Immunology Flashcards
What are the characteristics of innate immunity?
- Present at birth
- Rapid
- Relies on pattern recognition
- Not specific
- No memory
- Primarily mediated by neutrophils
What are the characteristics of adaptive immunity?
- Slow (on first exposure)
- Diverse
- Adapts to antigen (not pre-formed)
- Highly specific
- Generates memory and improved immunity w/ repeated antigen exposure
What is specificity?
The ability to distinguish between different substances
Describe specificity with regards to innate immunity
Proteins that recognize common patterns of infectious organisms
Not very specific
Describe specificity with regards to adaptive immunity
Surface protein recognizes unique molecules
Highly specific
What is passive immunity?
Describe the characteristics of passive immunity
Transfer of pre-formed antibody from one person or animal to another
Rapid
Short-lived
What are examples of passive immunity?
- Antitoxins for botulinum toxins
- Antibodies to rabies virus
- Maternal IgG antibodies crossing the placenta
- Maternal IgA antibodies in breast milk
What is active immunity?
Describe the characteristics of active immunity
Induction of an immune response (exposure to antigen)
Slow
Memory (long-lived)
What is an example of active immunity?
An immunization
Patient AJ is planning to travel internationally in 3 days to a region endemic for Hepatitis A. She will be there for one year. What is the best type of immunity-based therapy to offer her to prevent infection?
Immunization against Hepatitis A with Ig and the inactivated virus
Which immunoglobulin do nursing infants have?
Maternal IgA
Which immunoglobulin do all very young infants (under 6 weeks) have?
Maternal IgG
(And Maternal IgA if they are nursing)
Which sort of immune response are infants under the age unable to generate?
Infants under 2 years old cannot generate an effective T-cell independent B cell response
(such as to a polysaccharide capsule)
Which sort of immune response do older adults have a decreased ability to generate?
T-cell independent B cell response
Which two groups cannot generate / generated reduced T-cell independent B cell responses?
- Infants under age of two
- Older adults
Struggle w/ encapsulated bacteria
Have greater frequency and severity of infections
Why are encapsulated bacteria particularly dangerous to infants under the age of two?
Infants under two cannot generate an effective T-cell independent B cell response
Why are encapsulated bacteria particularly dangerous to older adults?
Older adults have decreased ability to generate an effective T-cell independent B cell response
What must pneumoccal vaccines consisting of polysaccharides be conjugated to in order for children under the age of 2 to allow for a protective immune response?
Proteins
What are cytokines?
Small proteins that are produced by cells and have effects on cells
Include chemokines, interleukins, lymphokines, tumor necrosis factors, interferons
What is the function of IL-2?
Promotes T cell growth and activation
What is “clusters of differentiation”?
Nomenclature system for the proteins used to identify cells
What does a CD refer to?
A protein expressed by cells
On which cells is CD3 expressed?
All T cells
On which cells is CD4 expressed?
What does CD4 bind to?
Helper T cells
Binds to MHC class II
On which cells is CD8 expressed?
What does CD8 bind to?
Cytotoxic T cells
Binds to MHC class I
On which cells is CD19 expressed?
All B cells
On which cells is CD56 expressed?
NK cells
What is CD28?
What does it bind to?
Co-stimulatory protein on T cells (2nd signal)
Binds to B7 on APCs
A 33 year old woman is planning to travel internationally in 3 days to a region endemic for Hepatitis A. What is the best type of immunity-based therapy to offer her to prevent infection?
Due to short time before her potential exposure to Hepatitis A, she should receive immune globulin (Ig), which is passive immunization, since the antibody is preformed and the protection is rapid.
This protection is short-lived, so she should also receive inactive Hepatitis A vaccine, which provides longer protection.
Ideally, she would also have a booster in 6 months for much longer protection.
What protein must antigen-presenting cells express on their surface to present a peptide to CD4+ T helper cells?
MHC II
Would exposure to only the polysaccharide capsule of bacteria lead to a T cell mediated immune response?
Could there still be an immune response?
No, if there is no protein present, there will not be a T cell-mediated immune response
There could be a T cell independent immune response driven by B cells
How do pathogens prevent being destroyed by innate immunity?
- Evade immune system
- Use elements of immune system for their own advantage
How does Bordetella pertusis evade the immune system?
Has proteins that bind to ciliated respiratory cells to enable infection
What is innate immunity?
Part of immune response that exists at birth and is present in all multicellular organisms
Rapid, relies on pattern recognition to identify pathogens, has no specificity, shows no memory or improvement in immunity with time or repeated antigen exposure
Which white blood cells are involved in the innate immune response?
- Neutrophils
- Monocytes/macrophages
- Basophils
- Mast cells
- NK cells
What is the role of neutrophils in innate immunity?
Neutrophils (granulocytes, PMNs)
- First responders
- Rapidly migrate from bone marrow to blood to tissue (peripheral blood neutrophilia)
- Engulf/kill pathogens
- Release additional pro-inflammatory cytokines
- Major cell of acute inflammatory response
- Do not present antigen on MHC class II
What is neutropenia?
What causes it?
What does it lead to?
Too few neutrophils
Often caused by chemotherapy
Leads to significantly increased susceptibility to infection
What is the role of monocytes in the blood / tissue macrophages in innate immunity?
Tissue macrophages
- Recognize pathogens through pattern recognition
- Release cytokines to recruit neutrophils
- Macrophages phagocytose organisms
- Antigen-presenting cells (express MHC class II)
Where are mast cells present?
What are mast cells activated by?
What do mast cells release?
Mast cells
- Present throughout connective tissue
- Activated by trauma, complement proteins (C3a and CD5a), and cross-linking of IgE (which is bound by IgE Fc freceptor)
- Express-tole like receptors that recognize bacteria and viruses
- Release histamine and other mediators of inflammation
Where are basophils present?
What are basophils activated by?
What do basophils release?
Basophils
- Present in blood
- Activated by trauma, complement proteins (C3a and CD5a), and cross-linking of IgE (which is bound by IgE Fc freceptor)
- Express-tole like receptors that recognize bacteria and viruses
- Release histamine and other mediators of inflammation
What is the role of NK cells in innate immunity?
NK cells (CD56+ and CD16+)
- Directly kill infected cells
- Recognize virus-infected cells and tumor cells via lack of MHC class I on those cells and by binding Fc (constant region) of antibody bound to those cells (antibody-dependent cellular cytotoxicity)
- Produce and secrete cytotoxic granules such as perforin and granzyme B
- Do not express specific antigen receptors
What are complement proteins?
>20 plasma proteins that augment inflammation
What do complement proteins circulate as?
Inactive precursors
How are complement proteins activated?
Activated in a cascade of cleavage reactions that allow proteins and immune complexes to be destroyed or eliminated
What are the functions of complement?
- Direct lysis of cells
- Generation of mediators of inflammation
- Opsonization (enhancement of phagocytosis)
Why is regulation of complement essential?
To prevent tissue damage
What do the three mechanisms of complement activation converge on?
C3 convertase
What does C3 convertase do?
Acts on C3 to make C3a and C3b
What does C3b do?
Acts on C5 to make C5a and C5b
What does C5b do?
Inserts into cell membrane of pathogen and is bound by C6, C7, C8, and C9 to make the membrane attack complex
What does the membrane attack complex do?
Which bacteria are particularly susceptible?
