Module 2 Flashcards
innate immunity
- first line of defense against foreign invaders
- operated non-specifically during early phases of an immune response, without the need for prior exposure to the invading pathogen
- fights all pathogens in the same way and is ready to be mobilized upon the first signs of infection
sub-sections of the innate IS
- immune barriers
- inflammation
- pattern-recognition
- phagocytosis
immune barriers sub-section of innate IS
immune system is made of physical, soluble and cellular barriers that are scattered throughout the body
inflammation - sub-section of innate IS
innate immunity responds immediately to an invading pathogen
inflammatory response
the first immune response events following the breach of the physical barrier by a pathogen
pattern-recognition sub-section of innate IS
- innate IS recognizes general patters not specific for any one antigen
- this is largely performed by pattern-recognition receptors (PRR) exposed on innate immune cells
phagocytosis sub-section of innate IS
- some immune cells have phagocytic properties
- the group of cells sharing those abilities are called phagocytes
3 types of immune barriers
- physical
- cellular
- soluble
physical immune barrier
- made of every structure located at the interface between the inside and outside of the body (prison walls)
- made of physical and chemical components
examples of physical immune barrier
- skin
- cilia
- bodily secretions
primary function of the physical immune barrier
prevent or slow down the invasion of pathogens
physical components to the physical immune barrier
- the skin is the largest organ of the body and it creates a barrier that pathogens cannot cross unless it is breached
- mucous membranes cover the cavities of the body including the respiratory, gastrointestinal, urinary, and reproductive tracts
- these membranes contain specialized stuctures such as cilia and produce mucous
cilia
hairlike vibrating structures that can trap particles, preventing them from reaching vulnerable areas of the mucous membrane
mucous
viscous substance secreted by mucous membranes
mucous and cilia working together as physical immune barrier
- microorganisms get caught in sticky mucous which prevent them from reaching the lungs
- then the cilia of the respiratory tract sweep these organisms up and out of the body through coughing or sneezing
chemical components to the physical immune barrier
- tears and saliva are mucous membrane secretions which contain active antimicrobial substances such as lysozyme
- gastric acid destroys most bacteria and toxins that enter the stomach
lysozyme
an enzyme that catalyzes the destruction of the cell walls of certain bacteria
gastric acid
digestive fluid formed in the stomach (pH ~2.5)
cellular immune barrier
made of the various cells that play a role in the innate immune response
(prison guards)
examples of the cellular immune barrier
- neutrophils
- macrophages
- dendritic cells
- natural killer cells
primary function of the cellular immune barrier
prevent or slow down the invasion of pathogens that have broken through the PHYSICAL BARRIER
neutrophils
most common leukocyte found in blood of mammals (~45-70%)
function of neutrophils
- phagocytes that patrol the body to find, engulf and destroy pathogens
- circulate in the blood for ~12hrs before entering tissues by diapedesis
- recruited to a site of infection by resident macrophages that have encountered pathogens
lifespan of neutrophils
1-3 days after entering the tissues
macrophages
- phagocytes that patrol the body to find, engulf and destroy pathogens
- can either take up residence in a specific tissue, or move freely/patrol throughout a larger area of tissues
- contribute to tissue repair and present antigens to other immune cells such as T-cells
- become activated after phagocytosing pathogens or in response to cytokine signaling
dendritic cells
phagocytes that are often in contact with the external environment (specifically Langerhans DC)
function of dendritic cells
- engulf foreign antigens that have invaded the initial barriers of the innate immune system
- present antigens on their cell surface through peptide: MHC complexes, which can be recognized by helper T-cells
- major link between innate and adaptive immune systems
functions of natural killer cells
- recognize abnormal cells lacking antigen-specific receptors
- destroy abnormal cells of the body, which include tumorous and virus-infected cells
- bind to cell surface of target cells and release chemicals causing pores to form in the cell membrane, leading to lysis
soluble immune barrier
- made of macromolecules which contribute to the mediation of an innate immune response (communication system)
- play a key role in the development of an inflammatory innate immune response, which is induced following the penetration of an infectious agent through the bodys physical barriers
examples of soluble immune barrier
complement and cytokines (two categories of the macromolecules)
complement system
made up of over 30 soluble proteins
functions of the complement system
- complement proteins circulate in the blood normally in an inactive form
- can be directly activated in the presence of extracellular pathogens or indirectly by pathogen-bound antibody
what does activation of the complement system induce?
