Immunity to infection Flashcards
Define
a) pathogen
b) opportunistic pathogen
c) commensals
a) Organsims that cause disease. Often have adaptations to enable colonisation of healthy hosts
b) Organisms that rarely cause disease enless host defence is compromised
c) One organism benefits from another, without harming the other (no damage to the host)
Outline the immune system and its functions
Major function is to protect us from infection. Also has a janitorial function dealing with foreign substances and removeing debris. It is a complex network of interacting cells, soluble cell products and tissues. The type of response made is tailored towards the infecting organism. It causes as little damage to the host as possible. It is expensive for the host, with over 10% human genes involved in defence.
Innate vs adaptive immunity
Innate (natural) - this is in place before infection occurs and is poised to react immediately
Adaptive (acquired) - this system takes time to develop (4-5 days) and helps deal with infections that the innate system may be unable to eliminate
The two systems work together so that an appropriate response is made to the infecting organism. The pathogen needs to be recognised and this information passed on to the adaptive system
Protective immunity against
a) extracellular sites of infection (2)
b) intracellular sites of infection (2)
a) Extracellular site - interstitial spaces, blood, lymph: can be infected by viruses, bacteria, protozoa, fungi, worms. Protective immunity is complement, phagocytosis, antibodies
Extracellular site - epithelial surfaces: can be infected by bacteria (Neisseria gonnorrhoea, Streptococcus pneumoniae, Vibrio cholerae, Helicobacter pylori), fungi (Candida albicans), worms. Protective immunity is antimicrobial peptides, antibodies (especially IgA that is integrated into membrane to kill organism)
b) Intracellular site - cytoplasmic: can be infected by viruses, bacteria (Chlamydia, Rickettsia), protozoa. Protevtive immunity is NK cells, cytotoxic T cells
Intracellular site - vesicular (especially macrophages) - can be infected by bacteria (Mycobacterium, Yersinia pestis, Legionella pneumophila, cryptococcus neoformans), protozoa (Leishmania). Protective immunity is T-cell and NK-cell dependent macrophage activation.
Three phases of response to a primary infection
i) Innate immunity (immediate, 0-4 hours): recognition is by preformed, broadly specific effectors. Acts to remove the infectious agent
ii) Early induced innate response (early, 4-96 hours): there is recruitment of effector cells, and then recognition of the pathogen. The effector cells are activated and there is inflammation. Acts to remove th infectious agent
iii) Adaptive response (late, >96 hours): There is transport of the infective antigen to the lymphoid organs, then recognition by naive B and T cells. The effector B and T cells then undergo clonal expansion and activation. Acts to remove the infectious agant.
Signs of acute inflammation (4)
Calour (heat), from increased blood flow. Dolor (pain), from the stimulation of nerve endings. Rubor (redness), from increased circulation and vasodilation. Tumor (swelling), from increased fluid in the tissues
Components of the immune system
a) epithelial barriers
b) secretions
c) cells of the immune system - haematopoiesis diagram
a) Physical epithelial barriers. Tight junctions betwenn squamous epithelial cells of the skin and mucosal glandular epithelia. Additional modifications include cilia (in the respiratory tract) and keratin (in the skin)
b) Mucous covers all glandular surface. Stomach acid (low pH). Antimicrobial peptides (defensins, cathlicidins) damage microbe membranes, along with pentraxins (C-reactive protein). Enzymes in tears and saliva (lysozyme) or stomach (pepsin)
c) See image
Cells of the immune system
a) neutrophils
b) Macrophage
a) Most abundant of all WBCs. Phagocytose microorganisms and then die (very short lived). Degranulate to release antimicrobial proteins. Form neutrophil extracellular traps (NETs) that trap microbes - seen as pus
b) Sentinel cell. Large phagocytic cells that recognise and engulf microbes and dispose of cell debris. They are activated by danger signals binding to their PRRs and secrete chemical signals to induce inflammation or repair. There are two effector cell subsets. M1 macrophages secrete cytokines and por-inflammatory mediators that stimulate the acute inflammatory response. M2/alternatively activated macrophages are associated with tissue repair and parasite killing and expulsion. Macrophages show great plasticity and can change their physiology in response to environmental cues.
