Midterm 1 Flashcards
1
Q
what is the immune response?
A
a reaction to components of microbes as well as to macromolecules, such as proteins and polysaccharides, and small chemicals that are recognized as foreign(non-self)
ex. Even self molecules can elicit immune responses (autoimmune responses)
2
Q
Innate Immunity
A
natural/native immunity:
- provides the early line of defence against microbes.
- reacts to products of microbes and injured cells and responds essentially the same way to repeated exposures
1. Physical and chemical barriers, such as epithelial (skin) and anti-microbial chemicals produced at epithelial surfaces
2. phagocytic cells (neutrophils-fast/abundant, macrophages), dendritic cells (WBCs/leukocytes) and natural killer (NK) cells and other innate lymphoid cells
3. blood proteins (members of the complement system and other mediators of inflammation-bringing weapons to fight)
3
Q
Adaptive immunity
A
acquired immunity:
- develops as a response to infection and adapts to the infection
- recognizes and reacts to a large number of microbial and nonmicroblal substances
- *has the ability to distinguish different substances, called specificity and can respond more vigorously to repeated exposures to the same microbes (memory)
- has cells called lymphocytes(WBC’s- T and B cells) and their secreted products, such as antibodies
4
Q
antigen
A
are foreign substances(virus, bacteria, toxins) that induce specific immune responses or are recognized by lymphocytes or antibodies
-stimulates the immune system to produce antibodies
5
Q
Cytokines
A
a number of small proteins secreted by various cells types and carry signals to a variety of cells
- the ‘bosses’ of the immune system
- regulate and turn off the immune response
- communication between immune cells
6
Q
compare innate and adaptive immunity
A
Innate: -rapid response -non-specific to pathogens -genetically determined -organism is born with it -does not alter with repeated exposure -primitive and board receptors -no immunological memory -blood proteins-> Complement, various lectins and agglutinins Adaptive: -slower response -specific to pathogens -not genetically determined -develops over a lifetime -improves with each successive exposure -highly specific receptors -has immunological memory -blood proteins-> Antibodies
7
Q
what are chemokines
A
general word for small molecules or small proteins that cells release as a kind of signalling mechanism
-regulate cell migration and movement
8
Q
Humoral immunity
A
-EXTRA-CELLULAR antigens/pathogens
-ANTI-BODY MEDIATED
1 of 2 types of adaptive immune responses that is mediated by molecules in the blood and mucosal secretions called antibodies (produced by cells called B lymphocytes/B cells)
-antibodies recognize microbial antigens, neutralize the infectivity of the microbes, and target microbes for elimination by various effector mechanisms
-principle defence mechanism against extracellular microbes and their toxins because secreted antibodies can bind to these microbes and toxins and assist in their elimination
-antibodies themselves are specialized and may activate different mechanisms to combat microbes (effector mechanisms)
-is so named because it involves substances found in the humors, or body fluids.
9
Q
what is cell-mediated immunity
A
- INTRA-CELLULAR antigens/pathogens
- CELL-MEDIATED: mediated by T lymphocytes/T cells
- intracellular microbes, such as viruses and some bacteria, survive and proliferate inside phagocytes, other host cells and are inaccessible to circulating antibodies.
- CM immunity promotes the destruction of microbes residing in phagocytes via macrophages or the killing of infected cells via cytotoxic T cell undergoing apoptosis, to eliminate reservoirs of infection
- T cells contribute to the eradication of extracellular microbes by recruiting leukocytes that destroy pathogens and by secreting cytokines to help B cells make effective antibodies
10
Q
what is active immunity
A
the form of immunity that is induced by exposure to a foreign antigen
- the immunized individual plays an active role in responding to the antigen
- individuals may be naive(not encountered a specific antigen) or immune (responded to a microbial antigen and are protected from subsequent exposures)
ex. pathogen invasion (recovers from the measles) or vaccination (vaccine for measles)
11
Q
what is passive immunity
A
individuals become immune to a particular antigen without ever been exposed to or having responded to that antigen
ex. transfer of maternal antibodies through the placenta of breast milk to the fetus, which enables newborns to combat infections before they develop the ability to produce antibodies themselves
ex. administration of antibodies from immunized animals for treatment of potentially lethal infections, such as rabies and snake bites
12
Q
compare active and passive immunity
A
active:
-memory cells are produced
-antibodies made by own white blood cells
-results from pathogen invasion or vaccination
Passive:
-NO MEMORY CELLS
-antibodies from outside of the body (ex. mother)
-antibodies produced by injection/breast milk/across the placenta
13
Q
immunogens
A
substances that stimulate immune responses (often interchangeable with antigen BUT only an immunogen can evoke an immune response.)
