Chapter 9- Immunity Mediated by B Cells and Antibodies Flashcards
1
Q
B-cell arm of the immune system
A
The component that produces antibodies.
2
Q
Functions of antibodies
A
Antibodies are present in the blood, lymph, and extracellular fluids, where they bind to extracellular bacteria and viral particles. They also concentrate at mucosal surfaces, where they control the populations of commensal microorganisms, pathogenic microorganisms, and parasites. Antibodies act by neutralizing pathogens
3
Q
Antibody structure
A
Antibody heavy and light chains form the V region, which binds to pathogens. They also form the C regions, which bind to complement components and receptors on effector-cell surfaces
4
Q
Neutralization
A
Antibodies prevent growth of pathogens and their entry into cells. They coat pathogens (along with complement) to facilitate their phagocytosis. Antibodies may also impact infection by covering sites on a pathogen’s surface that are necessary for growth or replication
5
Q
Cross-linking
A
When they bind to multimeric proteins or to multiple identical carbohydrate epitopes arrayed on a microbial surface, the B cell receptors become physically cross-linked to each other. They are clustered together at a localized area of B-cell contact with the microbe. The clustering of BCRs sends signals from the receptor complex to the inside of the cell.
6
Q
Initial steps of cross-linking (5)
A
- B cells express multiple, identical copies of its unique receptor on the cell surface
- Surface IgM becomes cross-linked by binding protein or
carbohydrate epitopes - Clustering sends signals from receptor to the nucleus (same as T cells)
- Receptor tyrosine kinases Lyn, Fyn, and Blk phosphorylate
ITAMs present on the cytoplasmic tails of Igα and Igβ on the BCR - “Signalosome’” is made of BCR, tyrosine kinases, and adaptor proteins
7
Q
Next phase of cross-linking (4)
A
- Phosphorylated ITAMS recruit the tyrosine kinase Syk- SH2 domains on Syk bind phosphorylated tyrosines
- Activated Syk phosphorylates the adaptor molecule B cell
linker protein (BLNK) - Eventual activation of PLC-γ results in generation of second messengers IP3 and DAG
- BCR engagement leads to changes in cell metabolism, gene
expression, and cytoskeletal organization
8
Q
“Brakes” for the cross-linking process
A
Includes phosphatases that inhibit B cell activation, like SHIP-1
9
Q
T-cell signaling
A
The TCR complex consists of TCR associated with CD3. ITAMs are present on CD3, γ, δ, ε, and ζ chains. They are phosphorylated by Lck when MHC binds to the T-cell receptor, and recruit ZAP70. ZAP70 then binds ζ chain ITAMs and is phosphorylated by Lck. B cell signaling occurs in a similar fashion
10
Q
B-cell co-receptor
A
Delivers activation signals when associated with the BCR. The co-receptor is composed of 3 proteins- complement receptor 2 (CD2 or CD21), CD19, and TAPA-1 (CD81). The co-receptor augment’s the BCR’s response to a specific antigen.
11
Q
Complement receptor 2 (CR2 or CD21)
A
A receptor protein on B cells (component of the co-receptor) that recognizes iC3b and C3d derivatives of the C3b fragments deposited on a pathogen surface. CR2 is long and flexible.
12
Q
CD19
A
A component of the B-cell co-receptor, forms the signaling chain and is involved in signal transduction
13
Q
CD81
A
A component of the B-cell co-receptor. It is a member of the tetraspanin protein family, and organizes the interactions o the BCR and co-receptor within functional microdomains of the plasma membrane. CD81 also binds CD19 to bring it to the B-cell surface
14
Q
Complement receptor 1 (CR1)
A
A complement receptor that binds to C3b on the pathogen’s cell surface. When CR1 binds, C3b becomes susceptible to cleavage by factor 1, creating C3d and iC3b. Therefore, Cr1 increases the abundance of ligands for the B cell co-receptor at the pathogen’s surface
15
Q
B cell co-receptor signaling and the complement system (5)
A
- CR1 binds to C3b, and C3b becomes susceptible to cleavage by factor 1, creating C3d and iC3b.
- Cr1 increases the abundance of ligands for the B cell co-receptor at the pathogen’s surface
- When the BCR binds to its antigen on the pathogen, the CR2 component of the B cell co-receptor flexes and binds to a nearby C3d fragment. The B cell receptor and co-receptor are brought close together
- Lyn, bound to Ig alpha, phosphorylates the cytoplasmic tail of CD19
- Interaction of phosphorylated CD19 with intracellular signaling components generates signals that synergize with those coming from the B cell receptor
16
Q
What is the importance of the simultaneous ligation of the BCR and co-receptor?
