough to each other to have the same effect (<=30 to 40nm apart)
What is C1r and what does it do?
Serine protease. Binding of two or more of the globular heads of C1q to IgG or IgM induces a conformation change in C1r, converting C1r to an active protease enzyme that is able to cleave and activate C1s.
What is C1s and what does it do?
Serine protease. Activated C1s cleaves C4 into larger C4b fragment and a smaller C4a fragment.
The C4b fragment has an internal thioester bond that binds to _________?
the target cell membrane in the vicinity of C1, unbound C4b decays in the medium. C4a is released into the fluid phase.
C2 is a proenzyme that binds to what to form what complex?
binds to the exposed binding site on the cell-bound C4b to form C4bC2 complex
After forming the C4bC2 complex what happens to C2?
C2 is cleaved by C1s into soluble C2a fragment and C2b. C2b remains bound to C4b to form a new enzyme complex: C4b2b
What is another name for C4b2b?
classical C3 convertase
C1s cannot act on C2 unless...
it is bound to C4b -- this is called substrate modulation
What must happen to C3 before the complement cascade can proceed?
C3 must be activated by proteolytic cleavage
C4b2b binds to and proteolytically cleaves ____ turning it into ____ and a small ___ fragment
C3 C3b C3a
How many molecules of C3b can a single C3 convertase enzyme generate?
what is the result of this?
more than 200 molecules of C3b this results in tremendous amplification at this step of the complement cascade
What are 3 pathways for C3b after amplification?
1) binds to C3 convertase to form C5 convertase [C4b2b3b]' 2) binds directly to cell membrane near C4b2b 3) diffuses away and coats immune complexes [antigen-antibody complexes] and particulate antigens [bacteria] functioning as opsonin and promoting phagocytosis
What is another name for C5 convertase?
What does the C3b component of C5 convertase do?
binds to C5 and alters its conformation allowing C4b2b to cleave C5 into C5a and C5b
What happens to C5a?
released into the fluid phase
what happens to C5b?
remains attached to the C5 convertase and initiates the terminal pathway of complement activation
Who originally described the alternative complement pathway and in what year?
Pillemer and his associates in 1954
What is the alternative complement pathway?
a system for activating complement beginning at C3 which does NOT involve an Ag-Ab rxn but instead the binding of C3b to the surface of a pathogen
What are four of the microbial structures that can activate the alternative pathway?
1) lipopolysaccharide (LPS from gram negative bacteria) 2) teichoic acid (gram positive bacteria) 3) zymosan (fungal cell walls) 4) viral envelopes etc
Which is more important the first time an individual/animal is infected by a microorganism--the classic pathway or the alternative pathway?
The alternative pathway because the IgG or IgM required to trigger the classical pathway is not present
What happens to C3 in the alternative complement pathway?
C3 is slowly and continuously hydrolyzed to C3a and C3b due to the H2O induced cleavage of an unstable thioester bond in C3
What is C3 "tick over"
The hydrolyzation of C3 to C3a and C3b in the alternative pathway
In the alternative pathway, the thioester bond between C3 can be cleaved by what?
water, plasmin, phagocyte proteases, trypsin, etc
What can the C3b fragment bind to in the alternative complement pathway?
proteins and carbohydrates on host cell surfaces or to foreign antigens (bacteria, virus particles, etc)
C3b binding to host cell surfaces in the alternative complement pathway can be inactivated by what two factors?
Factor H and Factor I
Factor H has an affinity for ___ acid which is a derivative of ___ and found where?
sialic acid derivative of neuraminic acid, a nine carbon sugar constituent of host cell membrane glycoproteins
How do Factor H and Factor I inactivate C3b binding to host cells?
Factor H binds to C3b deposited on host cells, then C3bH is cleaved by factor I and made inactive (C3b, iC3b, etc) which stops the alternative complement pathway
What happens to C3b bound to most microbial surfaces?
