Immunology 9- Host Defence Overview Flashcards
What does the immune system need to defend against
Has to detect and react to dangerous things not the foreign but safe
What are the ideal modes of transmission for pathogens
The respiratory and GI tracts- they have to be open to carry out their roles- this makes them nodes for transmission of infection
Describe the statistics associated with the common cold virus
Pre-school children get
6-10 colds per year (adults: 2-5)
Cause 17% of GP consultations
Annual expenditure on remedies:
~ $2 billion/year (USA)
Describe the differences between influenza and respiratory syncital virus
Influenza
No re-infection by same strain
Imperfect vaccines:
Vaccine-induced immunity rapidly wanes
Mainly homotypic immunity
Annual vaccination required
RSV
Recurrent re-infection with similar strains
No vaccine
Poor immunogenicity
Vaccine-enhanced disease
Very active research field
Why do we have an immune system
It can be argued that the immune system has developed to provide us with a survival advantage against infection, and that all other functions are a by-product. Our internal and external surfaces are bathed in microbes. We inhale potentially lethal microbes with every breath we take and our cells are outnumbered by our bacterial by 10:1, which form about 3% of our body mass. The essential challenge of the immune system is to remain indifferent to non-pathogenic microbes, while responding rapidly and appropriately to constant microbial onslaught.
Which two body systems have capacity to learn
Nervous and immune systems.
Describe the chemical defence barriers in the body
Acids- kill many ingested microbes
- Mucus
- Anti-microbial proteins (lysozyme, lactoferrin, alpha and beta defensins).
The normal flora in our gut also prevents other bacteria from getting a foothold, so affecting susceptibility to gut infections following antibiotic treatment.
Describe the ‘wall of death’
A vital barrier to the entry of pathogens is the so-called ‘wall of death’, made up of surface layers of skin that are dead or dying and constantly being shed. Unless the skin is broken by trauma or biting insects, it is very unlikely that infection can gain access except through the lung or gut.
Describe the roles of the gut and lungs and why they are susceptible to infection
The lung and gut are organs specialised to provide a large area of contact with the environment, necessary for gas exchange and absorption of food and water. The mucosal surfaces turn over at a very fast rate, with all the superficial cells being sloughed within a few hours or days. Any microbe that attaches to these cells is soon lost along with the dead and dying cells. The mucocilliary system in the lungs clears microbes from the lungs.
Why are patients with cystic fibrosis susceptible to infections
Cystic fibrosis patients cannot form mucus properly and suffer from recurrent respiratory respiratory infections similar in patients with burns or wounds. Mechanical defence should not be underestimated.
Describe mucosal surfaces defences
Coughing Sneezing Mucus Cilia Rapid cell turnover The wall of death… Tissue resident phagocytes produce antimicrobial peptides.
Describe the sequential actions of the immune system
‘first line’ avoidance smell taste mucus physical barriers surface environment
second line’ phagocytes opsonins some lymphocytes interferons acute phase proteins Toll-like receptors
‘specific /
acquired’
T cells
antibody
Response gets more specific, breadth decreases, capacity for learning increases
Describe innate sensing
Recognition of pathogens is based on the sensing of common molecular patterns (PAMPs and DAMPs) on the surface of pathogens, a signal that is contingent on whether or not that particular foreign component is normally present at the site concerned. Therefore, a molecular pattern may be sensed at the surface and lead to no response, whereas the same molecular pattern sensed in the cytosol may induce a vigorous reaction. The toll like receptors are an excellent examples of this pathogen sensing system.
Describe the innate immune system
The innate immune system is our first line of defence against infection. Its components are generally innate, i.e pre-formed, and rapidly react to pathogen invasion. Classically, the innate immune system does not ‘adapt’ and therefore shows no memory response.
Describe the complement system
The complement system is a pre-formed protein cascade which can rapidly punch holes in the outer membrane of microbes. coat them for phagocytosis (opsonisation) and produces chemoattractants which recruit cellular components of the immune system.
What are interferons
The production of interferons is crucial to host defence. Interferons are soluble, low molecular weight mediators released by cells in response to infection, that act on cells that release them (autocrine) and on other neighbouring cells (paracrine) to induce an antiviral state and increase defence. The importance of the interferon system to viruses is shown by the very large number of viruses that have evolved mechanisms to block their synthesis and mode of action. Increase the expression involved in processing and presenting viral proteins on the cell surface.
Describe the different types of interferons
TYPE I/III: a/b/l activates NK cells upregulates MHC, Mx proteins activates RNase L, PKR induces anti-viral state TYPE II: IFNg - proinflammatory - Th1 cytokine - “immune interferon
Describe phagocytes
Cells that engulf invaders
Antigen is destroyed in intracellular vesicles
Describe chemokines
Low molecular weight mediators are also very important in recruiting other cells to sites of infection. Cells that circulate in the blood and lymph migrate out into the tissues in response to infection, particular combinations of mediators attracting particular cells (by secretion of chemoattractants called chemokines). Neutrophils, for example. are attracted by a chemokine called interleukin 8. The eosinophoils, on the other hand respond to eotaxin or RANTES.