A
Simultaneous ligation increases the overall signal by 1000-10000 fold. This increases the B cell’s sensitivity to antigen. People without a B cell co-receptor due to defective CD19 or CD81 genes have low antibody levels, almost no isotype switching, and poor B-cell responses to infections and vaccines
17
Q
Mononucleosis symptoms
A
Sore throat, fever, malaise, fatigue, pharyngitis, enlarged tonsils, swollen lymph nodes, enlarged spleen, high lymphocyte count in the blood
18
Q
Mononucleosis
A
An infection caused by Epstein-Barr virus (EBV). The virus uses CR2 (CD21) to infected B cells. The infection is mitogenic for B cells and induces the production of IL-10 and IL-6, as well as antibodies. EBV persists latently in B cells and can transform them (Burkitt’s lymphoma). Defense involves EBV-specific CD8 T cells
19
Q
How do TFH cells contribute to B cell-mediated immunity?
A
In primary immune responses, the activation of most naive B cells requires conjugation with a CD4 TFH cell, which recognizes peptides presented by MHC class 2. The cognate helper T cell delivers cytokines and other signals to the B cell which induce its division and differentiation. DiGeorge syndrome demonstrates what occurs when this process goes wrong
20
Q
DiGeorge syndrome
A
Patients lack a thymus and therefore have almost no T cells in their circulation. Although they have normal numbers of B cells, they don’t make effective antibodies to most antigens. This disease results in opportunistic infections and is usually fatal
21
Q
T-independent antigens
A
Antigens that do not require T cell help in order for B cells to respond to them. These antigens, which can be recognized by the IgM antibodies in DiGeorge syndrome patients, are composed of repetitive carbohydrate or protein epitopes. They are present at a high density on the surface of the microorganism, and can cross-link with B cell receptors through multiple activation events. This leads to clustering of BCRs and co-receptors. The signals generated by BCRS and co-receptors are sufficient to activate a minority B-cell population
22
Q
T-dependent antigens
A
Antigens that require T cell help in order for B cells to respond to them.
23
Q
How do B cells enter the lymph node?
A
B cells enter the lymph node from blood through the walls of HEVs. The chemokine CCL21, which is produced by stromal cells, is what directs B cells to the HEV. The cells are also attracted by CCL21 and CCL19, which are produced by follicular dendritic cells. Naive B cells arrive at the lymph node at the subcapsular sinus, where they screen the antigens being held by subcapsular sinus macrophages
24
Q
Follicular dendritic cells
A
Cells that are found in the follicles of secondary lymphoid organs. They are not the same as typical dendritic cells- they lack phagocytic activity and do not express MHC class 2 molecules. Produces CCL21 and CCL19 that attract B cells to HEVs. They also express CD2 and CR1 and display clusters of antigen, which can persist for months to years
25
Follicular dendritic cell functions (4)
1. Produce CCL21 and CCL19 that attract B cells to HEVs
2. The dendrites of the cells take up intact pathogens and antigens, preserving them for long periods. This forms the pathogen/antigen clusters on the cell surface, and they form beads at intervals along the dendrites
3. Extensive interdigitation of dendrites organizes the B cell areas of the lymph nodes into primary follicles
4. FDCs act as a depository of intact antigens, which have not been degraded and are available for interaction with the antigen receptors of circulating B cells
26
Which features of FDCs allow them to perform their function?
They have an extensive dendritic surface area. This allows large quantities of antigens and intact viral particles to be stored. FDCs also have a lack of phagocytic activity, which preserves antigens on the cell surface
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Follicular dendritic cell receptors
CR2 and CR1 are important for activating naive B cells during a primary immune response. These receptors extract antigens from the lymph
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CR2 and CR1 function
Complement activation during the innate immune response leads to attachment of C3b (to CR1) and its breakdown product C3d (to CR2) to pathogens and their antigens. C3b and C3d-tagged antigens are taken up by their cognate complement receptors and held by those receptors at the surface of the FDC
29
Subcapsular sinus macrophage
A specialized macrophage found in the subcapsular sinus of the lymph node. It captures complement-tagged antigens from the afferent lymph and holds them at the cell surface. These macrophages express CR2 and CR1
30
C3d function
Critical for both antigen trapping and B cell co-receptor signaling. Evidence- depletion of the complement component C3 by cobra venom factor strongly reduces T-cell-dependent B-cell responses
31
What is the purpose of the antigen clusters on FDCs?
