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313 Cards in this Set

  • Front
  • Back
How does the skin protect against microorganisms?
They prevent a renewing barrier, as well as actively challenging microbes through sweat components
What is the stratum corneum?
A hydrophobic barrier formed by antimicrobial peptides and lipids that are secreted by skin cells when damaged
How much of the total adult body weight does the skin account for?
16%
What is the general function of mucosal surfaces?
Fluid flow carries away microbes away from vulnerable surfaces
What do non-specific surfactants and specific innate and adaptive receptors do at the mucosal surfaces?
Reduce microbe adhesion to the epithelial cells
Opsonize for phagocytosis, and neutralize toxins
What are examples of specific innate receptors that function at the mucosal surfaces?
SP-A, SP-D
What is the adaptive receptor that functions at the mucosal surfaces?
IgA
The receptors of which cell type opsonize microbes for phagocytosis in the lung?
The alveolar macrophage in the lung
What is MALT?
Mucosa-Associated Lymphoid Tissue
What does MALT do?
It is the tissue just beneath the epithelial layer that contains structures which promote efficient antigen presentation to lymphocytes
How are platelets activated?
Once they are adhered by collagen to the damaged blood vessel. They can also be activated by other platelets.
What do activated platelets bind to?
Fibrinogen
What happens when activated platelets bind to fibrinogen?
They aggegate
How is the clotting cascade initiated?
When clotting factor VII comes into contact with tissue facro on cell surfaces of the outer part of the blood vessel
How are activated platelets trapped?
Thrombin converts fibrinogen to fibrin and the fibrin becomes cross-linked, trapping the platelets
What is produced by the clotting cascade and activated platelets?
Inflammatory mediators which act on blood vessels and leukocytes
Besides activated platelets and the clotting cascade, when are other inflammatory mediators produced?
By cells responding to tissue damage
By cells responding to microbial material entering the wound
In the complement cascade
What is the main purpose of inflammation?
Recruit leukocytes to the damaged area and they can kill the microorganism and remove the damaged tissue. They can also provide signals that cause further inflammation
What is similar about macrophages, neutrophils and dendritic cells?
They all degrade the pathogens they take up
How are dendritic cells different from neutrophils and macrophages?
They process foreign material and present it to T lymphocytes, which in turn activates the T cell
At what point in the lifespan of a dendritic cell is it able to take up foreign material, or activate a T cell?
Immature dendritic cells are phagocytic and mature dendritic cells are antigen presenting
What is the precursor to a macrophage?
A monocyte
Where do activated dendritic cells migrate?
Lymph nodes
Where do immature T cells circulate?
In the blood, to the lymph nodes, throughout the lymphatic vessels, and back into the blood
How are effector T-cells generated?
Once the immature T lymphocyte binds the foreign peptide being presented by the dendritic cell, it will be activated, proliferate, and differentiate into effector T cells
What do T helper 2 cells do?
They interact with B lymphocytes that pass through the lymph node, in particular the B cells that have receptors for the foreign peptide that triggered the activation of the helper T cell
What happens when B cells are activated?
They proliferate and differentiate to produce antibodies
What do T helper 1 cells do?
Interact with macrophages to make them kill and clear pathogen
What do cytotoxic T cells do?
They kill cells that have become infected with intracellular pathogens
What are the four humors?
Blood, phlegm, yellow bile, black bile
What are the four early theories of immunity?
Expulsion, Distention, Depletion, and Retention
What does the theory of expulsion encompass?
Something in the body from birth is expelled. Once gone it is no longer there to be expelled
What is the theory of distention?
The release of something through the skin leaves the skin permeable to it in the future
What is the theory of depletion?
Something needed by the agent (bacterium) is used up and not replenished
What is the theory of retention?
Bacteria produce substances which remain in the body and inhibit future growth of the microbe
What are some characteristic symptoms of an individual infected with smallpox?
Blisters turn into highly contagious scabs that fall off the body, leaving the victim permanently scarred and in some cases blind
Who is Edward Jenner?
The origin of Immunology is often traced to him. He discovered vaccination, using the weaker cowpox to protect against smallpox.
When was smallpox officially eradicated?
1979
What did Lazzaro Spallanzani try and do?
He tried to disprove the theory of spontaneous generation
How did John Needham provide a basis for the theory of spontaneous generation?
He heated substances in a flask in such a way as to sterilize them. After this treatment, the microbes emerged in the solutions
How did Spallanzani's work help to disprove this theory?
