Module 2 Innate Immunity and Adaptive Immunity Principle Flashcards
What are the physical barriers protect against infection?
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1. The epithelial tissues provide effective physical and chemical barriers
- Commensal microorganisms that are colonizing the skin and mucosal surfaces of a healthy individuals are in.
Microbiota
The population of commensal organisms (they have a develop a symbiotic relationships with their human hosts that mutually improve their nutritions metabolism and general health)
Extracellular infections
Pathogens that populated the spaces between human cells
Intracellular infections
Pathogens that replicate inside human cells; many pathogens have life cycles that involve both extracellular and intracellular forms
What are the characteristics of complement proteins?
- They are made in the liver.
- They are soluble proteins.
- They are present in the blood lymph and extracellular fluids.
- Many complement components are proteolytic enzymes (proteases)
- There are over 30 complements, C3 most important
What is a complement fixation?
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In the presence of a pathogen, C3 complement cleaves into two pieces:
- C3b: C3b fragment is attached / fixed / covalent bond to the surface of a pathogen —> the C3b tags pathogens for phagocyte-mediated destruction & forms protein complexes, that damage the pathogens membrane
- C3a: C3a fragment recruits phagocytes
What are the three complement pathways?
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1. Alternative pathway of complement activation (although last to be discovered, it is the first a pathway to be initiated)
- Lectin pathway of complement activation.
- Classical pathway of complement activation (also first to be discovered, it is more likely evolved last due to the cooperation needed between the innate and adaptive immune response)
Alternative pathway initiation
Two ways to initiate:
- Tickover: C3 spontaneously changes shape, and exposes its thioester bond. The thioester bond quickly makes a covalent bond with the water molecule. This hydrolysis process is called to tickover. It is a slower process to initiate the alternative pathway. C3 convertase: iC3Bb (easily diffused and not very stable)
- Activated by pathogens. C3 convertase: C3bBb (cannot diffuse away and more efficient at cleavage and fixation of C3b; can have runway reaction)
What is a runaway reaction?
C3 convertase, C3bBb is capable of rapid run away reactions because one molecule of C3bBb catalyzes the formation of numerous additional C3bBb molecules
Where are the regulatory proteins determine the extent and the site of C3 deposition and stops the run away reaction?
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There are two broad categories of complement control proteins (CCP):
- Plasma proteins:
Properdin (factor P): increase the reaction
Factor H&I : counteracts factor P
I immunodeficiency suffered by people who lack factor I: C3bBb runaway unchecked until the C3 reservoir is depleted
- Membrane proteins.
DAF (Decay accelerating factor): keeps C3bBb in check
MCP (membrane cofactor protein): stops the runway reaction
Where are the regulatory proteins determine the extent and the site of C3 deposition and stops the run away reaction?
See pic
There are two broad categories of complement control proteins (CCP):
- Plasma proteins:
Properdin (factor P): increase the reaction
Factor H&I : counteracts factor P
I immunodeficiency suffered by people who lack factor I: C3bBb runaway unchecked until the C3 reservoir is depleted
- Membrane proteins.
DAF (Decay accelerating factor): keeps C3bBb in check
MCP (membrane cofactor protein): stops the runway reaction
MAC / membering attack complex
A large pore that is assembled in the membrane of bacteria and eukaryotic pathogens
Comprised of C5, C6, C7, C8 and C9
Regulatory proteins of MAC
Soluable proteins:
S protein, clusterin, factor J
Membrane proteins:
HRF / homologous restriction factor
CD59 / protectin
PNH / Paroxysmal Nocturnal Hemoglobinuria
Disease is categorized by episodes of a complement mediated lysis of erythrocytes due to lack of DAF, HRF or CD59 on their surfaces
Anaphylatoxins
Induce the contraction of smooth muscle, and degranulation of mast cells —> release of histamines, and other vasoactive substances —> increase capillary permeability
Anaphylatoxins are a group of small proteins that are generated as a result of the activation of the complement system, which is a part of the innate immune system. The complement system plays a critical role in host defense against invading pathogens by opsonizing them for phagocytosis, recruiting immune cells to the site of infection, and directly killing pathogens.
The activation of the complement system results in the formation of several complement proteins, including anaphylatoxins such as C3a, C4a, and C5a. These proteins are called anaphylatoxins because they can trigger anaphylaxis, which is a severe and potentially life-threatening allergic reaction characterized by symptoms such as difficulty breathing, low blood pressure, and swelling of the face, lips, and throat.
