Immunology Exam One Flashcards
1
Q
Stages of Immunity
A
Innate and Adaptive
2
Q
Innate Immunity
A
First line of defense that is non-specific and responds rapidly to infections
Clears out dead tissue and initiates the repair of damaged tissue
Exists since birth
Receptors are located in plasma membrane, endosomal membrane, cytosol
3
Q
Adaptive Immunity
A
Exists before infection occurs and a slower response to infection because the response depends on signals from the innate immune system
Is specific and activation leads to memory clonal expansion and cellular differentiation
Receptors only located in plasma membrane
4
Q
Components of Innate Immunity
A
Barriers such as skin (Lysozymes, collectins and fatty acids), mucous membranes and stomach acids
Cells and plasma membranes
5
Q
Components of Adaptive Immunity
A
B lymphocytes and T lymphocytes
They make immune memory
6
Q
Types of cell and plasma proteins of innate immunity
A
Acute phase proteins, complement, phagocytic cells, interferon, natural killer (NK) cells and innate lymphoid cells (ILC’s)
Alert Adaptive Immunity components
7
Q
B lymphocytes
A
Humoral response
Make anti-bodies and comes from bone marrow
Binds to foreign antigen, activates and undergoes clonal expansion and differentiation
Becomes effector cells-activate plasma cells that produce antibodies or memory B cells.
8
Q
T lymphocytes
A
Cell mediated response
Makes helper and cytotoxic cells and is from the thymus
9
Q
Types of T lymphocytes
A
T-helper
T-cytotoxic
T-regulatory (formerly T-suppressor)
10
Q
T-helper
A
Activate humoral response
Activate into T helper 1 and T helper 2 cells
Cytokine-producers that activate destruction of microbes within phagocytes, and “call in” more phagocytes to the area of infection
The cytokine activated phagocytes kill ingested microbes
Have CD4+ cells on surface
11
Q
T-cytotoxic
A
Activate into effector cells or memory cells
Kill the host cell, along with the intracellular microbes
Have CD8+ cells on surface
12
Q
T-regulatory (formerly T-suppressor)
A
Work to suppress activity if previously activated B or T lymphocytes
13
Q
Types of adaptive immunity
A
Humoral and Cell-mediated
14
Q
Humoral adaptive immunity
A
Mediated by antibodies made by B lymphocytes
Circulate through the lymphatic system
Antibodies bind extracellular microbes to neutralize toxins, prevent infection of tissues and enhance uptake by phagocytic cells
T cell-B cell interactions
15
Q
Cell-mediated adaptive immunity
A
Mediated by T-lymphocytes
Defends against intracellular microbes
Has Helper T lymphocytes and cytotoxic T lymphocytes
16
Q
Active Immunity
A
Exposure to antigen through active infection which is then eradicated
Individual goes from naive to immune to the microbe
17
Q
Passive Immunity
A
No exogenous exposure of antigen with no active infection
Antibodies are transferred from immunized individual or administered using laboratory manufactured infusions
Naturally occurs in newborns from their mothers
18
Q
Clonal expansion
A
When several like lymphocytes bind like antigens and that “clone” of lymphocytes proliferate
19
Q
Properties of adaptive immune responses
A
Memory: Primary Immune Response and Secondary Immune Response
Nonreactivity to self: Immunologic tolerance. It is designed to react against foreign agents and return to homeostasis when infection is resolved
20
Q
Immunologic tolerance
A
the presence of self antigens is tolerated by the immune system
21
Q
Write out clonal selection (Expansion/Differentiation)
A
Good Job!
22
Q
Hematopoiesis
A
The production of blood cells in the bone marrow of flat bones, in adults
23
Q
Myeloid
A
Phagocytes and Antigen-presenting cells
24
Q
Lymphoid
A
Lymphocytes
25
Lymphocytes
Only cells that produce clonally distributed receptors specific for diverse antigens.
Mediator of adaptive immunity
They are all morphologically the same but serve different functions, lineage and phenotype
Are distinguished based on surface molecules
26
Cluster of Differentiation (CD)
Molecules on the surface of lymphocytes which identify the lymphocytes function
27
How do lymphocytes mature? How are they distributed?
1. Begin as lymphoid precursor cells in bone marrow. B lymphocytes mature in bone marrow and T lymphocytes mature in the thymus
2. Stay in the generative (central/primary) lymphoid organs where they were created.
3. Move to secondary (peripheral) lymphoid organs where the immune action happens
28
Stages of life for Effector B cells
1. Naive lymphocytes
2. Effector B cells make antibodies and the memory cells are inactive until the specific antigen is encountered in the future
29
Stages of life for CD4+ (T helper cells)
1. Naive lymphocytes
2. Helper T cells produce cytokines and the memory cells are inactive until the specific antigen is encountered in the future
30
Stages of life for CD8+ (T cytotoxic cells)
1. Naive lymphocytes
2. Are equipped to kill infected host cells and die after they attack. The memory cells are inactive until the specific antigen is encountered in the future
31
Cytokines
Initiate cellular reactions in innate immunity
Secreted by dendritic cells, MPs, mast cells, ILCs, etc
Are soluble proteins which mediate immune and inflammatory reactions
Are responsible for communication between leukocytes and other cells
Called interleukins + a number or a name associated with how they were discovered
32
Antigen-presenting cells
Are in potential entry sites for microbes such as the skin, genitourinary tract, respiratory tract and the gastrointestinal tract
They capture the antigens of the microbes and bring them to a secondary lymphoid organ to present them to lymphocytes.