Describe cytokines
Cytokines are chemical signals used for communication by the immune system. They may have local and systemic effects and direct the extent and the nature of the immune response. For example, interferon-gamma can be produced by T cells to enhance activation of macrophages. The cytokine TNF-alpha has many systemic effects associated with infection, including fever and weight loss.
Why is primary response to antigen slow
Important concept – each B cell only recognises and makes antibody to one antigen.
Proliferation and differentiation takes time which is why the primary response to an antigen is slow.
How is Fc domain diversity created
Fc domain diversity is generated during an immune response via the selection of different antibody isotypes, subclasses and post-translational glycosylation profiles.
Describe the characteristics of each isotype
Each isotype has monomers and/or multimers, linked by disulfide bridges, polypeptide J chains or the secretory component (a proteolytic cleavage product of the polymeric immunoglobulin that remains associated with secreted dimeric IgA)
Describe the actions of antibodies
Direct neutralisation Surface blockade (IgA) Virus clumping Complement mediated lysis and engulfment Opsonisation and ADCC
Describe the cellular defences once in the tissues
The inflammatory cells produce additional chemoattractive or activating mediators, and may themselves be phagocytic (they take up particles that are degraded by vesicles within the cells). Macrophages are important phagocytes which may be tissue resident or be recruited during infection.
Describe neutrophils
Neutrophils, which make up the majority of circulating leukocytes are rapidly recruited to sites of infection
Describe the roles of phagocytes
Phagocytes can use their surface receptors to directly recognise the outer surface of microbes or to recognise other components of the immune system, including complement and antibody, that have coated or opsonised the microbe surface. The phagocyte’s defence mechanisms include toxic enzymes, reactive radicals and defensins that are produced in the phagosome once the pathogen has been taken up.
Describe NK cells
NK cells are regulated by a combination of inhibitory and stimulatory receptors. Surface receptors on NK that recognise a normal cell (one displaying MHC class 1) stops the NK cell from becoming active. Lack of MHC on the surface of the cell may indicate that a virus is trying to hide within the cell. On the other hand, a stimulatory receptor may be triggered by recognition of cell surface proteins on other cells that signify an abnormal state of infection or transformation, leading to NK activity.
Describe how NK cells form a bridge between the innate and acquired immune system
They kill abnormal or infected cells; if they are defective (in rare inherited deficiency states), common virus infections can be sever and fatal. They are an important source of some of the mediators produced by T-cells. By producing different combinations of T-cell cytokines, they can help to shape the adaptive immune response.
Describe T cells and their receptors
Each T cell expresses one TcR
There are potentially 1018 different TcRs
Each TcR sees a specific combination of MHC and peptide at high affinity
Describe the properties of cytokines
small proteins secreted for local, short-lived cell-to-cell communication; act as messengers of the immune system yet have a biological effect at very low concentration so need short half life to control effects
Describe the different type of cytokines
interleukins (IL-x): between leukocytes interferons (IFN): anti-viral effects chemokines chemotaxis (cell movement) growth factors proliferation and differentiation of cells cytotoxic tumor necrosis factor (TNF)
Describe the release of cytokines
Stimulus in cytokine producing cell causes production and granule fusion with the membrane if already present
Cytokines bind to specific receptors on other cells, affecting gene expression in target cell causing biological effects (can affect
What cells can cytokines act on
Autocrine: cytokines act on self
Paracrine: works on nearby cells
Endocrine: travel via circulation to distant cell
List some important cytokines secreted by activated macrophages
IL-1 ALARM CYTOKINE, FEVER
TNF- ALARM CYTOKINE
IL-6 ACUTE PHASE PROTEINS (LIVER)
IL-8 CHEMOTACTIC FOR NEUTROPHILS
Describe dendritic cells
produce cytokines - network of cells located near likely sites of infection (e.g. Skin [langerhans] and mucosal surfaces); have pattern recognition receptors and will capture pathogens before migrating to lymph nodes to present antigens
What is the ultimate purpose of the complement system
The antibody alone will not kill the pathogen, thus complement system is require to assist it, hence its name.
Plays a major role in complementing the activity of specific antibody in lysing bacteria
How many complement proteins are there
complex series of ~30 proteins and glycoproteins, total serum conc. 3-4 mg/ml
Split into small and large fragments
Small= C3a, C4a etc
Describe the enzyme cascade system that activates complement
Complement components are inactive until cleaved.
Component is cleaved by upstream molecule
The large fragment then becomes an enzyme (the smaller an anaphylatoxin)
These are sensitive to small stimuli (few bacteria) and thus the amplification steps are dramatic.
The fragments can also interact with inhibitory molecules to shut down the amplification process.
