Basic Principles - Teeling Flashcards
What is the hematopoietic stem cell?
All immune cells are derived from a common progenitor known as the hematopoietic stem cell (HSC)
The HSC develops into two progenitor types:
- Lymphoid
- Myeloid
Most lymphoid cells contribute to adaptive immunity, while most myeloid cells contribute to innate immunity.
What cells are under the lymphoid lineage?
B Cells
T Cells
NK Cells
These are the cells of the adaptive immune system
Responsible for fighting antibody/cell mediated immune responses
What cells are under the myeloid lineage?
Neutrophil
Eosinophil
Mast Cell
Basophil
Monocyte
- Dendritic cell
- Macrophage
These are the cells of the innate immune system
Responsible for first interaction with pathogens
Role and structure of the innate immune system?
Immediate response
Non Specific
No immunological memory
Humoral:
- Pattern receptors
- Complement
- Enzymes
- Cytokines
Cellular:
- Phagocytes
- Natural Killer Cells
Role of the adaptive immune system?
Long term
Specific to antigen
Lag time from exposure to response
Immunological memory after exposure
Humoral:
- Antibodies
- Cytokines
Cellular:
- T Cells
- B Cells
What is the role of the immune system?
Defence (of host) against threat of disease by pathogenic infectious organisms (pathogen)
IS complexity due to range of organisms encountered – evolved to deal with many challenges
IS protects against tumours (some)
Vaccines offer exciting new hopes for infections and cancer therapy
Chronic immune responses can cause disease, for example sepsis, autoimmunity, Type-2 Diabetes
What are some innate physical barriers?
Anatomic:
- Skin
- Mucous membranes
Physiological:
- Temperature
- Low pH
- Chemical mediators
What is inflammation?
It is a complex biological response to harmful stimuli like pathogens or injury
Swelling, redness, heat, pain and immobility
Fluids leak from blood vessels and collect in tissues
Leukocytes will also begin to exit from blood vessels to investigate the local tissue in a process known as extravasation
What are the signs of inflammation?
Cardinal signs of inflammation:
- Rubor (redness)
- Tumor (swelling)
- Calor (heat)
- Dolor (pain)
- Functio Laesa (loss of function)
What are PPR (Pattern Recognition Receptors)
PRRs are a class of proteins expressed by cells of the innate immune system to recognise specific molecular patterns associated with pathogens
They detect the presence of foreign pathogens or danger signals and initiate innate immune responses
Examples:
- Toll-like receptors (TLRs)
- NOD-like receptors (NLRs)
- RIG-I-like receptors (RLRs)
- C-type lectin receptors (CLRs)
What are PAMPs (Pathogen-Associated Molecular Patterns)
PAMPs are conserved molecular structures commonly found on pathogens but not on host cells
They are recognised by PRRs as signals of microbial invasion
Activation of PRRs by PAMPs triggers immune responses such as inflammation, phagocytosis, and the release of antimicrobial molecules
It also activates innate responses such as:
- Chemokines / cytokines to recruit cells
- Phagocytosis of pathogens
- Lysis of pathogens by antimicrobial peptides
What are DAMPs (Damage-Associated Molecular Patterns)
DAMPs are endogenous molecules released by damaged or dying host cells in response to tissue injury or stress
They alert the immune system to tissue damage and activate immune responses
DAMPs signal danger and trigger inflammation, repair processes, and the recruitment of immune cells to the site of tissue damage
What are TLR (Toll-like Receptors)
TLRs are a class of PRRs present on the surface or within cells of the innate immune system
They recognize specific PAMPs and DAMPs, initiating immune responses
They trigger an intracellular signalling cascade
Activation of TLRs leads to the production of cytokines, chemokines, andother molecules that promote inflammation and coordinate immune responses against pathogens.
What is the TLR signalling cascade in mammals?