33
Dendritic cells
Most specialized antigen-presenting cells in immune system
Shows antigens on infections on its surface to show other lymphocytes.
34
Tissues of the immune system
Primary/Generative and Secondary/Peripheral
35
Primary/Generative tissues
Bone marrow and thymus sites of lymphocyte production and maturation
36
Secondary (Peripheral)
Lymph nodes, spleen, mucosal and cutaneous immune systems
Arranged in such a way as to concentrate antigens where there is a high number of lymphocytes present. Cells that need each other for activation also "hangout" together in the same general area
37
Lymph Nodes
Encapsulated nodular aggregated of lymphoid tissue located along lymphatic channels throughout the body
Antigens flow through nodes via lymphatic fluid
38
What happens to antigens which flow through nodes via lymphatic fliud?
They are captured by antigen presenting cells or they are transported by dendritic cells and become concentrated in nodes
39
Lymph
Fluid that leaks out of epithelia, connective tissues, and parenchymal organs, via blood vessels
40
Vascular system
moves by means of pressure gradients via skeletal muscle movement, respiratory movement and contraction of smooth muscle in vessel walls
One-way valves in vessels keep lymphatic fluid moving in the right direction
41
Cortex
Contains follicles-B cells
Germinal center-B cells beginning activation
42
Paracortex
Interior to cortex-T cells
43
Medulla
Innermost area of node-plasma cells and activated cells ready to exist
44
Spleen
Highly vascularized abdominal organ
Functions similar to lymph nodes, only blood carriers antigens/cells
blood flows through sinusoids
Antigens captured by dendritic cells/MPs
Phagocytes ingest and destroy
MP's also destroy old, irregularly shaped RBCs, or RBCs with inclusions
45
red pulp in spleen
RBC's and MP's
46
white pulp in spleen
B + T cells
47
Mucosal Immune system
GI and respiratory tracts, tonsils and Peyer's patches in intestine
Has memory cells that transport antigens
Has dendritic cells that bind and present to helper T cells which present to B cells which activate into plasma cells and secrete IgA
Combo of innate and adaptive immune system
48
M cell
Specialized to transport antigens from lumen to the lymphoid tissue underneath
49
goblet cells
produce mucus to attract microbes and antigens
50
Paneth cells
secrete antimicrobial peptides
innate immune system
51
Cutaneous Immune system (skin)
Collection of lymphoid tissues and APC's in and under the epithelia of the skin because of the large surface area
No anatomically defined structures
Main players are keratinocytes, Langerhans cells and intraepithelial lymphocytes
52
Mast cells
release histamines
Inflammatory response
53
Langerhans cell
specialized dendritic cells. APC's.
54
High endothelial venules (HEVs)
In paracomplex of lymph nodes
Specialized post-capillary venules
T-cells attracted by chemokines
Activated by antigen presented by dendritic cell
Leave node and migrate to site of infection
55
What happens when lymphocytes are activated?
Turn into effector cells
migrate to site of infection
56
What B cell does
Stay in the lymph node when activated and secrete antibodies into circulation
Rarely will see these plasma cells in circulation. If there are many that could be a sign of leukemia or another disease.
57
Major histocompatibility can lead to
T cell activation or HLA human leukocyte antigen which occurs in the transplantation of organs
58
MHC 2 Complex
Binds to the peptide chain from the invader and presents it on the surface of the phagocyte/APC.
Allows Adaptive immunity to come in.
59
Types of phagocytes
Are all white blood cells/leukocytes
Neutrophils, Macrophages, dendritic cells
60
Neutrophils
fast and abundant
61
Macrophages
Heavy lifting
62
Dendrite
Best activators of specific immune system
63
Nonspecific
Barriers of first line defense
Inflammatory
Phagocytes
64
Specific Immune system
adaptive
lymphocytes
65
Lymphocytes
type of leukocyte
specific
B lymphocytes and T lymphocytes
66
epitope
part of the pathogen that binds to our variable sequencing.
After it binds, the B cell is activated. B cell sometimes needs help being activated with helper T cells as well.
Pathogen is engulfed by B cell to make memory or plasma B cells.
67
MHC I complex
Majority of presenting cells
68
Main types of innate immune system reaction
Inflammation and Antiviral Defense
69
Inflammation
Accumulation and activation of leukocytes and plasma proteins at sites of infection or tissue injury
70
Antiviral Defense
Mediated by Natural Killer cells and Type I Interferons
71
Natural Killer Cell (NK)
Leukocytes which kill virally infected cells and cancer cells.
Are lymphocytes
Respond to IL-12 and secrete IFN-gamma to activate killing mechanism of MPs
Can destroy pathogens without prior exposure to pathogens
Receptors in the NK cell activate (No MHC-1 receptor or low amount to bind to on cells) or inhibit (MHC-1 receptor on other cells) it from killing cells it is scanning
Releases perforin which opens the target cells
Releases granzymes which goes into the opening and kills the cell
72
Type I Interferons (IFNs)
Shields from viral infection, are antiproliferative and elicit immunomodulatory responses by binding to the type I interferon receptor.