-An immunogen is any antigen that is capable of inducing humoral and/or cell-mediated immune response rather than immunological tolerance. This ability is called immunogenicity.
14
Q
determinants/epitopes
A
the parts of antigens that are specifically recognized by individual lymphocytes/antibodies (where they attach)
- each antigen can have several epitopes
- the immune system of an individual can discriminate 10^7 to 10^9 distinct antigenic determinants due to the variability in antigen binding sites of lymphocytes receptors for antigens (diversity*)
15
Q
clonal expansion
A
an increase in the number of cells that express identical receptors for an antigen and thus belong to a clone
-enables adaptive immune response to keep pace with rapidly dividing infectious pathogens
16
Q
describe what specialization is
A
the immune system responds in distinct and special ways to different microbes, maximizing the effectiveness of the antimicrobial defence mechanisms
-humoral and cell mediated immunity are elicited by different classes of microbes or by the same microbe at different stages of infection (extracellular and intracellular)
17
Q
what is contraction and homeostasis of the immune system
A
the immune system returns to its resting baseline state (homeostasis) overtime after antigen stimulation
18
Q
why does contraction of the immune system occur?
A
largely because the responses that are triggered by antigens function to eliminate the antigens, thus eliminating an essential stimulus for lymphocyte survival and activation.
-lymphocytes (other than memory cells) that are deprived of these stimuli die by apoptosis
19
Q
what is tolerance?
A
- immunologic unresponsiveness
- not reacting harmfully to an individual’s own (self) antigenic substances
- tolerance to self antigens is maintained through several mechanisms:
- > eliminating lymphocytes that express receptors specific for some self antigens
- > inactivating some self-reactive lymphocytes
- > or suppressing these cells by the actions of other regulatory cells
- autoimmune diseases (immune responses against self/autologous antigens) may occur when there is abnormalities in the maintenance of self-tolerance
20
Q
what are the principle cells of the adaptive immune system?`
A
lymphocytes, antigen-presenting cells (APC) and effector cells
21
Q
what are B lymphocytes?
A
B cells:
- only cells capable of producing antibodies
- recognize extracellular soluble and cell surface antigens and differentiate into anti-body secreting plasma cells, thus functioning as the mediators of humoral immunity
- neutralization of microbes, phagocytosis and complement activation
22
Q
what are T lymphocytes?
A
T cells;
- cells of cell mediated immunity
- recognize the antigens of intracellular microbes and the T cells either help phagocytes to destroy these microbes or they kill the infected cells
- their antigen receptors are membrane molecules distinct from but structurally related to antibodies
- have restricted specificity for antigens; they recognize peptides derived from foreign proteins (produced by infected cell) that are bound to host proteins called *major histocompatibility complex (MHC) molecules, which are expressed on the surfaces of other cells.
- respond to cell surface-associated but not soluble antigens
23
Q
helper T cells?
A
in response to to antigenic stimulation, helper T cells secrete cytokines, which are responsible for many of the cellular responses of both innate + adaptive immunity and thus function as “messenger molecules”
-the cytokines secreted stimulate the proliferation ad differentiation of the T cells themselves and activate other cells (B cells, macrophages, other leukocytes)
24
Q
Cytotoxic T lymphocytes (CTLs)
A
CTLs kill cells via apoptosis and cytotoxins, that produce foreign antigens, such as cells infected by viruses
25
regulatory T cells
inhibit immune responses via suppression of other lymphocytes
26
Natural killer T cells (NKT cells)
small population of T cells that express some cell surface proteins found on NK cells
-role not well understood
27
what are antigen presenting cells? (APC)
capture and display antigens to specific lymphocytes
ex. dendritic cells -capture microbial antigens that enter from the extracellular environment, transport them to lymphoid organs and present them to naive T lymphocytes to initiate immune responses
28
what are effector cells
mediate the final effect of the immune system which is to get rid of the microbes
29
inflammation
- one of the two main types of reactions of the innate immune response
- process of recruitment of leukocytes(mainly phagocytes, neutrophils and monocytes which develop into tissue macrophages) and plasma proteins from the blood, their accumulation in tissues and their activation to destroy the microbes
- involves cytokines
30
antiviral defence
- one of the two main types of reactions of the innate immune response
- cytokine mediated reaction in which cells require resistance to viral infection and killing of virus infected cells by specialized cells of the innate immune system, NK cells
31
what are the 3 main strategies the ADAPTIVE IMMUNE SYSTEM USES TO COMBAT MICROBES?