Forms a hole in the membrane causing the pathogen to lyse
Gram-negative bacteria are particularly susceptible
Describe the classic pathway of complement activation
C1 binds to the constant fragment of IgG or IgM (antigen-antibody complex)
Describe the alternative pathway of complement activation
Microbial products directly activate complement
Describe the lectin pathway of complement activation
Mannose-binding lectin (serum protein) binds carbohydrate antigens on the surface of micro-organisms (such as encapsulated bacteria)
What is the function of C1?
Recognizes antigen-antibody complexes in the classical pathway of complement activation
What is the function of C3 convertase?
Associates with pathogen cell membrane and cleaves/activates other complement proteins
What is the function of C3a?
Triggers mast cells to degranulate and release histamine (anaphylatoxins)
What are the functions of C5a?
- Triggers mast cells to degranulate and release histamine (anaphylatoxins)
- Chemotactic for neutrophils
What is the function of C3b?
Opsonin for phagocytosis (iC3b and C3d are breakdown products of C3b)
What do C5b, C6, C7, C8, and C9 form?
The membrane attack complex
What is the function of C1 esterase inhibitor?
Inhibits the formation of C3
What is the function of decay accelerating factor (CD55)?
Inhibits the formation of C3
What condition does a deficiency in C1 esterase inhibitor cause?
What is the biomolecular cause of the condition?
What are the symptoms?
Hereditary angiodema
Uncontrolled generation of bradykinins
Persistent swelling in extremities, face, lips, genitals, and GI tract
What do deficiencies in the membrane attack complex (C5b, C6, C7, C8, C9) lead to?
Predispose to infections with Neisseria
What does C1 bind to initiate the classical complement pathway?
IgG bound to antigen
What are defensins?
Where are defensins found?
Small cationic peptides that bind to and create pores in microbes
Alpha definsins are in the GI tract
Beta defensins are in the respiratory tract
What are interferons (alpha and beta)?
Anti-viral proteins that bind to the cell surface and induce an anti-viral state in cells
Inhibit viral replication
Produced by lymphocytes and macrophages
How do bacterial capsules reduce the effectiveness of the complement system?
- Prevents complement activation
- Decreases C3b binding
(Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae)
How are monocytes/macrophages involved in inflammation?
- Monocytes and macrophages express pattern recognition proteins
- Recognize PAMPs (ex: CD14/TLR4 recognizes LPS)
- Release pro-inflammatory cytokines/mediators and stimulate acute phase reponse
Macrophages also release anti-inflammatory cytokines to control immune response
What do pro-inflammatory cytokines trigger?
What occurs?
Acute phase response
Increased synthesis of plasma proteins by the liver, including C-reactive protein, mannose-binding lectin, Factor XII
Contributes to sepsis
What is IL-1?
- Pro-inflammatory cytokine
- Endogenous pyrogen
- Induces acute phase response
What is IL-6?
- Pro-inflammatory cytokine
- Endogenous pyrogen
- Induces acute phase response
What is IL-8?
- Pro-inflammatory cytokine
- Recruits neutrophils (chemokine)
Clean up in aisle 8 (IL-8)
What is tumor necrosis factor alpha (TNFa)?
- Pro-inflammatory cytokine
- Numerous pro-inflammatory effects
- Stimulates cell growth and proliferation
- Recruits neutrophils
- Increases cyclooxygenase
What is the function of cyclooxygenase?
Acts on arachidonic acid from cell membrane to produce prostaglandins
Prostaglandins mediate vasodilation and increased vascular permeability, pain, and fever
What is IL-10?
- Anti-inflammatory cytokine
- Turns off immune response
What is transforming growth factor beta (TGFb)?
- Anti-inflammatory cytokine
- Turns off immune response
On which cells is CD14 expressed?
What is the function of CD14?
Monocytes/macrophages
Co-receptor for TLR4 that recognizes LPS
What elements of innate immunity might defend against infection by bacteria in the GI tract?
- Intact mucosal epithelium
- Mucous
- pH
- Microbial molecules such as defensins
- Macrophages
- Dendritic cells
The classic complement pathway is initiated by interaction of C1 with what?
IgG or IgM
What is the role of pattern recogniton in triggering inflammation?
Pattern recognition receptors (PRRs) such as TLRs on monocytes/macrophages, mast cells, and other cells of the immune system recognize the pathogen-associated molecular patterns (PAMPs)
The signal leads the cell to release pro-inflammatory cytokines
In a patient with a chronic inflammatory disease mediated by the release of pro-inflammatory cytokines, which cytokines could oppose the inflammation and tissue damage?
Anti-inflammatory cytokines such as IL-10 and TGF-beta
(However, anti-inflammatory cytokines can also contribute to tissue damage under certain circumstances)
What is acute inflammation? What are the cells involved?
Predominantly an innate immune response (rapid, not specific) mediated by fluid in the tissues (edema) and neutrophil migration into tissues
Macrophages arrive after neutrophils and release further cytokines
Can resolve (such as fibrosis or scar tissue) or progress to chronic inflammation
What is the role of neutrophils in acute inflammation?
- Drawn towards inflammatory mediators from macrophages and mast cells
- Phagocytose and destroy organisms
- Release further cytokines to draw additional neutrophils
What is chronic inflammation? Which cells are involved?
Predominantly an adaptive immune response (delayed, specific) mediated by lymphocytes, plasma cells, and monocytes/macrophages
What are the causes of chronic inflammation?
Persistent infection, prolonged exposure to a toxic agent, or autoimmunity
What is granulomatous inflammation?
What is a granuloma?
A subtype of chronic inflammation characterized by granuloma formation
A granuloma is a collection of macrophages, sometimes with giant cells (large macrophages with multiple nuclei) and surrounding lymphocytes
What is the difference between a caseating and non-caseating granuloma?
A caseating granuloma has central necrosis (TB, fungal infection)
A non-caseating granuloma lacks central necrosis (foreign material reaction, sarcoidosis, cat scratch disease)
What type of response to extracellular pathogens tend to give rise to?
Which cells/molecules are involved?
Pyogen (pus-producing) response
Neutrophils, antibodies, complement
What type of response do intracellular pathogens tend to give rise to?
Which cells/substances are involved?
Granulomatous response
Macrophages, CD4+ T cells
What are the basic steps in inflammation produced by the innate immune system?
- Cells of the innate immune system recognize pathogens through PAMPs
- These cells release pro-inflammatory cytokines
- Cytokines acute phase response and releazse of numerous mediators of inflammation
What releases TNFa?
What is the function of TNFa?
Macrophages
Pro-inflammatory effects including increased cyclooxygenase
What does cyclooxygenase do?
Acts on arachidonic acid from the cell membrane to produce prostaglandins which mediate vasodilation and increased vascular permeability, pain, and fever
What does 5-lipooxygenase do?
Acts on arachidonic acid to produce leukotrienes (LTB4, LTC4, LTD4, LTE4) which attrachts neutrophuls and causes bronchospasm and increased vascular permeability
(contributes to anaphylaxis but is slower acting than histamine)
What are bradykinins produced from?
What do bradykinins do?
Bradykinins are produced from the kinin system (cleavage of high molecular weight kinogen/kalikrein)
Mediate vasodilation, increased vascular permeability, and pain
Hint: Tom Brady = Brady-kinin
- Dilates the defense and creates holes in it
- Causes pain to opponents
Which cell releases IL-1, IL-6, and IL-8?
Macrophage
Which cell releases histamine?
What does histamine do?
Mast cells (stimulated by binding of C3a and C5a complement)
Leads to vasodilation, endothelial cell contraction, and increased vascular permeability
What are the vascular components of inflammation?