It is not cleaved because microbes lack sialic acid or have low levels in their membranes so Factor H is not attracted to it. Therefore the C3b finds to a protein called factor B and forms the C3bB complex
What do some bacteria do to inhibit the alternative pathway using factor H?
some bacteria express high levels of sialic acid on cell surfaces OR SCAVENGE it from the host/environment and transfer the sugar to their cell surfaces. This enhances factor H binding to C3b on bacterial membrane
Another name for Factor D is
What does Factor D cleave in the alternative pathway? What is the progression of events after this?
Factor D cleaves Factor B bound to C3b (after Factor B binds to C3b it undergoes a substrate modulation), yielding Ba and Bb (really C3bBb). C3bBb is alternative C3 convertase and cleaves more C3 molecules, amplifying C3b presence
What is another name for C3bBb?
alternative C3 convertase
Is C3bBb a stable molecule? What effects its stability?
extremely unstable (half-life 5min) unless it binds to Properdin (factor P).
What is the half-life of C3bBbP?
30 minutes (more stable than C3bBb)
What happens when C3b released from C3 convertase, binds to C3 convertase?
it forms C3bBb3b complex--the alternative C5 convertase which cleaves C5 and initiates the terminal pathway
What does C5 convertase cleave?
What happens next?
cleaves C5 into a soluble C5a and C5b. While still attached to the C5 convertase C5b first binds to C6 and then C7
C5b67 complex undergoes a conformational change, causing what?
causing its release from C5 convertase and exposing hydrophobic regions that enable the complex to bind to membrane phospholipids.
Membrane bound C5b67 binds to
what is the C5b678 complex responsible for?
How is a fully active MAC accomplished?
slow membrane leakage.
by polymerization of up to 18 molecules of C9 to form a tubular pore in the cell membrane, allowing the entry of water and ions
Osmotic swelling occurs, resulting in
cell lysis. extracellular calcium also enters the cell and in nucleated cells, high calcium concentrations can induce apoptosis.
what are complement receptors?
are cell-surface proteins on various cells which recognize and bind to various complement fragments. This facilitates the effector functions of complement.
Fill in the missing information
Most of the effector functions of complement are mediated by...?
the binding of proteolytic fragments of complement proteins to various cell surface receptors, only cell lysis is mediated by the MAC
insertion of the MAC into the cell membrane leads to....?
killing or lysis of many cell types, including erythrocytes, gram negative bacteria, tumor cells, and enveloped viruses.
why are gram positive bacteria not susceptible to the MAC?
because their cell membranes are protected by the thick peptidoglycan layer
is MAC hydrophobic or Hydrophillic?
C5a causes_______ and is ______
inflammation and is chemotaxic
C3b C4b and iC3b bound to microbial surfaces can simultaneously bind to....?
complement receptors on neutrophils and macrophages, stimulating engulfment and intracellular killing
C5a>C3a>C4a (anaphylatoxins) Bind to.....?
What does the mast cell reaction result in?
mast cells and blood basophils and induce degranulation, with the release of histamine and other vasoactive mediators.
infulxes of phagocytic cells and plasma proteins to the site of microbial invasion
Anaphylatoxins can also bind directly to_______ and cause what?
smooth muscle cells of the bronchioles and cause bronchospasm
C5a and C3 a bind to _____ or ____ receptors on endothelial cells
C5a or C3a receptors on endothelial cells, inducing the expression of P-selectin (promotes neutrophil binding) and vascular permeability, events that promote leukocyte extravasation into tissue.
what does the rearrangement of integrin adhesion molecules do?
increase adherence to endothelial cells
Activation of phagocytes is increased expression of_______ and ______
CR1 and CR3
what does Bb activate?
macrophages, causing them to adhere to and spread on surfaces, thus inhibiting macrophage migration from the site of antigen deposition
what is C3d is a break down product of?
What does it attach to and using what type of bond?