He repeated Needham's experiemtn but with higher temp and longer sterilization time, and no microbial growth occured.
What did Robert Koch prove?
That infectious diseases are caused by microorganisms, and each one is responsible for a particular disease
What are some of Koch's other key attributions to the field of immunology?
He developped stains for mcirobes,
The use of solid media for microbial growth
Identified several microbial pathogens
What did Louis Pasteur contribute to immunology?
He worked on fermentation, contributed to the demise of the belief in spontaneous generation, and to the proof of microbes as agents of disease

He also produced a vaccine against cholera in chickens and against rabies
What are the two "schools of thought" that were thought to be the natural defenses against infection?
-Antibodies
-Cells (phagocytic)
What did Elie Metchnikoff discover?
He discovered phagocytosis and argued that they are important effectors of immunity. He considered antibodies to be helpers of phagocytosis
-His work was a strong basis for the concept of innate immunity
Why is Paul Ehrlich considered one of the fathers of immunology?
He developed the first immunological theories, and postulated Ab-Ag complementarity
He demonstrated passive transmission of antibodies from mother to newborn
What component of serum proteins contain the antibodies?
The globulins
Who is Emil von Behring?
The founder of serum therapy
Who is Shibasaburo Kitasato?
Developed an effective therapeutic serum against tetanus for passive immunization
What is the basis of the use of therapeutic serum?
Toxins produced by bacteria can be rendered harmless by the serum of animals that have attenuated forms of the toxins, "antitoxins"
What is the principle of the precipitin reaction?
Serum can generate a precipitate because the antibodies within can cross link antigens and form large aggregates of antigen
What did Jules Bordet show?
Serum also contained a heat labile substance now known as COMPLEMENT
What did Ray Owen do?
Showed the genetically different twin calves were tolerant to grafts from the other
-Led to mechanism discovery of how the immune system distinguishes self and non-self
What did Sir Macfarlane Burnet do?
Came up with the theory of clonal selection
What is clonal selection?
There are preexisting cells that display surface receptors that are membrane bound forms of antibodies.
The theory states that specific lymphocytes proliferate in response to antigen and differentiate into effector cells that are antigen specific.
What is clonal deletion?
The elimination of immature lymphocytes when they bind to self antigens, which produces tolerance to self as required by the clonal selection theory.
What did James Gowan demonstrate?
That lymphocytes recirculate continuously between the blood and lymph and that lymphocytes are the centre of the adaptive immunological response
What are lymphocytes?
A class of white blood cells that bear variable cell-surface receptors for antigen
-T cells and B cells are the two classes
What is the main purpose of the lymph nodes?
Fluid from tissues that carry foreign material are drained here.
What is the thoracic duct?
Where lymphocytes exit the lymphatics, to go to the blood
What are lymphoid organs?
Aggregates of lymphocytes in a framework of non-lymphoid cells
What is the common lymphoid progenitor?
A precursor of antigen-specific lymphocytes as well as NK cells
What are NK cells?
Natural Killer cells, which are a type of lymphocyte that respond to the presence of infection but is not specific for antigen, and is thus considered to be part of the innate immune system.
What do B cells proliferate and diffentiate into once they bind to antigen?
Plasma cells, the effector form of B cells that produce antibodies
What are the three types of effector T lymphocytes?
Cytotoxic, Helper, Regulatory
What are central lymphoid organs?
These are where lymphocytes are generated, thymus and bone marrow.
What are peripheral lymphoid organs?
Where mature lymphocytes are maintained and adaptive immune responses are intiated
What are the peripheral lymphoid organs in the body?
Lymph nodes, spleen, and mucosal lymphoid tissues of the gut, nasal and respiratory tract, and the urogenital tract
Where to B and T lymphocytes originate?
They both originate in the bone marrow
Where do B lymphocytes mature?
In the bone marrow
Where do T lymphocytes mature?
In the thymus
What happens when B lymphocytes and T lymphocytes mature?
They circulate in the blood and in the peripheral lymphoid tissues, in which an adaptive immune response is generated if necessary
Where does the thoracic duct empty?
Into the subclavian vein
What did Peter Brian Medawar show?
Mice became immunologically tolerant of tissues if exposed to them in embryonic development
What did George Snell do?
He invented the congenic mouse strain that he used to discover the H histocompatibility complex
what was the H histocompatibility complex associated with?
Graft rejection
What did Peter Gorer discover?
The H2 antigen, by studying antibodies that are involved in rejection of TUMOR grafts
What are components of the innate immune system?
