16 - innate defences against infection Flashcards
what is innate immunity?
- simple recognition systems
- limited capacity
- there before infection starts
- no memory
innate defence mechanisms
- barriers
- cellular defences
- molecular defences
physical barriers to infection
skin
• fatty acids
• commensals (humoral factors)
mucus membranes • mucus - helps to clear infectious agent • cilia - clearing • commensals • low pH
chemical barriers to infection
lysozyme in tears
acid in stomach (pH 2)
antibacterial enzymes
lysozyme - digests the peptidoglycan layer to degrade the bacteria
secretory phospholipase A2
tears, saliva and phagocytes
what do antimicrobial peptides (AMPs) do?
make holes and break down the membranes
recognition by the innate system
need to discriminate between self and non-self
effective in combatting many pathogens
see problems when you have deficiencies of a component of immunity
what are pattern recognition receptors (PRRs)
allow identification of pathogens
recognise simple molecules and regular patterns
located on host cells
• macrophages
• neutrophils
• dendritic cells
examples of PPRs
toll-like receptors (TLRs)
NOD-like receptors
RIG-I-like helicases
what are toll-like receptors (TLRs)?
- membrane surface receptors
- evolutionary conserved
- 10 identified in humans
- each has its own repertoire of PAMPs - lock and key
what are NOD-like receptors?
- intracellular receptors
* nucleotide-binding oligomerisation domain
what are PAMPs?
pathogen-associated molecular patterns
- mannose-rich oligosaccharides
- peptidoglycans
- lipopolysaccharides
- unmethylated CpG DNA
what is blood made up of?
- RBCs
- WBCs
- plasma
- platelets
what is haematopoiesis?
the formation of blood cellular compartments
all cellular blood compartments are derived from haematopoietic stem cells
what are leucocytes?
white blood cells
produced from pluripotent haematopoietic stem cells in the bone marrow
what are the types of leucocytes?
lymphocytes (B, T and NK)
monocytes (tissue macrophages)
granulocytes
tissue mast cells
what are the 3 types of granulocytes?
neutrophils
eosinophils
basophils
neutrophils
most common WBC in blood
multi lobed nucleus
eosinophils
involved in allergic reactions and can attack multicellular parasites such as worms
basophils
involved in allergic reactions
able to release histamine, which helps trigger inflammation, and heparin, which prevents blood from clotting
cellular defences
phagocytosis - neutrophils and macrophages
extracellular killing
inflammation is the goal
what happens if we have a problem with are phagocytes?
- bacterial infections
- fungal infections
- recurrent infections
what is phagocytosis?
ingestion and killing of microorganisms by specialised cells
main phagocytic cells:
• neutrophils
• mononuclear phagocytes
neutrophils in phagocytosis
- first line of defence
- short lived cells - days
- polymorphonuclear (PMN) cell
- abundant in sites of acute inflammation
mononuclear phagocytes
- more sophisticated
- longer lived cells - months
- blood monocytes, Kuppfer cells, alveolar macrophages
- monocyte –> macrophage
process of phagocytosis
- recognition
- internalisation - phagosome
- fusion - phagolysosome
- killing
- digested products released
what allows recognition to initiate phagocytosis?
common bacterial components (mannose, LPS)
complement (C3b)
antibody (Fc)
phagocytic killing mechanisms
- acidification
- toxic oxygen products
- toxic nitrogen oxides
- antimicrobial peptides
- enzymes
- competitors
oxygen dependent killing
- hexose monophosphate shunt generates NADPH
- NADPH oxidase generates reactive oxygen intermediates
- reactive oxygen intermediates are bacteriostatic or bacteriocidal
additional functions of macrophages
can be activated by bacterial products or cytokines
secrete soluble factors - cytokines
present antigen to lymphocytes
extracellular killing is active against…
- organisms too large for phagocytosis
* infected cells
cells involved in extracellular killing are…
eosinophils - killing of antibody-coated parasites
NK cells - release lytic granules that kill some virus-infected cells and attack some tumour cells
NK cells
activated by IFN-alpha/beta and IL12
• interferon and interleukin
can produce IFN-gamma - helps to control infections
contain viral infections whilst adaptive/specific responses kick in
what are cytokines?
low molecular weight proteins secreted by cells that stimulate or inhibit the activity, proliferation or differentiation of other cells
includes the subgroups: • interferons • interleukins • lymphokines • chemokines
link the innate and adaptive responses
general properties of cytokines
- secretion is a brief, self-limited event
- action is often pleiotrophic and redundant
- influence the synthesis and actions of other cytokines
- action may be local and systemic
- imitate their actions by binding to specific membrane receptors on target cells
what is the cellular response to most cytokines?
changes in gene expression in target cells, resulting in the expression of new functions and sometimes proliferation of the target cell
3 major categories of cytokines
mediators and regulators of innate immunity
mediators and regulators of adaptive immunity
stimulators of haematopoiesis
cytokines - mediators and regulators of innate immunity
produced mainly by mononuclear phagocytes in response to infectious agent
cytokines - mediators and regulators of adaptive immunity
produced mainly by T lymphocytes in response to specific recognition of foreign antigens
cytokines - stimulators of haematopoiesis
produced by bone marrow stromal cells, leukocytes and other cells
stimulate the growth and differentiation of immature leukocytes
important cytokines
- IL2
- IL1
- TNF alpha
- interferons
2 distinct groups of chemokines
CXC
CC
effects of cytokines secreted by macrophages
inflammation
fever
acute phase response - involves liver
act on lymphocytes - influence function
what does inflammation do?
brings cells and molecules from blood into site of infection
- increases blood supply - via vasodilation
- increases vascular permeability - leaky
- increases expression of adhesion molecules
what does inflammation trigger?
- macrophage derived cytokines
- complement
- mast cells - histamine release
- T-cell derived cytokines
what is endotoxic shock?
excessive cytokine release in gram-negative bacterial infection
widespread effects of cytokines on vascular epithelium
• circulatory shock
• disseminated intravascular coagulation (DIC)
