Module 3 Flashcards
adaptive immune response phases
- antigen recognition (antigen presentation)
- lymphocyte activation
- elimination or pathogens or non-self perceived antigens
- apoptosis of immune cells (contraction)
- establishment of immunological memory
antigen recognition (antigen presentation)
- PAMPs are seen by APCs such as DCs and macrophages
- APCs will present antigens to naive T-cells via their surface MHC proteins
purpose of antigen recognition
identify and activate the cells that can recognize and bind the antigen from the specific pathogen that is invading
lymphocyte activation
requires a series of cellular interactions (communication) which lead to T-cell and B-cell differentiation and clonal expansion
what does lymphocyte activation include?
- B-cells (plasmocytes)
- T-cells (helper T-cells or cytotoxic T-cells)
purpose of lymphocyte activation
produce a large quantity of immune cells specific to the pathogen in order to stop the invasion
clonal expansion
production of a large quantity of identical cells from the same original cell
elimination of pathogens or non-self perceived antigens
most efficient defenced are unleashed
purpose of elimination of pathogens or non-self perceived antigens
to completely destroy the pathogen that invaded
humoral
plasmocytes produce antibodies that bind to extracellular pathogens
cell-mediated
cytotoxic T-cells destroy cells infected by intracellular pathogens or get activated by antigens presented by APCs
apoptosis of immune cells (contraction)
once pathogen is eliminated, the vast majority of activated lymphocytes undergo apoptosis, and the immune response gradually declines
why do cells undergo apoptosis?
the cells duty is accomplished and most immune cells are not needed anymore and could produce more damage than good, they die off)
apoptosis
programmed cell death that occurs in a way controlled by the cell itself, which generate almost no damage to the surrounding cell
establishment of immunological memory
- the few immune cells that survive the contraction
phase turn into memory cells - when re-exposed to the same antigen, these memory
cells proliferate quickly to generate an immune response that is faster and more robust than first response to the pathogen
ex of immunological memory
vaccination
self and non-self recognition
the MHC serves as a self-label, and helps identify and recognize self from non-self-molecules, to ensure the immune system does not attack the host (you)
MHC
display antigenic peptides on surface of cells
- can be recognized by the TCR and its co-receptors (CD4 or CD8) to initiate an adaptive immune response leading to elimination of foreign antigens
classes of MHC molecules
- MHC class I (CD8+ cytotoxic T-cells)
- MHC class II (CD4+ helper T-cells)
- distinguish between different recognition patterns
autoimmune disorders
arise when the body’s immune response is unable to differentiate between self and non-self, and the immune system begins to attack its own tissue
antigen presenting cells (APCs)
- internalize pathogens, by phagocytosis or receptor-mediated endocytosis, and process them into peptides (antigens)
- antigens are displayed on the MHC on the surface of the APC and can be recognized by T-cells
- since T-cells are unable to recognize extracellular pathogens by themselves, APCs present T-cells to the antigen in the body
receptor-mediated endocytosis
an endocytic process in which a cell absorbs external material by invagination of the plasma membrane – relies on receptors specific for the material being absorbed
2 types of APCs
- professional APCs
- non-professional APCs
professional APCs
most efficient cells that both present antigens through MHC class II and express co-stimulatory signals to activate Helper T-cells
examples of professional APCs
- macrophages
- B-cells
- DCs
most effective professional APCs
dendritic cells because DCs constitutively express a high level of MHC class II molecules and co-stimulatory molecules
non-professional APCs
- rarely needed in this specific function and only for short periods of time in case of a sustained inflammatory response
- fibroblasts and glial cells
antigen processing
each antigen presented by a MHC molecules (class I or II) needs to be processed to form an effective peptide
2 pathways forming cell surface complexes
- endogenous pathway
- exogenous pathway
endogenous ptahway
forms peptide – MHC class I complex (recognized by CD8+ Cytotoxic T-cells)
- allows the cell to process self or foreign intracellular
particles and present them at the cell surface in
order to be recognized by T-cell receptors on cytotoxic T-cells
exogenous pathway
forms peptide – MHC class II complex (recognized by CD4 Helper T-cells)
5 main steps in exogenous antigen processing
- antigen engulfment
- proteolytic processing
- formation of MHC-antigen complex
- cell surface expression
- recognition by helper T-cell
antigen engulfment
- APCs engulf the foreign antigen by endocytosis forming an endosome
- antigen is generally recognized by PRRs
proteolytic processing
foreign antigens inside the endosome are broken down into fragments by proteolytic processing
proteolytic processing
protease cleaves one or more bonds in a target protein to modify its activity (activation, inhibition, or destruction of activity)
formation of MHC-antigen complex
the vesicle containing the foreign fragments fuses with vesicles containing MHC molecules, forming MHC-antigen complexes