- Vasodilation
- Increased vascular permeability
What does vasodilation lead to?
Increased blood flow
What causes increased vascular permeability?
What is the function of increased vascular permeability?
Caused by endothelial cell contraction and damage
Allows fluid and cells to reach areas of infection
Which molecules mediate vessel changes?
Histamine, prostaglandins, and leukotrienes
What are the basic stages of phagocytosis?
- Recognitin and attachment
- Engulfment
- Destruction
- Resolution
Describe the recognition and attachment stage of phagocytosis
Binding of IgG antibody or C3b complement to the bacteria improves recognition and attachment of the bacteria for engulfment by neutrophils (opsonization)
Which receptors are involved in the recognition and attachment stage of phagocytosis?
- Pattern recongnitionr receptors for PAMPs: TLRs, NOD, RIG-I
- Receptors for opsonins: complement C3b, IgG, IgM
What molecular compounds that neutrophils have allow them to opsonize bacteria in the recognition and attachment stage of phagocytosis?
Receptors for the IgG Fc (constant region) fragment and for C3b
What sort of bacteria is opsonization a critical part of phagocytosis for?
Encapsulated bacteria
cWhat effect do bacterial capsules have on phagocytosis?
Capsules decrease ability of neutrophils to phagocytose bacteria
What compounds are key to immunity against encapsulated bacteria?
Antibodies and complement
Describe the engulfment stage of phagocytosis
Neutrophils ingest bacteria by invagination of the cell membrane around the bacteria to form a vacuole (phagosome)
Describe the destruction phase of phagocytosis
Phagosomes containing bacteria merge with lysosomes (containing myeloperoxidase, lysozyme, and other degradative enzymes) to form phagolysosomes, where killing occurs
Is oxygen-dependent killing or oxygen-independent killing more effective?
Oxygen-dependent
What occurs in oxygen-dependent killing by neutrophils?
- In the respiratory burst, NADPH oxidase forms the superoxide radical
- Superoxide dismutase forms hydrogen peroxide
- Myeloperoxidase in neutrophils catalyzes production of hypochlorite io
Which sort of bacteria is hydrogen peroxide not effective against?
Catalase-producing organisms (staphylococci)
What is the most effective mediator of the pathogen destruction?
Hypochlorite ion
Describe oxygen-independent killing
Involves other numerous enzymes and is not as effective as oxygen-dependent killing
Describe the resolution phase of phagocytosis
Neutrophils undergo rapid apoptosis after the inflammatory stimulus is removed
What is the cause of chronic granulomatous disease?
What do patients suffer from?
Caused by a defect in NAPDH oxidase and failure to produce hydrogen peroxide and kill bacteria
Patients have recurrent infections from catalase-producing organisms
What causes Chediak-Higashi syndrome?
What are its symptoms?
Caused by failure to form phagolysosomes
Leads to neutropenia, giant granules in the neutrophils and monocytes, albinism, and increased risk of pyogenic infections
What may occur if a patient has low numbers or suppressed neutrophils and monocytes/macrophages?
Patient may not show the same signs and symptoms of infection with pathogens as quickly as someone that has an intact immune system, masking a serious illness
What processes does inflammation resolution involve?
- Some tissues can regenerate
- Macrophages release anti-inflammatory TGF-beta
- Macrophages recruit fibroblasts and release vascularization factors (granulation tissue)
- If tissue architecture is lost, fibroblasts deposit collagen and ECM to form scars
What are the two types of healing of cutaneous wounds?
- Healing by first intention (primary union)
- Healing by second intention (secondary union)
When does healing by first intention (primary union) occur?
When the injury involves only the epithelial layer and the wound edges are approximated (i.e. clean surgical incision approximated by sutures)
What is the principal mechanism of repair in healing by first intention?
Epithelial regeneration
What are the stages of repair in healing by first intention?
- Hemorrhage and formation of a blood clot
- Acute inflammation
- Proliferation of the epithelial cells
- Organization of the wound
- A scar composed of connective tissue w/ scant inflammatory cells
What occurs in the first stage of healing by first intention?
Hemorrhage and formation of a blood clot involving activation of the coagulation cascade, platelets, and fibrin
What occurs in the second stage of healing by first intention?
Acute inflamamtion occurs initially with neutrophils and then macrophages (24-48) hours
The tissue is edematous with increased fluid and necrotic debris
Dehydration of the external surface of the clot and the overlying necrotic material forms a scab over the wound
What occurs in the third stage of healing by first intention?
Proliferation of the epithelial cells where the basal cells at the edge of the epidermis proliferate and migrate along the dermis
The epithelial cells meet in the middle to close the wound and form and intact layer under the scab
Neutrophils regress and granulation tissue invades the wound space with macrophages, fibroblasts, and new blood vessels
What occurs in the fourth stage of healing by first intention?
Organization of the wound occurs over weeks to months and involves collagen accumulation and fibroblast proliferation with decreased inflammation and regression of the vessels
What occurs in the fifth stage of healing by first intention?
A scar composed of connective tissue with scant inflammatory cells
The epidermis is fairly normal and dermal appendeges are absent
Maximum strength slowly increases but never reaches the same level as before the wound
When does healing by secondary intention (secondary union) occur?
When tissue loss is extensive and the wound edges cannot be brought together (e.g. ulcer)
What are the similarities and differences between healing by secondary intention to healing by first intention?
In healing by secondary intention,
- The clot is larger
- Inflammation is more intense
- There is more granulation tissue with greater likelihood of complications
- Wound contraction occurs due to myofibroblasts
Which cells are involved in wound contraction in healing by secondary intention?
Myofibroblasts
What is fibrosis?
A similar process to wound healing that occurs in parenchymal organs with excessive deposition of collagen and other extracellular matrix components in the tissue in response to injurious stimuli
What can continued/extensive fibrosis lead to?
Loss of organ function
What is the major cytokine involved in fibrosis?
TGF-beta
Why does a child with leukocyte adhesion deficiency, a defect in integrin (CD18 subunit) have increased peripheral blood neutrophils?
Integrins are required for adhesion of the neutrophils to the endothelium
Without adhesion to endothelium, neutrophils cannot cross the endothelium to exit in peripheral blood and other tissues
The number of neutrophils in peripheral blood will increase because the neutrophils cannot leave the peripheral blood
What is the role of myeloperoxidase in neutrophils?
Myeloperoxidase catalyzes formation of hypochlorite ion, which is the most effective mediator of pathogen destruction
What type of infections occur in patients with neutropenia?
Severe bacterial and fungal infections
Organisms that are typically not harmful or have low virulence can be fatal (opportunistic infections)
The bacterial infections include a wide range of bacteria (such as coagulase negative staph, other Gram positive, and Gram negative bacteria)
Sepsis is a major concern
Fungal infections can be invasive (Candida and Aspergillus) and can also involve the blood
What is the function of prostaglandins?
Mediate vasodilation and icnreased vasculafr permeability, pain, and fever
What do leukotrienes do?
Attrach neutrophils, mediate bronchospasm, and increased vascular permeability
What is the function of the vascular component of inflammation?
Allows fluid, proteins, and cells to reach pathogen or tissue damage
What are the mediators of endothelial cell contraction?
- Prostaglandins
- Leukotrienes
- Bradykinins
- Histamines
- Others
What are the soluble mediators of inflammation?
- Proinflammatory cytokines
- Arachidonic acid products
- Bradykinins
- Histamines
What are the cellular mediators of inflammation?
