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F2 Week 1 > Immunology > Flashcards

Immunology Flashcards

1
Q

Immunology

A

the study of mechanisms by which the body defends itself again antigens (non-self pathogens, molecules, transformed cells)

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2
Q

Immunization

A

vaccination, protective immunity; process whereby disease is prevented by prior exposure to the antigen in a form that cannot cause disease; immune memory created

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3
Q

Cytokine

A

aka interleukin or lymphokine; protein molecule released by a specific immune cell that alters the behavior of a target cell; acts in either an autocrine or paracrine manner; unstable mRNA, short-lived protein; play a vital role in differentiation process; provide a mechanism for different cells to communicate with each other, alter the behavior or function of cells by changing gene transcription

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4
Q

Chemokine

A

Cytokines that guide white blood cells to sites in the body where they are needed; classified as CCL or CXCL (L=ligand).

Acts as a chemoattractant to recruit immune cells to a site of infection, also guides WBCs to secondary lymphoid tissue like the spleen or lymph node

Nomenclature:  
L stands for ligands
R for receptor
CXCL8 also called IL-8 (problem molecules discovered by multiple investigators and given more than one name)
CC-- adjacent cytosine residues
CXC-- separated by another a.a.
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5
Q

What are the steps in innate immune response?

A
  1. Bacterial cell surface induces cleavage and activation of complement
  2. One complement fragment covalently bonds to the bacterium, the other attracts an effector cell
  3. The complement receptor on the effector cell binds to the complement fragment on the bacterium
  4. The effector cell engulfs the bacterium, kills it and breaks it down
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6
Q

What are the steps in inflammation cause by innate response to infection?

A

(wound)

  1. Surface wound introduces bacteria, which activate resident effector cells to secrete cytokines
  2. Vasodilation and increased vascular permeability allow fluid, protein, and inflammatory cells to leave blood and enter tissue
  3. Infected tissue becomes inflamed, causing redness, heat, swelling, and pain.
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7
Q

How do macrophages develop? Are they associated with innate or acquired immunity?

A

Develop from monocytes that circulate in the blood, associated with innate immunity, activate T cells and initiate immune response at site of infection.

Binding of macrophage receptors to their microbial ligand initiate receptor mediated endocytosis, the pathogen is sent to phagosomes and lysosomes to make phagolysosomes which destroy the pathogen

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8
Q

What are the two ways macrophages respond to pathogens?

A
  1. Binding of bacteria to phagocytic receptors to induce receptor mediated endocytosis to phagosome and eventual degradation
  2. Binding of bacterial components to signaling receptors on macrophage to induce the synthesis of inflammatory cytokines by turning on transcription factors

AKA professional antigen presenting cells because of their ability to present antigens to T cells

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9
Q

How do dendritic cells work?

A

Involved in innate immunity, travel to site of infection, antigen uptake in peripheral sites, activates T cells in secondary lymphoid tissue to start the adaptive immune response

Phagocytic cells that reside in the skin and mucosa; also known as professional antigen presenting cells because they can take antigens from sites of infection to lymph nodes and present antigens to T cells

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10
Q

What leukocytes are associated with innate immunity?

A

Macrophages, dendritic cells, natural killer cells, neutrophils, mast cells

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11
Q

What do natural killer cells do?

A

kills cells infected with certain viruses

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12
Q

What do neutrophils do?

A
  • Phagocytosis and killing of microorganisms, reserves of neutrophils are stored in bone marrow and released when needed to fight infection, travel to infected tissue where they engulf and kill bacteria, die after killing bacteria and are cleaned up by macrophages
  • Possess a range of receptors to recognize microbial products, as well as complement receptors that facilitate the phagocytosis of pathogens opsinized by complement fixation
  • Mature neutrophils are programmed to die young, devote more resources to storage and delivery of antimicrobial weaponry than longer lived macrophages
  • LPS receptor (CD14)– bacteria recognizes LPS and CR4, then endocytosis of bacteria

“Phagocytic cell that enters sites of infection in large numbers to engulf and kill pathogens; most efficient at limiting pathogen load while adaptive immune responses are developing”

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13
Q

What are mast cells?

