Chapter 10: The Humoral Immune Response Flashcards
What does the NFkB family consist of? Do the Del homology domain have transcriptional activation domains?
- 5 transcription factors P50, p52, RelA(p65), c-Rel, RelB
- Form dimers through RHD
- RelA/p50, c-Rel/p50, RelB/p52
- RelA, c-Rel, RelB contain transcriptional activation domains (TADs)
- p50 and p52 do not have TAD and need to be bound to TAD-containing protein
- They’re all derived from p105 and p100 precursor
- Contain ankyrin repeats (ANK)
- Inhibited by IkB proteins in cytoplasm
What is the canonical/classical pathway? What is the noncanonical pathway?
Canonical
- IKK complex is activated by transforming growth factor-beta-activated kinase 1 (TAK1)
- Activated IKK phosphorylates IkBalpha
- Degraded by proteosome
- Predominant dimer is RelA/p50
Noncanonical
- IKKalpha is activated by NFkB-inducing kinase (NIK)
- Phosphorylates p100
- Undergo processing to p52
- Predominant dimer is RelB/p52
What is humoral immunity? How do antibodies protect (3)?
- Immunity due to proteins in the blood
- Complement and antibodies
- Protects extracellular spaces
- Neutralization
- Opsinization
- Complement activation
How are B cells activated? What are three signals like T cell activation?
- Activation by antigen involves signals from BCR and either helper T cells or microbial antigens
- BCR
- Costimulatory with TCR or microbial antigens
- Cytokines
How does B cell activation by antigen and helper T cells occur?
- Thymus dependent antigen
- Requires T cell help to produce antibodies
- Signaling by BCR is enhanced by co-receptors CD21, CD19 which interact with C3b on opsinized microbial surfaces
- TCR and co-stimulation provides second signal
What causes the transcription factor STAT3 to become activated? What happens?
- IL-21 actives the tf which enhances B cell proliferation and survival
How does a thymus independent antigen activate a B cell?
- Do not require T cells to produce antibodies
- TLR may provide second signal
- Less affinity and less functionally versatile
- Mostly IgM antibodies
- Two types of antigens
What does linked recognition of antigens result in?
- Linked recognition of antigen by T or B cells promotes robust antibody response
- Epitopes recognized by both B and T cells must be physically linked
What happens when a B cell encounter its antigen?
- B Cells that encounter their antigens migrate toward the boundaries between B and T cell areas in secondary lymphoid tissue
How do opsinized antigens entering the lymph nodes reach a Follicular dendritic cell and why do they go there?
- Opsinized antigens enter lymph node form afferent lymphatic vessel and bind are bound by receptors on macrophages. Antigens are then transported to Follicular dendritic cells which allow for the activation of memory and effector B cells
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What do BAFF and APRIL do?
Promote B cell survival and differentiation
How is TFH cell development promoted?
- T cells express surface molecules and Cytokines that activate B cell to promote TFH cell development
- Activated B cells express ICOSL which is ligand for ICOS on T cell
- Signaling through ICOS completes TFH differentiation as it Induces Bcl-6
- Induction of SAP in TFH cells allow SLAM family receptors to mediate sustained contact with B cells
What are plasmablasts and plasma cells?
- Activated B cells that differentiated
- Plasmablasts are immature plasma cells that have the characteristics of activated B cells
- Proliferate, secrete antibodies, interact with T cells. Eventually die or mature into plasma cells and move into bone marrow
- Plasma cells are terminally differentiated effector B cells that secrete the most antibodies
What happens in the second phase of a primary B-cell immune response?
- Occurs when activated B cells migrate into follicles from the primary focus and Proliferate to form germinal centers
What is the mantle zone? What is the dark zone? What is the light zone?
- When germinal centers B cells displace the resting B cells towards the periphery of the follicle forming a mantle zone
- Site of proliferation of centroblasts. Express chemokine receptors CXCR5 and CXCR4
- Site of positive selection of centrocytes after somatic hyper mutation. Express CXCR5 but not CXCR4. Increased expression of BCR. Abundant FDCs for positive selection
What is the cyclic reentry of cells into the dark zone dependent on?
- Reexpression of CXCR4 on centrocytes
What happens to germinal centers B cells in the V region? How are mutations initiated?
- Undergo V region somatic hyper mutation and cells with mutations that improve antigen affinity are selected
- Intiated by the enzyme activation-induced cytidine daminase (AID)
- Expressed in extrafollicular and germinal centers B cells
- Mutation rate in V region is 10^3 vs 10^10 in other DNA regions
- Most mutations are detrimental which leads to apoptosis
- Involves class switching
What does positive selection of germinal centers B cells involve? Where do B cells move after hypermutation? What happens if a receptor has strong affinity? What if it has weak affinity?