How does this affect B cells?
covalently attaches to antigen
B cells can bind the antigen via their antigen receptors and simultaneously bind the attached C3d via CR2 (CD21). The combined signals result in B cell activation and antibody production.
what is the central role of C3b?
-Binds to factor B, C5, and cell surface proteins and polysaccharides -Nonspecific opsonin -Clearance of immune complexes from the circulation -selection of B cells in germinal centers -sources of iC3b, C3d, etc.
Uncontrolled activation of complement can rapidly deplete______ ______..
What does this lead to?
Complement proteins; leads to formation of the MAC on normal host cells (bystander lysis) and results in excessive generation of inflammatory mediators
Regulation of complement is mediated by ________ and __________.
What happens as a result of this mediation?
circulating and cell surface proteins.
As a result, a delicate balance of activation and inhibition of the complement cascade is achieved which prevents damage to host cells and tissues but promotes the effective destruction of foreign organisms.
Soluble C1 inhibitor covalently binds to active_______and ______
C1r2 and C1s2 and dissociates them from C1q, thus stopping activation by the classic pathway.
Membrane bound decay accelerating factor (DAF) displaces Bb from......
C3bBb or C2b from C4b2b, the alternative and classic pathway C3 convertase.
What does Fluid phase (soluble) Factor I do?
Cleaves cell -associated C3b and C4b. C3b is cleaved to yield iC3b, C3c, C3d, C3f, and C3dg.
Factor I is active only in the presence of ________________? Explain the 3 examples from the book.
regulatory proteins or cofactors.
1) Membrane bound membrane-cofactor protein (MCP, CD46) and complement-receptor 1 (CR1) block the formation of C3 convertase by binding C4b or C3b. Cofactor for factor I-mediated cleavage of C3b or C4b.
2) soluble factor H -- cofactor for cleavage of C3b by factor I
3) soluble C4b-binding protein (C4BP) - binds to C4b on cell surface and competitively inhibits the binding of C2; prevents formation of the C3 convertase. Cofactor for factor I-mediated cleavage of C4b into C4b and C4d.
S protein (vitronectin) Binds to_____________?
What happens as a result of this?
C5b67 complex, preventing the complex from inserting into cell membranes.
In this way, S protein can diminish the potentially indiscriminate lysis of host cells (bystander lysis) by insertion of soluble C5b67 complexes released from other activation surfaces
What is CD59? What does it inhibit?
Protectin. inhibits Formation of the MAC because it is a widely distributed cell membrane protein on normal host cells
How does Cd59 work?
What can most nucleated cells do to fight this?
by binding to C5b678 on the cell surface and preventing C9 polymerization.
most nucleated cells can endocytose C5b-8 or the entire MAC. Therefore if C5b-8 is removed early enough, the cell is able to repair any membrane damage and restor its osmotic stability.
Most nucleated cells can endocytose _____ or ________
C5b-8 or the entire MAC
Fill in the cells from this lineage
Add in the details from this chart:
What are cluster of differentiation molecules?
how are they designated?
CD molecules; cell surface molecules on a variety of cell types in the immune system
designated by CD followed by a number (ex: CD1, CD2, etc)
What happens to large size molecules (with regards to antigenicity)
They are rapidly internalized and processed by APCs.
True or false: although immune responses are generated against both internal and surface epitopes, only those epitopes on the outside of the parent molecules are able to bind to their antibodies?
What are the 4 "isms" that can apply to cytokines?
Pleiotropism - a single cytokine may have multiple activities
redundancy - a single activity can be caused by multiple cytokines
synergism - a cytokine may work best in assoication with another cytokine
antagonism - a cytokine may antagonize the effects of another cytokine
What's CXCL8 chemotactic for?
what does it activate? What does it enhance?
it is chemotactic for neutrophils and effector C cells
activates neutrophils, increasing their expression and arrangement of integrins
enhances degranulation, the respiratory burst, etc
What are cytokine agonists? (page 25)
What two ways do they function?
what are the three main types of agonsists?
they are proteins that inhibit the biological activity of cytokines, they are sometimes of a microbial origin
functions: 1) they bind directly to a cytokine receptor without activating it (ex IL-ra) or 2) they can bind directly to a cytokine and inhibit its activity
main types: viroceptors, virokines and soluble cytokine receptors
What are viroceptors? (bottom of page 25)
secreted viral proteins that inhibit cytokine signaling by mimicking host cytokine receptors.