Captured antigens are screened by naïve B cells arriving from
blood (HEV) or afferent lymph
32
Secondary lymphoid structure (3)
1. Primary lymphoid follicle- outermost region
2. Paracortical area- mostly T cells are found here
3. Medullary cords- macrophages and plasma cells are found here, toward the middle of the lymph node. Innermost region
33
CXCL13
Directs naive B cells to lymph node follicles, so they can interact with FDCs
34
What happens if naive B cells recognize an antigen on FDCs? (5)
1. The sphingosine-1 phosphate (S1P) receptor is not expressed
2. The B cell stays in the lymphoid tissue, as they are unable to respond to the S1P gradient
3. The antigen is endocytosed, and its peptides are presented on MHC class 2 molecules
4. B cell CCR7 expression is induced, which binds to CCL21 and CCL19 and allows B cells to move to the boundary between the B and T cell areas
5. In this location, antigen stimulated B cells can interact with TFH cells
35
What happens if naive B cells do not recognize an antigen on FDCs? (2)
1. CD69 is not expressed, S1P receptor is expressed, the B cells are able to respond to the S1P gradient
2. The B cell moves to the medulla, then leaves via the efferent lymph
36
Lymph node boundary
Located between the primary lymphoid follicle and paracortical area
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S1P gradient
Draws naive B cells out of the B cell area and into the medulla, where they exit the lymph node in the efferent lymph
38
How are TFH cells activated?
When naive B cells recognize antigen on FDCs and move to the boundary between the B and T cell area, the antigen-activated CD4 TFH cells move to this boundary as well. The TFH cells then sample the antigens presented by MHC class 2 on activated B cells. DCs arriving from the site of infection carry antigens, and antigen-specific TFH cells are activated by antigen-presenting DCs. If they find a specific antigen, the TFH cell and B cell form a cognate pair. CD40 and NFκB interactions strengthen the stnapse
39
CD40 ligand
When the TFH cell and B cell form a cognate pair, TFH cells express CD40 ligand. CD40L binds to CD40 on the B cell. This leads to activation of the transcription factor NFκB.
40
NFκB
A transcription factor that induces increased surface expression of the adhesion molecule ICAM-1, which engaged integrin LFA-1 on the TFH cell
41
How are immunological synapses form?
The TFH cell's cytoskeleton and Golgi apparatus are reorganized. The secretory apparatus reorients toward the B cell. This allows for a focused delivery of cytokines onto the B cell surface. These cytokines include IL-5, IL-6, and BAFF
42
Cytokines secreted by TFH cells
IL-5, IL-6, and BAFF
43
CD40L deficiency symptoms
History of recurrent infections, low white blood cell count, poor antibody responses. Patients have high IgM but almost no IgG, IgA, and IgE. A lymph node biopsy shows no secondary follicles or germinal centers
44
CD40L deficiency
Isotype switching requires B cell CD40 to bind to the CD40L of the TFH cell. People with CD40L deficiency are immunodeficient because they can't carry out isotype switching. They have high levels of IgM, but almost no IgG, IgA, or IgE. This condition is X linked, so most patients are male
45
Primary focus
A temporary aggregate of proliferating, activated antigen-specific B cells and T cells that form in a secondary lymphoid tissue at the beginning of an adaptive immune response. This phase of clonal expansion gives rise to plasmablasts that secrete IgM
46
Plasmablasts
Large dividing mature B lymphocytes that secrete IgM antibody, but aren't yet terminally differentiated into plasma cells. The IgM travels out of the efferent lymph into blood
47
What induces differentiation of lymphoblasts into plasma cells?
Induced by IL-5 and IL-6. BLIMP-1 transcription factor is turned on
48
Where is the TFH-B cell cognate pair located in the lymph node?