Phagocytes and complement
What does innate immunity respond to?
Structures that are commonly found on potentially harmful non-self material
How has innate immunity evolved?
Through the selection of useful receptors during evolution of a species (NOT indivdual)
What are the components of the adaptive immune system?
Antiobodies and lymphocytes
What does the innate system respond to?
-Can recognize a vast range of surfaces
-Produces alot of effector cells with specific receptors
-Produces antibodies that are specfic to foreign material
What is the difference concerning the time frame of response between the innate immunity and the adaptive immunity?
Innate immunity protects immediately or generates a maximal response quickly
Adaptive immunity requires several days to deliver high affinity antibodies or bring Ag specific T cells to the site of infection
What do all cellular elements of the blood, including the cells of the immune system, arise from?
Pluripotent hematopoeitic stem cells in the bone marrow
What is formed when the pluripotent stem cells divide?
Common lymphoid progenitor and common myloid progenitor
What do common lymphoid progenitor cells give rise to?
T cells, B cells, and NK cells
What does the common myeloid progenitor give rise to?
The granulocyte/macrophage progenitor and the megakaryote/erythrocyte progenitor
What does the granulocyte/macrophage progenitor give rise to?
Neutrophils, Eosinophils, Basophils, Mast cell precursors, and monocytes
WHat are granulocytes?
Neutrophuls, Eosinophils and basophils
Where do dendritic cells originate from?
Mostly the common myeloid precursors, but some from the common lymphoid precursor.
Where do platelets originate from?
The megakaryote
Where do erythrocytes originate from?
The erythroblast
What can macrophages differentiate into in the CNS?
The microglia
What do macrophages differentiate into in the liver?
Kupffer cells
What do macrophages differentiate into in the lung?
Alveolar macrophages
What do macrophages differentiate into in the bone?
Osteoclasts
What is the activated function of macrophages?
Phagocytosis and activation of bactericidal mechanisms
Antigen presentation
What is the activated function of dendritic cells?
Antigen uptake in peripheral sites
Antigen presentation in lymph nodes
What is the activated function of neutrophils?
Phagocytosis and activation of bactericidal mechanisms
What do neutrophils and othe rgranulocytes have in common?
They store potentially bioactive molecules in their granules
What happens to the granulocytes upon activation?
They release regulatory molecules that provide signals to other cells
What is the main function of eosinophils?
Killing of antibody coated parasites
What is the main function of mast cells?
Release of granules containing histamine and other active agents
What is the appearance of lymphocytes like when not activated?
They are small and have a more prominent nucleus than cytoplasm
In the case of CD4 T cell,s what does the TCR bind to?
MHC class II on antigen presenting cells
The CD4 also binds to the MHCII
How are more antigen specific T cells produced?
Signalling between APC and T cell promote the proliferation and differentiation to produce more specific T cells
What type of cells do effector T cells interact with?
THose that have the same MHC/peptide combination that activated them
What is the function of cytotoxic T cells?
They force apoptosis of virally infected cells, and interact with MHCI complexes
What is the function of TH1 cells?
Help activate macrophages to kill intracellular bacteria that were taken up
-Activated by MHCII
What is the function of TH2?
Activates antigen specific B cells by presenting them with specific antigen pieces, that bind to the surface IgG and promote the release of anti-toxin antibodies
-Activated by MHCII
Where are MHC class I proteins found?
On the surface of almost all nucleated cells
T cells that are CD8+ (cytotoxic) may interact with these as well
Where are MHC class II proteins found?
They are on Antigen presenting cells, including macrophages, B cells and dendritic cells.
-T cells with CD4+ marker interact with thse complexes
Where do monocyte-derived dendritic cells differentiate?
In tissues where they become resident
What are PAMPs?
Pathogen-associated molecular patterns
What do PAMPs do?
They activate dendritic cells by promoting innate immune responses to the pathogen derived material
What is the pathway of MHC 1 antigen presentation?
-Proteins are produced in the cytosol
-Cytosolic proteins are degradaded in the proteosome
-Peptides are transported to the ER and the peptide/class 1 complexes are assembled here
-The complexes are then transported in exocytic vesicles to the membrane, whre they are expressed at the surface of the cell
What is the pathway of MHC II antigen presentation?
-Extracellular proteins are taken up in vesicular compartments
2- The proteins are processed in endosomes
3- Synthesized class II molecules are associated with the peptides in vesicles
4- The MHC-peptide complexes are expressed at the cell surface
What is the difference between what a B cell binds and what a T cell binds?