1. Antibodies: secreted and bind to extracellular microbes, block their ability to infect host cells and promote their ingestion
2. Phagocytosis: Phagocytes ingest microbes and kill them, and antibodies and helper T cells enhance the microbial abilities of the phagocytes
3. Cell killing: cytotoxic T lymphocytes destroy cells infected by microbes that are inaccessible to antibodies and phagocytic destruction
32
functions of the immune system
defence against infectious microbes AND noninfectious foreign substances and products of damaged cells
33
how does Clonal selection work
one cell is selected from billions of B cells that is sensitive to the microbe and then identical clones have been created from it
- creates an army of B cells that mass-produce antibodies into surrounding fluid and circulate in the blood and travel into tissues to get rid of the microbe
- they bind to the microbe which flags them for destruction by the immune system
34
compare the phagocytes neutrophils and macrophages
neutrophils:
Origin-hematopoietic stem cells (HSCs) in bone marrow
Life span in tissues- 1-2 days
Responses to activating stimuli- Rapid, short lived, enzymatic activity
Phagocytosis- Rapid ingestion of microbes
Cytokine production- Low levels per cell
Secretion of lysosomal enzymes- prominent
Macrophages:
Origin- hematopoietic stem cells (HSCs) in bone marrow or stem cells in yolk sac or fetal liver
(early in development)
Life span in tissues- Inflammatory macrophages: days
or weeks, Tissue-resident macrophages: years
Responses to activating stimuli- More prolonged, slower, often dependent on new gene transcription
Phagocytosis- Prolonged ability to ingest microbes, apoptotic cells, tissue debris, foreign material
Cytokine production- Major functional activity, large amounts per cell
Secretion of lysosomal enzymes-Less
35
Mast cells
-Bone marrow-derived cells present in the skin and mucosal epithelia
• Upon activation release potent inflammatory mediators that defend against parasite infections
• These inflammatory mediators (I.e.histamin) cause symptoms of allergic diseases.
36
Basophils
* Blood granulocytes with similarites to mast cells
| * Role is still uncertain
37
Eosinophils
Can release enzymes that are harmful to infectious parasites, which can also damage host tissues.
38
• Natural killer (NK) cells
Cytotoxic effector functions similar to CD8+ Cytotoxic T lymphocytes
39
• Innate lymphoid cells (ILCs)
* Cytokine secreting
| * Similar function to CD4+ T helper lymphocytes
40
bone marrow lymphoid tissue
generation site of all blood cells from a common hematopoietic stem cell (HSC) which are self renewing through asymmetric division and can be identified through surface markers
- HSC give rise to two types of multipotent cells:
- common lymphoid progenitor
- common myeloid progenitor
* proliferation/maturation of blood cells in marrow is stimulated by cytokines made mainly by stromal cells and macrophages in the bone marrow
41
thymus lymphoid tissue organization
each lobe consists of an outer cortex dense with T cells and an inner medulla mainly with DC's and macrophages
- cortex epithelial cell provide IL-7 for T cell development
- epithelial cells in the medulla present self antigens and cause deletion of T cells with self receptors
- lymphocytes in the thymus are called thymocytes and are T lymphocytes at various stages of maturation
* only mature T cells leave the thymus
42
what are the three essential functions of the innate immune system that protect us from microbes and tissue injury
1. it is the initial response to to microbes that prevents, controls or eliminates infection of the host by many pathogens
2. has mechanisms that eliminate damaged cells and initiate the process of tissue repair
3. stimulates adaptive immune responses and can influence the nature of the adaptive responses to make them optimally effective against different types of microbes (bacteria vs. viruses)
43
what is the words for peptides that are toxic to bacteria and fungi and are found in plants and mammals
defensins
44
what are PAMPs?