Conjugated TFH and B cells travel together out of the T cell area to the medullary cord (innermost area). Some cognate pairs differentiate to give plasma cells, others return to the primary follicle in the cortex
49
BLIMP-1
An important transcription factor in B cell differentiation. It prevents the transcription of genes that are necessary for lymphoblast proliferation. This halts B lymphoblast division while increasing the expression of the immunoglobulin chains and factors involved in their synthesis and secretion
50
Centroblasts
B cells divide rapidly to become centroblasts, induced by IL-6, IL-5, and BAFF (produced by FDCs)
51
Activation-induced cytidine deaminase (AID)
TFH cells use their CD40 ligand to bind to B cell CD40. This interaction induces the B cells to make AID, which is a DNA modifying enzyme. It is important for somatic hypermutation and isotype switching. These processes occur in dividing centroblasts
52
Which changes in the lymph node occur during B cell proliferation?
The primary follicle changes its morphology to become a secondary follicle, which changes its morphology to become a germinal center
53
Dark zone
When centroblasts in the germinal center of the lymph node become increasingly close packed, causing a darkly staining area in histological sections. The centroblasts give rise to centrocytes, which divide more slowly and express cell-surface level immunoglobulin. When cells leave the dark zone, they move to the light zone
54
Light zone
The part of the germinal center that contains nondividing centrocytes interacting with follicular dendritic cells. Surface IgG is re-expressed. There is a lower density of B cells and a higher density of FDCs and TFH cells. In the light zone, the centrocytes compete with each other in gaining access to the CD40 ligand of the TFH cell and to specific antigen deposited on an FDC. The centrocytes will die by apoptosis unless surface Ig is bound by antigen on FDCs, and CD40 binds to CD40L
55
Somatic hypermutation
Mutations are introduced in hypervariable regions of antibody molecules. Mutations impact the contacts between the antibody and the antigen. In B cells, somatic hypermutation can produce centrocytes with a diversity of receptors with a range of affinities
56
Affinity maturation
Newly formed centrocytes move from the dark zone of the germinal center to enter the light zone, where they compete for access to the limited amounts of antigen displayed on the dendrites of FDCs. Only centrocytes with the highest affinity are activated by the limited amount of antigen, and are selected for survival and differentiation. In this way, the average affinity of the antigen-specific antibodies increases during the immune response and subsequent exposures to the same antigen. The process ensures that B cells concentrate their resources on making the best possible antibodies
57
How are centrocytes with high-affinity antigen receptors rescued from apoptosis?
Centrocytes whose B cell receptors have acquired mutations that reduce the affinity for antigens are induced to die by apoptosis. However, centrocytes with receptors that have superior affinity for antigen are induced to express Bcl-XL. This is an intracellular protein that prevents apoptosis and ensures the cell's survival. Centrocytes that survive will differentiate into plasma cells
58
B cell activation (6)
1. When antigens enter tissues, B cells are summoned to the infected region. They use their BCRs to bind to the antigen
2. Once they bind, the B cell internalizes the BCR with antigen, and the antigen is degraded
3. Antigen peptides are presented on MHC class 2 molecules
4. A helper T cell binds to the B cell if it recognizes the MHC and antigen molecule (using its CD4 marker and TCR)
5. When the T cell binds to the B cell, it will release interleukins which will activate the B cell to proliferate
6. The B cell produces memory cells and plasma cells
59
Memory cells
Produced by B cells, return to the secondary lymphoid tissue for future infections
60
Plasma cells
Actively secrete antibodies (have a high rate of Ig secretion). The antibodies are used to clear the pathogen
61
Antibody mechanisms of action (6)
1. Binding to the antigen and tagging it for opsonization by phagocytes- enhances phagocytosis
2. Neutralizing the antigen, stopping it from binding to target tissue
3. May cause the antigen to agglutinate- enhances phagocytosis and reduces the number of infectious units to deal with
4. Activate the classical pathway of complement activation, triggering cell lysis
5. Inflammation- disruption of the cell by complement/reactive protein attracts phagocytic and other defensive immune system cells
6. Antibody-dependent cell-mediated cytotoxicity- antibodies attached to the target cell cause destruction by non-specific immune system cells
62
Which antibodies do B cells make first?
Naive B cells make IgM and IgD first, but can switch their heavy chain isotype to IgG, IgA, or IgE after antigen-mediated activation
63
Where does isotype switching take place?
In activated B cells within the germinal center
64
What determines which isotype a B cell switches to?