73
Interferons
Type of cytokine that possesses antiviral, antiproliferative and antitumor attributes. Plays roles in the innate and adaptive immune responses.
Have been classified into two types based on interactions with IFN receptor subunits, peptide mapping and sequencing homology.
Minor variation in their primary sequences of the IFNA genes cause distinct antiviral and immunoregulatory functions in T cells, B cells and dendritic cells.
74
Where are NK cells located?
Develop in bone marrow, move to other lymphatic system organs and tissues (lymph nodes, spleen, tonsils and thymus).
Mature NK cells go into the bloodstream, the lungs, the liver, lymph tissues and lymphatic system associated organs.
75
PAMPs
Pathogen associated molecular patterns
ex. phagocytes-receptors for bacterial endotoxins
Attach to toll-like receptors
76
Cytokines
general category
function in communication, initiation of inflammation and general immune response
77
Chemokines
Subset of cytokine
communication among leukocytes
lymph nodes are where they exist
78
Difference between natural killer cells and cytotoxic cells?
NK cells attack any cell that is scanned as a threat and are part of the innate immune system. Are the first line of defense and act quickly (~three days after infection)
Cytotoxic T-cells can only attack cells it has encountered before because it is part of the adaptive immune system which therefore means it identifies the pathogen and sends a specialized attack. Takes a week after infection to send the correct T-cell.
79
Damage associated molecular patterns (DAMPs)
Molecules released from damaged or necrotic host cells.
Response to DAMPs works to eliminate damaged tissue and initiate repair via macrophages.
Ex. Extracellular ATP
80
cellular receptors for damaged cells and microbes
Pattern receptors detect microbes and damaged cells which are expressed on phagocytes, dendritic cells, epithelial cells and more
Located in different cellular compartments where microbes or their products can be found
81
Five major families of cellular receptors
TLR's, C-type lectin receptors, NOD like receptors, RIG-like receptors and cytosolic DNA sensors
82
Toll-like receptors (TLR's)
10 different types in humans
Dimerize to form 9 different functional receptors, specific for different components of microbes. Ex. bacterial or viral molecules
Have ligand binding domain and a toll-like interleukin receptor
Signals made by TLR's activate transcription factors which stimulate expression of cytokines and other proteins involved in the inflammatory or antiviral response and in antimicrobial functions of activated phagocytes and other cells
NF-kB-transcription factor activated by TLR signals
Promotes expression of interferon-regulatory factors (IRF's)
83
MD2
Enhances binding to LPS
84
What happens when there is a mutation in a TLR receptor?
autoimmune diseases
85
NF-kB-transcription factor
Nuclear factor kappa-beta transcription factor
Promotes cytokines and adhesion molecules
Acute inflammation and stimulation of adaptive immunity
86
IRFs
Regulate transcription of interferons
Antiviral response
Pathogen is identified by the TLRs and the pathways P's IRFs with IRF kinases
The IRFs go to the DNA and start transcription of type I IFN's
multiple IRFs (IRF1, IRF2, IRF4, and IRF8) play essential roles in the development of immune cells, including dendritic, myeloid, natural killer (NK), B, and T cells
87
IRF1 and IRF5
Induce production of proinflammatory cytokines
88
IRF2 and IRF4
Regulate activation of IFNs and proinflammatory cytokines via inhibition
IRF2 contains a repressor region that downregulates expression of type I IFNs
IRF4 competes with IRF5, and inhibits its sustained activity.
89
NOD-like receptors (NLR's)
Large family of innate receptors that sense DAMPs and PAMPs in the cytosol and initiate signaling events that promote inflammation
Have a C-terminal nucleotide oligomerization domain (NOD)
90
C-terminal nucleotide oligomerization domain (NOD) of NLR's
Different NLRs have different N-terminal ligand building domains
NOD1 and NOD2 expressed on mucosal barrier epithelial cells and phagocytes
91
Inflammasomes
Multiprotein complexes that assemble in the cytosol in response to microbes or changes associated with cell injury
Proteolytically generate active forms of inflammatory cytokines interleukin-1B (IL-1B) and IL-18
Composed of a sensor, an enzyme (inactive caspase-1) and an adaptor that links the two other components
Can cause autoinflammatory syndromes such as gout
Can sense uric acid crystals, cholesterol crystals, extracellular ATP, decrease of intracellular K+, ROS's
92
NOD2
expressed in Paneth cells in small bowel
stimulate defensin
93
Paneth Cells
Located in the small bowel
produce antimicrobial peptides and proteins and other components that are important in host defense and immunity.
Secrete the antimicrobial factors into the lumen to control enteric bacteria
94
NLRP3
NOD-like receptor family, pyrin domain containing 3
Expressed in MP's, neutrophils and keratinocytes (on skin)
95
Pyroptosis
form of apoptosis that causes inflammation
Interleukins-beta
causes fever
Host cell death caused by an infection
Increase in active caspase-1
Cell membrane leaks and the cytoplasm flattens
96
Gout
A form of arthritis characterized by sharp pain, redness, and tenderness of the joints.
Pain and inflammation occur when too much uric acid crystallizes and deposits in the joints.