Pathogen-Associated Molecular Patterns (PAMPs) are microbial substances that stimulate innate immunity and are produced by microbial pathogens
- different types of microbes (viruses, gram-neg bacteria, gram-pos bacteria and fungi) express different PAMPs (ex. Lipopolysaccharide/LPS in gram-neg bacteria)
* Innate immunity responds mostly to molecular structures that are shared by classes of microbes (PAMPs) using pattern recognition receptors whereas the adaptive immunity can recognize many more diverse foreign substances whether or not they are products of microbes using distinct antibodies
45
compare innate receptors with adaptive receptors
innate:
-encoded in germline; limited diversity (pattern recognition receptors/PRRs)
-nonclonal: identical receptors on all cells of the same lineage
-ex. toll-like, formyl peptide, mannose, scavenger
adaptive:
-encoded by genes produced by somatic recombination of gene segments; greater diversity
-clonal: clones of lymphocytes with distinct specificities express different receptors
46
the innate immune system recognizes microbial products that are often essential for survival of the microbes, give examples of these essential products or PAMPs
- nucleic acids such as double stranded viral RNA which is an essential intermediate in the life cycle of many viruses
- or LPS and lipoteichoic/LTC acid which are structural components of bacterial cell walls
47
what are DAMPs? give examples
DAMPs= Damage-Associated Molecular Patterns
- endogenous molecules that are produced by or released from damaged and dying cells (sometimes healthy cells produce DAMPs called alarmins which enhance the innate immune response to infections)
- the innate immune system recognizes these molecules
ex. stress-induced proteins, crystals, nuclear proteins
48
how does the innate immune system recognize PAMPs and DAMPs?
- several types of cellular receptors present in different locations in cells (ex. TLRs/membranes and NLRs/cytosol)
- soluble molecules in the blood (ex. complement proteins)
- mucosal or mucus membrane secretions
49
what are PRRs?
cell-associated Pattern Recognition Receptors (PRRs)
| -cellular receptors (of the innate immunity) for pathogens and damage-associated molecules
50
where are PRRs expressed
- on the cell surface
- in phagocytic vesicles
- in cytosol of various cell types
* all are locations where microbes might be present
51
what happens when PRRs bind to PAMPs and DAMPs?
they activate signal transduction pathways that promote the antimicrobial and pro-inflammatory functions of the cells in which they are expressed
52
what are toll-like receptors ***
Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) expressed on many cell types that recognize products of a wide variety of microbes (PAMPs) as well as molecules expressed or released by stressed and dying cells (DAMPs)
- nine TLRs in humans, named TLR1 through TLR9
- found on plasma and endosomal membranes of dendritic cells, phagocytes, B cells, endothelial cells and other cell types
- extracellular regions for PAMP/DAMP ligand biding and signalling in their cytoplasmic tails
- leucine rich repeat motifs and TIR domain
- may form homodimers or heterodimers
* different combinations of accessory molecules (such as MD2 or CD14) in TLR complexes may broaden the range of microbial products that can induce innate immune responses
53
what are HSPs and HMGB1 molecules?
they are both host molecules that engage TLRs
- HSPs =heat shock proteins (stress-induced protein)
- HMGB1 = high mobility group box 1 (nuclear protein)
* both are normally intracellular but may become extracellular when released from dead or dying cells
- from the location where they are released, they activate TLR2 and TLR4 signalling in dendritic cells, macrophages and other cell types
54
which TLRs are mainly expressed inside cells on endoplasmic reticulum and endosomal membranes and what ligands do they detect?