A

Derived from an unknown precursor from the common myeloid progenitor

Expulsion of parasites from body through release of granules containing histamine and other active agents

Allergic response

IgE mediates allergic response– when IgE binds to mast cells, mast cells release histamines which cause allergy symptoms

“present in connective tissues that have granules that store chemical mediators such as histamine; possess Fcε receptors that bind IgE, resulting in degranulation, release of histamine and
onset of allergic symptoms”

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14
Q

What cells are involved in acquired immunity?

A

T cells (cytotoxic and helper functions), B cells (production of antibodies), plasma cells (secretes antibodies)

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15
Q

How is a plasma cell different than a B cell?

A

A plasma cell is a fully differentiated form of B cell that secretes antibodies, differentiate upon activation by infection

Plasma cells move to the medulla of the lymph node, where they secrete pathogen specific antibodies, which are taken to the site of infection by the efferent lymph and subsequently the blood. Some plasma cells leave the lymph node and travel via the efferent lymph and the blood to the bone marrow, where they continue to secrete antibodies..

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16
Q

What do T cells do?

A

T cells recognize specific antigen peptides in associated with MHC II via the TCR.

T cell precursor cells from BM go to thymus to mature (where they are called thymocytes), and the mature T cells go to all lymphoid tissues.

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17
Q

What are naive CD4 T cells?

A

Effector Th (T helper) cells that secrete cytokines ( IFNy, IL4, IL17, IL10)

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18
Q

What are naive CD8 T Cells?

A

Effector Tc (T cytotoxic) cells that secrete cytoxin

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19
Q

What do B cells do?

A

B cells recognize specific antigen via the BCR, endocytose and degrade antigens, and present antigenic peptide to T cells.

B cells leave BM as mature B cells.

Naive B cells from bone marrow –> effector B cell in periphery –> plasma cell

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20
Q

What is the source of all immune cells?

A

Hematopoietic stem cell, CD34+

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21
Q

From what cells do the cells of acquired immunity derive?

A

Common lymphoid progenitor cells (B cells, T cells), also NK cells which are part of innate immunity

Very effective, have “memory”

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22
Q

From what cells do the cells of innate immunity derive?

A

Common myeloid progenitor (neutrophil, basophil, eosinophil, dendritic cell, macrophage, mast cell), common lymphoid progenitor (NK cell)

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23
Q

What cells are derived from the common granulocyte precursor?

A

Neutrophil, Eosinophil, Basophil

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24
Q

What cells are derived from the monocyte?

A

Dendritic cell, macrophage, mast cell

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25
Q

What cells are derived from the common erythroid megakaryocyte progenitor?

A

Megakaryocytes (which make platelets) and erythroblasts (which make erythrocytes)

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26
Q

Where does adaptive immunity begin?

A

Begins in lymphoid organs, then is initiated in secondary lymphoid tissues

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27
Q

Describe lymphocyte circulation

A

Lymphocytes leave the blood and enter lymph nodes, where they can be activated by pathogens in the afferent lymph draining from a site of infection. When activated by pathogens, lymphocytes stay in the node to divide and differentiate into effector cells. If lymphocytes are not activated, they leave the note in the efferent lymph and are carried by the lymphatics to the thoracic duct, which empties into to blood at the left subclavian vein. Lymphocytes recirculate all the time, irrespective of infection.

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28
Q

Describe lymph nodes

A

Form junctions where a number of afferent lymph vessels bringing lymph from tissues unite to form a single, larger efferent lymph vessel. During infection, pathogens and dendritic cells carrying pathogens arrive in draining afferent lymph. The lymph node is packed with lymphocytes, macrophages, and other cells of the immune system through which the lymph percolates. Dendritic cells settle in the lymph node; pathogens are picked up by resident macrophages and then degraded. Both dendritic cells and macrophages are important simulators of lymphocytes.