induce a cascade of reactions between various complement proteins, leading to formation of MAC and in parallel enhances, or complements the efficiency of other immune functions, such as inflammation and phagocytosis
3 major pathways the complement system can be activated
- classical
- alternative
- lectin
inflammation process of the complement system
- includes attraction of various immune cells in the site of infection through release of chemotactic molecules (histamine and cytokines)
- activated CP bing to complement receptors on immune cells, such as mast cells and basophils, inducing the release of these substances which enhance the inflammatory response
chemotactic molecules
inducing the movement of cells toward the site where the substances are originally released
phagocytosis of the complement system
activated complement proteins mostly C3b, opsonize pathogens thereby targeting them for destruction by phagocytosis
opsonize
making a foreign particle more susceptible to phagocytosis by binding to the antigen and marking for ingestion
membrane attack complex (MAC) of complement system
- destroy extracellular foreign invaders through the formation of membrane attack complexes
- create holes in the pathogen which leads to its lysis and death
main functions of the complement system
- opsonization which induces phagocytosis
- chemotaxis which induces inflammation
- lysis through its MAC
cytokines
- small proteins secreted by various immune cells in response to a number of different stimuli
- chemical mediators that play a key role in cell-to-cell communication
- strong affinity for specific type of cytokine receptor
what is the function of cytokine signalling?
regulate immune processes, such as immune responses, inflammation and hematopoiesis
characteristics if cytokines
- autocrine vs. paracrine vs. endocrine
- specificity and affinity
- alter gene expression
- pro-inflammatory vs. anti-inflammatory
autocrine
sending and receiving cell is the same
paracrine
sending and receiving cells are near each other
endocrine
sending and receiving cells are distant from each other
where do the majority of cytokines act?
locally, having an autocrine or paracrine effect
what do auto, para and endocrine characterize?
the location of action depending on the site of secretion of cytokines by an immune cell
specificity and affinity of cytokines
- cytokines bind to specific receptors on the membrane of their target cells
- cytokines and their receptors exhibit very high affinity for one another
ligand
biological molecule that attaches to a protein (receptor) to induce a signal
alter gene expression (cytokines role)
binding of cytokine to its receptor initiates a series of reactions that ultimately alter gene expression
- this may affect cell growth and maturation and have lots of roles in the hosts response to infection and disease
pro-inflammatory cytokines
- made by most immune cells
- when secreted these cytokines will induce an inflammatory response within the body
anti-inflammatory cytokines
- made by several immune cells
- work to limit the inflammatory response within the body by inhibiting pro-inflammatory cytokine production and activating the immune cells that promote healing
what happens if pro-inflammatory cytokines are not properly controlled?
leads to complication such as tissue damage due to an excessive inflammatory state
what happens if anti-inflammatory cytokines are not properly controlled?
a lack of an immune response to pathogen may occur which can result in spreading of the pathogen
inflammation
- occurs in response to a pathogen invading the physical barrier of the innate immune system
- series of biological reactions to invasion of harmful infectious agents into the body
characterization of inflammation
- redness
- pain
- heat
- swelling
steps of inflammation
- Alteration of blood flow to the injured area
- Influx of phagocytic and other immune cells
- Removal of foreign antigens
- Healing of damaged tissue
physical response of inflammation
can result in a loss of function
purpose of inflammation
purpose is to localize and eliminate the invading pathogen, in an effort to stop it from spreading, and to remove damaged tissue
major events of inflammation process
- breach
- vasodilation
- permeabilization
- extravasation
- phagocytosis
breach - inflammation
- pathogens must find a breach in order to be able to enter the body due to the physical barrier being sealed
- can occur via a wound created by a nail or glass
- will damage cells and give opportunity for pathogens
to break through the physical barrier
vasodilation - inflammation
- first major event
- increase in diameter of the blood vessels, and permeabilization
of the capillaries near the affected area
what does vasodilation in inflammation induce?
physiological changes by vasoactive and chemotactic factors secreted by damaged tissues and activated immune cells, such as macrophages and mast cells
typical consequences of vasodilation in inflammation?
