innate immunity

week 1 ctb

immune system

• provides protection against infectious disease, but also relevant to neoplasia, allergy, autoimmune disease, transplantation, diagnostics, etc

• spread throughout body so a functional (cellular) approach is more meaningful than an anatomical one

• immune function can be divided into innate and adaptive immunity although these are interlinked

• antigen= any molecule capable of inducing immune response but is often thought in terms of specific adaptive immune response

innate vs adaptive table

innate immunity

• defences against disease that are naturally present rather than induced by prior exposure to a pathogen

• non-specific defence mechanisms that become active immediately (within hours) upon exposure

• not long-lasting and without immunological memory

• relatively poor amplification or regulation of response leading to threat to self-antigens

• evolutionarily ancient and therefore widespread among species: pathogens have immunity too

components of the innate immune system

1. physical barriers: epithelia and secretions

2. leukocytes

   • phagocytic cells

   • granulocytes

   • NK cells

3. plasma proteins: humoral response

integration of innate and adaptive immune responses

• innate and adaptive immune responses are not isolated processes but act together to optimise response to pathogens

• adaptive immune response is very powerful/specific but many pathogens would kill in the days needed for a good adaptive response in the absence of non-specific innate immune responses

barrier immunity

physical barriers

• skin

• mucus

• respiratory cilia

biochemical barriers

• sebaceous secretions in skin

• lysozyme in tears

• gastric acidity

• commensal organisms

most infectious agents enter via the mucosal surfaces of

• nasopharynx

• respiratory tract

• gastro-intestinal tract

• genito-urinary tract

epithelial defences

• interior epithelial surfaces are covered with mucus containing mucins (help prevent pathogens from adhering and facilitate their clearance by cilia)

• peptides in mucus called defensins kill/inhibit growth of pathogens

cells of the blood

myeloid lineage cells (main cells involved in innate immunity)

phagocytosis (including an oxidative burst)

1. chemotaxis/adherence of microbe to phagocyte

2. ingestion of microbe by phagocyte

3. formation of a phagosome

4. fusion of phagosome with lysosome to form phagolysosome

5. digestion of ingested microbe by enzymes

6. formation of residual body containing indigestible material

7. discharge of waste materials

monocytes and macrophages

• monocytes circulate in the blood

• macrophages are formed by differentiation of monocytes nad are 5-10x bigger and found in tissues

• macrophages ingest small pathogens and other material by phagocytosis

dendritic cells

• present in most tissues and they have long cytoplasmic extensions (dendrites) to maximise antigen presentation to T cells and stimulation of adaptive immune response

granulocytes

• neutrophils are phagocytic with lytic enzymes within granules including peroxidase and lysozyme: very effective in killing ingested bacteria

• eosinophils are most important in defence against larger parasites

• basophils are non-phagocytic and release active substances from their granules

NK cells

• lymphoid lineage cells that are a part of the innate immune system

• cytotoxic cells that kill virally infected/malignant cells: similar to T cells but without same activation requirements

• cytotoxicity comes from pore forming molecules that are inserted into the target cell membrane and cytotoxic chemicals that enter target cell cytoplasm

PAMPs and PRRs

• pathogen-associated molecule patterns (PAMPs) are molecular motifs commonly found in broad classes of pathogens and absent from humans

• often glycoconjugates with the lipo-polysaccharides present in outer membrane of gram -ve bacteria being the prototypical example

• pattern recognition receptors (PRRs) are present on innate immune cells (macrophages/dendritic cells)

  • recognise PAMPs and initiate a response

inflammatory response

• recognition of pathogens by macrophages triggers signalling molecules (cytokines and chemokines) which together cause inflammation

• blood vessels become more permeable and cause area to swell

• leukocytes adhere to endothelial cells of blood vessels and pass between them to enter tissue

• neutrophils are first to arrive, followed by monocytes, which differentiate into macrophages

• inflammation is important in adaptive immunity as well: lymphocytes migrate into site of inflammation later

signalling and humoral response

• cytokines are small protein signalling molecules of the immune system

• e.g: interleukins, chemokines (induce chemotaxis) and interferons (released by virus-infected cells)
  

• acute phase proteins: humoral factors that are upregulated or downregulated in response to inflammation

• positive APPs: CRP and complement factors: both of which can function as opsonins, labelling microbes for phagocytosis

complement

• part of innate immune system with links to adaptive immune system (ABs)

• consists of 20+ different globular proteins found in blood plasma mostly produced by the liver 

• these proteins work in a cascade where one protein cleaves next to produce active fragments

• 3 pathways (classical, alternative, MBL) that converge with the cleavage of inactive C3 protein into active C3a and C3b fragments

• result of cascade: to form membrane attack complexes which disrupt cell membranes of the pathogenic bacteria

classical pathway

1. ABs bound to antigens on bacterial cell surfaces bind the C1 complex

2. C1s cleaves C4, which binds bacterial surface, then cleaves C2

   • resulting split molecules form C4b2b enzyme complex (also called C3 convertase) which remains covalently bound to bacterial surface

3. C3 convertase cleaves C3 into C3a and C3b

   • C3b and its degradation products especially iC3b on pathogen surfaces, enhance phagocytosis

4. complex of C4b, C2a and C3b (termed C5 convertase) cleaves C5 into C5a and C5b

5. MAC assembles on target cells

alternative pathway

• C3bBb can bind to another molecule of C3b and together they convert complement protein C5 into: C5a and C5b

• C5b combines with complement proteins C6, C7 and C8 and forms a ‘stalk’ that anchors the protein complex into the bacterial cell wall

• complement protein C9 completes the membrane attack complex (MAC), making a channel that opens a hole in the surface of the bacterium

MBL pathway

• triggered by the soluble PRRs: Mannose Binding Lectin (MBL) and Ficolin: focuses on patterns not present on surface of human cells

• MBL binds in the blood to a serine protease (MASP-1, MASP-2)

• when MBL binds to terminal mannose sugars on microbial proteins, MASP functions like a convertase, cleaving C3 into C3b

• C3b fragments then bind to bacterium and start the complement chain reaction