C3 and 5 have biological activity- anaphylatoxins.
Where are the majority of complement components produced
The Liver
Why is C3 the aim of most complement activation
C3 amplifies the initial signal by activating many downstream components.
Describe the classical pathway
Antigen+
Antibody
(Immune complex)
Produces C3b
Describe the Alternative pathway
Complement directly activated by bacterial surfaces (they lack complement inhibitors).
Describe the lectin pathway
Lectins bind to Mannan-binding Lectin and C reactive proteins on surface of bacteria.
What does the classical pathway also produce
C5a (pro-inflammatory molecule).
Describe the formation of the membrane attack complex
Activated C3 activates the final part of the cascade of complement components C5-C9. Formation of membrane attack complex- allows free passage of water and solutes across the membrane- killing the cell directly.
Describe the control mechanisms of complement
Lability of components Dilution of components in biological fluids Specific regulatory proteins circulating membrane bound
What are the functions of complement
Cell lysis of bacteria.
Opsonisation
Pro-inflammatory effects- low molecular weight peptides- increase vascular permeability.
Clearing of immune complexes - phagocytes have complement receptors
Describe the systemic acute phase response
local inflammatory response may be accompanied by a systemic response, “acute phase” after 1-2 days
fever, increased production of white blood cells (leukocytosis), production of “acute-phase” proteins in the liver
induced by cytokines
What are the acute phase proteins
C-reactive protein (CRP) C polysaccharide of pneumococcus activates complement level may increase 1000 fold mannan binding lectin (MBL) activates complement complement fibrinogen (clotting)
What is the role of CD4+ T helper cells
CD4+ T helper cells orchestrate the adaptive immune response
CD4 cells are helper cells
Many subsets of CD4+ cells
Cytokines produced by different subsets of CD4+ T helper cells direct other cells of the immune system (eg Th1, Th2)
Present antigens to APCs to activate them.
What is the role of CD8+ T helper cells
They are cytotoxic- they kill virally infected cells.
Describe the different subsets of CD4+ T helper cells
CD4 T cells can differentiate into 6 subsets of helper cells.
Influenced by co-stimulation, cytokines, antigen dose etc etc
By their ability to produce cytokines and chemokines, they orchestrate the immune response.
Describe the different T helper cells for different pathogens
Th1 – anti-viral/bacterial
Th2 – allergies
Th17- fungi/bacteria
Tregs – regulatory
What is the role of tissue resident immune cells
are poised to respond rapidly to local pathogen re-encounter
Describe the characteristics of tissue resident immune cells
A large number of cells are found in the lungs
Both CD4 and CD8 they undergo little recirculation
Tissue-resident memory T cells (TRMcells) are poised to respond rapidly to local pathogen re-encounter. The early phase of local immunity in epithelial tissues (for example, the skin or the female reproductive tract) is mediated by CD8+TRMcells that release cytokines including interferon-γ (IFNγ), interleukin-2 (IL-2) and tumour necrosis factor (TNF) and that potentially directly lyse infected cells. Local cytokine release by TRMcells induces several immune cell- and tissue-specific effects, including the recruitment and activation of natural killer (NK) cells and dendritic cells (DCs), as well as endothelial cell upregulation of vascular cell adhesion molecule 1 (VCAM1) in local blood vessels, which can lead to increased recruitment of memory CD8+T cells and B cells from the circulation. TRMcell reactivation induces an antiviral state in the tissue that assists in the clearance of infection.
How are tissue resident immune cells re-activated
Whether TRMcells proliferate in response to antigen or whether their activation facilitates tissue exit remains uncertain. In the later phase of the response, secondary effector T cells generated following restimulation of central memory T (TCM) cells in lymphoid organs are recruited to the tissue. These might develop into epithelial TRMcells after pathogen clearance, although it has not been determined whether TRMcells originally present in the tissue are retained following reinfection. CCR7, CC-chemokine receptor 7; TEMcell, effector memory T cell.
List some of our defences against bacteria
Surface defences (mechanical and chemical)
Antibody opsonisation
Complement (alternative pathway) causing lysis/opsonisation
Phagocytosis
Release of inflammatory mediators and acute phase proteins (also opsonins) etc.
Fever
List some of the defences against viruses
Surface defences Interferons Inflammatory mediators and acute phase proteins/opsonins etc. NK cells Antibody, complement, ADCC T cells (mostly resolving infection)
What are the characteristics of an eradicable infectious disease
Simple (and cheap) to diagnose Genetically stable pathogen Accessible host species Eliminates persistent infection, or persistently infected host can’t transmit Safe and effective vaccine
What are the characteristics of an ideal vaccine
Completely safe Easy to administer Cheap Stable Active against all variants Life-long protection
What does the TCR recognise
T cell receptor (TCR) only recognises foreign antigen as a peptide on an MHC molecule on an antigen presenting cell (APC)