The isotype is determined by a B cell's cognate interactions with TFH cells. Specifically, the isotype is determined by the cytokines secreted by the TFH cell, which is turn are determined by the nature of the infection and the dendritic cell that nurtured the TFH cell. The specificity of the antibody does not change during this process
65
IL-4 function
Induces isotype switching to IgG1, IgG4, and IgE. IL-4 is important in inducing an anti-parasitic immune response
66
IL-21 function
Induces isotype switching to IgG1, IgG3, and IgA1. It causes B cell differentiation to plasma cells secreting IgM, IgG, IgA, and IgE. IL-21 also synergizes with IL-4 to induce switch and secretion of IgG and IgE
67
When centrocytes survive selection in the germinal center, what is the purpose of their interaction with TFH cells?
The engagement of ligands and receptors on the two cells generates an exchange of signals, which induces further proliferation of both the B cells and T cells. This expands the population of selected high-affinity, isotype-switched B cells. Individual B cells are also triggered to differentiate into plasma cells or memory B cells
68
Which TFH cytokines allow centrocytes to differentiate into plasma cells or memory B cells?
IL-10 and IL-21 drive centrocytes to differentiate into antibody-producing plasma cells or into the memory B cells at different stages of the immune response
69
How does affinity maturation occur?
The centrocytes interact with and bind to high-affinity antigen displayed by FDCs, and present the antigen to TFH cells. TFH cells then secrete cytokines to trigger the centrocytes to differentiate into plasma cells or memory cells
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Antibody isotypes (5)
1. IgG
2. IgM
3. IgA
4. IgD
5. IgE
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What determines antibody effector function?
Effector function is linked to the Fc portion, number of binding sites, and specific receptors expressed on cells in the body
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Which antibody isotypes protect the internal tissues of the body? (3)
1. IgM
2. IgG
3. Monomeric IgA
These antibodies also bind to and neutralize any microorganisms that enter the blood, preventing septicemia
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IgM
Secreted as a pentamer by plasma cells and enters the blood stream. It has a low affinity, but can bind well to microbes and particulate antigens. IgM also activates complement. It is bulky and can't penetrate infected tissues.
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IgG
More effective than IgM- it is smaller and has higher affinity. IgG protects the internal tissues of the body. It is transferred from the blood to extracellular spaces between tissues, and is taken up by pinocytosis.
75
FcRn receptor
An Fc receptor that transports IgG across the epithelia and has a structure resembling an MHC class 1 molecule. This receptor is expressed by epithelial cells, dendritic cells, and neutrophils. FcRn diverts the IgG away from lysosomes (where other plasma proteins go) and direct it to the basolateral surface of the cell, where the basic pH of the extracellular fluid causes the receptor to release its cargo of IgG.
76
FcRn receptor structure
Its structure resembles an MHC class 1 molecule. It has alpha 1 and alpha 2 domains, which form the site that binds to the Fc region of the antibody. In the antibody-receptor complex, 2 molecules of FcRn bind to the Fc region of one IgG molecule.
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FcRn receptor functions (2)
1. Maintains a high level of IgG in the extracellular fluids of connective tissues
2. Selectively protects IgG from the process of degradation, which other plasma proteins undergo. Therefore, IgG has a longer half life than other plasma proteins
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Dimeric IgA
Protects the body's mucosal surfaces- it is found in GI, respiratory, urinary, and genital tracts. Produced in mucosal lymphoid tissues and prevents the colonization of mucosal epithelium
79
Poly-Ig receptor (pIgR) mechanism (4)
1. IgA or IgM binds to the receptor on the basolateral face of the epithelial cell
2. The antibody is taken into the cell by receptor-mediated endocytosis
3. The antibody-receptor complex is carried across the cell in endocytic vesicles to the apical surface. This process is called endocytosis
4. The receptor is cleaved, IgA binds to mucus with its secretory piece
80
Which antibodies are specialized to protect the surfaces of the mucosal epithelia? (2)
1. Dimeric IgA
2. Pentameric IgM (in addition to fluids/tissues)
These antibodies bind to microorganisms and facilitate expulsion of the microorganisms from the body in feces, sputum, tears, and other secretions
81
Why must dimeric IgA and IgM be transported across the epithelium?
IgA-secreting plasma cells are on one side of the mucosal epithelium, while their target pathogens are on the other. Dimeric IgA and IgM are individually transported across the epithelium by means of a receptor (the pIgR receptor) on the basolateral surface of epithelial cells
82
Transcytosis
When molecules are transported from one side of the epithelium to other. Molecules are endocytosed into vesicles within the epithelial cells at one face, and the vesicles are released at the other face
83
How does PIgR bind to antibodies?