TLRs 3, 7, 8, and 9
-detect nucleic acid ligands such as dsRNA and ssRNA that are typical of virus microbes
(Host cell RNA and DNA are not normally present in endosomes but microbial RNA and DNA may end up in endosomess of neutrophils, macrophages or dendritic cells when the microbes are phagocytosed by these cells)
55
what happens when TLRs recognize microbial ligands
results in activation of several signalling pathways(MYD88 and TRIF) and ultimately transcription factors(ex. NF-kB, AP-1, IRF3), which induce the expression of genes whose products are important for inflammatory and antiviral responses
56
what transcription factors activated by TLR signalling pathways stimulate the expression of genes encoding many of the molecules required for inflammatory responses and stimulation of adaptive immunity
Nuclear factor kB (NF-kB) and activation protein 1 (AP-1)
-stimulate cytokines (such as TNF and IL-1), chemokines (CCL2 and CXCL8) and endothelial adhesion molecules (eg. E-selectin)
57
what transcription factors activated by TLR signalling pathways promote production of type 1 interferons (IFN-a and IFN-B) important for anti-viral innate immune responses
Interferon response factor 3 (IRF3) and Interferon response factor 7 (IRF7)
58
what are the cytosolic receptors for PAMPs and DAMPs
Three major classes of cytosolic receptors are NOD-like receptors, RIG-like receptors and cytosolic DNA sensors
*these (like TLRs) are also linked to signal transduction pathways that promote inflammation or type 1 interferon production for anti-viral response
59
what are NLRs
NOD-like receptors are a family of more than 20 different cytosolic proteins, some of which recognize PAMPs and DAMPs and recruit other proteins to form signalling complexes (inflammasomes) that promote inflammation
-inflammasome= NLRP3(sensor) + Adaptor + Caspase-1
60
describe the function of the NLRP subfamily of NLRs
receptors that respond to cytosolic PAMPs and DAMPs by forming singling complexes called *inflammasomes, which generate active forms of the inflammatory cytokines IL-1 and IL-8 that leave the cell and perform proinflammatory functions
61
how are the NLRP-inflammasome responses induced?
by a wide variety of cytoplasmic stimuli that are often associated with infections and cell stress, including microbial products (ex. Flagellin, LPS, bacterial/viral RNA), environmentally or endogenously derived crystals, reduction in cytosolic potassium ion concentrations and the generation of reactive oxygen species which are often produced during cell injury
62
inflammasome activation of caspase-1 may also cause a form of cell death which results in the death of certain microbes that gain access to the cytosol. what is this cell death called
pyroptosis
63
what are auto-inflammatory syndromes?
- characterized by spontaneous inflammation without an overt or readily apparent inciting trigger
- periodic fever syndromes caused by excessive production of or responses to inflammatory cytokines
64
what are Cryopyrin Associated Periodic Syndromes (CAPS)
- due to dysregulated activation of the inflammasome
- inappropriately triggered and excess IL-1 production
- recurrent attacks of fever and localized inflammation, most commonly in joints and intestines
- subset of auto-inflammatory syndromes
- can be treated with IL-1 antagonists
65
describe RLRs
RIG-like receptors are cytosolic sensors of viral RNA that respond to viral nucleic acids by inducing the production of the antiviral type 1 interferons
- expressed in a wide variety of cell types including bone marrow-derived leukocytes and various tissue cells
- on binding viral RNA, the RLRs initiate signalling events that lead to phosphorylation and activation of IRF3 and IRF7 as well as NF-kB, and these transcription factors induce production of type 1 interferons
66
what are cytosolic DNA sensors (CDSs)?
molecules that detect cytosolic DNA (from intracellular microbes) and activate signalling pathways that initiate anti-microbial responses, including type 1 interferon production and autophagy (used to deliver cytosolic microbes to the lysosome where they are killed by enzymes)
*there are several cytosolic DNA sensing molecules and pathways (ex STING)
67
what is the STING pathway?
