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Lecture 2Innate immunity
•General features of innate immunity
•Example of an inducible innate immune mechanism
interferon
•Example of a preformed innate immune mechanism
complement
Reading: Parham chapters 1 and 7.15 to 8.10
Example: Complement (C’)
Example: Interferon
Innate defense is both preformed and inducible
See Fig 8.38 Parham
Figure 8.1
Defensins (epithelium)
Figure 8.6
Progression of Immunity
At least three cell types reside within or beneath the epithelium and induce inflammation in response to trauma or microbial products: Macrophages, Mast Cells, and Langerhan’s cells (a skin dendritic cell)
Figure 8.5
Features of innate immunity
Cellular components: •Phagocytic cells, granulocytes: release toxins, release cytokines, some can move rapidly •High precursor frequency of reactive cells•Multiplicity of receptors for conserved aspects of
microbes
Soluble components:•Blood plasma proteins that recognize (tag) microbes•Plasma proteins that destroy microbes •Proteins that sequester molecules needed for microbial
nutrition
Components Principle FunctionsBarriersEpithelial layers Prevent entryDefensins and Cryptidins Microbial killing
Circulating and Tissue Effector CellsNeutrophils Early phagocytosis and killing of microbesMast Cells Release of inflammatory granulesMacrophages Efficient phagocytosis and killing of microbes: cytokinesEosinophils Nasty toxic cells designed to kill helminths (worms)Natural killer (NK) cells Lysis of infected cells, activation of macrophages
Circulating ProteinsComplement (C’) Killing of microbes, opsonization of microbes, actvn leukocytesMannose-binding protein Opsonization of microbes and activation of C’C-reactive protein Opsonization of microbes and activation of C’Lysozyme Bacterial cell wall lysis
CytokinesTNF, IL-1, 6, 18 InflammationIFN Resistence to viral infectionIFN Macrophage activationIL-12 IFN production by NK cellsIL-15 Proliferation of NK cells, memory T cellsIL-10, TGF Control of Inflammation
Adapted from: Abbas (Saunders)
Components of Innate Immunity
Alveolar macrophages (lung) Histiocytes (connective tissue) Kupffer cells (liver) Mesangial cells (kidney) Microglial cells (brain)Tissue macrophage
Figure 1.6ij
Macrophages are important first responders to infection and tissue damage.
Receptors on Macrophages:
LPS receptor-CD14
Toll-like receptors
Fc receptors
Mannose receptor
Complement receptors
IFN receptor
Chemokine receptors
Figure 1.13Macrophages phagocytose and degrade foreign particles,bacteria and dead (and dying) host cells.
High affinity FcRI receptor. Effective against worm infections. Granules contain mediators-smooth muscle contraction and worm toxicity
Express some of the same receptors found on macrophages. These cells are specialized in killing and swallowing microbes
Figure 1.6ef
LPS receptor:
CD14
toll-like receptor-4
CR3,4:
Complement (C’) receptors (C3b)
Scavenger receptor:
sialic acid-bearing protein
Mannose receptor:
Binds mannose on bacteria, activates C’
Glycan receptor:
Polysaccharides
IN ADDITION: TLRs
Figure 8.8
Figure 2-6
Function in disease, not entirely understood
Contains high affinity receptors for IgE, and preformed granules that contain inflammatory mediators including: histamine; heparin; TNF; chondroitin sulfate; neutral proteases; and other.
Mast cells can also secrete: cytokines to induce inflammation; chemokines to induce infiltration by monocytes, and neutrophils, leukotriences to induce muscle contraction and increase vascular permeability
Mast cells are capable of inducing an inflammatory cascade
Figure 1.6gh
Mast cells are also found in the tissues
Mast cells can release histamines which induce inflammation
Redness, swelling(erythema, edema)
Neutrophils and monocytes are recruited
Figure 1.14
TNF
Figure 1.6ab
Lymphocytes are entirely involved with acquired immunity. The come in two types: T lymphocytes (T cells) that differentiate in the thymus and B lymphocytes or B cells that differentiate in the bone marrow.
B cells can further differentiate after antigen-activation to plasma cells that produce antibodies
Figure 1.6cd
Natural Killer Cells play several interesting roles in the immune system. One is to monitor cells for identification. If a cell doesn’t reveal its identity papers, it is killed. You’ll see this later in the course.
Dendritic cells are the most important antigen presenting cells (APCs) in the immune system
Figure 8.10
**
**The most important inflammatory cytokine (at least in this course)
Figure 8.14
The story of interferon
LIVE Influenza virus
Chick cells
Dead cells + more virus
incubate
The story of interferon
Isaacs and Lindenmann 1957
Heat killed Influenza virus
Chick cells
3-4 hrs
LIVE Influenza virus
Resistance to infection!
The story of interferon
Isaacs and Lindenmann 1957
LIVE Influenza virus
Resistance to infection!
Virus free supernatantfrom cells treated withkilled virus
interferon
Concepts
• The cells that produced interferon were non-specialized, i.e, non-immune cells.
• The heat killed influenza was recognized as foreign.• Interferon in this context behaved as a danger signal to
nearby cells.