-T cell receptors only bind peptides that are in the groove of MHC
-B cell receptors can bind to epitopes on surfaces of proteins, or carbs or lipids
-They can bind to aggregates of macromolecules, whole pathogens, or even chemical compounds
What are haptens?
Small chemical antigens
What happens when a B cell encounters material which has an epitope for its surface Ig?
It binds and internalizes the material
What happens if a protein moiety associated with the surface Ig and was internalized?
It is processed into peptides and some of these are presented by class II MHC, which is recognized by helper T cells which activate the B cell.
What type of peptides are presented on class I MHC?
Viral peptides, which are synthesized in the cytosol of the infected cells
What is stochastic gene rearrangement?
It explains the fact that it is likely for a T cell receptor or B cell receptor to recognize a foreign molecules
How is stochastic gene rearrangement controlled to prevent autoreactivity?
Negative selection and self-tolerance
How do the few naive T cells which have receptors for peptides from an infecting pathogen meet one of the few dendritic cells which are presenting them?
Lymphocyte recirculation and the structure of lymphoid tissues facilitates this chance encounter
What is a difference between how the TCR alpha chain and beta chain are expressed?
The beta chain is glycosylated during processing, and the TCR alpha chain is not
What is a difference between TCR alpha and beta gene recombination and transcription?
The beta chain has joining of the D and J and then V regions, while the alpha chain only has joinging of the V and J regions
How is variability generated in the sequences encoding the TCR Complementarity Determining Regions?
Splicing
What is required to activate a T cell?
Strong binding of the peptide to the TCR
What is positive selection?
In the thymus, T cells are allowed to develop if they have some affinity for self-peptide loaded MHC
WHat is negative selection?
Ensures that autoreactivity does not take place
MHC cant have too much of an affinity (tight binding) to the T Cell.
What are three types of cell surface receptors?
Cell surface proteins, soluble proteins in body fluids, and cytoplasmic proteins which sense viral infection
How do cell receptors bind microbes?
Via multivalent binding to PAMPs.
Which complement protein is known for binding IgM and IgG in immune complexes?
C1q
What can C1q also bind to?
Directly to microbial surfaces even in the absence of antibodies
What are MBL receptors?
Mannan-binding-lectin, a soluble protein that binds certain carbohydrates and associates with MASPs
What are MASPs?
Serine proteases of the lectin pathway of complement activation; they bind to mannose-binding lectin and cleave C4
What are SP-A and SP-D?
Soluble receptors
Pulmonary surfactant proteins that opsonize microbes for alveolar macrophages
What are ficolins?
They are like collectins, but NOT lectins. They bind patterns of acetyl groups on carbohydrates
Associate also with MASPs
What is CRP?
A soluble receptor, C-reactive protein
-Pentaxin which binds PAMPs via phosphocholine.
-It also triggers complement by binding the C1q collagen domain
What do macrophage membrane receptors generally recognize?
-Many molecules that are normally found in the body: such as normal intracellular molecules or altered molecules (chemically, degradation or chemical modification)
-Also collectins, complement, and antiobdies
-Also for foreign material
What is the Mannose Receptor Family?
A membrane receptor for foreign material, have multiple C-type lectin-like carbohydrate binding domains
What is DEC205?
Dendritic Cell C-type multi-lectin receptor, membrane receptor
What are scavenger receptors?
They are surface receptors that bind negatively charged ligands, such as lipoteichoic acid found in the Gram positive cell wall.
What are toll-like receptors?
Surface receptors, that are not for the uptake of foreign material but are used in signalling the PRESENCE of foreign material
What is the f-MLP receptor?
Formyl-methionine at polypeptide N terminal is the signal here
Who discovered the toll-like receptor?
Christiane Nusslein-Volhard
How do TR's work in Drosophila?
Fungal expression results in expression of Anti-Microbial Peptides, that bind the TF dorsal and activate it in conjunction with TR
What is TLR-1 against?
Lipopeptide
What is TLR-2 against?
Lipotechoic acid, peptidoglycan, zymosan, lipoprotein, and HSP70
What is different about HSP70 from all the other TLR-2 ligands?
It is released from damaged cells (not part of a foreign microorganism)
What does TLR-3 target?
dsRNA
What does TLR-4 target?
LPS, Hyaluronic acid fragments, HSP 60 and 70
What does TLR-5 target?
Flagellin
Out of the TLR-4 targets, which are not part of foreign proteins?