- Neutrophils and monocytes first
- Then monocytes, lymphocytes, and plasma cells
How do catalase producing organisms such as Staphylococci evade oxygen-dependent destruction?
Catalase breaks down hydrogen peroxide
This decreases the formation of hypochlorite by myeloperoxidase
A 4 yo pt has recurrent infections, currently with Staph aureus pneumonia. Her peripheral blood neutrophil count is low and testing shows neutrophil NADPH oxidase function is normal. Which disease does she likely have?
Chediak-Higashi syndrome
What are antibodies?
Proteins produced by B-cells and plasma cells that are composed of two heavy chains and two light chains
They play a major role in providing protection against infection
Antibody = immunoglobulin
A light chain of an antibody can have which components?
Lambda
Kappa
A heavy chain of an antibody can have which components?
Mu (IgM)
Delta (IgD)
Gamma (IgG)
Alpha (IgA)
Epsilon (IgE)
What two parts do each heavy chain and light chain have?
Constant region
Variable region
Which isotype/cass of antibody is a B cell receptor?
B cell receptor is surface IgM or IgD
Which region of a chain on an antibody determines class/isotype?
Constant region
What is the B cell receptor?
An antibody (IgM and IgD in naive B cells) on the surface of B cells that has a transmembrane domain and is associated with Ig-alpha (CD79a) and Ig-beta (CD79b)
Also has CD19
Describe the specificity of a BCR on a B cell
Each B cell has a BCR specific for one antigen
Which two genes are involved in the VJD recombinase?
RAG1
RAG2
Which segments does a variable region of heavy chain have?
V, J, and D
Which segments does a light chain of a variable region have?
V and J segments
Apart from VDJ recombinase, what are RAG 1 and RAG 2 involved in?
TCR gene rearrangement
Mutations in RAG1 or RAG2 can cause which immune disorder?
SCID
What two types of diversity do B cell receptors have?
Combinatorial diversity
Junctional diversity
What is combinatorial diversity?
Somatic recombination of the V and J gene regions occurs for antibody light chain variable regions and V, D, and J antibody regions for the heavy chain variable regions
Mediated by VDJ recombinase
What are the characteristics of junctional diversity?
- Nucleotides are added and removed during recombination
- Occurs at the joining ends of the gene segments
- Significantly increases diversity of the VDJ and VJ regions
- Known as hypervariable regions
What regions does junctional diversity affect?
Hypervariable regions
Describe the “steps” in isotype determination of an antibody
Isotype of antibody is determined by constant region of heavy chain
- Constant region genes join to variable region genes
- IgM is produced first
- Successful gene rearrangement and protein production leads to B cell development
What are the stages in B cell development with regards to the B cell receptor?
- Pro-B cell has no heavy chains
- Pre-B cell has cytoplasmic mu heavy chains and is pre-BCR, successful gene rearrangement of mu heavy chain
- Immature B cell has IgM surface BCR, successful gene rearrangement of the light chain (kappa or lambda)
- Naive B cell has IgM, IgD surface BCR
How does the pro-B cell to pre-B cell transition occur?
Successful gene rearrangement of the mu heavy chain
How does the pre-B cell to immature B cell transition occur?
Successful gene rearrangement of the light chain (kappa or lambda) which allows for expression of an IgM BCR
What is Bruton’s tyrosine kinase?
A signal transduction protein required for pre-B cells to differentiate to B cells
What causes X-linked agammaglobulinemia?
What does a patient with X-linked agammaglobulinemia experience?
Mutation in Bruton’s tyrosine kinase (cannot go from pre-B cell to immature B cell)
Markedly decreased B cells, low antibodies of all types, no tonsils
What type of infections would patients with X-linked agammaglobulinemia be most susceptible to?
Pyogenic infections
(No antibodies -> decreased opsonization -> trouble w/ extracellular bacteria especially ones with capsules -> get a neutrophil pus-producing response)
What two things are critical for increased antibody affinity for antigen?
- Germinal centers
- CD40L: CD40 interactions
What are the steps of antigen recognition and B cell activation?
- Antibody variable region of the IgM component of the BCR recognizes and binds a specific antigen
- Binding leads to receptor cross-linking in association with Ig-alpha/Ig-beta (CD79a/CD79b) and phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs)
- ITAM phosphorylation triggers downstream signaling pathways
What does binding antigen signal through?
ITAMs
What is CD21 (CR2)?
A complement receptor expressed with CD19 on the B cell surface
How does CD21 serve as a second signal for B cells?
CD21 interacts with the C3d complement component bound to antigen (alternative complement pathway)
Enhances B cell activation ~1000 fold
Where does the B cell migrate after antigen binding?
Why?
Secondary lymphoid tissues
To interact with T cells, antigen-presenting cells, and follicular dendritic cells
What occurs in the germinal center of the lymphoid tissues to antigen activated B cells?
- Rapidly divide
- Antigen-specific B cells express antigenic peptides on MHC class II to CD4+ T helper cells
- Interact with antigen-specific T cells, APCs, and follicular dendritic cells
- Undergo isotype switching, somatic hypermutation, and affinity maturation
How do B7 and CD40 act as a second signal for B cells?
After binding of antigen, B cell upregulates costimulatory molecules (B7 and CD40)
CD40 interacts with CD40L on T cell
B7 interacts with CD28 on T cell
BCR takes up the antigen and expresses protein antigens on MHC class II protein
What does T cell express to provide a second signal?
T cell expresses CD40L which binds to CD40 on the B cell to provide a second signal
(also B7 of B cell which interacts with CD28 of T cell)
Production of which molecules leads to isotype/class switching?
Production of cytokines by the CD4+ T cells in the presence of CD40:CD40L interaction
What signal triggers B-cell isotype switching?
Certain cytokines in the setting of CD40 binding by CD40L
What occurs in B cell isotype switching?
B cells switch the heavy chain constant region from the IgM constant region to a downstream isotype (IgG, IgA, or IgE)
Antigen specificity (VJD) is not altered by isotype switching
Why do B cells undergo isotype switching?
Different antibody isotypes are specialized for different protective responses
Note: isotype switching does not alter antigen binding specificity
What is deleted during B cell isotype switching?
Intervening heavy chain DNA
B cells cannot revert back to expressing IgM antibodies after isotype switching
Describe the succession of isotype switching in B-Cells
Can the order ever change?
IgM -> IgG -> IgA -> IgE
The order can never change; in order to switch isotypes, DNA is deleted (this is irreversible)
What are the functions of follicular dendritic cells?
- Capture complement/antigen complexes on the cell surface
- Present antigen complexes to B cells and allow selection for B cells with higher affinity/avidity antibodies
What does T cell co-stimulation cause B cells to undergo?
What occurs in this process?
Somatic hypermutation in the germinal center
Antibody variable regions are subject to random point mutations (activation-induced cytidine deaminase [AID])
Some of the mutations give rise to higher affinity/avidity antibodies which are selected for by FDCs and T cell interactions
What is affinity maturation?
The process of selection for increased affinity/avidity in B cells in the germinal center
This occurs after B cells have undergone somatic hypermutation in the germinal center
What do B cells undergo in the germinal center?
B cells are antigen-selected
- Antigen-specific B cells interact with antigen-specific CD4+ T cells, antigen-presenting cells, and follicular dendritic cells
- B cells mutate the antibody genes to improve binding to antigen
- B cells that are highly antigen-specific differentiate into plasma cells and memory B cells
In the germinal center, what is the fate of B cells that are highly specific for antigen??