=Stimulator of IFN Genes
- major mechanism of DNA-induced activation of type 1 interferon responses
- STING is an ER localized transmembrane protein
- DNA binds to an enzyme cGAS, cGAMP is generated and interacts with/stimulates STING translocation to Golgi-derived membranes where IRF3 is phosphorylated and induces type 1 interferon gene expression
68
what are some other cell-associated pattern recognition receptors (PRRs)
1. C-type lectin family(CLRs): receptors that recognize carbs on the surface of microbes facilitate the phagocytosis of the microbes and the secretion of cytokines that promote subsequent adaptive immune responses
ex. mannose(CD206) receptors and dectins (located on the plasma membranes of phagocytes)
2. Scavenger Receptors:
ex. CD36
(located on the plasma membranes of phagocytes)
3. N-Formyl met-leu-phe receptors(formyl peptide receptors):
ex. FPR and FPR1
(located on the plasma membranes of phagocytes)
69
what are the names of two structurally distinct families of antimicrobial peptides produced by epithelial cells as well as some leukocytes
**************
defensins and cathelicidin
70
what cells are the first line of defence against microbes that breach epithelial barriers
specialized phagocytic cells, primarily macrophages and neutrophils
71
describe the role of dendritic cells in innate immunity
- perform essential recognition and effector roles in innate immunity
- present in epithelia and most tissues of the body
- express more TLRs and cytoplasmic pattern recognition receptors than any other cell type making them the most versatile sensors of PAMPs and DAMPs
- uniquely capable of triggering and directing adaptive T cell-mediated immune responses (they take up microbial protein antigens, transport them to lymph nodes where naive T cells home and display the antigens in a form that the T cells can recognize)
- TLR signalling also induces costimulators and cytokines that are needed in addition to antigens to activate naive T cells and their differentiation into effector T cells
72
what are innate lymphoid cells(ILCs)
bone-marrow derived cells with lymphocyte morphology that serve diverse antimicrobial functions
- unlike lymphocytes, they emerge fully capable of performing effector functions without the need for clonal expansion and differentiation
- three major subsets of innate lymphoid cells distinguished by the cytokines they produce, can be further divided based on the cell surface molecules and effector mechanisms they use to perform their protective functions
73
what are natural killer cells ?
- the first and best described innate lymphoid cells
- subset of type 1 ILCs which play important roles in innate immune responses mainly against intracellular viruses and bacteria
- similar to cytotoxic T lymphocytes(CTLs) in that their main job is to kill infected cells. however they dont need further differentiation (hence natural)
- contain numerous cytoplasmic granules
- use germline encoded DNA receptors to distinguish pathogen infected cells from healthy cells
- produces IFN-y which activates macrophages to destroy phagocytosed microbes
- has proforin which facilitates the entry of other granule proteins, called granzymes, into the cytosol of target cells and causes death of the cell by apoptosis
- eliminate reservoirs of infection
74
how is natural killer cell (NK cells) function regulated
by a balance between signals that are generated from activating receptors and inhibitory receptors that either promote or inhibit NK responses
- activating receptors recognize ligands on infected/injured cells that need to be eliminated (stimulate protein kinases) and stimulates the killing activity of the NK cells and promotes them to secret cytokines
- inhibitory receptors recognize normal healthy cells that need to be preserved (stimulate phosphatases)
75
what are killer cell immunoglobin (Ig)-like receptors (KIRs)
the name for NK cell-activating receptors
| ex. CD16 receptors on NK cells may activate them to kill
76
what is the process: antibody-dependent cell-mediated cytotoxicity ?
- it is an effector function of adaptive immunity
- CD16 activating receptors on NK cells can bind to the Fc region of antibodies that are bound to antigens on the surface of infected cells and activate the NK cell to kill the infected cells that have been coated with antibodies
77
Most NK cells express inhibitory receptors such as KIRs or lectins, that bind to and recognize what?
```
they recognize class 1 major histocompatibility complex (MHC) molecules, which are cell surface proteins normally expressed on all healthy nucleated cells of the body
-the absence of class 1 MHC molecules is an indication of infection or damage and this activated NK cells (recognition of missing self)
```
78
what are the structural motifs in the cytoplasmic tails of activating and inhibitory receptors of NK cells that engage the signalling pathways that respectively promote or inhibit target cell killing and cytokine secretion
activating receptors have: immunoreceptor tyrosine-based activation motifs (ITAMs)
inhibitory receptors have: immunorecptor tyrosine-based inhibitory motifs (ITIMs) that block signalling pathways of activating receptors
79
what are the major cytokines of the innate immune system that can enhance/stimulate the functional responses of NK cells?
IL-12, IL-15, IL-18 and type 1 interferons
- enhance the cytotoxic activity of NK cells
- can cause NK cells to secret IFN-Y
- IL-12 and IL-15 are also important growth factors for NK cells
80
Describe mast cells
- present in the skin and mucosal epithelium-usually adjacent to blood vessels
- express TLRs and TLR ligands can cause the granules to release their contents promoting acute inflammation
- rapidly secret pro-inflammatory cytokines and lipid mediators in response to infections and other stimuli
- contain abundant cytoplasmic granules that may contain histamine that causes vasodilation and increased capillary permeability, and enzymes that can kill bacteria or inactivate microbial toxins
- secret cytokines such as TNF
81
describe the two major ways that soluble effector molecules function in the blood and extracellular fluid to promote innate responses
1. by binding to microbes, they act as *opsonins and enhance the ability of macrophages, neutrophils and DCs to phagocytose the microbes. this is bc the phagocytic cells express membrane receptors specific for opsonins
2. after binding to microbes, soluble mediators of innate immunity promote inflammatory responses that bring more phagocytes to sites of infections, and they may also directly kill microbes
82
list the major components of the humoral innate immune system (soluble effector molecules)
the complement system, collectins, pentraxins, and ficolins
83
what does the complement system consist of?