Hyaluronic acid fragments, HSP 60 and 70
What does TLR-6 target?
Zymosan
What does TLR-9 target?
Unmethylated CpG islands
Which TLRs are on the cell surface?
TLR1, 2, 4, 5 ,6
Where are TLR 3, 7, 8 and 9?
They are in the endosomal compartment and make contact with agonist in the phagolysozome in phagocytic cells
How do TLRs act?
As dimers
Which TLRs act as homodimers?
TLR-5, TLR-4, TLR-3, TLR-7, and TLR-9
Which TLR's act as heterodimers?
TLR-6/TLR-2 and
TLR-1 and TLR 2
What does the TLR-6 and TLR-2 heterodimer recognize?
Diacyl lipopeptides
What does the TLR-1 and TLR-2 heterodimer recognize?
Triacyl lipopeptides
Where are the diacyl lipopeptides and triacyl lipopeptides derived from?
Lipotechoic acid of gram positive cell walls and the lipoproteins of Gram negative surfaces
How is signalling carried out through TLRs?
Cytoplasmic TIR domains (Toll IL-1 Receptor domains)
How do the TIR domains affect signalling cascades?
Via TIR adapters
What is an example of a TIR adaptor?
MyD88
What are the two pathways that TLR-4 activate?
MyD88 dependent and MyD88 independent
What is the MyD88 dependent TLR-4 activated pathway like?
Activates NFKb which is like a TF, that activates cytokine production (TNFalpha)
What is involved in the MyD88 independent pathway?
Induction of nitric oxide synthetase (iNOS) and type 1 interferons
What are some examples of type 1 interferons?
IFN alpha/beta
How is LPS detected by TLR-4?
3 steps:
1) LPS is bound by LPS binding protein in the fluid
2) This LPS/ LPSBP complex is passed to CD14 on phagocyte
3) LPS/ CD14 interacts with TLR-4
What do bronchial epithelial cells responding to dsRNA via TLR3 do?
They produce cytokines and beta defensins 2 and 3
What do tracheobronchial epithelial cells responding to LPS via TLR2 and TLR4 produce?
Beta defensin-2
Are there multiple types of dendritic cells, what differe between them if so?
Yes, there are many varieties of dendritic cells. Their expression of TLRs differ and consequently they respond differently to microbial materials
What are six different mechanisms of bacteriocidal agents produced by macrophages?
Acidification, toxic oxygen-derived products, toxic nitrogen oxides, antimicrobial peptides, enzymes, and competitors
What pH do phagocytes generate to kill bacteria?
3.5-4
What are some toxic oxygen derived products that phagocytes produce?
Superoxide O2, hydrogen peroxide H2O2, singlet oxygen O2, hydroxy radical OH, hypohalite OCl-
What are the toxic nitrogen derived products that phagocytes produce?
Nitric oxide NO
What are the antimicrobial peptides that macrophages produce?
Defensins and cationic proteins
What are the enzymes that phagocytes produce?
Lysozyme, and acid hydrolases
What does lysozyme do?
Dissolves cell wall of some Gram-positive bacteria
What do acid hydrolases do?
Further digest bacteria
What type of competitors do phagocytes produce?
Lactoferrin (binds iron)
and VB12 binding proteins
What are the main producers of IL-1?
Macrophages and keratinocytes
Where does IL-1 act and what type of effect does it exert?
It acts on the lymphocytes to enhance their responsiveness
It also acts on the liver to induce the production of acute phase proteins
What are the main producers of IL-6?
Macrophages and dendritic cells
Where does IL-6 act and what type of efffect does it exert?
-It acts on the lymphocytes to enhance their responses
-It also acts on the liver to induce the production of acute phase proteins
What is another name for CXCL8?
IL-8
Where is IL-8 produced?
By macrophages and dendritic cells
Where does IL-8 act and what type of effect does it exert?
It acts on phagocytes and is a chemoattractant for neutrophils
What is the main producer of IL-12?
Macrophages and dendritic cells
Where does IL-12 act and what type of effect does it exert?
On Naive T cells, it diverts immune response to T-helper cells 1 and is proinflammator, induces cytokine secretion
Where is TNFalpha produced?
By macrophages and dendritic cells
Where does TNFalpha act?
TNFalpha acts on the vascular endothelium
What type of effect does TNFalpha have on the vascular endothelium?
It induces changes in the vascular endothelium
What are some of these changes in the vascular endothelium?