Specifically binds to IgA dimers and IgM pentamers, using the J chain, which is unique to these antibodies. At the basolateral surface, a disulfide bond is made between one poly-Ig receptor and the J chain of either one IgA dimer or one IgM pentamer.
84
Secretory piece
The fragment of the poly-Ig receptor that is left attached to dimeric IgA that has been secreted across a mucosal epithelium. IgA dimers and IgM are retained at the mucosal surface by the secretory piece, as the carbohydrate in this component binds to glycoproteins in the mucus (mucins)
85
How is PIgR cleaved?
It is cleaved by a protease once the receptor-bound antibody arrives at the apical surface. The protease cleaves the receptor between the membrane-anchoring region and the disulfide bond with the antibody's J chain. Dimeric IgA is released from the membrane still bound to its secretory piece
86
Apical surface
The top of an epithelial cell that faces the outside of an organism or the lumen of a hollow organ
87
IgE function
IgE plays an important role in the anti-parasitic autoimmune response. Parasites are too large to phagocytose, so a different mechanism is necessary. IgE doesn't act as a soluble antibody, it acts as a cell-surface receptor for the antigen.
88
FcεR1 receptor
An Fc receptor that extracts plasma cell-secreted IgE from the circulation. It is found on the surface of mast cells, basophils, and activated eosinophils throughout the body's tissues, although they are especially found in connective tissues. In the absence of antigen, FcεR1 has a high affinity for IgE and strongly binds to it. Therefore, cells with this receptor are ready and waiting to bind pathogens and their antigens. Each cell that expresses FcεR1 carries a variety of IgE molecules that are each specific for a different antigen
89
Antiparasitic response
When a pathogen binds IgE and cross-links FcεR1 on the mast cell surface, the cell secretes mediators that activate smooth muscle. The antigen must cross-link at least two IgE molecules. This causes violent reactions like sneezing, coughing, vomiting, and diarrhea that forcibly eject pathogens from the respiratory and GI tracts
90
Effects of histamines and inflammatory mediators (4)
1. Increased vascular permeability- works to flush out parasites
2. Local accumulation of fluids
3. Swelling, reddening, pain
4. Recruitment of cells to sites of infection
91
Examples of parasites
Includes intestinal worms, tapeworms, and blood, liver, and lung flukes
92
Histamine
An amine stored in mast-cell granules. It is released when antigen binds to IgE molecules on mast cells. Causes the dilation of local blood vessels and the contraction of smooth muscle, producing some of the symptoms of immediate hypersensitivity reactions
93
Inflammatory mediators
Any substance released by various cell types that contributes to the production of inflammation at a site of infection or trauma. Mast cells have granules that contain inflammatory mediators, like histamine and serotonin. Mast cells are activated by cross-linking between IgE and the FcεR1 receptor, and inflammatory mediators are released
94
Antibodies that mothers pass to their fetus during pregnancy
During pregnancy, IgG from the maternal circulation is transported across the placenta by FcRn and is delivered directly into the fetal bloodstream. At birth, babies have levels of IgG in their plasma that are comparable to those found in their mothers. These antibodies also have a wide range of antigen specificities
95
In healthy adults, which antibodies predominate in the blood?
IgM, IgG, and monomeric IgA.
96
Where is IgE found?
Associated mainly with the mast cells in the connective tissue beneath epithelial surfaces, especially the skin, respiratory tract, and GI tract
97
Which antibodies predominate in the brain?
The brain is devoid of immunoglobulin
98
Which antibodies do mothers pass to the baby after birth?
Through breastfeeding, the infant's GI tract is supplied with dimeric IgA. This isotype is a major component of breast milk and protects against intestinal pathogens. Acts as passive immunization. At birth, infants have protection against pathogens that provoke an IgG response, but not against pathogens that infect mucosal surfaces and provoke an IgA response.
99
Which antibodies predominate in extracellular fluid?
IgG and monomeric IgA predominate in the extracellular fluid
100
Which antibodies predominate on mucosal surfaces?
Dimeric IgA
101
Are there immunological differences between infants given formula vs breast milk?
Commercial infant formulas don't contain the immunity-boosting elements of breast milk. There is a trend that breastfed babies have fewer infections and hospitalizations than formula-fed infants
102
How long does it take for infants to produce their own antibodies?