Anaphylatoxins act by binding to specific receptors on the surface of various immune cells, including mast cells, basophils, and neutrophils, leading to the release of inflammatory mediators such as histamine and leukotrienes. These mediators cause the characteristic symptoms of anaphylaxis, including bronchoconstriction, vasodilation, and increased vascular permeability. In addition to their role in anaphylaxis, anaphylatoxins also play a critical role in the immune response against pathogens and in the pathogenesis of various inflammatory diseases.
Other plasma proteins that can limit the spread of the infections?
- The coagulation system: a cascade of enzymes in plasma that cooperates with platelets to form blood clots. Immobilized in the clots, pathogens cannot enter the blood and lymph and transported to throughout the body.
- The kinin system: another enzymatic cascade and plasma proteins; induced by damaged tissue to produce bradykinin to increase vascular permeability so immune cells to enter damaged tissues more easily (nonamer peptide reduces hypertension, dilate blood vessels and relax smooth muscle)
- Defensins: anti-microbial peptides that kill pathogens by disrupting their membranes. & they are components of neutrophil granules
What are the characteristics of macrophages?
- Macrophage is the first line of cellular defense against the invading microorganism
- They have CR1 (complement receptor 1) binds C3b fragments that were deposited on pathogen surface during activation of the alternative pathway
- Other receptors on macrophage: CR3 and CR4
What are the three stages of immune response?
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What are the functions of the cell surface receptors of innate immunity such as macrophages?
Distinguish self from non-self and altered-self
These cellular receptors can recognize structural differences between the macrmolecules: carbohydrates proteins, lipids, and nucleic acids
How does macrophages to kill pathogens?
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Receptors capture pathogen —> endosomes / receptor-mediated endocytosis —> lysosome / phagocytosis
PRR / pattern recognition receptors
Receptors that recognize a structural feature common to many different types of pathogens
PAMP: pathogen associate molecular pattern
DAMP: damage associated molecular pattern
What types of PRR do macrophages have?
They’re mainly scavenger receptors such as Lectin
(The SR-E class of scavenger receptors)
Lectins are a diverse group of proteins or glycoproteins that can bind to specific carbohydrate molecules
SR-A1: binds HepC, beta amyloid
How is bacteria categorized?
Gram-positive
Gram-negative: bacterial lipopolysaccharide (LPS) the most abundant component of the outer membrane of gram-negative bacteria
What are Integrins?
Integrins are a family of transmembrane proteins (CR3 and CR4) that are found on the surface of cells. They function as receptors, meaning they are able to bind to specific molecules in the extracellular matrix or on other cells.
Integrins play important roles in many cellular processes, including cell adhesion, migration, differentiation, and proliferation. They are crucial for the formation and maintenance of tissues and organs, as well as for immune system function and wound healing.
TLR / Toll-like receptors
- TLRs are a family of signaling receptors that are present on immune system cells.
- Dimer structure, can be homodimer or heterodimers
- Three components of its structure:
(1) pathogen recognition domain (consists of a repeated motif of a 22-29 amino acid residues that has many Leucine residues and called leucine-rich repeat region / LRR
(2) transmembrane domain
(3) TIR / Toll/interleukin-1 receptor: for intracellular signaling
How does TLR 4 recognize the lipopolysaccharide of gram-negative bacteria?
MyD88: adaptor proteins
NFkB: transcription factor
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TLR senses the presence of the four main groups of pathogenic microorganisms
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Allotypes?
Proteins encoded by different alleles of the same gene are called allotypes.
This variation called a genetic polymorphism.
TLR4 polymorphism influences disease susceptibility
Septic shocks are usually caused by gram-negative bacteria
Two common TLR4 allotypes in patients is more susceptible to septic shock
What is septic shock?
Bacterial infections spread to the blood and becomes systemic _—> Innate immune response causes widespread dilation of blood vessels —> leading to massive leakage of fluid into tissues —> a state in which the blood supply is severely perturbed, and a vital organs can fail which is septic shock
NOD1 and NOD2
Soluble cytoplasmic receptors that detect products arising from the intracellular degradation of phagocytosed bacteria
Type I Interferon
- Cytoplasmic protein
- Can detect viral nucleic acid
- All nucleated human cells have this protein
- Interfere with viral replication in the infected cells, and to instructor nearby infected cells to get ready to fight off infection.
- Alerts NK cells
Type I and II Interferon Receptors and signaling cascade
All type I interferons (IFNs) bind a common receptor at the surface of human cells, which is known as the type I IFN receptor. The type I IFN receptor is composed of two subunits, IFNAR1 and IFNAR2, which are associated with the Janus activated kinases (JAKs) tyrosine kinase 2 (TYK2) and JAK1, respectively.