97
RIG-like receptors (RLRs)
RIG-1 and MDA-5
Recognize features of viral RNAs that are not the host cells RNA
Found in cells with a higher chance of being exposed to RNA viruses
Bind the RNA viruses, interact with MAVS (mitochondrial antiviral signaling), initiate signaling, activates transcription factors, induces the production if IFNs
98
IFNs
cytokines that inhibit viral replication in host cells by triggering innate immune responses through the transcriptional induction of various IFN-stimulated genes
Attach to cytokine receptor
99
Cytosolic DNA sensors (CDSs)
Recognize microbial dsDNA in the cytosol (bacteria and viruses)
Recognize self DNA that may accumulate in cytosol which could be associated with mutations which would lead to interferonopathies
Causes STING pathway
100
Interferonopathies
systemic inflammatory disease
101
STING pathway
Stimulator of IFN genes
Induces type I IFN production
Stimulates autophagy and lysosomal degradation of pathogens
102
Autophagy
A process by which a cell breaks down and destroys old, damaged, or abnormal proteins and other substances in its cytoplasm (the fluid inside a cell)
The breakdown products are then recycled for important cell functions, especially during periods of stress or starvation.
103
IRF3
IRF3 plays an important role in the innate immune system's response to viral infection.
Aggregated MAVS have been found to activate IRF3 dimerization.
Phosphorylation of innate immune adaptor proteins MAVS, STING and TRIF at a conserved pLxIS motif recruits and specifies IRF3 phosphorylation and activation by the Serine/threonine-protein kinase TBK1, thereby activating the production of type-I interferons.
103
Lectins
Receptor of innate immunity
Carbohydrate recognizing proteins
Involved with phagocytosis of fungi and bacteria
104
Dectins
Receptor of innate immunity
Receptors for fungal glucans
activation resulting in a wide range of processes including cytokine production, phagocytosis of the ligand and stimulation of the respiratory burst
Host protective such as fungal uptake and killing, and the production of inflammatory cytokines and chemokines
105
Formyl peptide receptor 1
Receptor of innate immunity
Cell surface receptor expressed on phagocytes
Recognizes bacterial proteins
Promotes migration of cell and antimicrobial activity
106
Components of innate immune system
Epithelial cells
sentinel cells in tissues
Circulating and recruited phagocytes (monocytes and neutrophils)
NKC
Plasma proteins
Innate lymphoid cells (not understood)
107
Sentinel cells
Chillin in tissues
Resident of macrophages, dendritic cells, mast cells
108
Epithelial barriers
Skin, gastrointestinal tract, respiratory tract, genitourinary tract
Protects by layers of epithelial cell that provide physical and chemical barriers
Have intraepithelial lymphocytes with T-cell lineage. They function like T cells
109
Physical barriers of epithelial barriers
Keratin and mucus
110
Chemical barriers of epithelial barriers
Defensins and cathelicidins
111
Neutrophils
Most abundant leukocytes in the blood
Respond to bacterial and fungal infections
Colony-stimulating factors (CSFs)
Ingests microbes in circulation and enter extravascular tissues. Phagocytose and destroy microbes.
Recruited to sites of tissue damage in absence of infection
Only live for several hours in tissue
112
Opsonization
a process that helps your immune system identify and destroy old cells or pathogens
Opsonins coat cells or pathogens so macrophages and neutrophils can find them, attach to them, swallow them and break them apart.
112
Five types of leukocytes/Polymorphonuclear leukocytes (PMNs)
From first being most abundant and last being least abundant in a healthy person: Neutrophils, lymphocytes, monocytes, eosinophils, basophils.
Eosinophils and basophils cause allergies and go after parasitic infection.
113
Opsonins
Extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound.
114
Monocytes
Less abundant than neutrophils
Ingest microbes in blood and tissues
Made in bone marrow
115
Macrophages
Monocytes that have entered tissues and differentiate
Survive for long periods of time
Work in adaptive immunity
regulate inflammation
have nod and toll receptors which mediate phagocytosis
116
Mononuclear phagocyte system
Tissue-resident macrophages
117
Macrophages roles in host defense
Ingest and destroy microbes
Clear dead tissues and initiate the process of tissue repair
Produce cytokines that induce and regulate inflammation
TLRs/NLRs and cytokines activate the MPs
Cell surface receptors mediate phagocytosis
118
Pathways of macrophage activation
Classical macrophage activation and Alternative macrophage activation
119
Classical macrophage activation
Induced by innate immune cells (TLRs and by cytokine IFN-gamma)
M1 or pro-inflammatory which destroys microbes and trigger inflammation
ROS, NO are signal molecules which induce microbicidal actions: phagocytosis and killing of bacteria and fungi
120
Alternative macrophage activation
Induced by cytokines IL-4 and IL-13 (absence of strong TLR signals)
M2 or pro-healing
Function in tissue repair and termination of inflammation
Inhibits inflammation that classical macrophage activation causes
121
Sentinel Cells
reside in tissue
Are dendritic cells, mast cells and innate lymphoid cells
122
Dendritic cells
Produce cytokines which initiate inflammation and stimulate adaptive immune response
Capture and display protein antigens to T cells to activate them
Serves as a "bridge" between adaptive and innate immunity
123
Mast cells
Present in skin, mucosal tissues, and connective tissues
Activated by TLRs or by antibody dependent mechanism
Granules contain vasoactive amines (histamine) and proteolytic enzymes
Synthesize and secrete lipid mediators and cytokines
124
Vasoactive amines (histamines)
cause leaky blood vessels
tissue juice flows into blood vessel
leukocytes can go into tissues to see what is bothering mast cells
125
Innate lymphoid cells
Produce cytokines similar to T-helper cells, but do not express TCRs
126
Complement system
A collection of circulating and membrane associated proteins
Enzyme-complement activation involves a sequence of actions to activate the enzymes
127
Pathways of complement system to activate the enzymes
alternative pathway, classical pathway and lectin pathway
128
Alternative pathway
Antibody independent
triggered by complement proteins on microbe
Part of innate immune system
129
Classical pathway
Antibody dependent
Triggered by antibodies bound to microbes or other antigens
component of humoral arm of adaptive immune system
130
Lectin Pathway
Mannose binding lectins bind carbohydrate ligand on microbe
activates classical pathway without antibodies
131
Complement "cascade"
Activated complement proteins function as proteolytic enzymes to cleave other complement proteins
All of the pathways produce plasma protein C3 which is cleaved by the enzymes
C3b is created from cleaved C3 and attaches to the microbe which activates complement proteins and recruits them
C3b gets microbes to bind to phagocytes which are then ingested and destroyed
132
Outcome of complement cascade
The membrane attack complex (MAC) is formed
Movement of leukocytes and plasma proteins into tissues at site of complement activation is promoted
Complement activation culminates in the formation of a polymeric protein complex that inserts into the cell membrane causing osmotic lysis
133
Osmotic lysis
occurs when the liquid outside a cell enters the cell causing it to burst.