several plasma proteins that work together to opsonize microbes, to promote the recruitment of phagocytes to the site of infection, and in some cases, to directly kill the microbes
84
the first step in activation of the complement system is recognition of molecules on microbial surfaces but not host cells, this occurs in three ways or distinct pathways.
what are the names of theses pathwyas?
the classical pathway
the lectin pathway
the alternative pathway
85
describe the classical pathway
- discovered first
- uses a plasma protein called C1q to detect antibodies bound to the surface of a microbe/other structure
- Ciq binds to the Fc region of the antibodies and C1r and C1s become active and initiate a cascade involving complement proteins
86
describe the lectin pathway
- triggered by a plasma protein called mannose-binding lectin (MBL) which recognizes terminal mannose residues on microbial glycoproteins and glycolipids
- after MBL binds to microbes, two zymogens called MASP1 and MASP2 (with similar functions to C1r and C1s) associate with MBL and initiate downstream proteoolytic steps identical to the classical pathway
87
describe the alternative pathway
- older than the classical pathway but discovered later
- triggered when a complement protein called C3 directly recognizes certain microbial surface structures such as bacterial LPS
- regulatory proteins on normal host cells inhibit C3 and so this pathway can distinguish self from foreign microbes on the basis of the presence or absence of the regulatory proteins
88
what results when any of the three complement pathways recognizes microbes?
results in sequential recruitment and assembly of additional complement proteins into protease complexes
89
describe what happens after the complement system has been activated by one of the three pathways
C3 convertase is made and cleaves C3 into C3a and C3b. the larger C3b fragment becomes covalently attached to the microbial surface and serves as an opsonin to promote phagocytosis of the microbes
- smaller C3a stimulates inflammation by acting as a chemoattractant for neutrophils
- C3b forms a protase called C5 convertase that cleaves C5 into C5a an C5b. the larger C5 b remains attached to the microbe and the smaller C5a also acts as a chemoattractant and induces changes in blood vessel to make them leak plasma proteins to sites of infection.
- C5b initiates the formation of a complex of the complement proteins C6, C7, C8, and C9 which forms a membrane pore called the * membrane attack complex (MAC) that causes lysis of the cells where complement is activated
90
what is acute inflammation
- it is the accumulation of leukocytes, plasma proteins and fluid derived from the blood at an extravascular tissue site of infection or injury
- stimulating acute inflammation is major way by which the innate immune system deals with infections and tissue injury
91
what are some of the important leukocytes and plasma proteins that are recruited to inflammatory sites during inflammation
- neutrophils are the most abundant leukocyte that gets recruited. Blood monocytes, which become macrophages in the tissue are also increasingly prominent
- important plasma proteins= complement proteins, antibodies, acute-phase reactants
92
in innate immunity, the delivery of the blood-derived components to the inflammatory site is dependent on what?
- reversible changes in blood vessels in the infected/damaged tissue due to arteriolar dilation, increased adhesiveness of circulating leukocytes to the endothelial lining of venules, and increased permeability of the capillaries and venules to plasma proteins and fluid
- these changes are induced by cytokines and small-molecule mediators such as histamine
93
describe what TNF is
TNF or tumor necrosis factor is one of the three most important pro-inflammatory cytokines of the innate immune system
- two TNF receptors (type 1 and type 2), can induce gene expression and/or cell death
- PAMPs and DAMPs stimulate TNF production in macrophages
- TNF (as well as IL-1) induce postcapillary venule endothelial cells to express E-selectin and to increase their expression of ICAM-1 and VCAM-1, the ligands for leukocyte integrins
- TNF (as well as IL-1) stimulate various cells to secret chemokines, such as CXCL1 and CCL2, that bind to receptors on neutrophils and monocytes to increase the affinity of leukocytes integrins for their ligands, and stimulate directional movement of leukocytes
- TNF (as well as IL-1) act on hypothalamus to increase body temp (fever)
94
what produces most innate immunity cytokines?