Within the lymph node there are anatomically discrete areas where B or T cells tend to congregate. A lymph node near a site of infection will increase in size due to proliferating activated lymphocytes.

Activated dendritic cells move to the T cell area of the lymph node, where they stimulate differentiation to either helper or cytotoxic T cells. These differentiated T cells either stay in the node to stimulate the division and differentiation of pathogen specific B cells into plasma cells, or travel to the infected tissue via the lymph and the blood.

Plasma cells move to the medulla of the lymph node, where they secrete pathogen specific antibodies, which are taken to the site of infection by the efferent lymph and subsequently the blood. Some plasma cells leave the lymph node and travel via the efferent lymph and the blood to the bone marrow, where they continue to secrete antibodies..

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29
Q

What is GALT?

A

GALT is Gut Associated Lymphoid Tissue.

Location where effector T and B cells develop for mucosal tissue.

Cells enter via blood and exit via lymphatics

In GALT, antigen enters via specialized epithelial cells called M cells

M cells cells in the gut epithelial wall deliver pathogens from the luminal side of the gut mucosa to the lymphoid tissue within the gut wall.

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30
Q

Hematopoiesis

A

The generation of cellular components of blood, including RBCs, WBCs, and platelets

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31
Q

What is EPO?

A

Erythropoietin, a cytokine produced by fibroblasts in the kidney that promotes the differentiation of erythroid precursors into erythrocytes

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32
Q

What is TPO?

A

Thrombopoietin, the primary cytokine that promotes the development of megakaryocytes (megakaryocytes make platelets (aka thrombocytes)

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33
Q

What cytokines contribute to differentiation of innate immune cells?

A

GM-CSF: granulocyte macrophage colony stimulating factor

M-CSF: macrophage colony stimulating factor

G-CSF: granulocyte colony stimulating factor

IL3: interleukin 3

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34
Q

What are natural killer cells?

A

Derived from common lymphoid progenitor cells, but are innate immune cells. Play an important role in viral infection and cancer.

Can tell the differences between health and non-healthy cells.

Mode of action:  
-Healthy cells express MHC class 1, bind NK inhibitory receptor, sends negative signal to NK cell, NK cell remains quiescent
  • If MHC class 1 no longer expressed (infection, malignant), NK activating receptors bind to ligands on host cells, does not bind inhibitory receptors. Combination of activating receptor binding and lack of inhibitory receptor biding will send signal to cause NK cell to release cytotoxic molecules
  • NK cells can recognize the loss of MHC 1, which then targets them for killing by NK cells

OR

  • Virally infected or malignant cells can upregulate expression of MIC proteins (which are only expressed on stressed cells)
  • When MIC proteins are expressed, they bind to receptor NKG2D and signal to NK cell to release lytic granules that then kill the affected cell.
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35
Q

Where does hematopoiesis occur during stages of human development?

A

Embryogenesis: yolk sac
Fetus: liver and spleen
Fetus/Neonate: bone marrow

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36
Q

What is the proportion of each immune cell?

A 
Neutrophil:  40-75%
Lymphocyte:  20-50%
Monocyte:  2-10%
Eosinophil:  1-6%
Basophil:  <1%

Never Let Monkey Eat Bananas

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37
Q

Cluster of differentiation (CD)

A

a system to naming and characterizing cell

surface molecules on immune cells.

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38
Q

CD34

A

a cell surface molecule expressed by hematopoietic stem cells

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39
Q

Thrombocytes (platelets)

A

platelets; derived from megakaryocytes

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40
Q

Innate immune cells

A

cells derived from myeloid progenitors and NK cells; these cells act early in infection and are not specific for the pathogen

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41
Q

Acquired immune cells

A

B cells and T cells which differentiate upon infection into cells that recognize the specific pathogen; responses have memory and
therefore, can rapidly recognize the same pathogen upon re-infection

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42
Q

What are some physical barriers to infection?