cell surface expression
MHC-antigen complex is transported to plasma membrane, where it will be displayed on the surface of the cell
recognition by helper T-cell
TCR on surface on a Helper T-cell binds to the MHC-antigen complex on the cell surface of APC, which will initiate an adaptive IR
B-cell receptor (BCR)
composed of a membrane-bound antibody and signal transduction molecules (ITAMs)
ITAMs
an immunoreceptor tyrosine-based activation motif is composed of a repeated sequence of four amino acids in the cytoplasmic tails of cell surface proteins
T-cell receptor (TCR)
formed of membrane-bound antigen-specific molecule and signal transduction molecules (CD3 and ITAMs)
- TCRs in associated with a co-receptor (CD4 or CD8) recognize and bind to peptide: MHC complex
what happens to the immune system with no communication
the body is left susceptible to infection and disorders
immune communication system
components of the IS communicate between using specific cell surface receptors found on immune cells and a well-developed cytokine network
2 major parts of immune communication system
- lymphocyte activation
- cytokine networks
lymphocyte activation
- involves many interactions with other immune cells, which will mediate the efficiency of the specific IR
- macrophage, DCs, B-cell, helper T-cell and cytotoxic T-cell
cytokine networks
coordinate appropriate IR and modulate the balance between humoral and cell-mediated immunity
types of cytokines based on function and structure of receptor
- chemokines
- interleukins
- interferons
- tumor necrosis factor
- growth factor
T-cell dependent B-cell activation
is an intricate process that involves specific signals essential to production of functional plasmocytes and memory B-cells
what does the interaction between T-cell and B-cell induce?
exchange of activation signals between the two lymphocytes allowing activation of strong and efficient humoral IR
- upon activation, B-cells can differentiate into antibody-producing cells
2 types of antigens that activate B-cells
- thymus-dependent
- thymus-independent
thymus-dependent
antigens that require a direct interaction between the B-cell and a Helper T-cell (majority)
thymus-independent
induce the production of antibodies by B-cells without presence of a T-cell
T-cell dependent B-cell activation - signalling pathway (3 signals)
- peptide-MHC class II complex
- signal 1:TCR - peptide: MHC complex
- expression of co-stimulatory molecules
- signal 2: co-stimulation
- signal 3: cytokines
- outcome of the three signals
peptide-MHC class II complex
- since the antigen binding to BCR on a specific B-cell does
not produce a strong enough signal to activate the cell, the
antigen is internalized by receptor-mediated endocytosis,
processed and displayed on the cell membrane in context of MHC - B-cell is acting as APC and expresses high levels of peptide: MHC complex on cell surface
signal 1: TCR - peptide: MHC complex
- the specific TCR complex and CD4 co-receptor on
T-cell recognizes and binds to peptide: MHC class II
complex expressed on B-cell
expression of co-stimulatory nolecules
signal 1 induces the expression of CD40L on the cell surface of the Helper T-cell
signal 2: co-stimulation
- CD40L and CD28 expressed on T-cell, bind to CD40 and B7
expressed on B-cell - this induces a co-stimulatory signal in both cells
signal 3: cytokines
activated helper T-cell secretes cytokines which
bind to their associated cytokine receptor located on both cells (a paracrine and autocrine effect)
outcome of the 3 signals
- the combination of 3 SIGNALS stimulate the proliferation and differentiation of B-cells into plasma cells and memory B-cells
- this forms the humoral IR against the specific antigen
immune synapse
formed by the interaction between a T-cell and an APC
when will T-cells not become properly activated?
T-cells will not become properly activated if only signal molecules such as T-cell receptor and a peptide: MHC complex interact
- immune synapse must be formed
how is an immune synapse formed?
via signal molecules and adhesions patterns
supra molecular activating clusters (SMAC)
“bullseye” pattern with three rings depicting three different cell clusters with similar functions
components of an immune synapse
- signal molecules (cSMAC)
- adhesion molecules (pSMAC)
- signal regulation molecules (dSMAC)
signal molecules (cSMAC)
the central SMAC contains the molecules responsible for signaling between the 2 cells such as TCR and peptide: MHC molecules
adhesion molecules (pSMAC)
the peripheral SMAC contain adhesion proteins, (integrins and cytoskeletal linker proteins) responsible for keeping the cells in contact for long enough for signals to propagate (breed/grow)
signal reduction molecules (dSMAC)
the distal SMAC consists of proteins with large extracellular domains that are responsible for helping regulate signal transduction
immune synapse functions
- effective activation of the T-cell
- hold signal proteins together to form stronger connection, which give enough time for right amount of signals to be produced
- leads to reorganization of structures inside the T-cell, directing the release of cytokines close to the target cell
- regulates lymphocyte activation
primary goal of immune synapse
effective activation of the T-cell
what would occur if immune synapse activation was incomplete?