- They differentiate into Antibody-producing plasma cells
- Some may become long-lived memory B cells
Describe the antibodies that plasma cells produce
Antibodies are highly specific for an antigen
This makes sense, because these plasma cells came from the B-cells with the highest affinity for a specific antigen (they were selected in affinity maturation)
What proteins do plasma cells express?
CD38, CD138, and cytoplasmic immunoglobulins
Where is CD19 expressed?
Expressed on B cell surface
Component of BCR
What are CD79a and CD79b?
B cell receptor associated proteins (Ig-alpha, Ig-beta) involved in signal transduction after antigen crosslinking
Their activation leads to phosphorylation of ITAMs to trigger downstream signaling pathways
Where is CD20 expressed?
B cell surface
What is CD21?
CD21 = Complement receptor (CR2)
It binds to the complement component C3d (on the antigen) when the antigen binds to the antibody on the B-cell.
This dramatically enhances the B-cell response
What is CD40?
CCD40 is a co-stimulatory molecule expressed on B cell surface. It binds to CD40L on helper T cells to provide a second signal to B cells.
Critical for class switching, affinity maturation, and differentiation
Where are CD38 and CD138 expressed?
Plasma cell surface
On an individual naive B cell expressing both IgM and IgD surface antibody, which regions of the surface IgM antibodies are identical to the surface IgD antibody?
Variable regions of both heavy and light chains are identical between the IgM and IgD antibody
B cells only express one heavy chain variable region and one light chain variable region, even when the constant regions differ
On an individual naive B cell expressing both IgM and IgD surface antibody…
which regions of the surface IgM antibodies are different from the surface IgD antibody?
The constant region of the heavy chain
IgM has a Mu heavy chain
IgD has a Delta heavy chain
What is the role of follicular dendritic cells in the adaptive immune response?
FDCs are present in the germinal center and trap complement/antigen complexes on their surface to present to B cells
B cells recognize and bind to the antigen on the surface of FDC
FDCs select for the B cells with antibodies on their surface (BCRs) that bind with high affinity/avidity to the antigen on the surface of the FDCs
Can class switching occur in the absence of T cells?
Why?
Yes, but it is very limited
T cells express CD40L, which binds to CD40 on B cells. This is critical in the formation of an effective germinal center response which gives rise to isotype switching and somatic hypermutation
What might happen if the immune system cannot recognize “self” component?
Autoimmunity
What might happen if the immune system fails to recognize “non-self”?
No protection from infection
What is humoral immunity?
What does it protect us from?
What mediates it?
Part of adaptive immunity
- Antibody-mediated
- Protects us from extracellular bacteria, viruses, toxins
- Mediated by B-cells and plasma cells
What are the roles of B-cells and plasma cells in adaptive immunity?
Mediate humoral immunity
- Neutralize toxins and viruses
- Opsonize pathogens
- Makes them tastier to macrophages :)
What is cell-mediated immunity?
What does it protect us from?
What mediates it?
- The cell-mediated arm of adaptive immunity
- Protects us from intracellular bacteria, viruses, fungi, parasites
- Mediated by T-cells and macrophages
What are the roles of T-cells and macrophages in adaptive immunity?
Mediate cell-mediated immunity
- Directly kill virus-infected cells
Which immune cells would respond to the presence of a bacterial polysaccharide capsule in the body?
B-Cells; B-cell receptors can recognize and respond to almost anything, including proteins, carbohydrates, drugs, etc.
(T-cells can only recognize peptides in the context of MHC)
What is the difference between an antibody and a B-cell receptor?
- An antibody is secreted by B-cells
- A B-cell receptor remains attached to the B-cell membrane
Antibodies and B-cells have similar structures and can bind similar molecules
T-Cell independent immune response
- Which type of immunity?
- What mediates it?
- What does it do?
T-Cell independent immune response
- Highly specific, humoral (antibody-mediated) arm of adaptive immunity
- Mediated by B-cells
- Produces IgM in response to multivalent non-proteins (ex: polysaccharide capsule)
What kinds of molecules would activate the T-cell independent response?
Multivalent non-proteins
Example: polysaccharide capsule, other non-protein non-self molecules
Antibody-driven immune response
- Which type of immunity?
- What mediates it?
- What does it do?
Antibody-driven immune response
- Highly specific, humoral arm of adaptive immunity
- Mediated by CD 4+ helper T-cells and B-Cells
- MHC II presents peptides to CD4+ helper T-cells
- The helper T-cells help out by secreting molecules that activate B-cells to produce antibodies
- The antibodies activate CD8+ cytotoxic T-cells to attack and destroy virus-infected cells
What is the difference between an immunogen and an antigen?
- An antigen is any molecule that reacts with an antibody
- Almost anything can react with an antibody
- An immunogen is any molecule that induces an immune response
- Not all antigens are immunogens
What do antibodies do?
- Neutralize toxins and viruses
- Opsonize bacteria (enhance phagocytosis)
What kinds of molecules will T-Cell receptors recognize?
T-cell receptors (TCRs) will ony recognize proteins
All T-cells require the activation of the TCR and co-receptor: CD4+ and CD 8+ co-receptors only recognize linear peptides presented by MHC
- CD4+ Helper T-cells recognize peptides presented by MHC II
- CD8+ Cytotoxic T-cells recognize peptides presented by MHC I
Which cells express MHC Class I?
All nucleated cells in the human body have MHC class I and can present antigen to CD8+ Cytotoxic T-Cells
Which cells express MHC class II?
Professional antigen-presenting cells have MHC class II. They present antigen to CD4+ Helper T-cells
In the most general sense, what is required for B-cell and T-cell activation?
2 signals
- Recognition of antigen
- Costimulatory signal
In general, what is required for B-cell activation?
2 signals
- Antigen recognition by a surface antibody (B-cell receptor)
- From T cells through…
a) Costimulatory molecules in T-cell dependent immune response
b) complement in T-cell indepenent immune response
In general, what is required for CD4+ Helper T-cell activation?
2 signals
- TCR and co-receptor CD4 recognize and bind the peptide bound to MHC II on the APC
- The APC also expresses B7, a protein that binds to CD28 on the T-cell
Activation -> Cytokine production
In general, what is required for CD8+ cytotoxic T-cell activation?
2 signals
- TCR and coreceptor CD8 recognize and bind to the peptide bound to MHC I, presented by an APC
- Cytokines secreted from CD4+ cells
How do CD8+ Cytotoxic T-cells kill their prey?
2 methods
- Production of cytotoxic molecules like perforin or granzyme
- Expresion of FasL (induces apoptosis when binding to the Fas protein)
Which cytokine promotes T-cells growth and differentiation?
IL-2
List the physical and physiological barriers that prevent infection
- Skin and mucous membranes
- Ciliated cells in the respiratory tract
- Enzymes in saliva, other secretions
- Low pH of skin and mucous
- Defensins in GI tract and respiratory tract
- Normal fluid flow
- Normal flora
What physical/physiological barriers protect against bacterial infection in the respiratory tract?
Ciliated cells (The ciliary elevator)
Beta-defensin
What might cause damage to the ciliary elevator?
Alcohol, cigarettes, viral infections
Why are individuals with heart valve defects more susceptible to infection?
Stagnant fluid allows for infection by bacteria
(normally, fluid flow prevents colonization and infection)
Why are patients with extensive burns at increased risk of infection?
Skin is the first line of defense against invasion by pathogens
Multiple holes/defects in this defense leave the body susceptible to infection
How do normal flora protect us from infection by harmful bacteria?