A

Part of the innate immune response

Goblet cells: secrete mucus that trap microorganisms and prevent them from penetrating epithelial barriers

Epithelium is colonized by non-pathogenic microorganisms that compete with pathogenic microorganisms for space and nutrients

Tears, urine, saliva, gastric acid, mucus, coughing, sneezing

43
Q

What is the coagulation system and how does it affect innate immunity?

A

A cascade of plasma enzymes that form blood clots which immobilizes microorganisms and prevent them from entering the blood and lymph in addition to minimizing blood loss

44
Q

What are platelets and how doe they affect innate immunity?

A

Formed from megakaryocytes, they release highly active substances such as prostaglandins, growth factors and cytokines that contribute to anti-microbial defense, wound healing, and inflammation

45
Q

What are defensins?

A

Soluble mediator, antimicrobial peptides, 30-40 a.a. in length

Can penetrate microbial membranes and disrupt membrane integrity.

Two types: alpha defensins are produced by neutrophils and paneth cells
beta defensins are produced by epithelial cells

46
Q

How do defensins work?

A
  • When viruses infect a cell, they enduce expression of beta defensins in mucosal epithelial cells; can protect non-affected cells from being infected by a virus
  • Can inactivate viral envelope proteins
  • In serum, can act on target cells, probably through a G protein coupled receptor, resulting in alterations in downstream signaling; can result in antibiral activity by blocking nuclear import of preintegration complex, or blocking transcription of viral RNA
  • Can inhibit infection of viruses by crosslinking viral glycoproteins necessary for fusion to the membrane
47
Q

What are paneth cells?

A

A type of epithelial cell in the small intestine that sense pathogens via TLR and trigger release of alpha defensins

Main source of defensins in intestine

Also secrete lysozymes

Specialized epithelial cells of small intestine, in base of crypts of intestinal villi

48
Q

What allows immune cells to differentiate between normal cells and pathogens?

A

-Pathogen receptors have carbohydrates and lipids, have components not present on eukaryotic cells

  • LPO receptors
  • Scavenger receptors
  • Complement receptors
49
Q

How does Toll-like Receptor Signaling work?

A

TLRs are most effective receptors for recognition of pathogens

  • Specific, expressed by different types of cells, leads to a varied immune response
  • Essential for innate immune response
  • Provides conditions necessary for adaptive immune response should it be needed
  • Induces cytokines
  • Can lead to maturation/activation of dendritic cells and macrophages, resulting in cytokine production and presentation of antigens to T cells

Macrophages: TLR4– have specificity for LPS and related compounds present on the outside of gram negative bacteria. In the presence of gram negative infection, TLR4 sends signal to nucleus that change pattern of gene expression– typical of receptor mediated signaling. Genes for cytokines that induce innate responses in inflammation at the cite of infection are switched on when TLR4 is engaged

TLR3– endosomes, recognizes the DNA of a pathogen due to differences in DNA structure

TLR1 and 2, for heterodimers required for signaling, ultimately in TLR signaling leads to changes in gene transcription and changes in cellular processes that are necessary for eradicating the pathogen.

50
Q

What are some TLRs and their associated pathogen specific recognition?

A

General: Recognize abnormal nucleotides, starts signaling

10 known TLRs

TLR4: LPS
TLR3: dsDNA in viruses
TLR7 and 8: single strand RNA genomes in viruses
TLR9: unmethylated cpgDNA

51
Q

What does IL6 cytokine signaling produce?

A

On sensing microbial products, macrophages may secrete pro-inflammatory IL6.

Systemic effects: Fever, induces acute-phase protein production by hepatocytes

52
Q

What does TNFalpha cytokine signaling produce?

A

On sensing microbial products, macrophages may secrete pro-inflammatory TNFalpha.

Local effects: Activates vascular endothelium and increases vascular permeability, which leads to increased entry of complement and cells to tissues and increased fluid drainage to lymph nodes.

Systemic effects: Fever, mobilization of metabolites, shock

53
Q

What does IL-1beta cytokine signaling produce?