Expression of cell adhesion molecules, changes in cell-cell junctions with increased fluid loss and local blood clotting
What are some examples of adhesion molecules?
E and P selectin
What is immediately beneath the first line of defense, the skin?
Beneath this are lymphoid tissues which are adapted to provide protection and efficient responses to infection
What are some key properties of the skin?
They are a flexible barrier, protect from water loss, protect from friction and impact wounds, produce vitamin D, regulate body temperature through sweat
What are four types of cells in the skin that are key for the immune system?
Keratinocytes, Langerhans cells, Mast cells, and lymphocytes
Why are the keratinocytes important?
-Provide structural and mechanical integrity
-Secrete cytokines
Why are Langheran cells important?
They are antigen presenting cells of the skin
What is an important role of mast cell in the dermis?
They release inflammatory mediators that stimulate the expression of adhesion molecules in the vascular endothelium, and encourage leukocytes to pass from the blood to the tissues
What are the langerhan's cells and lymphocytes of the skin apart of?
The SALT (Skin-Associated Lymphoid Tissue)
What does the MALT include?
NALT (Nasal associated lymphoid tissue)
GALT (gut associated lymphoid tissue)
BALT (bronchus associated lymphoid tissue)
Where is the NALT located?
In the tonsils and adenoids
Where is the GALT located?
In Peyer's patches
What is the difference concerning the epithelium between local infection and no infection?
Normally, molecules only adhere to the epithelial surface, but in local infection the epithelium is penetrated
What protects us from molecules that adhere to the cell surface?
Normal flora
Local chemical factors
Phagocytes
Once the epithelium is penetrated, how are we protected?
-Antimicrobial peptides, macrophages, and complement
-GammadeltaT cells are ACTIVATED
How are we protected when the infection progresses to the level of the tissue?
-Complement, Cytokines, Chemokines, phagocytes, NK cells, activation of macrophages, blood clotting, migration of dendritic cells to lymph nodes
How does adaptive immunity finally clear the infection?
Specific antibody, T-cell dependent macrophage activation and cytotoxic T cells
What are inflammatory mediators?
Regulatory molecules
What do inflammatory mediators cause?
Vasodilation, Vascular Permeability, Expression of adhesion molecules and clot formation
What is a consequence of the vasodilation induced by inflammatory mediators?
Increaed blood flow, resuling in increased redness and heat
What is a consequence of vascular permeability?
Fluid and proteins enter the tissues, resulting in edema
What does the expression of adhesion molecules result in?
The recruitment of neutrophils, macrophages and other leukocytes
How does clot formation protect us?
Helps prevent the spread of the pathogen throughout the blood vessels
What are the inflammatory mediators?
Lipid mediators (prostaglandins, leukotrienes, Platelet activating factor), TNFalpha, histamine, complement derived polypeptides C5a, bradykinin
How can TNFalpha be both damaging and protective?
Locally, the release of TNFalpha has a protective effect, but it can be damaging if released systemically
What is similar about the damaging and protective mechanisms of TNFalpha?
They both act on blood vessels to increase blood flow, vascular permeability to fluid, proteins and cells, and to increase endothelial adhesiveness for leukocytes and platelets.
What happens in local release of TNF alpha?
There is increased release of plasma proteins into the tissue. There is increased phagocyte and lymphocyte migration to the itssue and increased platelet adhesion. Blood clotting allows the prevention of spreading of infection, and finally the fluid travels to the lymph node where an adaptive immune response can occur
How can TNFalpha be both damaging and protective?
Locally, the release of TNFalpha has a protective effect, but it can be damaging if released systemically
What is similar about the damaging and protective mechanisms of TNFalpha?
They both act on blood vessels to increase blood flow, vascular permeability to fluid, proteins and cells, and to increase endothelial adhesiveness for leukocytes and platelets.
What happens in local release of TNF alpha?
There is increased release of plasma proteins into the tissue. There is increased phagocyte and lymphocyte migration to the itssue and increased platelet adhesion. Blood clotting allows the prevention of spreading of infection, and finally the fluid travels to the lymph node where an adaptive immune response can occur
What occurs in the systemic infection?
This is when sepsis occurs: TNFalpha is released into the blood stream by macrophages in the liver and spleen.
-It results in decreased blood volume, hypoproteinemia, and neutropenia (low neutrophils, followed by neutrophilia (high neutrophils).
-This results in shock, disseminated intravascular coagulation with depletion of clotting factors leading to bleeding, multi organ failure and death
What is IL-8 produced by?
