Innate Immunity Flashcards
Innate immunity
First line of defence, slow growth of infectious agents until adaptive immune responses can develop
Immediate effector function
Does not differentiate between particulate proteins but classes of pathogens
Include:
1. Anatomic barriers
2. Physiologic barriers
3. Soluble factor based and chemical barriers
4. Phagocytosis
Skin
Epidermis and dermis
Mechanical barrier, impermeable to most infectious agents
First line of defence
Several layers of epithelial cells
Outermost layer is dead cells filled with keratin
Antimicrobial peptides, lysozyme, fatty acids in sebum
Mucus membranes
Lining interiors surface of body
Secrete mucus which traps foreign particles and prevents them from adhering
Cilia, sneezing, coughing, swallowing
Bacterial flora prevents other pathogenic bacteria (gut commensals: colicins)
GI: enzymes, antimicrobial peptides, normal flora
Resp: mucus, cilia, alveolar macrophages
Uro: mucus, fluid flow
Physiological barriers
Acid pH of lactic acid Fatty acids in sweat Sebaceous sections Acid pH of stomach Fever repsonse
Antimicrobial peptide
Short cationic peptides with amphipathic structure
Defensins (intestinal paneth cells, epithelial cells, neutrophils, macrophages)
Active against bacteria, fungi, enveloped viruses
Bind to negative microbial structures
disrupt membrane, inhibit DNA, RNA, protein synthesis
Lysozyme
Mucosal/glandular secretion: tears, saliva, resp tract
Cleaves glycosidic bonds of peptidoglycan
Lactoferrin
Mucosal/glandular secretion: milk, intestinal mucus, nasal/resp, uro
Binds/sequesters iron, limiting growth of bacteria and fungi, disrupts microbial membranes, limits viral infectivity
Secretory leukocyte protease inhibitor
Skin, mucosal/glandular secretions
Block epithelial infection by bacteria, fungi, virus
S100 proteins
Psoriasin, calprotectin
Skin, mucosal epithelia (mouth, intestine, nasal, resp, uro)
Disrupts membranes, killing cells
Binds and sequesters divalent cations
Defensins
alpha, beta
Skin, mucosal epithelia (mouth, intestine, nasal, resp, uro)
Disrupts membranes
Toxic intracellularly effects
Cathelicidin
Mucosal epithelia (resp, uro) Disrupts membranes Toxic intracellularly affects
Surfactant protein
Resp
Block bacterial surface components
Promotes phagocytosis
Phagocytic barriers
Neutrophils, macrophages
Killed by reactive O and N, enzymes
Inducible nitric oxide synthase
Pathogen recognition mechanism
TLR and NOD receptors
Recognize structural motifs (PAMPs)
PAMPs
Pathogen associated molecular patterns
Highly conserved and usually necessary for survival
Absent from host cells
Soluble innate immune recognition elements
Mannose-binding lectin
C reactive protein
Complement
Interferons
Cellular receptors in innate immune cells
Toll-like receptors (TLR) NOD receptors (nucleotide binding oligomerization domain)
Toll-like receptors
Contain membrane spanning receptors with leucine rich repeats form ligand-binding domain
TIRAP and/or MyD88 function as interior signalling domain
Signalling activates MAP kinase pathway, interferon regulatory factor 3/7, and/or NF-cappaB
Inflammation promoting genes regulated by NF-cappaB
Inflammatory cytokines (TNF-alpha, IL1, IL6, IL12, GM-CSF, IFN-alpha/beta)
Chemokine’s (IL8, MCP, RANTES, eotaxin)
Adhesion molecules (ICAM1, VCAM1, Eselectin, Pselectin)
Immune effector molecules (iNOS, defensives)
Costimulatory molecules (CD40, CD80/86 on dendritic cells)
Anything that blocks NF-cappaB is a good anti-inflammatory
Dendritic cell maturation
TLR are direct inducers of DC maturation, including expression of CD80, 86, 40, up regulation of MHCII and IL12
Can be induced indirectly by TNF and IL1
Mature DC up regulate CCR7 (chemokine receptor) and migrate to lymph node
Collectins
Small proteins that are able to kill certain bacteria by cell wall disruption
Cause bacteria to aggregate, enhancing phagocytosis
Serum
Contains interferons, which are antiviral agent
Contains complement
Interferons
Alpha produced by leukocytes
Beta produced by fibroblasts
Gamma produced by T and NK cells
Complement
20+ serum proteins that act in combination and sequence
Both innate and adaptive
C3 is most important
Cascade to membrane damaging reaction
Activated by: Alternative, lectin, classical
Lectin pathway
Innate
Mannose-binding lectin (protein in tissue fluid and plasma) binds mannose residues on glycoproteins and carbohydrates of bacteria, fungi, viruses
Humans have sialic acid residues that cover and hide mannose residues
Activates complement cascade
C-reactive protein (in fluid and plasma) binds phosphatidylcholine and pneumococcal polysaccharide to active complement cascade
Alternative pathway
Innate
Microbial cell wall components
Classical pathway
Adaptive immunity
Antibody-antigen complexes
Membrane attack complex
MAC
Leads to cell lysis
Opsonin
C3b
Facilitates phagocytosis of microbes
Anaphylatoxins
C3a, C5a
Facilitate immune cell activation/recruitment
Acute phase response
Responsible for production of innate immune effector cells and soluble molecules
Results in production of certain cytokines (IL6, TNF)
Effect on hypothalamus (prostaglandins cause fever)
Adrenal cortex makes corticosteroids that cause production of acute phase proteins in the liver
Innate immunity to viral infections
Induction of Type 1 Interferons (IFNalpha/beta)
Presence of viral RNA/DNA activated production via TLR stimulation
Interferons induce antiviral response leading to mRNA degradation and inhibition of protein synthesis
NK cells are activated and kill virally infected cells (dual receptor with MHC1 and activating receptor, MHC1 missing on virally infected cells)
Plasmacytoid dendritic cells
Produce 100-1000x more type 1 interferon upon contact with viruses
Do not need a productive viral infection in order to up regulate type 1 interferon genes
Recognize mechanism for viral infection is most likely TLR7/8 that recognizes viral ssRNA
Drive NK response