A

On sensing microbial products, macrophages may secrete pro-inflammatory IL-1beta.

Local effects: Activates vascular endothelium, activates lymphocytes, local tissue destruction, increases access of effector cells

Systemic effects: Fever, production of IL-6

54
Q

What does CXCL8 cytokine signaling produce?

A

On sensing microbial products, macrophages may secrete pro-inflammatory CXCL8.

Local effects: Chemotactic factor recruits neutrophils and basophils to site of infection

55
Q

What does IL-12 cytokine signaling produce?

A

On sensing microbial products, macrophages may secrete pro-inflammatory IL-12.

Local effects: Activates NK cells

56
Q

How can cytokines cause septic shock?

A

In response to TNFalpha, vascular epithelial cells make platelet activating factor which triggers blood clotting and prevents pathogens from entering the blood to prevent systemic infection.

-If infection does get to blood, LPS can provoke widespread production of TNFalpha and cause sepsis

57
Q

What is septic shock?

A
  • Severe shock caused by the systemic release of TNFα after a bacterial infection in the blood.
  • Widespread blood clotting, failure of vital organs, compromised by lack of blood supply, causes death of 100k people each year
  • Heterozygous mutations in TLR 4 variant genes are overrepresented in patients suffering from septic shock
58
Q

Which cells produce a respiratory burst? How does the respiratory burst work?

A

Neutrophils– their killing potential is dependent on respiratory burst

A transient increase in O2 consumption:
In the absence of infection, the antimicrobial proteins and peptides in neutrophil granules are kept inactive at low pH.
After granules fuse with phagosome, the pH of the phagosome is raised, resulting in production of toxic oxygen species that can diffuse out of the cell damage other host cells (superoxide and hydrogen peroxide)

Catalase is an example of an enzyme that acts to limit the damage of H2O2 on the host tissue, breaking down H2O2 to H2O and O2

“metabolic change accompanied by a transient increase in oxygen consumption that occurs in neutrophils and macrophages when they phagocytose pathogens”

59
Q

What are Type 1 interferons? How do they work?

A
  • Infected cells typically result in expression of Type 1 Interferons INFalpha and INFbeta.
  • TLRs are present on most cells of the body, therefore infected cells also receive TLR signals.
  • INFalpha and INFbeta interfere with viral replication
  • TLR signaling causes induction of INFbeta, which can bind to neighboring cells to prevent healthy cells from being infected. Also INFbeta acts on receptors of infected cell itself to cause the expression of INFalpha, which can be secreted and bind receptors on neighboring cells
60
Q

What is MHC class 1?

A

Major Histocombatibility Complex class 1: expressed on healthy cells, used as a positive feedback for NK cells to remain quiescent

Absence of MHC class 1 causes NK cells to kill the cell

General MHC: proteins expressed on cells that
bind peptide antigens and present them to T cells; MHC class I molecules are expressed by most cell types; MHC class II molecules are expressed by
dendritic cells, macrophages and B cells

61
Q

What are MIC proteins?

A
  • Proteins expressed on stressed cells (infected with virus, malignant, trauma)
  • Expression of MIC proteins causes NK cells to release lethal lytic granules
62
Q

What are basophils?

A

Derived from common granulocyte precursor from the common myeloid progenitor

Allergic response

Antibodies created by allergens bind to basophils, which then release cytokines that can affect the production of T cells.

Have Fcε receptors that bind to IgE, contributing to allergic responses and parasite immunity

63
Q

What are eosinophils?

A

Derived from common granulocyte precursor from the common myeloid progenitor

Eliminates helminth and other types of worms, mediated by IgE antibody

64
Q

What are myeloid derived innate immune cells?

A

Macrophages and dendritic cells

Myeloid precursor in BM –> monocytes in blood –> macrophages in tissues

Resident macrophages have different names depending on the tissue (Langerhans, Kupffur, microglia, osteoclast)

Can be recruited to tissue

65
Q

What are interferons?