Monocytes
Macrophages
Fibroblasts
Keratinocytes
Endothelial cells
What are the receptors for IL-8?
CXCR1
CXCR2
Which cells are attracted by IL-8?
Neutrophils
Naive T cells
What are the major effects of IL-8?
-Mobilizes, activates and degranulates neutrophils
-Angiogenesis
What type of chemokine is IL-8?
It is a CXC chemokine, which is found on chromosome 17 and has an aa residue (X) between two adjacent cysteine (C) residues
What type of chemokine is MCP-1? (CCL2)
A CC chemokine, that has two cysteine residues adjacent. The genes for CC chemokines are on chromosome 4
What is MCP-1 produced by?
Monocytes, Macrophages, Fibroblasts and keratinocytes
What is the role of MCP-1?
It activates macrophages,
-Causes basophil histamine release
-Promotes TH2 immunity
What type of receptors are chemokine receptors?
G protein coupled receptors
What are the receptors for chemokines in the same famiyl as?
The receptors for the anaphylotoxins C3a and C5a
What are anaphylatoxins?
Small complement proteins that are released by cleavage during complement activation. They recruit inflammatory effectors and fluid to the site of release
How are neutrophils attracted and activated?
A small peptide of bacterial origin called f-MLP (formyl Met Leu Phe)
What type of receptor does f-MLP (formyl Met Leu Phe) act through?
A G protein coupled receptor
What do TNFalpha and f-MLP?
They activate the oxidative burst in neutrophils
What are the three categories of adhesion molecules?
Selectins, Integrins and Immunoglobulin superfamily
What is the general function of adhesion molecules?
They have a role in leukocyte migration, homing, and cell-cell interactions.
What are the types of Selectins?
P and E selectin
Where is P selectin found?
In activated endothelium and platelets
Where is E selectin found?
In activated endothelium
What is the ligand of P selectin?
sial-Lewis, and PSGL-1
What is the ligand of E selectin?
Sialyl-Lewis carbohydrate
Where are integrins found?
In monocytes, T cells, macrophages, neutrophils, dendritic cells, etc
What do integrins bind?
Cell adhesion molecules like ICAMs, C3b, fibrinogen, Fibronectin
What are some examples of Immunoglobulin superfamily cell adhesion molecules?
ICAM's, VCAM, and PECAM
Where are the immunoglobulin superfamily cell adhesion molecules typically found?
Activated, resting endothelium
Dendritic cells
Leukocytes/ cell-cell junctions
What is phagocyte adhesion to vascular endothelium mediated by?
Integrins
What happens when vascular endothelium is activated by inflammator mediators?
It expresses two adhesion molecules, ICAM1 and 2 which are ligands for intregrins on the phagocytes
What is L selectin important for?
For naive lymphocytes, it is an important cell adhesion molecule involved in traffiking leukocytes through endothelial venules into lymph nodes
What is a difference in expression of the endothelial cell selectins P selectin and E selectin?
P-selectin is preformed and stored in vesicles and is quickly expressed
E-selectin is synthesized and expressed later
What are some molecules that stimulate P selectin expression?
LTB4, Histamine, and C5a
Where is P selectin formed from?
Wiebel-Palade bodies- granules
What is the time frame of P selectin expression?
Within minutes
When are E selectin and I-CAM1 expressed?
In a few hours, induced by LPS and TNF-alpha
What does IL-8 do to leukocytes?
Increases integrin affinity, promote diapedesis, and chemotaxis
What is diapedesis?
The movement of blood cells, particularily leukocytes, from the blood across blood vessel walls into tissues
How are leukocytes able to roll along the endothelial cells in the blood vessel?
The association of selectins to sialyl lewis residues on the leukocyte is weak
Look at lymphnode structure!
GO
Where do activated B cells proliferate and differentiate?
Germinal centers in follicles of the lymph node
What is a lymph follicles?
Lymphocytes are densely packed in these, with cavities in the middle
What is the purpose of the High Endothelial Venules?
This is where lymphocytes migrate from the blood to the lymph node
What does L selectin on the T cell do?
It binds to sulfated sialyl Lewis molecules, CD34, other CAM's... on vascular endothelium in the lymphoid tissues
What is SLC?
Secondary Lymphoid Tissue Cytokines
What are SLC produced by?
High vascular endothelium
Lymphoid tissue stroma cells
Dendritic cells
What do SLC do?
Increases the affinity of LFA-1 for its ligand on endothelial cells, and promotes migration into the lymphoid organ
What is LFA-1?