MyD88 – Myeloid differentiation primary response gene (88) is a universal TIR adaptor (except TLR3)
MyD88 interacts via a TIR domain
MyD88 promotes association of IRAK1 & 4 kinases (interleukin-1 receptor-associated kinase)
IRAK4 phosphorylates IRAK1 creating a docking site for TRAF6 (TNF-receptor-associated factor 6)
TRAF-6-IRAK1 dimer complex dissociates
Complexes with TAK1 (+other proteins) (TGF-beta activated kinase 1) causing kinase activation
TAK1 is pivotal as it activates both NFkappaB and Map kinase pathways
Increased transcription of target genes
TAK1 activates IKK which phosphorylates IkappaB causing activation of NFkappaB
What does TLR activation in macrophages result in?
TLR activation in macrophages results in oxidative burst (phagocytosis) and inflammatory cytokine/chemokine release
What does TLR activation in dendritic cells result in?
TLR activation in dendritic cells results in maturation, antigen presentation, and cytokine production- bridge to adaptive immunity
What is a cytokine?
Small proteins released by cells
Have a specific effect on the interactions and communications between cells
Regulate the immune response
Can promote or inhibit inflammation
Are crucial in fighting infections and in immune responses to disease
What are natural killer cells?
Natural Killer cells are a type of lymphocyte (a white blood cell) in the immune system
They play a major role in the host-rejection of both tumours and virally infected cells
NK cells are known for their ability to kill without prior immunisation to the target
They release cytotoxic (cell-killing) granules that lead to the destruction of the target cell
Unlike T-cells, NK cells do not need antigen recognition to attack their targets
They are part of the innate immune system and provide a rapid response to virally infected cells and tumour formation
What are dendritic cells?
Dendritic cells are immune cells that form part of the mammalian immune system
They are antigen-presenting cells (APCs) which means they process antigen material and present it on the cell surface to the T cells of the immune system
Dendritic cells act as messengers between the innate and the adaptive immune systems
They have a unique ability to capture and present antigens, leading to the activation of T cells
Dendritic cells can be found in peripheral tissues such as the skin (where they are often referred to as Langerhans cells) and the inner lining of the nose, lungs, stomach, and intestines
They play a crucial role in initiating and modulating the immune response, especially in the context of infection, cancer, and vaccination
What are macrophages?
Macrophages are large white blood cells found in almost all tissues
They are part of the immune system and play a key role in the initiation, maintenance, and resolution of inflammation
Macrophages are involved in the detection, phagocytosis (engulfing and then digesting), and destruction of bacteria and other harmful organisms
They can also present antigens to T cells and initiate inflammation by releasing molecules known as cytokines
Macrophages play a role in wound healing and tissue repair by removing dead cells and stimulating the repair of damaged tissues
What do cytokines and interferons do?
Released from cell after immune response sensing and signal transduction pathway
They are able to:
- Signal neighbouring cells to ‘put up barriers’
- Signal infected cells to die
- Recruit white blood cells to stimulate long lasting immunity
What is the JAK-STAT pathway?
The JAK-STAT pathway is a signaling mechanism used by a group of cell surface receptors for cytokines and growth factors
It involves the activation of Janus Kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs)
This pathway is essential for transmitting information from extracellular signals to the cell nucleus, influencing gene expression
What are Janus Kinases (JAKs)?
JAKs have two functional sites:
- A binding site to associate with the cytokine R
- A catalytic site, which when activated, has tyrosine kinase activity
JAKs bind a receptor and tyrosine phosphorylation creates a binding site for the SHa domain of STATs, firstly on the receptor and then on the Stat itself- this leads to dissociation & dimerisation
WATCH THE VIDEO (QUICK AND SIMPLE)
What are Signal transducer and activator of transcription (STATs)?
It is a transcription factor (TF) that binds
DNA sequence-specifically and promotes transcription from GAS element in response to cytokine stimulation
STATs may operate with other TFs
WATCH THE VIDEO (QUICK AND SIMPLE)
Effect of IL-1Beta cytokine
Local Effects:
- Activates vascular endothelium
- Activates lymphocytes
- Local tissue destruction
- Increases access of effector calls
Systemic Effects:
- Fever
- Production of IL-6
Effect of TNF-alpha cytokine?