A

cytokines produced in response to viral infection

Type I interferons are IFNα and IFNβ, and protect cells from viral infections

Type II interferon is IFNγ which is produced by primarily by immune cells in response
to any type of infection

66
Q

What is IgE?

A

immunoglobulin E

Class of antibody that mediates immunity to parasites

Also mediates allergic responses by binding to Fcε receptors on mast cells and basophils.

67
Q

What is an antigen?

A

Molecules or portion of molecules that are recognized by immune cells

68
Q

What is a fever?

A

A rise in body temperature due to expression of cytokines IL-1beta, IL-6, and TNFalpha

69
Q

What is complement?

A

Complement is a set of plasma proteins that act in a cascade of reactions to attack extracellular forms of pathogens.

Complement proteins are primarily serine proteases.

Complement components coat pathogens will either kill the pathogen directly or facilitate its destruction by phagocytes.

-Made by constituatively by the liver, present in blood, lymph, and extra cellular fluid

70
Q

What is complement fixation?

A

Complement fixation is the attachment of C3b to the pathogen surface which labels the pathogen for phagocytosis.

71
Q

Why is C3 important?

A

When complement is activated by infection, will always lead to cleavage of C3 into small C3a and large C3b. C3b becomes covalently bound to pathogen surface–> complement fixation

C3 is constitutively expressed by the liver and is present in the plasma

72
Q

What are the three pathways of C3 activation?

A

Adaptive pathway, Classical pathway, Lectin pathway

73
Q

What is the Adaptive Pathway?

A

Complement Pathway

First to act

Pathogen surface creates local environment, the presence of a pathogen that induces the cleavage of C3.

74
Q

What is the Lectin Pathway?

A

Complement Pathway

Second to act

Initiated by the binding of mannose-binding lectin present in plasma to mannose-containing peptidoglycans on the surface of bacteria, inducing C4 and C2 to generate C3 convertases.

75
Q

What is the Classical Pathway?

A

Complement Pathway

Third to act

C-reactive protein or antibody binds to specific antigen on pathogen surface, inducing C1, C4 and C2 to generate C3 and C5 convertases.

76
Q

C3 convertase

A

Complexes that cleave complement component 3 (C3) into C3a and C3b.

77
Q

C5 convertase

A

Complexes that cleave complement component 5 (C5) into C5a and C5b.

78
Q

Complement Receptors (CR1)

A

Receptor on macrophages and other phagocytic cells that binds C3b-coated pathogens, resulting in phagocytosis and destruction.

79
Q

Opsonization

A

The coating of a pathogen with a protein that facilitates phagocytosis; this can refer to C3b in the complement system; this term is also used for coating of pathogens with antibodies.

80
Q

Membrane attack complex (MAC)

A

A complex of terminal complement components (C5-C9) that forms a pore in the membrane of the target cell or pathogen, damaging the membrane and leading to lysis.

81
Q

Antibody

A

Protein secreted from plasma cells (antibody producing B cell) that binds antigen (proteins or peptides recognized by adaptive immune cells).

82
Q

C-reactive protein

A

Soluble acute phase protein that binds phosphocholine on bacteria, making them more susceptible to phagocytosis either directly or via the classical complement pathway.

83
Q

Anaphylatoxins

A

Complement components C3a and C5a, which can induce inflammation, recruiting fluid and inflammatory cells to sites of infection.

84
Q

Mannose-binding lectin

A

Soluble acute phase protein in the blood that binds to mannose residues on pathogen surfaces and activate the lectin complement pathway.

85
Q

What are the steps of C3 activation through the adaptive pathway?