cell wouldn’t function effectively (anergic phenotype)
key role of immune synapse in T-cell activation
- the attachment of TCR to peptide: MHC complex is too weak to hold connection long enough for signal to be induced
- the formation of immune synapse by concentrating signal molecules into a circle surrounded by adhesion molecules holding the interaction between the 2 cells (T-cell and APC) gives enough time to signal activation
cytokine networks
classification of cytokines can differ depending on which criteria they are organized by… therefore we divide into groups based on function
chemokines
- induce chemotaxis
- call in cells to the region of infection or injury
key roles of chemokines
- inflammation; wound healing
- cell-mediated and humoral immune responses
- hematopoiesis
interleukins (IL)
contain over 10 subfamilies (IL-1, IL-2, IL-3, etc.)
functions of interleukins (IL)
- regulate immune and inflammatory responses
- affect the proliferation and differentiation of various hematopoietic and immune cells
interferons (IFN)
most common and well-known interferon molecules are IFN-a, IFN-B, and IFN-y
function of interferons (IFN)
- induce an antiviral state- inhibit replication process of viruses
- help regulate an immune response
tumor necrosis factor (TNF)
most common and well-known are TNF-a and TNF-B
function of tumor necrosis factor (TNF)
- involved in systemic inflammation (septic shock)
- involved in tumor regression
- can cause apoptosis (cell death)
septic shock
serious medical condition associated with a significant drop in blood pressure that can lead to respiratory or health failure and death
growth factors
regulate a variety of cellular processes such as immune responses
growth factors stimulate
- growth
- proliferation
- healing
- cellular differentiation
***T-cells (TH1 and TH2) are used for antifungal protection
immunological memory
- ability of lymphocytes to respond more efficiently to re-infection by a previously encountered antigen
- develop a greater and faster IR than first encounter
- basis of vaccines
what cells contribute to immunological memory?
contribution from T-cells in immunological memory, but more is known about B-cells
memory B-cells & immunological memory
- IM occurs when second encounter with an antigen, that induces a heightened state of immune re-activity
- mediated by memory B-cells
second exposure to an antigen
- memory B-cells differentiate from naïve B-cells and display the same membrane-bound antibody as their parent cells
- one a person becomes re-infected, the immune response is so efficient they never display symptoms
memory B-cells
have a longer lifespan than naïve B-cells, which contribute to lifelong immunity against many pathogens
naive B-cells
need to be activated through a series of cell interactions, including antigen presentation on MHC complex, before they can differentiate into plasma cells and memory B-cells
difference between naive B-cells and memory B-cells?
naive B-cells: must be activated before differentiation into plasma cells
memory B-cells: differentiate immediately into plasma cells, making IR more efficient
type of immunological memory
- natural passive immunity
- artificial passive immunity
- natural active immunity
- artificial active immunity
natural passive immunity
- acquired by fetus or newborn from mother
- placental transfer of antibodies during pregnancy or breastfeeding
- short-lived immunity (~6 months)
- no immunological memory for the recipient
ex of natural passive immunity
the transfer of placental IgG from the mother to fetus
artificial passive immunity
- acquired by injection of serum containing antibodies
- immunity is temporary
- no immunological memory for the recipient
ex of artificial passive immunity
rabis immunoglobin
serum
fluid portion of the blood, which is free of cells and clotting factors
natural active immunity
- acquired through infection by a pathogen, possibly leading to symptoms/a disease state
- development of innate and adaptive immune responses
- immunological memory has a significant chance of being developed
ex of natural active immunity
when the body builds immunity towards the chickenpox virus and thereby cannot get sick with the chickenpox virus again
artificial active immunity
- acquired through vaccination
- development of innate and adaptive immune responses
- normally, no symptoms/disease states are present
- immunological memory has a significant chance of being developed
ex of artificial active immunity
COVID-19 vaccine
challenges with developing novel vaccines
- determining what your correlate of protection is (what part of immune response neutralizes the pathogen – is it antibody, T-cell, B-cell?)
- developing that specific IR
chicken pox
- varicella-zoster virus (VZC)
- highly contagious disease causing a skin rash characterized by small, itchy blisters
how does transmission of chicken pox occur?
occurs from person to person, via direct contact or through airborne agents
what happens after being infected with chicken pox once?
cannot develop chicken pox again
what can second infection of chicken pox manifest as?
shingles
prevalence of chicken pox
95% of population demonstrates serologic evidence of infection by adulthood
- incidence is increasing
shingles
subsequent reactivation of latent virus of chicken pox
- anyone who has had chickenpox is at risk for shingles, but mostly older individuals and individuals with a poor immune system
symptom of shingles
painful rash on torso or face
shingles vaccine
- shingles vaccine reduces risk by 50-60% (one dose) (Merck)
- new vaccine reduces risk by 95% (two doses) (GlaxoSmithKline)
