10 The innate defenses of the the body Flashcards
Innate immune attempts to respond to every infection. If it fails, adaptive immunity kicks in.
What are major cells involved in innate and adaptive immune system
Innate
Phagocytes
NK cells
Adaptive
T + B Lymphocytes
What are major soluble factors involved in innate and adaptive immune system
Innate
lysosyme
complement
Acute phase proteins - CRP, IFN, other cytokines
Adaptive
Antibodies
Cytokines
Barriers are first defence against infection. What are natural physical defences to infection?
Skin - impenetrable. Fatty acid in sweat, and sebaceous secretions make it uninhabitable.
Mucus membranes - prevents adherence by bacteria. Allows to be removed by coughing/ sneezing/ ciliary action. flushing action of tears/ saliva/ urine also help. These secretions often contain microbicidal factors. e.g acid in gastric juice, spermine and zinc in semen, lactoperoxidase in milk, lysosyme in tears/ nasal secretions/ saliva
Commensals in gut and vagina - outcompete for nutrients. Produce inhibitory substances such as colicins
Once organism penetrates the body, there are still innate defences which can help kill infection
What are they?
Antimicrobial peptides -
- defensins - small cationic petide secreted by mucosa/ neutrophils/ T cells which lyse bacteria/ viruses/ fungi
- cathelicidin
Phagocytosis
Two major families of phagocytes -
- larger macrophages which reside in tissues, and develop from monocytes in circulaitng blood
- smaller neutrophils referred to as polymorphs or neutrophils (polymorphonuclear leukocytes) because cytoplasmic granules do not stain with haematoxylin and eosin. Closely related to eosinophils/ basophils, but more phagocytic
In general, smaller neutrophils generally fight of bacteria, and larger macrophages kill organisms which live within cells of host
How can macrophages increase their uptake of pathogens?
Opsonisation. Pathogens can be coated in plasma proteins from complement system. This increases uptake by phagocytes.
Example PAMPs - pathogen assoicated molecular patterns - C3a C5a dectin-1 mannose receptor
How do phagocytes kill ingested pathogens?
Internal lysosyme binds to pathogen, and contains digestive enzymes/ low pH to help kill pathogen.
Some pathogens such as TB have developed ways of blocking phagosome- lysosome fusion
Majority of tissue-resident macrophages originate during embryogeneisis and enter the tissue, where they differentitate into a macrophage that has properites depending on site which was entered. Can live long time, as have mitochondria, and rough-surfaced endoplasmic reticulum - live linger than neutrophils/ monocytes
List different sites of tissue macrophages
Blood monocyte - develop from bone marrow pro-monocytes. Become mature macrophages in blood, which move into tissues in states of disease and inflamamtion
Kupffer cells in liver
Intraglomerular mesangial cells of the kidney
Aleveolar macrophages in the lung
Connective tissue histiocytes. Can differentiate into Langerhans cells in lungs
Brain microglia
Spleen sinus macrophages
Lyphm node sinus macrophages
How can innate immune system boost macrophage activity?
To kill bacteria/ fungi
To kill helminths
Can become activated by IFNgamma, becoming more effeicient at killing intracellular pathogens.
T cells/ NK can make IFN gamma
These then become termed activated macrophages, and is classical activation.
IL4/ IL13 from Th2 cells will produce alternatively activated macrophages, which are used for killing helminths
Dominant white cell in bloodstream. Polymoprhs provide major defence against extracellular and acute bacterial infections. But can also help with chronic intracellular infections e.g TB
How does it get energy?
How long does it live
What is its structure?
What does it produce?
Uses abundant glycogen storage
Non-dividing and short lived
Segmented nucleus (polymorph) Cytoplasm has granules
Produce IL8 with other chemokines and cytokines
How do phagocytes know when to phagocytose?