A
  1. C3 is hydrolyzed in the plasma to iC3
  2. iC3 binds to other compliment factors, such as factor B and factor D, that generate the C3 convertase iC3Bb (convertase essential in cleaving and activating C3)
  3. C3 convertase cleaves C3 into small soluble C3a and larger C3b fragment that gets imbedded in the membrane of the pathogen
    - ——–point of similarity with lectin and classical pathways
  4. Factor B and Factor B can bind to hydrolyze C3, can also bind to C3b on the pathogen surface. When factors B and D bind to C3b on the pathogen surface this leads to formation of another C3 convertase
  5. C3bBb convertase formed by factors B and D and C3b– very potent that acts directly at the surface of the pathogen
  6. C3bBb binds C3 and cleaves it to C3a and C3b (because it is on the surface, a larger proportion of the C3b fragment become fixed to the surface)
  • Positive feedback: when some C3 convertase molecules have been assembled, they cleave more C3 and fix more C3b at the surface leading to the assembly of yet more convertase
  • Progressive amplification–> pathogen can rapidly become coated
  1. Complement receptor 1 (CR1) on macrophages binds to C3b fragments deposited at high density (opsonization) through the alternative activation of complement which facilitates the engulfment and destruction of the pathogen
86
Q

What are the steps of C5 activation through the alternative pathway?

A
  1. After C3 is activated, C3b on the pathogen surface can interact with factor B to form C3b2Bb (an alternative C5 convertase)
  2. C5 (complement component 5) will bind to C3b2Bb complex
  3. Alternative C5 convertase cleaves C5 into C5b and C5a
  4. C5b initiates formation of membrane attack complex to make holes in pathogen membrane (can also occur on eukaryotic cells)
  5. C6 and C7 bind to C5b which inserts into lipid bilayer, then C8 binds as well as components of C9. C9 molecules actually form the transmembrane pore that leads to destruction of pathogen’s membrane integrity and death of the pathogen

-Clearest effect– increased susceptibility to infection by bacteria in family that cause bacterial meningitis and gonorrhea
Inherited deficiencies in Japanese people have C9 deficiencies

87
Q

What are C3a and C5a called? What can they do?

A

Anaphylatoxins

Smaller, soluble C3a and C5a fragments are also physiologically active– increase inflammation at the site of complement activation through binding to receptors on several cell types (inflammation is a major response of the innate immune system).

Also called inflammatory response

  • C3a and C5a can cause anaphlactic shock. C5a more stable and potent; phagocytes, endothelial cells, and mast cells have receptors for C5a and C3a
  • Anaphalctoxins cause contraction of smooth muscle, and degranulization of basal cells and mast cells–> vasoactive effects
  • Make it easier for proteins in the blood to enter into the site of infection. C5a also acts directly on neutrophils and monocytes to increase adherence to blood vessel walls, acts of chemoattractant to sites where complement is being fixed, raises expression of complement on surface
88
Q

What role to serine proteases have in the lectin pathway?

A

MASP1 and MASP2– binding of the lectins initiates the lectin pathway of complement activation

89
Q

What are the steps in the lectin pathway?

A
  1. Mannose binding lectin associated proteases cleave C4 and C2 into C2a/b and C4a/b
  2. C2a binds to surface C4b forming C2aC4b complex– a C3 convertase
  3. C4b2a binds C3 and cleaves it to a C3a and C3b, C3b binds covalently to the microbial surface
  4. Pathway continues the same as the alternative pathway at point of C3 cleavage
90
Q

What are the steps in the lectin pathway?

A

Dependent on the formation of a C reactive protein or antigen specific antibodies (which take time to occur following infection, hence last pathway to be activated). C reactive protein is produced in the liver during an infection.

  1. Complement component 1 (C1r, C1q, C1a) formation initiates pathway; C1 binds C reactive protein to phosphocholine on the cell surface of pathogens
  2. C1 and C reactive protein initiate cleavage of C4 to C4a/b
    OR
  3. IgM or IgG bound to antigens on the surface of pathogens can also bind C1 leading to the cleavage of C4
  4. When C4 is cleaved, the pathway merges with the lectin pathway, inducing the cleavage of C2 and the formation of C2aC4b classical C3 convertase, which then cleaves C3 to C3a/b and follows the alternative pathway
91
Q

Cytokine receptor

A

receptors that bind cytokines; typically composed of multiple different chains and usually signal via JAK-Stat pathway.