134
Opsonization
an immune process which uses opsonins to tag foreign pathogens for elimination by phagocytes. Without an opsonin, such as an antibody, the negatively-charged cell walls of the pathogen and phagocyte repel each other.
Ex. during the complement system microbes are coated with C3b which allows them to attach to receptors of phagocytes which have C3b receptors. This then allows phagocytes to ingest and destroy the microbe.
135
Paracrine action
Cytokines act on cells near the ones where they were secreted
136
Autocrine action
Cytokines act on the same cells that produced them
137
Endocrine action
active distant from their site of secretion
138
Function of TNF and IL-1 and chemokinases
recruiting blood neutrophils and monocytes to sites of infection.
TNF and IL-1 also can induce fever and induce liver cells as well as IL-6 to make proteins that will kill microbes and wall off infection sites.
139
What happens if there is a high concentration of TNF?
reduced blood pressure from reduced myocardial contractility and vascular dilation and leakiness
140
What causes septic shock?
Low blood pressure, DIC and metabolic disturbances
May be caused by high levels of TNF which is produced from PAMPs
141
DIC
Disseminated intravascular coagulation
Blood clots form inside the blood vessels
Blood clotting factors are used up and can cause massive bleeding in other cases
142
IL-12
Produced by dendritic cells, macrophages in response to LPS, peptidoglycans and other microbial molecules
Activates NK cells
143
Peptidoglycan
is a large polymer that forms a mesh-like scaffold around the bacterial cytoplasmic membrane.
144
What provides protection from viruses?
type I IFNs and NK cells
Type I IFN inhibit viral replication and induce an antiviral state in which cells become resistant to infection
Type I IFNs bind receptors on infected or uninfected cells and induce enzymes that incapacitate virus ability to replicate. Also makes shield around non-infected cells
Receptor can make RNAase which will break down viral RNA, can P translation initiation factor which inhibits protein synthesis, can inhibit viral gene expression and virion assembly
145
What provides protection from bacterial cells?
Eliminated by phagocytes that are activated by TLRs, other innate sensors and cytokines
146
Sentinel cells
cells in tissue
147
Inflammation
Releases histamine, TNR, prostaglandins, etc... from sentinel cells which increases blood flow and exudation of plasma proteins
causes warmth, redness and swelling at site of injury
148
prostaglandins
a group of lipids with hormone-like actions that your body makes primarily at sites of tissue damage or infection.
signals to control several different processes depending on the part of the body in which they are made. Prostaglandins are made at sites of tissue damage or infection, where they cause inflammation (swelling, redness), pain and fever, as part of the healing process.
149
exudation
a fluid released by an organism through pores or a wound
150
Extravasation
when blood/lymph/body fluids "leak" from the vessels
151
How are phagocytes recruited to sites of infection?
TNF and IL-1 produced by dendritic cells and MPs start the process
Leukocytes roll
Firm adhesion
Leukocyte migration
Happens within minutes
152
Rolling of leukocytes how they move?
endothelial cells in vein or capillary express selectins
circulating cells (such as neutrophils) express surface carbohydrates that bind to selectins which makes the neutrophils bound to endothelium
When blood flows the binding is disrupted and bonds reform downstream where they are broken again. Therefore they are rolling. The rolling is slow so it can interact with chemokines.
153
selectins
adhesion molecules, sticky
154
Rolling of leukocytes, how do they adhere?
Integrins bind with integrin ligands which causes the rolling to stop.
Chemokines produced only at sites on infection which are bound to the endothelial surface by proteoglycans and are displayed in high concentrations
Chemokines bind to chemokine receptors on leukocytes which increases the affinity for the integrins and their ligands on the endothelium surface
Rolling stops
155
Rolling of leukocytes, how do they migrate?