Pattern recognition receptors (PRRs) on phagocytes attach to repeating pathogen-associated molecular patterns (PAMPs). Then engulfs pathogens by pseudopodia. Cytoplasmic granules then fuse with captive microorganism
PRRs are examples of Toll-like receptors (TLRs)
Can only phagocytose is binds to pathogen, Therefore release itnerleukins for chemotaxis to attract other macrophages, and complement help mobilise other macrophages
What is the role of each of these cytopasmic granules
Lysosyme Myeloperoxidase Defensins Cathepsin/ elastase Lactoferrin Nitric oxide
Lysosyme - splits proteoglycan cell wall of bacteria
Myeloperoxidase - oxidising agent. Cause apoptosis
Defensins - lyse cell wall
Cethepsin/ elastase - damage to microbial membranes
Lactoferrin - deprives bacteria of iron, an essential growth factor
Nitric oxide - apoptosis
Complement is an enzyme cascade which can produce rapid, highly amplified response to a trigger stimulus.
Begins with C3
Describe normal complement cycle without activation - also known as alternative pathway
C3 undergoes spontaenous activation at slow rate to C3b
C3b combines with factor B - C3bB
Complex then combines with factor D which is on normal plasma membranes - C3bBb termed C3 convertase
This C3 convertase can then convert C3 into more C3b to amplify cycle, or C3a
Regulatory mechanisms break down C3 convertase, to prevent complement fully activating
When does alternative complement pathway activate?
Activating surfaces
This is one of three ways it is activated
In presence of certain molecules, such as carbohydrates on surface of batceria, C3 can become stabilised against breakdown, so generates many more C3 convertase molecule.
During alternative complement activation, how does it destroy pathogen and recruit help?
This produces overall what is known as acute inflammatory response
C3 convertase auto-generates more C3 convertase
C3 cleaved into C3a and C3b
C3b converts C5 into C5a and C5b
C5b binds to bacteria - then binds to C6, C7, C8 and ultimately C9 known as membrane attack comlex, which causes lysis
C3a and C5a generated recruit mast cell mediators - mast cell in tissue, basophils in blood
Causes capillary dilation, exudation of plasma proteins (allows leakage of complement to sites it is needed), and chemotactic attraction.
C3b causes adherence of polymorphs to C3b-coated bacterium (opsonisation)
Polymorphs then activated for final kill
Plasma proteins can also cause upregulation of intercellular adhesion molecule-1 (ICAM-1), which allows complement to stick to damaged tissues
How is classical complement activated?
Antibody-antigen complex
Antigen-antibody complexes forms C1
Uses proteins C2a and C4b to convert C3 into C3a and C3b
C3b starts the cascade
How is mannose- binding lectin complement system activated?
Pathogen surface
Binding of mannose binding lectin to mannose residues on pathogen surface.
Activates MBL associated proteases.
This activates C2a and C4b to covert C3 into C3a and C3b
What diseases result from following complement defiencies?
C3 and factor B
C3b, C6, C8
C1, C2, C4
C1 inhibitor
C3 and factor B - severe bacterial infections
C3b, C6, C8 - severe neisseria infections
C1, C2, C4 - SLE, polymyositis, glomerulonephritis
C1 inhibitor - hereditary angioedema
Acute phase proteins increase in response to early alarm regulators such as IL1, IL6, TNF and IFNgamma. They are produced by the liver
The following examples rise rapidly, what is their role.
CRP
Mannose binding lectin
spLA2
Serum amyloid A protein
CRP - Binds to variety of bacteria using calcium, and opsonises bacteria. This also activates complement
Mannose binding lectin - fixes complement, opsonises by binding to mannose and other sugars on bacteria surface
spLA2 - kills gram-positive bacteria
Serum amyloid A protein - unknown
Following acute phase proteins moderately rise during inflammatory response, what is their role
alpha1 proteinase inhibitor
alpha1 anti-chymotrypsin
C3, C9
alpha1 proteinase inhibitor - inhibit bacterial proteases
alpha1 anti-chymotrypsin - inhibit bacterial proteases
C3, C9 - increase complement function
Following acute phase proteins moderately rise during inflammatory response, what is their role
Caerulosplasmin
Fibrinogen
Angiotensin
Haptoglobin
Fibronectin
Ferritin
Ferritin - binds to iron, inhibits bacterial utilisation of iron for metabolism
Haptoglobin - binds haemoglobin, prevents bacterial utilisation of iron for metabolism
Caerulosplasmin - oxygen scavenger. Oxidises ferritin
Fibrinogen - coagulation
Angiotensin - blood pressure
Fibronectin - cell attachment
Which proteins decrease during acute phase response?