92
Q

Chemokine receptor

A

G protein-coupled receptors that bind chemokines; typically classified as CCR or CXCR.

93
Q

Interleukin (IL)

A

Generic term used for many cytokines produced by leukocytes.

94
Q

Kinase

A

An enzyme that transfers phosphate groups from high energy molecules (i.e. ATP) to substrates; example: JAK

95
Q

Phosphorylation

A

Addition of a phosphate group to a protein; example: cytokine receptors

96
Q

G proteins

A

Guanine nucleotide-binding proteins; proteins composed of three subunits (α, β, γ) involved in transmitting signals from outside the cell to the inside.

97
Q

G protein-coupled receptors

A

Receptors that utilize G proteins to mediate signals; when G proteins are not bound to a receptor, it is bound to GDP; however, when a receptor binds to G protein, GDP is released and binds GTP; common receptor type for many ligands; example: chemokine receptors

G protein complex dissociates to give alpha and beta/gamma subunits

Alpha and beta/gamma bind to other proteins which generate signals that change the cell’s pattern of gene expression

98
Q

What are some examples of cytokines?

A

Growth Hormone
Prolactin
EPO
TPO

Can be produced by non-immune cells

99
Q

How does JAK/STAT activation work with cytokines?

A

Cytokines bind to cell specific receptors, with a ligand, they dimerize. When a cytokine is present in the environment and begins to bind to receptors, the chains of the receptor are brought together.

Kinases-enzymes that phosphorylate substrates (ATP being the source of phosphate). JAK will phosphorylate the Cytokine receptor

Transcription factors known as STATs bind the phosphorylated receptors and in turn are phosphorylated by the JAKs.

Phosphorylated STATs form dimers, move into nucleus. Bind to promoter regions of specific genes and initiate their transcription

100
Q

What is an example of JAK/STAT signaling in immunology?

A
  1. Naïve T-cells express a low affinity IL-2 receptor composed of a IL-2Rbeta and IL-2Rgamma chain only
  2. Upon cytokine activation, is IL-2Ralpha is also transcribed. The upregulation of the alpha chain will bind to the beta/gamma chains and result in high affinity IL2 receptor

Once a T-cell has become activated, it is important that the T-cell proliferates and expands, in order to have adequate effector function. Binding of IL-2 to IL-2 receptor on the cell surface induces signaling that results in the proliferation of T-cells.

101
Q

What genes are transcribed (turned-on) by IL-2 receptor signaling?

A

Genes associated with cell cycle and proliferation (proto-oncogenes and cyclins)

102
Q

What does IFNy receptor signaling regulate?

A

Acts through JAK/STAT pathway

Regulates the expression of over 30 genes associated with anti-viral, inflammatory and anti-tumor responses. Enhances the expression of Major Histocompatibility (MHC) genes that are required for T cell responses, enhances the expression of transcription factors and cytokine receptors that are required for T cell differentiation, and induces isotype switching in B cells to produce specific types of antibodies.

103
Q

How are chemokine receptors classified?

A

Chemokine receptors are classified based on the ligand, so they are typically either CCR or CXCR. Chemokine receptors are G- protein coupled receptors.

104
Q

How does IL-8 direct neutrophils to sites of infection?

A

IL-8 (CXCR8) is produced by macrophages at sites of infection. Neutrophils which express CXCR1/ CXCR2, the receptors for IL-8, will engage the IL-8 and promote the extravasation of neutrophils into the site of infection.

When IL-8 bind to its receptor, neutrophils undergo G protein coupled receptor mediated signaling to upregulate genes that enhance the ability of neutrophil to enter the site of infection, as well as phagocytose and kill pathogens are upregulated
Chemokine receptor signaling enhances gene transcription of molecules that will allow the neutrophils to cross from the blood into the tissue itself, also genes associated with phagocytosis and killing pathogens are up-regulated.

F2 Week 1 (4 decks)

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