Normal flora prevent pathogen invasion
Nobody really knows exactly how this works, but it it hypothesized that the normal flora occupies receptors that could be used by a pathogen to enter the body
Note: Normal flora in the wrong palce can be pathogenic
Which complement protein first recognizes antigen-antibody complexes in the classic pathway?
C1
(C1 = the #1 antigen-antibody recognizing protein)
Which complement proteins trigger mast cells to degranulate and release histamine?
C3a, C5a
Which complement protein is chemotactic to neutrophils?
What does this mean?
C5a
Chemotactic = ~attractive~
C5a recruits neutrophils
Which complement protein opsonizes bacteria?
C3b
Which complement proteins form the membrane attack complex?
C5a, C6, C7, C8, C9
-> Direct microbe killing
Which complement proteins inhibit the formation of C3 convertase?
C1 esterase inhibitor
Decay accelarating factor (CD55)
What is a PAMP?
PAMP = Pathogen-associated molecular pattern
Not present on eukaryotic cells
Basically, a PAMP is the pattern that the innate immune system uses to recognize non-self and initiate an immune response
What is the pattern on pathogens that cells of our innate immune system recognize?
PAMPs (pathogen-associated molecular patterns)
What components of our immune system recognize extracellular pathogenic patterns?
Toll-Like Receptors (TLRs)
Mannose Receptors
- What are TLRs?
- Where are they found?
- What do they do?
- TLRs = Toll Like Receptors
- A family of 10 receptors - TLRs are found on the surfaces of macrophages, dendritic cells, mast cells, and B cells
- Cells that help connect the innate and adaptive immune systems - TLRs recognize microbial components (like PAMPs) and initiate the synthesis of cytokines
What is TLR4?
What does it do?
TLR4 = Toll-like receptor 4
Recognizes LPS on the surface of gram negative bacteria
(Works together with CD14 expressed by monocytes and macrophages to recognize LPS)
Which receptors participate in the recognition of LPS?
TLR 4
CD14
Both are expressed by monocytes and macrophages
- What are Mannose receptors?
- Where are they found?
- What do they do?
- Mannose receptors recognize mannose, a polysaccharide commonly found on the surface of bacterial and yeast cells
- Mannose receptors are found on the surfaces of dendritic cells and macrophages
- When the mannose receptor binds mannose on the bacterial cell, it induces phagocytosis
What components of our immune system recognize intracellular pathogens?
NOD receptors
RIG-1 helicase
- What are NOD receptors?
- Where are they found?
- What do they do?
- NOD receptors are pattern-recognition receptors that regognize pathogens within our cells
- In the cytosol of immune-competent cells
- NOD receptors recognize peptidoglycan
- What is RIG-1 helicaase
- Where is it found?
- What does it do?
- RIG-1 helicase is a pattern recognition protein that recognizes intracellular pathogens
- RIG-1 helicase is found in cytoplasm of immune-competent cells
- RIG-1 helicase recognizes nucleic acids of viruses
Which receptor is especially important in fighting a listeria infection in our bodies?
NOD receptors
Listeria is an intracellular pathogen; NOD receptors in the cytoplasm of immune-competent cells can recognize the pathogen and help mount an immune response
Which cytokine recruits neutrophils?
IL-8
A pro-inflammatory cytokine
Which cells link innate and adaptive immunity?
Antigen presenting cells (APCs): Macrophages and dendritic cells
How do antigen-presenting cells connect adaptive and innate immunity?
Innate
- APCs use pattern recognition to recognize pathogens
Link
- APCs digest pathogens and turn them into antigens that they present to T-cells
- APS produce cytokines that activate the adaptive immune response of T-Cells, B-Cells, and plasms cells
Adaptive
- activated T-Cells, B-Cells, and plasma cells carry out the adaptive immune response
Pattern recognition is part of the innate immune response.
Why then, do cells of the adaptive immune response also express TLRs?
TLRs are used to recognize patterns of invader cells; pattern recognition is the driver of the innate immune system
Macrophages are the mediators of the adaptive immune response, but they are also important for connecting the innate and adaptive immune systems
They use TLRs to recognize patterns of invader pathogens so they can initate the adaptive immune response
Define inflammation
The body’s response to infection or tissue necrosis.
Inflammation allows inflammatory cells, plasma proteins, and fluid to enter the interstitial space.
Inflammation can cause extensive damage to our tissues.
Why then, does our body produce an inflammatory response?
The goal of inflammation is to eliminate pathogens and clear debris.
The process is not easy on our body, but failure to eliminate pathogens can lead to disease progression and death
Which mediators of inflammation mediate pain?
Prostaglandins
Bradykinin
What mediates a pyogenic response of our immune system?
Pyogenic (pus-forming) immune responses are due to the action of neutrophils, antibodies, and complement during accute inflammation.
Often triggered by extracellular pathogens
What is a giant cell?
Where can we find them?
A giant cell is a large macrophage with multiple nuclei
We typically find them surrounding granulomas
What kinds of pathogens are often associated with chronic inflammation?
Intracellular pathogens
Often triggers granulomatous response mediated by macrophages, CD4+ (helper) T cells
Which mediators of inflammation promote mediate vasodilation?
Prostaglandins
Bradykinins
Histamines
Which mediators of inflammation increase vascular permeability?
Prostaglandins
Leukotreines
Bradykinins
Histamines
Which interleukins are pyrogenic?
Pyrogenic = causes fever
IL-1, IL-6
In phagocytic cell recruitment and migration, what molecules direct neutrophils to the site of inflammation?
IL-8, C5a
These molecules are chemokines; they are chemotactic for neutrophils
This occurs after diapedesis (neutrophil escape from the blood vessel), when the neutrophil is in the tissue
Which cytokine increases cyclooxygenase?
TNF-alpha
What are the steps of phagocytic cell recruitment and migration into sites of inflammation?
- Margination
- Rolling
- Adhesion
- Diapedesis and Chemotaxis
Describe the margination step of phagocytic cell recruitment and migration
Margination includes…
- Vasodilation
- Increased vascular permeability
- Slowing of blood flow
- White blood cells moving to the periphery of flow
Describe the rolling step of phagocytic cell recruitment and migration
Sialyl Lewis X on neutrophils binds to P-selectin and E-selectin. This causes the neutrophil to roll slowly along the endothelium
Sialyl Lewis X is expressed constituitively on neutrophils
P-selectin and E selectin are induced by histamine, IL-1, and TNF-alpha
What is Sialyl Lewis X?
What process is it involved in?
Sialyl Lewis X is a protein expressed constituitively on the surface of neutrophils
It binds to P-selectin in E-selectin in the “rolling” step of phagocytic cell recruitment and migration
Which molecules induce P-selectin and E-selectin?
Where are P-selectin and E-selectin expressed?
Why is this important?
Histamine, IL-1, and TNF-alpha induce P-selectin and E-selectin expression on the inner walls of blood vessel endothelium
They are induced in response to inflammation; they are important in the rolling step of phagocytic cell recruitment and migration. Without P-selectin and E-selectin, neutrophils cannot reach the site of inflammation
Describe the adhesion step of phagocytic cell recruitment and migration
Integrins expressed on neutrophils bind to ICAM and VCAM, causing firm adhesion of the neutrophil to the endothelium
- Integrin expression is induced by C5a and leukotrine
- ICAM and VCAM are cellular adhesion molecules induced by TNF-alpha and IL-1
Which molecules induce integrin expression on neutrophils?
Why is this important?
