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