redness and heat
- induces a higher blood volume around the infected tissue
vasoactive
components affecting the diameter
of blood vessels
chemotactic factors
components inducing the movement of cells in response to a chemical stimulus
permeabilization - inflammation
- allows accumulation of excess fluid at the site of infection called exudate
- includes both pro-inflammatory cytokines (specifically chemokines) and complement proteins that will be activated in the presence of the extracellular pathogens
exudate fluid
contains proteins that contribute to the mediation of inflammatory response
what is the function of the proteins in permeabilization?
to attract the cellular barrier key players to site of infection
swelling in permeabilization
is a consequence of accumulation of fluids at infection site, forming what is called an edema
extravasation - inflammation
- the chemotactic factors released by cells during vasodilation and permeabilization steps induce the recruitment of more immune cells to site of infection
what are the first type of cells to arrive by chemotaxis to site of infection?
neutrophils
neutrophils arriving to infection site - extravasation
when neutrophils first reach site of infection they stick to blood vessel walla (margination) then they squeenze through the blood vessel walls (extravasation/diapedisis) to help fight infection
phagocytosis - inflammation
- at infection site, neutrophils and other phagocytes (macrophages and dendritic
cells) engulf the pathogens - destroys extracellular pathogens
- in innate IR is not effective in neutralizing the threat, the adaptive IR will be induced
correct order in which the inflammatory response steps occur
- vasodilatation
- permeabilization
- chemotaxis
- margination
- extravasation
the inflammatory response (3 D’s)
- detect
- deflect
- destroy
symptoms if illness with inflammation
signs of healing
pus
made of neutrophils - most common phagocyte
what happens to neutrophils after destroying a pathogen?
they self-destroy
how do macrophages destroy pathogens?
macrophages use cytoplasmic extensions to destroy pathogens and can do this repeatedly
how do natural killer cells destroy pathogens?
protrude them
fever
macrophages come after neutrophils to take over, if they don’t work they release pyrogen chemicals that tap the hypothalamus and raise your body temperature to burn everything
- adaptive immune defences come in after
how does heat induce healing?
increases the metabolic rates of cells allowing them to repair themselves faster
how does swelling induce healing?
swelling leaks proteins, which help clot blood and form scabs
- also recruits local phagocytes and lymphocytes to help destroy pathogens and clean up dead cells
pattern recognition receptors (PRRs)
- capable of recognizing repeated molecular patterns of pathogens
- can be expressed by both innate and adaptive immune cells (mostly innate)
families of PRRs
- C-type lectin receptors
- NOD-like receptors
- toll-like receptors (TLRs)
molecular pattern
- recognized by PRRs
- conserved motifs and certain subsets that can be found in various groups of pathogens, where they are called Pathogen-Associated Molecular Patterns (PAMP’s)
pathogen-associated molecular patterns (PAMPs)
molecular structures either expressed on the surface of or found inside pathogens
examples of PAMPs
- lipopolysaccharides (LPS) are found on cell surface of gram-negative bacteria
- double-stranded RNA found inside dsRNA viruses
2 major categories of molecular patterns recognized by PRRs
- pathogen-associated molecular patterns (PAMPs)
- danger-associated molecular patterns (DAMPs)
***play a key role in ability of innate immune cells to recognize invaders
PAMPs
molecules associated with groups of pathogens that are recognized by immune cells
what do PAMPs include
- functional structures of pathogens
- repeated sequences of protein, glycoprotein, lipoprotein, amino acids, etc that are conserved across specific groups of microbes
***allows to initiate a quick response to infection by inducing an innate IR
DAMPS
- molecules released by stressed cells undergoing necrosis
- are host biomolecules
- indicate damage to the body
- initiate an inflammatory response
examples of DAMPs
- abnormal location of a cell structure (DNA found outside of mitochondria of nucleus)
- cell-stress indicator molecules (heat-shock proteins)
necrosis
morphologic changes that accompany death of cells and that release large amounts of intracellular components to the environment
toll-like receptors (TLRs)
class of PRRs whose signaling plays an essential role in the innate IR
where are TLRs expressed?
- plasma membrane
- endosomal/lysosomal membranes of mammalian cells
(depends on type of PAMP or DAMP)
what do TLRs initiate the transcription of genes?