The only type II IFN, IFN-γ, binds a distinct cell-surface receptor, which is known as the type II IFN receptor. This receptor is also composed of two subunits, IFNGR1 and IFNGR2, which are associated with JAK1 and JAK2, respectively.
Activation of the JAKs that are associated with the type I IFN receptor results in tyrosine phosphorylation of STAT2 (signal transducer and activator of transcription 2) and STAT1; this leads to the formation of STAT1–STAT2–IRF9 (IFN-regulatory factor 9) complexes, which are known as ISGF3 (IFN-stimulated gene (ISG) factor 3) complexes. These complexes translocate to the nucleus and bind IFN-stimulated response elements (ISREs) in DNA to initiate gene transcription.
Both type I and type II IFNs also induce the formation of STAT1–STAT1 homodimers that translocate to the nucleus and bind GAS (IFN-γ-activated site) elements that are present in the promoter of certain ISGs, thereby initiating the transcription of these genes. The consensus GAS element and ISRE sequences are shown. N, any nucleotide.
Autocrine vs paracrine
When cytokine and its a receptor are both made by the same cell they interact to give autocrine signals, whereas paracrine signals that are given when the cytokine and receptor are products of different cells
What is the dedicated cell for type I interferon production?
Plasmacytoid Dendritic Cells secreted up to a thousandfold more interferon than other cells and they are professional interferon producing cells
PDC is only in blood and lymphoid tissues
PDC receptors: TLR7 and TLR9, which is a used to detect the presence of viral infection —>. MyD88 activation —> NFkB activation
Interleukin-1 beta (IL-1beta)
- Master regulator of the inflammation
- On the front line in responding to the crisis of infection.
- Made and stored in large quantity by macrophages as inactive pro-form, typical cleaved by proteolytic proteins and secreted en mass in response to infection
IL-1 alpha
Also, similar structure to IL-1 beta, it is more important for a homeostasis and not on the front line in responding to the crisis of infection
Different from IL-1 beta, IL-1 alpha pro-form is constitutively expressed in moderate amounts by healthy cells
IL-1beta pathway
Infection —> activate, tissue resident macrophages —> release IL-1beta —> activate more macrophages —> release cytokines (TNF-alpha, IL-6, CXCL8, CCL2, IL-12)
Extravasation
The overall process of leaving the blood through the help of adhesion molecules
The characteristics of neutrophil?
Neutrophil have two kinds of receptors:
scavenger receptors to recognize microbial products
Complement receptors
It is programmed to die
Killing process: engulfment of bacteria —> endosomes fuses with granules —> fusion with lysosomes —> bacteria, degrade —> neutrophils dies by apoptosis and phagocytosed by macrophages
Pyrogens
Cytokines and other substances that induce fever
Functions of IL6?
Change the spectrum of plasma proteins made by the liver
Concentration increase of 30 plasma proteins that contributed to innate immunity but decreasing for other plasma proteins. The sum of these changes constitutes the acute phase response.
Lectin pathway of complement activation
- Initiated by Mannose-binding lectin
- C3 convertase: C4bC2a
Classical pathway of complement activation
- Initiated by C-reactive protein
- C3 convertase: C4bC2a
Summary of the three complement pathways
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Summary of the three complement pathways
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What are the five types of innate lymphoid cell derive from a common innate lymphocyte precursor?
NK cells
ILC1
ILC2
ILC3
LTi
NK cell characteristic?
- Express CD56 not CD3, a defining marker of T cells
- Functions:
Kill infected tissue cells, which interferes with viral replication and propagation
Secretion of cytokines that can act on the resident macrophages to increase the inflammation and phagocytosis
How many types of NK cells are there?
CD56dim NK cells (more than 90% of blood NK cells): have less CD56 on their surface; differentiated cytotoxic effector cells
CD56bright NK cells, weakly cytotoxic and committed to making cytokines
During NK cell development, CD56bright gives rise to CD56dim
NK activation / killing process
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What TLR does NK cell express?
TLR3: viral dsRNA
TLR7 &8: ssRNA
How does NK cells and macrophages cross-activate each other at sites of infection?
IL-12: main function is to activate and recruit NK cells and Th1 cells
IFN-gamma: potent, inflammatory cytokines, and the principle cytokine produced by NK cells, it is type II interferon
How does the interaction between dendritic cells and NK cells work?
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NK cells also control when to call up help from the adaptive immune response
NK cell memory
Tumors and virus infected cells, often escape T cell attack by reducing or losing expression of HLA class one. To counter this threat, NK cells have surface receptors that identify cells with abnormally low HLA class I expression and cause them to be killed