mostly macrophages and DCs
95
describe interleukin 1 (IL-1)
- one of the three most important pro-inflammatory cytokines of the innate immune system
- similar actions to TNF but produced by many more cell types
- its production requires two distinct signals; one that activates gene transcription and one that activates the inflammasome
96
describe interleukin 6 (IL-6)
- one of the three most important pro-inflammatory cytokines of the innate immune system
- both local and systemic effects
- one function it does is stimulates neutrophil production in the bone marrow and promotes the differentiation of IL-17-producing helper T cells
97
describe interleukin 12 (IL-12)
secreted by DCs and macrophages and stimulates IFN-y production of NK cells and T cell, enhances NK cell and CTL-mediated cytotoxicity, and promotes differentiation of TH1 cells
98
what are the three classes of important microbial molecules that kill the phagocytosed microbe once within the phagolysosome (in the phagocyte)
reactive oxygen species (produced by process called respiratory burst), nitric oxide and proteolytic enzymes
99
what is chronic granulomatous disease
caused by inherited deficiency of one of the components of phagocyte oxidase; compromises the capacity of neutrophils to kill certain species of bacteria
100
whats are NETs?
neutrophil extracellular traps
-composed of strands of DNA and histones to which are bound high concentrations of antimicrobial contents such as defensins that kill the microbe and also leads to neutrophil cell death as well
101
what may happen if TNF quantity is so large that it gets into the blood stream and acts at distant sites
- may inhibit myocardial contractibility- lower BP or shock
- causes intravascular thrombosis(blood clots)
- wasting of muscle and fat cells, called cachexia
102
what innate receptors receptors respond to viral nucleic acids
RLRs. TLRs 3 7 8 and 9 (in endosomal vesicles), cytosolic DNA sensors
-these initiate signalling pathways that activate the IRF family of transcription factors and induce type 1 interferon gene expression which is involved in the antiviral response
103
what can interferons do
- activate transcription factors of several genes that confer on the cells a resistance to viral infection called an antiviral state
- cause the sequestration of lymphocytes in lymph nodes, thus maximizing the opportunity for encounter with microbial antigens
- cause the cytotoxicity of NK cells and CD8+ CTLs and promote the differentiation of naive T cells to TH1 subset of helper T cells
- upregulate expression of class 1 MHC molecules and thereby increase the probability that the virally infected cells will be recognized and killed by CD8+ CTLs
104
what is the two-signal hypothesis for lymphocyte activation
two signals are required for lymphocyte activation:
first/signal 1- antigen recognition by lymphocytes
second/signal 2- molecules that are produced during innate immune responses to microbes or injured cells, such as costimulators (for T cells), cytokines, and complement breakdown proteins (for B cells)
*the second signal generated during innate immunity responses to different microbes not only enhance the magnitude of the subsequent adaptive immune response but also influence the nature of the adaptive response
105
what cytokines produced by cells during the innate immune responses to microbes stimulate the proliferation and differentiation of lymphocytes in adaptive immune responses?
- IL-12 (stimulates the differentiation of naive CD4+ T cells to the TH1 subset of effector cells
- IL-1, IL-6, IL-23 (differentiation of naive CD$4+ T cells to the TH17 subset of effector cells
- IL-15 (promotes the survival of memory CD8+ T cells
- IL-6 promotes the production of antibodies by activated B cells
106
what are adjuvants
substances that need to be administered together with purified protein antigens to elicit maximal T cell-dependent immune responses, work by stimulating innate immune responses at the site of antigen exposure
- they can activate DCs to express more MHC molecules that are part of the antigen (signal 1) that T cells recognize
- can increase the expression of costimulators needed for T cell activation
- can stimulate migration of the DCs to lymph nodes where T cells are located
107
what interleukin cytokine inhibits activation of macrophages and DCs
IL-10 produced by macrophages and DCs also inhibits them and inhibits the production of various inflammatory cytokines that those phagocytes produce (such as IL-1, IL-12 and TNF)
- it is a neg feedback regulator
- also produced by regulatory T cells
108
what is IL-1RA
IL-1 receptor antagonist is a competitive inhibitor of I-1 and binds to the same receptors