- inflammatory cytokines
- chemokines
- costimulatory molecules
*** these contribute to the activation of innate immune cells, which increase the ability of phagocytes to engulf pathogens and enhance their ability to present antigens to adaptive IS
2 major roles of TLRs
- recognize PAMPs and/or DAMPs
- induce expression of signalling to activate T-cells
how do TLRs sense the presence of an infection?
through recognition of PAMPs and/or DAMPs
TLR signalling process
- after engulfing bacterium, immune cell (APC) will present pieces of the pathogen (antigens) on its cell surface
through the peptide: MHC complex - APC will increase its production of
costimulatory molecules, which are involved in the strength
and stability of the antigen presenting process - an immunocompetent naïve T cell specific for the antigen presented by the dendritic cell will bind to the peptide: MHC complex through its TCR
- this interaction will activate and initiate an adaptive IR
phagocytosis
second line of defence against the invading pathogen within innate immunity
- type of endocytosis, in which a cell takes up particulate material (such as bacteria) from its environment by invaginating its membrane to form a vacuole
what are the ways phagocytosis can be induced?
- the recognition of a PAMP by a phagocyte through its PRR
- through pathogen opsonization
major innate immune cells involved in maintaining cellular barrier
- neutrophils
- macrophages
- DCs
neutrophils
- first cells to arrive from blood to site of infection
- perform early phagocytosis, eliminating pathogen quickly
- can initiate an inflammatory response
macrophages
- migrate from the blood to tissues to become macrophages
- perform phagocytosis most efficiently (called “big eaters”)
- release cytokines that stimulate inflammation and recruit other immune cells
dendritic cells
- recognize microbes and initiate phagocytosis
- most efficient antigen presenting cell
- play a major role in the initiation of the adaptive immune response
steps of phagocytosis
- attachment
- ingestion
- fusion
- digestion
- release
attachment - phagocytosis
pathogen becomes attached to membrane
evaginations called pseudopodia
ingestion - phagocytosis
pathogen is ingested, forming a vacuole,
called phagosome within the cell
fusion - phagocytosis
phagosome fuses with a lysosome, releasing
lysosomal enzymes that degrade macromolecules
and other materials, such as bacteria
digestion - phagocytosis
pathogen is destroyed and digested by the lysosomal enzymes
release - phagocytosis
digestion products are released from the cell via exocytosis
exocytosis
process in which the vacuole membrane fuses with
the cell membrane
evaginations
a protruding structure produced by turning a membrane outward
adaptive IS
- second line of defence against foreign invaders
- longer time to initiate
- creates specific response against pathogens
- produces memory cells that will be able to respond faster and stronger in case if re-infection
main characteristics of the adaptive IS
specificity and diversity
specificity
- cells recognize one specific epitope of a pathogen
- creates a unique immune reaction to eliminate the infectious agent
diversity
adaptive IS is composed of countless numbers of cells to be able to fight any pathogen encountered
humoral immunity
B-cells and antibodies
cell-mediated immunity
T-cells
B-cell
- key component of humoral response
- mature in the bone marrow
- get so tired they want to die off but Helper T-cells tell them to keep going
surface receptor of B-cells
B-cell receptor (BCR)
function of B-cells
antibody factory
subsets of B-cells
- plasmocyte
- mamory B-cell
plasmocyte
- effector cell
- produce large quantities of antibodies
memory B-cell
- memory cell
- express BCR on their cell surface
T-cell
- key component of cell-mediated response
- mature in thymus
surface receptor of T-cells
T-cell receptor (TCR)
function of T-cells
cytotoxic activity or help the activation of IR
diversity of T-cells
- CD4+ Helper T-cell
- CD8+ Cytotoxic T-cell
- memory T-cells
CD4+ Helper T-cells
- effector cells
- help the activation of the adaptive IS
CD8+ Cytotoxic T-cells
- effector cell
- kill infected cells
memory T-cells
- memory cells
- express TCR and CD4 or CD8 on their cell surface
activation of adaptive IS
antigen presenting cells (APCs) such as dendritic cells, that have engulfed pathogens by phagocytosis can present the antigens to naïve CD4+ Helper T-cells (TH)
differentiation of adaptive IS
depending on type of antigen it encounters, TH cells can differentiate 2 subsets
subset to induce humoral immunity