Local Effects:
- Activates vascular endothelium and increases vascular permeability, which leads to increased entry of IgG, complement, and cells to tissues and increased fluid drainage to lymph nodes
Systemic Effects:
- Fever
- Mobilisation of metabolites
- Shock
Effects of IL-6 cytokines?
Local Effects:
- Lymphocyte activation
- Increased antibody production
Systemic Effects:
- Fever
- Induces acute-phase protein production
Effects of CXCL8 chemokines?
Local Effects:
- Chemotactic factor recruits neutrophils, bascphils, and T calls to site of infection
No systemic effects
Effects of IL-12 cytokines?
Local Effects:
- Activates NK cals
- Induces the differentiation of CD4 T-cells into TH1 cells
What is the complement system?
It is a part of the immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen’s cell membrane
It consists of a series (around 40) of small proteins found in the blood, generally synthesised by the liver, and within tissues throughout the body
These proteins work together in a cascade fashion, where the activation of one component leads to the activation of the next, resulting in a rapid response to threats
The system is part of the innate immune response but also bridges with the adaptive immune system
It can be activated through three main pathways:
- The classical pathway
- The lectin pathway
- The alternative pathway
Each initiated in different ways but converging on the same terminal pathway that leads to the destruction of pathogens
What is complement activation?
It is the process by which complement proteins are activated in the blood, leading to a series of immune responses aimed at defending against pathogens
Activation can occur via three pathways:
- The classical pathway (triggered by antibody-antigen complexes)
- The lectin pathway (initiated by mannose-binding lectin binding to pathogen surfaces)
- The alternative pathway (activates spontaneously on pathogen surfaces)
Upon activation, a series of proteolytic reactions ensue, resulting in the production of key components that enhance inflammation, opsonisation (marking of pathogens for destruction), and the formation of the membrane attack complex (MAC) that can lyse pathogen cell membranes
The activation cascade is tightly regulated by complement control proteins to avoid damage to host cells
The outcome of complement activation includes direct killing of pathogens, facilitation of phagocytosis, and enhancement of the inflammatory response
What is the compliments classical activation pathway?
- Stimulated by an antigen bound to an antibody (antigen/antibody immune complex)
- Interacts with C1q-C1r-C1s
- Then recruits further components
What is the compliment systems alternative activation pathway?
- Activated by direct presence of bacteria, fungi, virus
- C3 (protein in blood) is hydrolysed in presence of stimuli
- C3 changes conformation
- C3 recruits proteins B, D and P to form complex which is then cleaved into C3a
Merging of different compliment pathways
All pathways merge at the key event, the proteolytic activation of the central C3 to C3b
What are the basic functions of the compliment system?
- Lysis of cells, bacteria and viruses
- Opsonisation which promotes phagocytosis of antigen
- Binding to specific compliment receptors triggering cell activation
-Immune complex clearance
Neutrophil overview
Also called polymorphonuclear leucocyte (PMN)
Short lived cell
First line of defence – recruited to infection (IL-8, C5a)-chemokine
Detect and phagocytose pathogens
Effector mechanisms to kill pathogens (lysosomal killing mechanisms)
What are C3a and C5a known as, and what are their main functions in the complement system?
Known as anaphylatoxins
Potent inflammatory mediators
Increase vascular permeability, leading to edema
Attract and activate phagocytes (neutrophils, macrophages)
C5a is particularly potent in attracting neutrophils
What role does C3b play in the complement system?
Functions as an opsonin
Binds to pathogen surfaces, marking them for destruction (opsonization)
Involved in the amplification loop of the alternative pathway
How does C4b contribute to the complement system?
Plays a role in the classical and lectin pathways
Binds to surfaces and forms a complex with C2a to create the C3 convertase
C3 convertase cleaves C3 into C3a and C3b