Lymphoid Function-Associated Antigen-1
What do Naive T cells bind in the mucosal endothelium via their L-selectin?
Mad-CAM-1
What do Naive T cells bind in the high endothelium venules via their L-selectin?
Gly-CAM1
or
CD34
What do integrins on T cells bind to on APC's?
ICAM-1
What do integrins on some T cells bind to in the mucosal endothelium?
Mad-CAM-1
What do integrins on effector T cells bind to in the activated endothelium?
VCAM-1
What event is similar to leukocyte extravasation into infected tissues during the inflammatory response?
The lymphocyte entering the lymph node through the high endothelial venules
How does the process of lymphocytes entering the lymph node via the high endothelial venules work?
-Circulating lymphocytes enter the HEV
-Binding of L-selectin to Gly-CAM1 and CD34 allows rolling interaction
-LFA-1 is activated by chemokines
-Tight binding of LFA-1 to ICAM
-Lymphocytes migrate to lymph node by diapedesis
What is the difference between spleen and lymphoid tissues?
The spleen catches the antigen from the blood
What are the two main parts of the spleen?
The red pulp and white pulp
How is the red and white pulp arranged?
The red pulp is interspersed with white pulp
What is PALS?
Periarteriolar lymphoid sheath made of T cells that is surrounding the central ateriole.
What is the PFZ?
Perifollicular zone- where fanning blood vessels terminate.
What is the purpose of the PALS?
This is where lymphocytes and antigen loaded dendritic cells come together
What is the purpose of the white pulp?
This is where blood flows into a trabecular artey into a central arteriole
Where does the follicular arteriole originate?
In the PALS, it then traverses the folicle, goes through the marginal zone and opens into the perifollicular zone
What does a Peyer's patch contain?
Numberous B cell follicles with germinal centers
T cells in the areas between follicles
What is the subepithelium dome?
The layer between the surface epithelium
What are Peyer's patches?
They have no afferent lymphatics and the antigen enters directly from the guit across a specialized epithelium known as M cells.
What is characteristic about these M cells?
They have characteristic membrane ruffles
What is transcytosis?
The active transport of molecules across epithelial cells
What type of cells perform transcytosis and why?
M cells in Peyer's patches take up antigens by this process
What is a classical definition of Peyer's patches?
They are lymphoid organs along the small intestine, especially the ileum. They contain lymphoid follicles and T-cell areas.
What are multi-fenestrated cells?
They have multiple openings and facilitate antigen uptake
What happens if lymphocytes do not encounter antigen in the lymph node?
The leave through the efferent lymphatic vessel and eventually re-enter the blood via the thoracic duct.
How do naive lymphocytes gain survival skills?
When passing through lymphoid tissues
How do lymphocytes recirculate after activation?
Not randomly= If activated in a mucosal tissue, will migrate back to the MALT
What binds and activates a T lymphocyte?
A dendritic cell
What bind and activates a B lymphocyte?
A T lymphocyte
What are some differences between a dendritic cell activated by LPS and an immature dendritic cell?
Mature DC's are often located in the lymphoid tissues, have reduced endocytosis and have high surface MHC II and co stimulators. Mature DCs function to stimulate T cells.

Immature DC cells are also located in the peripheral tissues as well as the lymphoid. They are highly endocytotic, and have low MHCII expression. Immature DC function to accumulate antigen
What does the TCR of CD4+ cells bind to?
MHCII/peptide complex
What does the CD4 marker of CD4+ tells bind?
MHC II- stabilizes it
What are the three types of T cells?
CD8+ (Cytotoxic T Cell)
CD4+ (T helper cell 1= binds to macrophages
T helper cell 2= binds to B cells)
How are NK cells prevented from killing the normal human cell?
The NK cell posseses Killer Inhibitory Receptors (KIRs) that interact with MHC I molecules.
In what case would an NK cell exert its cytotoxic function?
When the cells have reduced MHC expression, and therefore the NK cell does not receive the negative signals and is stimulated by its activating receptors
-It releases its granule contents that induce apoptosis in the cell.
Which cytokines increase NK cell activity?
IFN-alpha
IL-12
What does a synergistic action of IFN-alpha and IL-12 result in?
The secretion of IFN-gamma from the NK cells
What are some roles of IFN-gamma?
Can help activate the macrophage
Causes more TH1 cells to be made in the CD+ category
What other cell releases IFN-gamma?
TH-1 helper cells
How do TH1 cells help macrophages?
They help them clear mycobacterium