Several poxviruses enconde homologs of IFN-gammaR, soluble TNF-binding protein, and soluble IL-1 binding protein
What are virokines? (page 26)
secreted viral proteins that mimic host cytokines. Epstein-barr virus encodes a homolog of IL-10
What are soluble cytokine receptors? (page 26)
where are they found?
what do they include?
how do they work?
generated by enzymatic cleavage of the extracellular domains of cytokine receptors. They have been found in the bloodstream and extracellular fluid. They include Il-2 receptors (sIL-2R), sIFN-gammaR, etc.
bind with their respective cytokines and prevent the cytokine from interacting with the membrane-bound receptor
What's so important about soluble cytokine receptor sIL-2R?
It is used as a clinical marker of chonic T cell activation and has been observed in various pathologies, including autoimmune disorders, allograft rejection and AIDS
High concentrations of cytokines or chronic exposure to cytokine can result in what?
High levels of IL-2 results in what?
fever, chills and vascular leak syndrome
What is toxic shock syndrome caused by?
What is another name for it?
What are some symptoms?
enterotoxins produced by some strains of S. aureus can act as superantigens and trigger polyclonal T cell response.
cytokines secreted by these cells (TNF-alpha) can cause fever, hypotension, and damage to the liver and kidney
What does cytokine therapy involve?
What are some examples?
includes the use of monocolonal Abs produced against specific cytokines, recombinant cytokines and soluble cytokine receptors.
IL-ra, EPO, GM-CSF and G-CSF, IFN-alpha
What is IL-ra under investigation for?
possible treatment for chronic inflammatory disease
What is EPO used in therapy for?
used in cats and dogs with nonregenerative anemia due to endogenous EPO deficiency in chronic renal failure
What are colony stimulating cytokines used in therapy for?
given after chemotherapy or radiation therapy to improve bone marrow recover (stimulate production of myeloid progenitor cells)
GM-CSF (sargramostim - granulocytes and monocytes) and G-CSF (Filgrastim - granulocytes only))
What is interferon-alpha (IFN-alpha) used in therapy for?
induces an antiviral state in host cells; has antitumor activity and promotes processing and presentation of cytosolic proteins.
horses--treatment of inflammatory airway disease
cats--treatment of feline leukemia; feline infectious peritonities (when used in combination with corticosteroids)
In humans, what is the serum concentration of complement proteins?
varies between 20 micrograms/mL for C2 and 1200 micrograms/mL for C3
What is another name for MAC?
(The membrane attack complex)
C5a, C3a and C5b67 cause chemotaxis of what?
monocytes/macrophages and polymorphs
What four things influence the activation of phagocytes?
rearrangement of integrin adhesion molecules, increased expression of CR1 and CR3, stiumlation of the respiratory burst and production of reactive oxygen intermediates (ROI), relase of inflammatory cytokines, proteases, etc
Antigen with bound C3b, C4b or iC3b are also bound by what?
Where are these bound antigens displayed? Why is this important?
bound by follicular dendritic cells in the germinal centers of lymphoid organs
FDCs display the bound antigens to daughter B cells;
this process is critical for the selection of high affinity B cells that will become Plasma cells and memory B cells
Spontaneous decay of what is one regulation method of the complement system?
what is included?
spontaneous decay of activated complement components
including time and temperature-dependant dissociation of some of the active complexes, such as C4b2b, C3bBb and C5b67 complexes
What does soluble anaplylatoxin inactivator do?
proteyolytically removes terminal arginine residues and inactivates the anaphlatoxins (C3a, C4a, and C5a)