Leukocytes crawl to and through porous junctions of endothelial walls along the endothelial cells
In tissue they move along the ECM
Leukocytes follow concentration gradient of chemokines in order to go to the site of infection
156
Integrins
adhesion molecules on leukocytes
157
proteoglycans
Major cell adhesion molecules
158
How are microbes destoryed?
Neutrophils and MPs ingest and destroy microbes via intracellular vesicles
Microbe binds receptor, pseudopod extensions engulf microbe which creates a phagosome.
Phagosome + lysosome = phagolysosome
Respiratory burst= ROS, NO and lysosomal proteases
159
phagocyte oxidase
When microbe attaches, cell receives signal to make enzymes one of which is phagocyte oxidase which assembles in the phagolysomal membrane
Converts O2 into superoxide anion and free radicals which is called oxidative burst. Free radicals are ROS's.
Happens in the neutrophils
160
Enzyme produced by macrophages to kill microbes?
inducible nitric oxide synthase (iNOS) which catalyzes arginine to nitric oxide
161
What do lysosomal proteases do?
Break down microbial proteins
162
What happens when neutrophils die?
Extrude their nuclear contents to form networks of chromatin called neutrophil extracellular traps (NETs)
NETs contain antimicrobial substances which are normally sequestered in neutrophil granules
They trap bacteria and fungi and kill them
163
Chronic granulomatous disease
When neutrophils are unable to eradicate intracellular microbes and the infection is contained by calling in more macrophages which results in collections of activated macrophages around the microbes called granulomas
Is caused by a deficiency of the phagocyte oxidase enzyme in neutrophils
164
granuloma
is a tiny cluster of white blood cells and other tissue
165
Ways the immune system regulates inflammation
IL-10 which inhibits microbicidal and proinflammatory functions of macrophages. Blocks IL-1. Are produced by dendritic cells and macrophages
166
Are there some feedback mechanisms that induce proinflammatory cytokine production and induce expression of inhibitors of cytokine signaling?
Yes!
Ex. TLR signaling stimulates the expression of suppressors of cytokine signaling (SOCS) which blocks a cells reaction to cytokines such as IFNs
167
How is inflammasome activation controlled?
Posttranslational modifications such as ubiquitination and phosphorylation which blocks inflammasome assembly or activation. It also blocks some micro RNAs which inhibit NLRP3 messenger RNA
168
NLRP3
The NLRP3 inflammasome is a multiprotein complex that plays a pivotal role in regulating the innate immune system and inflammatory signaling. Upon activation by PAMPs and DAMPs, NLRP3 oligomerizes and activates caspase-1 which initiates the processing and release of pro-inflammatory cytokines IL-1β and IL-18.
169
Why is pneumococci resistant to phagocytosis
Capsular polysaccharide inhibits phagocytosis
170
Why is Staphylococci able to resist ROS intermediates in phagocytes?
They produce catalase which breaks down ROS intermediates
171
How do Neisseria meningitidis and Streptococci resist the complement activation (alternative pathway)?
Neisseria meningitidis makes sialic acid expression which inhibits C3 and C5 convertases
Streptococci has an M protein which blocks C3 binding to organisms and C3b binding to complement receptors
172
How does pseudomonas resist to antimicrobial peptide antibiotics?
Synthesis of modified LPS that resists action of peptide antibiotics
173
How does coronaviruses evade recognition by viral RNA sensors?
Chemical modification of viral RNA
174
How does the innate immune system stimulate the adaptive immune system?
Two signal requirement: Antigen recognition on lymphocyte antigen receptor and molecules induced by innate immune response such as costimulators-T cells and C3d- B cells which will attach to the corresponding receptor on the lymphocyte
This leads to lymphocyte proliferation and differentiation
175
Differences between B and T lymphocytes
B-lymphocytes are plasma membrane-bound antibodies which recognize structural features of a wide variety of macromolecules.
Recognize (proteins, polysaccharides, lipids, nucleic acids
T-lymphocytes can only "see" peptide fragments of protein antigens
The peptide antigens must be displayed on the outside of the cell surface (antigens bound on MHC on APC)
Therefore responses are generated only against protein antigens that are produced in or taken up my host cell
They are both very different from pattern recognition receptors of innate immune system
176
What is wanted to produce antibodies?
CD4+ helper T cells need to be activated
177
What happens when microbes infect the host cell and are safe from antibodies?
CD8+ cytotoxic T lymphocytes are activated to kill the infected cells and eliminate the revisor of infection
178
How are antigens recognized by T lymphocytes?
MHC display the peptide of the microbe.
CD4+ and CD8+ T cells only see peptides bound to MHC
TCR recognizes some amino acid properties of the antigen peptide AND the MHC molecule that is displaying the antigen
Each clone of CD4+ or CD8+ cells recognizes one peptide displayed by one of many MHC molecules
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How are protein antigens captured by APCs?
The antigen enters the body and is captured by a dendritic cell which is taken to a secondary lymphoid organ
Microbes or their antigens could be carried to lymph nodes through lymph or the spleen by the blood where the antigens are then captured by the dendritic cells and presented to T cells
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Dendritic cells
Cells with long processes which form a network in epithelial and subepithelial tissue
Present in T cell rich areas of secondary lymph organs and other non-lymphoid organs (in small numbers)
Bind microbes and take the microbes into the cell by phagocytosis
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Two major classes of dendritic cells
Conventional and plasmacytoid
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Conventional (classical) dendritic cells
In tissues and lymphoid organs
Langerhans cells in the epidermis (skin)
Capture and present most antigens to T lymphocytes
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Plasmacytoid dendritic cells
Resemble plasma cells; present in blood and tissues
Major source of Type I interferons in innate immune responses to viral infections
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What do the products of microbes do while dendritic cells are capturing antigens by phagocytosis or receptor mediated endocytosis?