Albumin - likely reduced production by liver
Transsferrin - inhibits bacterial utilisation of iron for metabolism. Also reduced production by liver
The following are inflammatory mediators.
Where are they produced, and what is their main action
Histamine
5HT - serotonin
Platelet activating factor
Histamine - mast cells, basophils. Increased vascular permeability, smooth muscle contraction, chemokinesis
5HT - serotonin - platelets. Increased vascular permeability, smooth muscle contraction, chemokinesis
Platelet activating factor - basophils/ neutrophils/ macrophages. Increased vascular permeability, smooth muscle contraction, chemokinesis
The following are inflammatory mediators.
Where are they produced, and what is their main action
IL8
C3a
C5a
IL8 - mast cells/ endothelium/ monocytes/ lymphocytes. Polymorph/ monocyte localisation
C3a - C3. Mast cell degranulation, smooth muscle contraction
C5a - C5. Mast cell degranulation, chemotaxis, increased vascular permeability, smooth muscle contraction, chemokinesis
The following are inflammatory mediators.
Where are they produced, and what is their main action
Bradykinin
Fibrin breakdown products
Bradykinin - kinin system. Vasodilation, smooth muscle contraction, increased capillary permeability, pain
Fibrin breakdown products - clotting system. Increased vascular permeability, chemotaxis
The following are inflammatory mediators.
Where are they produced, and what is their main action
Prostaglandin E2 (PGE2)
Leukotriene B4
Leukotrine D4
Prostaglandin E2 (PGE2) - vasodilation, increased vascular permeability
Leukotriene B4 - chemotaxis, increased vascular permeability
Leukotrine D4 - smooth muscle contraction, increased vascular permeability
Interferon alpha produced by leukocytes
IFN beta produced by fibroblasts/ all cells
IFN gamma - produced by NK cells and lymphoid cells
What is role of IFN?
How does it work?
IFN is to prevent further infection spread, rather than treat viral infection.
IFN alpha/ beta released by infected cells, which bind to receptors on nearby cells. They then upregulate proteins to interfere with viral replication, and upregulated MHC molcules on cell surface, which enhances susceptibility to NK cells and cytotoxic T cells
NK cells are large granular lymphocytes. Classed as innate lymphoid cells. They are subset of T cells, but lack specific antigen receptors expressed by T cells. Instead they are recruited via cytokines, alarmins, and inflammatory mediators
They aim to kill infected cells before they can release more virions. They bind to cells, and release granular contents to lyse cell.
How do they recognise which cells to kill?
MHC class 1 receptors are upregulated to indicate if cell needs to be killed. And vice versa
How do NK cells kill the damaged cells?
Granzyme B, and proteolytic enzyme termed a capsase. This causes capsase cascade to result in death
TNFalpha can also activate capsase pathway by binding to TNF receptors on damaged cells
Eosinophils are too small to engulf helminths. Helminths can typically evade complement pathway.
How do eosinophils aim to kill pathogen?
Have distinctive cytoplasmic granules, containing -
major basic protein (MBP) - damage parasite membrane
eosinophilic cationic protein - damage parasite membrane
peroxidase - chemical burn
perforin-like molecule - lysis
Surface has C3b receptors - generates copious amounts of oxygen metabolites and complement
What are roles of complement?
Opsonisation
Direct pathogen killing - MAC