C5a, leukotrine
Integrins are important because they bind to ICAM and VCAM in the ahesion step of phagocytic cell recruitment and migration.
Without integrins (and C5a and leukotrine), neutrophils would not be able to reach the site of inflammation
Which molecules induce ICAM and VCAM?
Where are ICAM and VCAM expressed?
Why is this important?
ICAM and VCAM are induced by TNF-alpha and IL-1
ICAM and VCAM are cellular adhesion molecules expressed on the inner endothelium of blood vessels
ICAM and VCAM bind to integrins on neutrophils in the adhesion step of phagocytic cell recruitment and migration; without ICAM and VCAM, neutrophils would not reach the site of inflammation
Describe the diapedesis and chemotaxis step of phagocytic cell recruitment and migration
Diapedesis = neutrophil migrates through endothelium to escape from the blood vessel
Chemotaxis = neutrophil migrates through tissue toward chemokines IL-8 and C5a
S. pyogenes secretes C5a peptidase
Describe the effect of C5a peptidase on phagocytic cell recruitment and migration
C5a peptidase destroys C5a, which is a chemokine for neutrophils
Without C5a, neutrophils chemotaxis will be decreased; they won’t be able to effectively move toward the site of inflammation
A patient has had multiple, recurrent bacterial infections without appropriate pus formation.
What might be the problem?
What evidence would support your diagnosis?
This patient might have Leukocyte Adhesion Deficeincy (LAD), due to a defect in the CD18 subunit of integrins. As a result, neutrophils cannot escape from blood vessels to get ot the tissue (Neutrophils can’t adhere to endothelium = they can’t undergo diapedesis)
Normal to high neutrophil count in the peripheral blood would support your diagnosis
A defect in the CD18 subunit if integrins causes…
Leukocyt adhesion deficiency (LAD)
Neutrophils can’t adhere to the endothelium, which means they cannot migrate to the site of inflammation
A defect in NADPH oxidase leads to…
Chronic granulomatous disease
- Defective NADPH oxidase
- -> Failure to produce hydrogen peroxide
- -> Cannot make hypochlorite ion
- Cannot kill bacteria effectively
- -> Cannot make hypochlorite ion
- -> Failure to produce hydrogen peroxide
What destructive enzymes are contained in the lysosome?
Myeloperoxidase
Lysozyme
Other degradative enzymes
A patient has a history of recurrent infections from catalase (+) bacteria with the formaiton of multiple granulomas
What might be the problem?
Chronic granulomatous disease;
A defect in NADPH oxidase results in downstream failure to produce the hypochlorite ion from hydrogen peroxide;
Hydrogen peroxide alone is not effective at killing catalase (+) bacteria, because these bacteria can break down hydrogen peroxide.
Which inherited immune disorder prevents the formation of phagolysosomes?
What is the clinical presentation?
Chediak-higashi syndrome; a defect of organelle trafficking
The patient may also have:
- Neutropenia
- Giant granules in neutrophils and monocytes
- Albinism
- Increased risk of pyogenic and opportunistic infection
How might chronic inflammation cause cancer?
- Chronic inflammation means chronic complement activation
- This causes activated neutrophils to release free oxygen radicals in a nonspecific manner
- This is great for killing bacteria, but not great for our cells
- Persistent exposure to free oxygen radicals can cause cell proliferation and DNA damage
- This increases the risk of dysplastic or neoplastic changes in tissue
What type of infections occur in patients with neutropenia?
Neutropenia = fewer neutrophils than normal. The body is misisng the “first responders” to infection, which can result in more innocuous organisms taking hold and causing disease
- Infection by opportunistic pathogens
- Bacterial and fungal infections
- Even organisms with typically low virulence can cause disease
- Example: catalase (-) organisms
- Fungal infections may be invasive
- Increased risk for sepsis
What conditions might result in weakened accute inflammation?
Any condition that prevents an adequate number of neutrophils from reaching the site of infection/injury
Examples:
- Neutropenia (Chediak-higashi syndrome, chemotherapy)
- Failure of neutrophils to migrate to the site of infection (Leukocyte Adhesion deficiency)
What two chains are present in an antibody?
Heavy chain
Light chain
Which chain and region of an antibody determines the isotype?
Heavy chain constant region
What are the possibilities for the constant region of a heavy chain?
- Mu (IgM)
- Delta (IgD)
- Gamma (IgG)
- Alpha (IgA)
- Epsilon (IgE)
What are the possibilities for the constant region of a light chain?
- Kappa
- Lambda
What is light chain restriction?
All antibodies on a B cell must be either all kappa or all lambda
Cannot have two different light chains expressed on B cell or plasma cell
(light chain can be used to identify clonal B cells)
What does the Fc portion of an antibody for?
Fragment, crystallizable
Where is the complement binding region (IgM and IgG) of an antibody found?
Fc portion
When does the complement binding region become accessible?
Why?
When antigen binds
Only want complement active when immune response is necessary
What are the two parts of the Fc region of an antibody?
Complement binding region
Phagocyte binding region
What region does the Fc portion of the antibody contain?
Constant region
What sorts of cells have receptors that bind the Fc portion of antibodies?
Phagocytes
What are the two main functions of the Fc portion of an antibody?
- Enhances phagocytosis (opsonization)
- Mediates many effector functions
What does the Fab portion of an antibody stand for?
Fragment, antigen-binding
What two regions does the Fab portion of an antibody contain?
- Variable regions
- Complementarity-determining regions (CDRs)
Each B cell makes an antibody with a ____ variable region that binds to ____ antigen(s)
Each B cell makes an antibody with a unique variable region that binds to one antigen
What are the main points about the T cell dependent immune response?
- Surface IgM BCR recognizes a protein antigen
- B cells express peptides on MHC class II
- T cell-B cell interaction of CD40/CD40L leads to germinal center formation, class switching, and somatic hypermutation
- Antibodies produced are of high affinity
In the T cell dependent immune response, surface ____ BCR recognizes _____
In the T cell dependent immune response, surface IgM BCR recognizes a protein antigen
In the T cell dependent immune response, B cells express _____ on _____
In the T cell dependent immune response, B cells express peptides on MHC class II
In the T cell dependent immune response, T cell-B cell interaction of ___ leads to ___, _____, and _____
In the T cell dependent immune response, T cell-B cell interaction of CD40/CD40L leads to germinal center formation, class switching, and somatic hypermutation
In the T cell dependent immune response, antibodies produced have ____ affinity
In the T cell dependent immune response, antibodies produced have high affinity
What are the main points about the T cell independent immune response?
- B cells recognize a non-protein antigen (e.g. polysaccharide cell wall) which can crosslink surface IgM and activate the B cell
- Antigens often have repeated identical antigenic epitopes that cause crosslinking of the BCR complex
- This leads to production of secreted IgM (sometimes IgG and IgA) which is specific for the antigen
- Complement (through CD21) and TLR are involved in B cell activation
- Affinity generally lower
- Splenic B cells (marginal zone) and mucosal B cells (B1) are involved
In the T cell independent immune response, B cells recognize _____ antigen (e.g. polysaccharide cell wall) which can crosslink surface _____ and active the _____ cell
In the T cell independent immune response, B cells recognize a non-protein antigen (e.g. polysaccharide cell wall) which can crosslink surface IgM and activate the B cell
In the T cell independent immune response, antigens often have _____ ______ antigenic epitopes that causes crosslinking of the BCR complex
In the T cell independent immune response, TI antigens often have repeated identical antigenic epitopes that causes crosslinking of the BCR complex
In the T cell independent immune response, ____ (sometimes IgG and IgA) that is ____ for the antigen is secreted
In the T cell independent immune response, IgM (sometimes IgG and IgA) that is specific for the antigen is secreted
In the T cell independent antigen response, ____ (through CD21) and ___ are involved in B cell activation
In the T cell independent antigen response, complement (through CD21) and TLR are involved in B cell activation
In the T cell independent antigen response, antibodies have ____ affinity
In the T cell independent antigen response, antibodies have lower affinity
_____ B cells (marginal zone B cells) and ____ B cells (B1 B cells are involved in the T cell independent antigen response
Splenic B cells (marginal zone B cells) and mucosal B cells (B1 B cells) are involved in the T1 antigen response
Compare and contrast the T cell dependent and T cell independent responses in terms of chemical nature, isotype switching, affinity maturation, memory, and location
What is the chemical nature of the antigen for the T cell dependent immune response?