They stimulate the innate immune reactions by binding to TLRs and to other innate pattern-recognition receptors in the dendritic cells, tissue epithelial cells and tissue-resident macrophages
This results in the production of inflammatory cytokines (TNF and IL-1). The innate receptor signaling and the cytokines activate the dendritic cells which results in changes in their phenotype, migration and function
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What happens after dendritic cells are activated?
They lose their adhesiveness for epithelial and peripheral tissues and express the chemokine receptor CCR7.
The chemokines that attach direct the cell to leave the epithelium and go to the lymphatic vessels to the lymph nodes.
As they are moving they go from cells capturing antigens to an APC to turn on naive T lymphocytes. You can see this with the increased amount of MHC molecules being produced.
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What is the relationship between dendritic cells and T cells?
Dendritic cells are the main inducers of T cells because they are at the main sites of entry and migrate to lymphocytes where naive T cells are located. Also they are the main ones to activate T cells because they have a lot of MHCs
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What is the relationship between macrophages and T cells?
Macrophages are in all tissues and will accumulate in sites of infection
In cell-mediated immune responses macrophages take in microbes through phagocytosis and display the antigens to T cells which are reactivated and then activate the macrophages to kill them.
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Three types of APCs
Macrophages, Dendritic cells and B lymphocytes
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What is the relationship between B lymphocytes and T cells?
B lymphocytes endocytose protein antigens and display them to helper T cells in lymphoid tissues.
This is important for the development of humoral responses against protein antigens
Cells that take in protein antigens can display the peptides from the antigens to any CD8+ effector T cell.
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How are antigens displayed to T lymphocytes?
MHCs
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Dendritic cells
Antigen presenting to naive T cells in the initiation of T cell responses to protein antigens (priming)
Express Class II MHC which they make themselves and increase as they age.
[MHCs] increases when there is more IFN-gamma
Express costimulators which they also make themselves
The concentration of costimulators increases by TLR ligands, IFN-gamma and T cells (CD40-CD40L interactions)
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Macrophages
Antigen present to CD4+ effector T cells
Have a low amount or no MHC which is inducible by IFN-gamma
The amount of costimulators is low and is inducible by TLR ligands, IFN-gamma, and T cells (CD40-CD40L interactions)
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Costimulators
A heterogenous group of cell surface molecules that act to amplify or counteract the initial activating signals provided to T cells from the T cell receptor following its interaction with an antigen/major histocompatibility complex, thereby influencing T cell differentiation and fate.
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B lymphocytes
Antigen presenting to CD4+ helper T cells in humoral responses (T cell-B cell interactions)
Make their own MHC which increases by cytokines (like IL-4 which would be anti-inflammatory)
Their costimulators are induced by T cells (CD40-CD40L interactions)
Antigen receptor cross-linking
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B cell receptor activation
B cell will by chance come into contact with a pathogen and its receptors cluster together to that one side which is called B cell receptor cross-linking
Tyrosine kinases (Blk Lyn, Fyn) in the B cell add phosphate to tyrosine hydroxy and hang out with the Ig chains
Ig-alpha and Ig-beta have conserved tyrosine residues on them. Are on the cytoplasmic tail of the Ig-alpha and Ig-beta proteins. Part of the Intracellular tyrosine activation motifs (ITAM)
From the cross-linking the tyrosine kinases exchange P's and send them to other tyrosine's near the B cell receptors
The Phosphates go to the ITAMs. After the ITAMs are phosphorylation signal transduction occurs from the cytoplasm into the nucleus which tells the cell to start making clones and dividing
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B cell receptor cross-linking
When the B cell is in the presence of an antigen, the receptors on its surface will cluster together
Is the first step needed for B cell activation
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Kinase
Protein which adds a phosphate to a hydroxyl group
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B cell activation
1. Need B cell receptor activation
2. B cell-coreceptor activation
Need these as checkpoints to make sure the B cell needs to be activated against a pathogen
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How is the B cell coreceptor activated?
Made of CR2, CD19 and CD81 which form a complex on the surface of the B cell
CR2 is a complement receptor which will bind a complement and start activation
CR1 is also on the cell surface of B cells
C3b's on a pathogen which is complement to these receptors on the B cells
CR1 binds C3b; this recruits factor I which is a protease which cleaves C3b into iC3b. iC3b is a C3b which cannot make anymore C3 convertases which we don't want because we are complement
Factor I will continue to cut iC3b which forms C3D which is the ligand for the B cell co-receptor
Now the B cell got two signals saying there is a pathogen because of the other signal we got (B cell receptor activation)
Now the B cell is activated
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How do innate immune responses enhance adaptive immunity?
The lymphocyte needs two signals to be activated: antigen receptor with microbial antigen attached and then another receptor with a molecule induced during innate immune response to microbe attached
These signals will cause lymphocyte proliferation and differentiation
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What are human MHC molecules called?