IgM is produced soon after birth, and IgG is produced around 6 months after birth. Infants are in a vulnerable period for 3-12 months, which is when IgG levels are lowest- maternal IgG is catabolized and the consumption of breast milk decreases. The period of vulnerability is also when the symptoms of genetic deficiencies in immune system genes begin to appear
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Immunological differences in premature babies
Babies born prematurely have lower levels of maternal IgG, and after birth, they take longer to attain immune competence than term babies
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Viral attachment
The microbe must first attach to the outside surface of the body, either the skin or a mucosal surface. Attachment occurs due to specific interactions between a component on the microbial surface (a ligand) and a complementary component on the human epithelial cell surface, which the pathogen exploits as its receptor
105
Neutralizing antibodies
Antibodies that bind to the microbial ligand and prevent it from attaching to the human epithelium. This prevents the infection before it starts. Most neutralizing antibodies are dimeric IgA, because many infections begin at the mucosal surface
106
Influenza hemagglutinin
A glycoprotein found in the coat of the influenza virus. It binds to certain carbohydrates, like sialic acid, on human cells. This is the first step in influenza infection. Changes in hemagglutinin (which has a high mutation rate) are the major source of antigen shift that causes a new influenza pandemic. It is called hemagglutinin because it can agglutinate (clump together) red blood cells
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Adhesins
Molecules on the surfaces of bacteria that bind to epithelial cells, which allow the bacteria to colonize epithelial surfaces. Generally, IgA antibodies against adhesins limit bacterial populations within the mucosal tissues and prevent the occurrence of disease-causing infections
108
Protein F
The adhesin found in Strep pyogenes, which binds to fibronectin (a large glycoprotein of the ECM). Secreted IgA antibodies that are specific for protein F limit the growth of resident S. pyogenes and prevent the bacteria from causing disease. In the presence of another infection or stress, the mechanism may not be protective, and a sore throat develops
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Toxoid
An inactivated toxin, where the toxic chain is denatured so it can no longer be toxic. Diphtheria and tetanus toxoid are found in the DTP vaccine, where they induce the production of neutralizing antibodies against the receptor-binding chain
110
Diphtheria toxin
An exotoxin secreted by Corynebacterium, which blocks protein synthesis. Inhibition of protein synthesis leads to epithelial cell damage and myocarditis. A lethal dose in humans in .1 micrograms of toxin per kg of body weight, which causes liver and heart necrosis
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Bacterial toxins
Many bacteria secrete protein toxins that cause disease by disrupting the normal function of human cells. The toxin must bind to a specific receptor on a human cell surface to have an effect. In some toxins, like diphtheria and tetanus toxins, they are composed of one polypeptide chain that has binding activity and another chain that has toxic function
112
Tetanus toxin
Blocks inhibitory neuron action, leading to chronic muscle contraction
113
Diphtheria antitoxin
This is an earlier version of how we protected against diphtheria, prior to vaccination. Scientists grew diphtheria-causing bacteria in the laboratory to harvest its toxin. Then, horses were injected with the toxin. As an immune response, the horses produced diphtheria antitoxin in the blood. The blood was collected, and the antitoxin rich serum was separated. Then, the antitoxin serum was purified to be used as a medicine. This is a form of passive immunization, because the protection is gone once the antibody half-life is up
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Classical pathway
The pathway of complement activation which can be activated by antibodies
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Complement component C1
The C1 proteolytic molecule is a complex of C1q, C1r, and C1s. C1q has a stalk-like structure that contains 6 identical subunits, each one has a binding site for the Fc region of antibodies (IgM or IgG)
116
IgM and classical pathway activation (3 steps)
1. IgM exists as a planar (flat) form when it is secreted. However, when it binds to the microbial surface, it develops into a "staple" form that can attract the C1 molecule. This conformation has up to 5 binding sites for the C1q molecule.
2. Once it binds, the activated C1 molecule cleaves C2 and C4, forming the classical C3 convertase (C2aC4b).
3. Deposition of C3b leads to phagocytosis via CR1 or eventually assembly of the MAC through formation of the C5 convertase
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IgG complement activation
Unlike IgM, for IgG to activate the classical pathway, it requires 2 or more IgG to cross-link to C1q. The mechanism differs based on whether IgG binds to antigens on the bacterial surface or to soluble multivalent antigens. Complexes of soluble antigens, antibody, and C3b are readily taken up for phagocytic cells. This allows for clearance of toxins from the system. Ultimately, phagocytosis of the pathogen or formation of the MAC occurs.