activated Th cells can differentiate into a subset called TH2
subset to induce cell-mediated immunity
activated Th cells will differentiate into a subset called TH1
humoral immunity and Th2 cells
- activated and differentiated Th2 cells activate B-cells and induce their differentiation into plasmocytes
- plasmocytes produce antobodies specific for the invading pathogen
humoral vs cell-mediated immunity
humoral: antibody-mediated response
cell-mediated: cytotoxic-mediated response
cell-mediated immunity and Th1 cells
- activated and differentiated Th1 cells activate CD8+ cytotoxic T-cells and induce their differentiation into CTL
- CTL recognize and eliminate any cells displaying the specific antigen presented at their cell surface by MHC class I complex
CTL
cytotoxic T lymphocyte
antibody (immunoglobin or Ab)
- large Y-shaped protein
- each antibody is highly specific and recognizes one epitope
- produced by B-cells and exist in 2 forms
2 forms of antibodies
- surface antibodies
- soluble antibodies
surface antibodies
membrane bound on B-cells, forming part of the BCR
soluble antibodies
secreted by B-cells (plasmocyte) and circulate freely in the blood
- one B-cell will produce one specific antibody for one specific epitope
B-cell receptor (BCR)
made of a membrane-bound antibody and signal transduction molecules
functions of antibodies
eliminate a pathogen through various processes
processes in which antibodies eliminate a pathogen
- neutralization
- opsonization
- complement activation
- effector cell activation
neutralization
neutralize the biological effect of a pathogen or toxin
opsonization
mark foreign invaders for phagocytosis
complement activation
induce the formation of membrane attack complexes and opsonization
effector cell activation
recognized by immune cells when bound to antigen and activate the cell’s effector functions
immunoglobins
two heterodimeric proteins that are held together by disulfide bones (S-S)
heterodimeric
protein composed of 2 different polypeptide chains
basic structure of human immunoglobins
- 2 light chains
- 2 heavy chains
- 2 antigen binding regions
- 1 Fc regions (fragment crystallizable)
light chain
protein subunit that, as one of a pair, forms part of the
main antigen-binding region of an antibody
heavy chain
protein subunit that makes up the majority
of the structure of the antibody
- forms part of the antigen-binding region and forms the Fc region
2 antigen binding regions
- this region is variable and changes from one antibody to another,
but remain the same on one antibody - responsible for diversity and specificity of immunoglobins
1 Fc regions (fragment crystallizable)
- is constant for every antibody of the same class
- part that interacts with immune cell surface receptors called Fc receptors
classes of immunoglobulins
5 different classes distinguished by type of heavy chain within their structure
- each type targets a different type of antigen
variation in heavy chain polypeptides
allows each immunoglobulin class to function in a different type of immune response or during a different stage of the body’s defence response
where are the specific amino acid sequences that confer functional differences?
mainly within the Fc domain
5 different classes of immunoglobulins
- IgG have y-heavy chains
- IgM have u-heavy chains
- IgA have a-heavy chains
- IgE have e-heavy chains
- IgD have 8-heavy chains
serum
when blood is put into centrifuge, the blood plasma or serum is the liquid that has been separated from the blood cells in whole blood
IgM
- forms a pentamer from IgM monomers when secreted by B-cells
- first antibody to be formed in an IR
- activated the complement which then amplifies the inflammatory and adaptive IR
IgG
- monomer when secreted by B-cells
- coats pathogens to promote phagocytosis and immune cell recruitment
- only class that can cross the placental barrier
placental barrier
the semipermeable layer of tissue in the placenta that serves as a selective membrane to substances passing from maternal to fetal blood
IgA
- generally forms a dimer from IgA monomers when secreted by B-cells
- first line of defence and predominant antibody class located in the body’s mucosal membranes (respiratory and gastrointestinal tracts)
IgE
- monomer when secreted by B-cells
- found in large quantity on the surfaces of antigen-naive mature B-cells
- function or importance is UNCLEAR, thought to have a role during B-cell development
Y-chain
- IgD
- IgE
- IgG
double Y-chain
IgA (dimer)
5 Y-chains
IgM (pentamer)
- form very large antibody molecule