Protein
What is the chemical nature of the antigen for the T cell independent immune response?
Repetitive polymeric antigen (polysaccharide, glycolipid)
Describe isotype switching in T cell dependent immune response
IgG, IgE, and IgA
Describe isotype switching in T cell independent immune response
Limited (some IgG and IgA)
Does affinity maturation occur in the T cell dependent immune response?
Yes
Does affinity maturation occur in the T cell independent immune response?
No
Is there memory in the T cell dependent immune response?
Yes
Is there memory in the T cell independent immune response?
Limited
Where does the T cell dependent immune response occur?
Germinal center
Where does the T cell independent immune response occur?
Splenic marginal zone and mucosal regions
What are natural antibodies?
Some antibodies (namely IgM) present prior to exposure
What sort of response to natural antibodies promote? To what antigens?
T cell independent B cell response to environmental antigens
What is notable about cross-reactivity with regards to natural antibodies?
Some degree of cross-reactivity between similar antigen
What is the most clinically significant example of natural antibodies?
Natural antibodies against ABO glycoproteins on patient’s RBCs that lack the A or B antigen
Antibodies present w/o prior exposure to foreign RBCs
An 82 yo male comes in to get a pneumoccocal vaccination. You explain he needs the vaccine that contains the diphtheria toxoid attached to pneumoccocal polysaccharide capsule (PCV13). For an effective antibody immune response to the capsule, what is essential?
Helper T cells recognize the diphtheria toxoid
There are ____ receptors on neutrophils that bind the IgG ___ portion
There are IgG receptors on neutrophils that bind the IgG Fc portion
A 3 yo boy has had multiple recurrent bacterial infections (pneumonia and ear infections) and diagnostic studies show his T cells do not express CD40L after activation. What finding would you expect upon evaluation of serum immunoglobulins?
Increased IgM and decreased IgG and IgA (hyper IgM syndrome)
What class of antibody is most effective at blocking bacteria from attaching to the mucosa in the stomach?
IgA antibodies
How can an effective vaccine be developed against a hapten (a molecule that does not elicit an immune response)?
Attaching a hapten to a protein will drive a B and T cell immune response, leading to the development of antibodies against the hapten
What is an example of an antigen that can induce a T cell independent immune response?
Polysaccharide capsule vaccine against pneumococcus (Pneumovax 23)
What three types of cells does the T cell dependent immune response involve?
- Antigen presenting cells (presenting antigen and producing cytokines)
- CD4+ helper T cells
- B cells
Which cell type does the T cell independent immune response involve?
B cells
Describe the antibody response to a T cell independent antigen in the marginal zone or mucosa
- Naive B cells (marginal zone, mucosal) recognize antigen through IgM BCR
- Co-stimulation occurs through complement receptors (CD21) and/or TLRs
- Antigen-specific B cells differentiate to short-lived plasma cells and produce predominantly IgM
- Limited isotype switch can occur (IgG, IgA)
- No effective affinity maturation
- Limited memory
Where are the naive B cells located that are involved in the antibody response to a T cell independent antigen?
- Marginal zone
- Mucosa
In the antibody response to a T cell independent antigen, naive B cells (marginal zone, mucosal) recognize _____ through ____ BCR
In the T cell indendent immune response, naive B cells (marginal zone, mucosal) recognize antigen through the IgM BCR
In the antibody response to a T cell independent antigen, ____ occurs through ____ (e.g. CD21) and/or ____
In the antibody response to a T cell indepdent antigen, co-stimulation occurs through complement receptors (e.g. CD21) and/or TLRs
In the antibody response to a T cell independent antigen, antigen-specific B cells differentiate to short-lived ____ cells and produce predominantly ____
In the antibody response to a T cell independent antigen, antigen-specific B cells differentiate to short-lived plasma cells and produce predominantly IgM
In the antibody response to a T cell independent antigen, there is ____ isotype switching (IgG, IgA), _____ affinity maturation, _____ memory
In the antibody response to T cell independent antigen, there is limited isotype switching (IgG, IgA), no effective affinity maturation, and limited memory
Describe the steps of the antibody response to a T cell depdent antigen for naive B cells outside of the germinal centers
- Recognize antigen through IgM BCR
- Internalize antigen on the IgM
- Degrade antigen to peptides to present on MHC class II
- Express CD40 and B7 (CD80/86)
- Can receive additional signals from complement, TLR, CD4+ T cells, and/or cytokines
- After binding antigen and activation, B cells migrate towards B cell-T cell zone border (secondary lymphoid tissues)
Where are the naive B cells in a T cell dependent antigen response located?
Outside of the germinal centers
In the antibody response to a T cell dependent antigen, naive B cells recognize ____ through the ____ BCR
In the antibody response to a T cell dependent antigen, naive B cells recognize antigen through the IgM BCR
In the antibody response to a T cell dependent antigen, naive B cells ____ the antigen on the IgM
In the antibody response to a T cell dependent antigen, naive B cells internalize the antigen on the IgM
In the antibody response to a T cell dependent antigen, naive B cells degrade antigen to peptides to present on ________
In the antibody response to a T cell dependent antigen, naive B cells degrade antigen to peptides to present on MHC class II
In the antibody response to a T cell dependent antigen, naive B cells express _____ and _____
In the antibody response to a T cell dependent antigen, naive B cells express CD40 and B7 (CD80/86)
In the antibody response to a T cell dependent antigen, naive B cells can receive additional signals from _____, _____, _____, and/or ____
In the antibody response to a T cell dependent antigen, naive B cells can receive additional signals from complement, TLR, CD4+ T cells, and/or cytokines
In the antibody response to a T cell dependent antigen, naive B cells migrate _______ (secondary lymphoid tissue) after binding ____ and ____
In the antibody response to a T cell dependent antigen, naive B cells migrate towards B cell-T cell zone border (secondary lymphoid tissue) after binding antigen and activartion
Diagram the steps in T cell development
What tissue is this?
What are the correct labels for the two arrows?
Thymus
What type of hypersensitivity is this?
How do you know?
Type IV hypersensitivity
This is predominantly a lymphocyte response (type IV hypersensitivity is cell-mediated)
Describe the basic structure of the T-cell receptor
- Alpha-beta heterodimer (except a small subset of gamma-delta)
- Alpha-chain undergoes VJ gene recombination during maturation
- Beta-chain undergoes VDG gene recombination during maturation
- No class-switching
- Antigen recognition region is variable between T-cells
- But remains the same for the life of the T-cell
- ITAMs mediate signaling from TCR to rest of cell
- Expresses CD3