Questions
• What was seen as foreign?• What rendered the warned cells resistant to infection?
How was virus recognized as non-self?Virus was detected in this case by a sensor for
double stranded RNA called Toll-like receptor 3 (Tlr3)
Virus enters here
dsRNAdetected here
by Tlr3
Interferon can be induced with a synthetic dsRNA,poly I:C (inosine:cytidine)
The RNA of normal cells typically is not double stranded, but dsRNA is often a feature of viruses.Influenza is a positivestrand RNA virus that generates a negative strand by RNA-dependent RNA polymerase, a process that generates dsRNA Signal to nucleus
Interferon produced
INF-(interferon)
Adapted from Fundamental Immunology , WE Paul, Ed. Chap 39
INF receptor
Induced synthesis(2’-5’)-oligoandenylate synthase
ATP 2-5(A)
RNAseL(inactive)
RNAseL(active)
mRNA degraded
Protein kinase PKR
dsRNA
dsRNA
(inactive)
+ATP
Active PKR
Inhibition of protein synthesis
eIF2 (translation intiation factor)
How interferon signaling inhibits viral growth
Effects on viralgrowth
Improved recognitionby adaptive immunity
Increased innate immune activity
Effects of interferon
Fig 8.7
From Takeda and Akira 2005
The toll like receptors in humans
cytoplasm
ssRNA
Non-specialized cells can detect and respond to infection by recognizingconserved motifs of microbes using Tlrs
Tlrs tranmit signals about microbial constituents detected to the nucleus, thus regulating the type of genes expressed, and the subsequent response
Seen by Tlr4
Seen by Tlr2
Toll family of receptors is evolutionarily ancient. Toll receptors in Drosophila were discovered first, and shown to confer resistance to bacteria and fungi by regulating the expression of anti-microbial peptides.
What is the basis for innate immunity, and how does is relate to vertebrates? Drosophila melanogaster mutants were found that were susceptible to fungal and bacterial infections.
Immunity in Drosophila (Innate)
Toll mutant lacks defense against fungal infections
18 Wheeler lacks defense against bacteria
This led to the discovery of a family of receptors known as the Toll-related receptors (TLR) present in vertebrates
Fig 7.27 Parham
Complement pathways
Figure 2-20
Figure 2-24
Mannose binding lectin is an innate recognition molecule that recruits complement
Figure 2-11
Figure 2-21
Binds to antibody:antigen complex
C1q binds to antibody:antigen complexes. Thus it recruits complement to antigen tagged by antibody.
Figure 7.30
Figure 2-19 part 1 of 2
C1q couples the innate(invariant) complement system to the adaptive
immune system (Antibody).
Here specificity comes from invariant molecules
Figure 2-22
For MB lectin MASP1/2cleave C4
The rest is the same
Complement activation is a proteolytic cascade, in which one protease activates by proteolysis the next protease.
Zymogen= inactive enzyme that is activated by proteolysis
See Figs 7.33, 7.34
Figure 2-25C4 (and C3) carry a unique
thioester bond
….Cys-Gly-Glu-Gln-……amino acid chain
Activated C3 and C4(C3b and C4b) rapidly bind covalently to nearby surfaces and proteins.
Fig 7.32
Figure 2-28Complement activation includes feed forward amplification steps
Macrophages, neutrophils and other white blood cells carry C3b receptors that they use to rapidly phagocytose and destroy microbes C3b.
Figure 7.38
Figure 7.39
Figure 7.35
Figure 2-26
The alternative C’ pathway illustrates the important role of negative regulators.
Mammalian cells protect themselves from complement-mediated lysis by expressing inhibitory proteins on the plasma membrane.
Small amounts of C3b are continually being produced by spontaneous “tick over”. If C3b binds to a pathogen, the reaction continues, if it binds to a host cell in low amounts, the reaction is usually terminated.
(This figure is similar to Fig 8.7 in Parham)
DAF binds to C3b and C4b causing the dissociation of existing C3 convertases and preventing the assembly of new ones.
CR1 and MCP bind to C3b and C4b, making them susecptible to proteolytic cleavage by factor I.
Figure 7.43
Figure 7.40
Anaphylatoxins: C5a > C3a > C4a
Smooth muscle contraction, degranulation of mast cells and basophils.
Vasoactive effects directly on local blood vessels.
Result: inflammation, edema, increased fluid flow into the lymphatics, and transfer of antigens to local lymph nodes
Figure 2-9
Summary of lecture 2
•Innate immune activity is preformed and inducible•Innate immunity involves all cells (e.g. interferon)•Conserved motifs of microbes are detected (ligands for Tlrs)•Innate response involves
•altered circulation- increased vascular permiability•ridding mechanism- toxic mediators, NO, hydrogen peroxide•alarm mechanisms- cytokines, histamine•both local and sytemic signals are transmitted (fever, local swelling)
•Leukocyte migration is important•Response is often toxic•Self cells protect themselves (e.g., complement inhibitors)•Innate immunity is coupled to adaptive immunity (classical C’ pathway)•Innate immunity is highly conserved over evolution