Cells of the immune system
a) Mast cells
b) Eosinophils and basophils
c) Dendritic cells
a) Sentinel cell. Play a key role in inflammation. They contain preformed mediatiors (hence response is rapid) of inflammation such as histamine (which causes immediate vasodilation), TNFα, prostaglandins, and leukotrienes. Their function is to rapidly induce inflammation. A wide range of factors can induce degranulation including allergens (IgE), danger signals (PAMPS, DAMPs), cell stretching, complement components (C3a, C5a), and substance P (neurogenic inflammation).
b) Non-phagocytic granulocytes. Providing defence against helminths, worms and other parasites. Basophils provide an early source of IL-4 that promotes a Th2 response
c) (Langerhan cells in skin). Function as a bridge between innate and adaptive systems. They recognise pathogens at the site of infection in the periphery and carry the pathogenic antigens to the draining lymph nodes to initiate the adaptive response.
NK cells
a) overview
b) NK receptors
c) NK effector functions (3)
a) Third major player in the innate system (in addition to phagocyted and complement). They circulate in the blood in a partially activated state ready to response immediately, they move into the affected tissue and proliferate. They’re very important in viral infections where they kill infected cells and maintain or increase the state of inflammation in infected tissue. They work alongside macrophages.
b) NK cells recognise infection and damage to cells using receptors that report on i) loss of molecules that normal cells express - missing self ii) expression of self molecules that are induced in stressed cells - induced self. Activation depends on the balance of signalling derived from activating and inhibitory receptors. (eg viral infection, some viral proteins are displayed in MHC of infected cells, which is recognised by T-cells (destroy cell). Some viruses respond to this by removing MHC so they can’t be detected by T-cells, however this activates the missing self response) (See image)
c) i) kill target cells directly by the release of cytoplasmic granules containing perforin which forms pores in the cell membrane allowing apoptosis-inducing granzymes into the cell ii) antibody dependent cell cytotoxicity (ADCC) - NK cells have receptors for the Fc portion of antibodies and will kill cells that are bound by antibody. Signalling through this, acitvating the Fc receptor is very strong and is enough to activate the NK cell by itself iii) macrophage activation - macrophages produce cytokines that recruit and activate NK cells (CXCL8 and IL-12). NK cells produce cytokines (IFNγ) that activate macrophages, increasing their killing capacity and help initiate the adaptive immune response. Activated macrophages secrete inflammatory cytokines. (see image)
Innate lymphoid cells
a) ILC1
b) ILC2
c) ILC3
a) pro-inflammatory. Protect against viruses and intracellular pathogens (similar to Th1 T cells)
b) assist mucosal and barrier immunity against parasite and helminth infections, causes lots of mucous production and gut muscle contractions (similar to Th2 T cells)
c) protect against extracellular bacteria and fungi, lead to neutrophil recruitment (similar to Th17 T cells)
Soluble components of the innate system - cytokines
Small protein messengers that exert their effects by binding to receptors on target cells. Autocrine - acts on the same cell that secreted it. Paracrine - acts on nearby cells. Endocrine-like - enters the circulation and acts on distal sites. Cytokines show redundancy (different cytokines have the same function), pleiotropism (have different effects on different cells), antagonism (one cytokine blocks the action of another), and synergy (multiple cytokines work together to achieve an effect that is greater than the additive effect of each alone).
The Jak/STAT pathway
A central communication system of the immune system. Cytokine receptirs are multimeric and have signalling chains. There are a limited number of Jaks (4) and a limited number of STATs (7). Cytokines bind to their receptor, and causes Jak to be phosphorylated, causing STAT to dimerise and is transported to the nucleus, where it then activates transcription
Important groups of cytokines
a) Interleukins
b) Interferons
c) Tumour necrosis factor
a) IL (eg IL-1, IL-2) - affect cell activation
b) IFN (eg IFNα, IFNβ, IFNγ) - antiviral, cell activation
c) TNF (eg TNFα, TNFβ) - diverse inflammatory functions
Soluble components of the innate system
a) Histamine
b) Acute phase proteins, antimicrobial peptides, pentraxins
a) Histamine (generated from histidine) is stored in granules in mast cells (and basophils and eosinophils). Acts on local blood vessels causing immediate capillary vasodilation
b) 100x more potent than histamine, but take longer to have effect (eg in anaphylaxis, initial response is from histamine, wears off, then a secondary, more sever response). Macrophage activation leads to the production of cytokines that have systemic effects. IL-6 stimulates hepatocytes to release acute phase proteins. These include C-reactive protein (opsonin and complement activation, used clinically to determine if there is an infection) and fibrinogen (fibrin clot formation). Antimicrobial peptides eg defensins. Pentraxins eg serum amyloid P component and PTX3.
Prostaglandins and leukotrienes
Protein cascades activated by tissue damage
Clotting system. Kinin system. Fibrinolytic system. Complement system