118
Mechanism of IgG complement activation (2 options)
1. IgG binds to antigens on the bacterial surface, and C1q binding to 2 or more IgG initiates complement activation. Or:
2. IgG binds to soluble multivalent antigen, and C1q binds to a soluble immune complex and initiates complement activation
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Removal of immune complexes from the circulation
Erythrocytes drastically outnumber leukocytes, so they are the most numerous blood cells expressing CR1. Immune complexes covered with C3b bind CR1. Therefore, most immune complexes will bind to the cell surface of erythrocytes. During their circulation in the blood, erythrocytes pass through the liver and spleen, where macrophages remove and degrade the complexes of complement, antigen, and antibody. The erythrocytes are left undamaged
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Erythrocyte removal of immune complexes (4)
1. A small antigen-antibody complex forms in the circulation and activates complement
2. The immune complex is coated with covalently bound C3b
3. CR1 on an erythrocyte surface binds C3b-tagged immune complex
4. Erythrocyte carries immune complex to the liver or spleen, where it is detached and taken up by a macrophage
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What happens if immune complexes are not removed?
The complexes tend to enlarge by aggregation and then precipitate at the basement membrane of small blood vessels. This occurs most commonly in the glomeruli of the kidneys. Systemic lupus erythematosus is characterized by a high level of immune complexes in the blood, which causes a massive deposition of immune complexes in the renal podocytes. This damages the kidneys, putting lupus patients at risk for kidney disease. This may also occur in patients with inherited deficiencies of the complement pathway
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FcγR1 receptors
A receptor that is specific to myeloid cells- present on macrophages, neutrophils, and eosinophils, and binds the Fc regions of IgG antibodies. Binding stimulates the internalization and destruction of antigen-antibody complexes, degrading pathogens. Cross-linking is what induces uptake. This receptor binds most strongly to IgG3, and has different binding affinity to the 4 IgG subclasses.
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Hierarchy of FcγR1 binding
1. IgG3
2. IgG1
3. IgG4
4. IgG2
The hierarchy reflects structural differences in the hinge and the CH2 domain of the IgG subclasses
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FcγR1 structure
Contains an α chain, which is associated with a dimer of γ chains that have ITAM motifs for transducing activating signals
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Mechanism of macrophage receptors (4)
1. Macrophage receptors recognize components of microbial surfaces. They work in a cooperative fashion to capture the pathogen
2. Microorganisms are bound by phagocytic receptors on the macrophage surface
3. Microorganisms are internalized by receptor mediated endocytosis
4. Fusion of the endosome with a lysosome forms a phagolysosome in which microorganisms are degraded
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Fcγ receptors and phagocytosis (4)
1. Fc receptors, located on phagocytes, bind antibody-coated bacteria
2. Binding of aggregated antibody molecules to Fc receptors causes the cell to engulf the bacterium
3. The phagocyte produces pseudopods (ruffles) that surround the bacterium and fuse. The bacteria is then trapped in an intracellular vesicle- the phagosome
4. Lysosomes fuse with the phagosome, and their enzymes degrade the engulfed bacterium
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FcγR2 and FcγR3
Fc receptor. Bind IgG with lower affinity, but they do not bind monomeric IgG. They bind 2 or more IgG molecules cross-linked to antigen
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FcγR2A
A low-affinity Fc receptor responsible for pathogen uptake and destruction. The H131 variant carries out effective binding. The R131 variant is less effective- found in 25% of the African and European population, which are susceptible to meningococcal disease
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FcγR2B1 and FcγR2B2
These receptors act to control inflammation. They have an inhibitory ITIM motif in their cytoplasmic tails. Inhibit B cell and mast cell function
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FcγR3
The only Fc receptor expressed on NK cells. It is involved in the recognition and killing of cells that are coated with IgG1 or IgG3. These receptors are said to exhibit antibody-dependent cell-mediated cytotoxicity, destroying virally-infected cells and tumor cells
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Rituximab
A drug that targets Fcγ receptors for therapeutic use. Rituximab is a monoclonal antibody specific for CD20, which is expressed at high levels on B cell tumors (Non-Hodgkin's lymphoma, CLL). It can also be used as a treatment for rheumatoid arthritis, by killing auto-reactive B cells
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IgA receptor
Expressed by neutrophils, macrophages, and dendritic cells. Important at mucosal areas. It is responsible for phagocytosis of pathogens coated with IgA