HLA's
They are antibodies that recognized proteins on the leukocytes of paternal or donor origin
Pregnancy and blood transfusions expose people to cellular antigens of other people. When antibodies are produced against these cells reflect histocompatability
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What are MHC molecules? What are the functions of MHC molecules?
They display peptides derived from microbial protein antigens to antigen-specific lymphocytes (T-cells)
There are class I and class II MHC genes and class I and class II MHC molecules
Are membrane proteins that each contain an extracellular peptide binding cleft
Highly polymorphic
Are codominantly expressed from both parents
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MHC I
Expressed in nucleated cells
Binds CD8+ T cell coreceptor
When intracellular cell has been infected. T-cytotoxic cell will kill it
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Structure of MHC I
Has an alpha chain noncovalently associated with beta2-microglobulin
Alpha chain has three extracellular domains followed by transmembrane and cytoplasmic domains
Alpha 1 and 2 make walls and a floor to make a binding cleft at the top which peptides bind to. Amino acid residues on bottom of cleft in order to bind to peptides
The top walls make contact with T cell receptors and peptide
Difference between MHC 2 is the alpha domains at the binding cleft. Also there is variation at the floor of the binding cleft which allows different MHCs to bind to different sets of peptides
Alpha 3 domain at the base of the MHC attaches to membrane and is associated with beta2-microglobulin
Alpha 3 domain contains a site that binds to CD8+ receptor of T cell.
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What does CD8+ T cell need to be activated?
Needs the recognition of the MHC-associated peptide antigen and at the same time recognition of the MHC molecule by the coreceptor
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MHC II
Expressed on APCs
MPs = low
B cells= med
Dendritic cells = high
Binds CD4+ T cell receptor
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MHC II structure
Contains two transmembrane chains called alpha and beta
Each chain has two extracellular domains with transmembrane and cytoplasmic regions
Amino-terminal regions (alpha 1 and beta 1 domains) form a cleft that accommodates more peptide residues than MHC I. Contain polymorphic residues that make up the cleft
The nonpolymorphic alpha 2 and beta 2 domains at the bottom contain the binding site for CD4+ coreceptor. CD4+ T cells can only respond to peptides presented by class II MHC molecules
CD4+ binds to both alpha2 and beta2 domains at the base of the MHC II that is closest to the PM
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Three polymorphic class I genes are...
HLA-A, HLA-B, HLA-C
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Class II genes
Individuals inherit from each chromosome:
Separate genes encode alpha and beta chains of DP (beta subunit of the HLA-D protein) and DQ (a component of the HLA-DQ protein)
The gene for DR-alpha
1-3 genes encoding DR-beta
Alpha chains can pair with beta chains from the other chromosome
Number of class II molecules expressed much greater than 6
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MHC haplotype
The set of MHC genes present on each chromosome and their encoded MHC proteins
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DR-alpha
An alpha chain of the MHC class II molecule, which is part of the antigen-presenting complex. DR-alpha works with the beta chain (HLA-DRB) to display antigenic peptides on antigen presenting cells (APCs). This allows the alpha-beta T cell receptor (TCR) to recognize the peptides.
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DR-beta
The beta chain of the MHC class II molecule. Allelic variations in the HLA-DRB1 gene have been associated with asthma and rheumatoid arthritis in different populations.
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Features of peptide binding to MHC molecules
Bind to many peptides
Can only present one peptide at a time
Display peptides derived from protein antigens inside host cells
Peptide binding required for stable surface expression; slow off rate
Can also display peptides from "self"
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Pathway of class I MHC
A cell is infected and the protein is taken to the proteasome where it is turned into peptides
The protein is unfolded, covalently tagged with multiple copies of ubiquitin
Tagged proteins are threaded through proteosome and enzymatically cleaved into peptides
Transporter associated with antigen processing (TAP)
MHC synthesize in ER, peptides in cytosol; bound together by TAP
The peptides enter the ER and bind to class I MHC
Peptide MHC complex stabilized and transported to cell surface
A vacuole brings the MHC I to the plasma membrane where it is identified by a cytotoxic T cell and then the cell is killed
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Pathway of class II MHC
Extracellular protein is brought into cell where it is turned into peptides by the endosome or the lysosome
An invariant chain (Ii) is kept in the MHC II in the ER so then it will exist and not be degraded
The Ii leaves the MHC II when it finds the peptide which binds to the MHC II
The receptor is brought to the plasma membrane where a helper T cell is activated
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Cross-presentation of internalized antigens to CD8+ T cells
Some dendritic cells can present ingested antigens in class I MHC molecules to CD8+ T lymphocytes
Dendritic cell ingests host cells, dead tumor cells, microbes, and microbial and tumoral antigens and put the digested antigens in the cytosol for the proteosome
Antigenic peptides go to ER and bind class I molecules and display them for CD8+ T lymphocytes
Therefore dendritic cells can present antigens of other infected or dying cells to CD8+ T lymphocytes
When the CD8+ T lymphocytes have differentiated and become CTLs, they kill infected host cell or tumor cells without the need for dendritic cells or signals other than antigen recognition
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Physiologic significance of MHC associated antigen presentation
Restriction of T cell recognition to MHC associated peptides ensures T cells see and respond only to cell associated antigens and not cell soluble antigens
Segregation of pathways allows the immune system to respond to extracellular and intracellular pathogens in specialized ways