- Involves contact with TFH cells and CD40 signaling
- After hyper mutation B cells move to the light zone
- If receptor has strong affinity on FDCs then B cell will internalize antigen and present it on MHC II molecule. TFH will recognize MHC II and will promote the B cells survival
- If receptor has weak affinity, Antigens on FDC cannot outcompete B cells with higher affinity and will die to apoptosis
What happens when when activation induced cytidine deaminase introduces mutations into genes transcribed in B cells?
- Deamination of cytidine results in uridine. Occurs in ssDNA during transcription
- When AID deaminates cytidine residues in the immunoglobulin V region, somatic hyper mutation is initiated
- When cytidine residues in switch regions are deaminated, class switch recombination is initiated
What pathways contribute to somatic hyper mutation after initiation by AID?
- Mismatch and base excision repair pathways
- Triggered by the presence of Uridine in DNA
- In Mismatch repair, DNA synthesis is error prone due to error prone polymerase (Pol n and Pol 0)
What does AID initiating class switching allow for?
Allows the same assembled VH exon to be associated with different Ch genes in the course of an immune response
What must occur in the switch regions?
- Transcription
- Switch region of isotype is determined by specific transcription factors activated by specific chemokines
- Transcription produced is sterile
What do Cytokines made by TH cells direct?
- Direct the choice of isotype for class switching in T dependent antibody response
ex. IL-4 will lead to IgG1 or IgE
What are Tl-1 antigens?
- Antigens that do not require T cell help to induce antibody response
- Helps in early stages of infection
Ex. B cell mitogens, LPS. Activates immature and mature B cells. Do not lead to affinity maturation nor memory B cells
What are TI-2 antigens?
- Highly repetitive structures such as bacterial capsule
- Can only activate mature B cells. Marginal B cells. Infants lack marginal B cells
What are some qualities of TD antigens, Tl-1 antigens, and Tl-2 antigens?
Where do antibodies of different classes operate(distribution) and what are their effector functions (IgM, IgD, IgG1, IgG2, IgG3, IgG4, IgA, IgE)
How are immunoglobulin classes distributed in a pregnant woman?
- IgG and IgM are primarily in blood and both activate compliment
- IgG and monomeric IgA are the major antibodies in extracellular fluid within the body. IgA mainly responsible for neutralization
- Dimeric IgA predominates in secretions across epithelia (breast milk)
- IgE mainly associated with mast cells just beneath epithelial surfaces (resp, gastro, skin)
- Fetus recieves IgG from mother by transplacental transplant
How are IgA and IgM transported across the epithelial layer?
- Polymeric immunoglobulin receptor binds to the Fc region and transports them
What does neonatal Fc receptor do?
- FcRn carries IgG across the placenta and prevents IgG excretion from the body
- Baby can get IgA via breast milk to protect the baby’s gut
What do high affinity IgG and IgA do?
- Neutralize toxins and block infectivity of viruses and bacteria
Outline the steps involved in antibodies blocking adhesins from being uptaken.
- Bacteria binds to surface via adhesins and some is internalized via vesicle and may propagate
- Antibodies are able to block colonization and uptake
What happens when an antigen:antibody complex binds to C1q?
- Activation of the complement pathway
What do complement receptors and Fc receptors contribute to?
- The removal of immune complexes from circulation
What is the purpose of the Fc receptors of accessory cells?
- Signaling receptors for immunoglobulins of different classes
- A variety of Fc receptors can be found on macrophages, neutrophils, eosinophils, platelets, Langerhan cells, mast cells, basophils, and B cells with a variety of effects
How are Fc receptors on macrophages activated and what happens?
- Activated when antibodies bound to surface of pathogens and enable phagocytes to ingest and destroy pathogens
- Can involve C3b and CR1
How do Fc receptors activate NK cells?
- Antibodies bind to antigen surface, Fc receptors on NK cells recognize antibodies and cross linking signal results in target cell dying to apoptosis
Why are mas cells relevant to Fce receptors?
- Mast cells and basophils bind IgE antibody via high affinity Fce receptor
- Antibody is bound to receptor
- Initiate the immune response at epithelial surfaces
- Recruit and promote inflammation
- Play major role in allergies
- Allergens bind to antibodies
- Trigger muscle contraction to help expel parasite
What is histamine?
- Hormone/neural transmitter
- Different receptors found in different cells
- Mechanism of action is dependent on receptor and cell type
What is IgE mediated activation of accessory cells?
- Plays an important role in resistance to parasite infection
Steps:
1. Activated CD4+ results in IgE production
2. Mast cells is activated by toxic proteins
3. Eosinophils are activated resulting in deganulation
4. S IgA produced to kill infection
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