I&I humoral immune system Flashcards
What antibodies to mature B cells express?
Mature naïve B cells express a membrane-bound IgM and IgD
What do membrane IgM act as?
Membrane IgM acts as B cell Ag receptor (B cell receptor/BCR)
What are the steps in B cell activation with IgM?
Ag recognition by membrane IgM => activation of signalling
pathways => B cell activation
What is IgD co-expressed with?
IgD is co-expressed with IgM on mature naïve B cells
What is the 1st immunoglobulin to be produced?
IgM is the 1st immunoglobulin to be produced; Ag receptor
What is IgD produced at the same time as?
IgD is produced at the same time with IgM
What is the mechanism by which allows co-expression of IgM and IgD?
-Differential splicing
–Exons for Cμ and Cδ are transcribed as part of a single
precursor RNA
–Differential splicing can remove Cμ exons => now Cδ exons are
used => IgD (same VDJ as IgM joined to Cδ)
Where are follicular B cells found?
Spleen, lymph nodes
What do follicular B cells recognise?
recognise protein antigens => antibodies (anti-protein Ag)
What do follicular B cells produce?
produce mainly high-affinity IgG class/switched antibodies
Where are marginal zone B cells?
Spleen and lymph node
What do marginal zone B cells recognise?
recognise polysaccharide; glycolipid; nucleic acid antigens
What antibodies to marginal zone B cells produce?
produce mainly IgM class antibodies
Where are B-1 B cells found?
Peritoneal cavity
Mucosal tissue
What do B-1 B cells recognise?
recognise polysaccharide; glycolipid; nucleic acid antigens
What do B-1 B cells produce?
produce mainly natural low-affinity IgM class antibodies
What signals do B cells need in order to produce antibodies?
-helper T cell dependent B cell responses
-helper T cell dependent antibodies
What do B cells produce mainly?
produce mainly high-affinity IgG class/switched antibodies
How are B cell zone/follicles and T cell zone connected?
-Linked recognition
-Sustained contact by SLAM family
-Receptors and cytokines for B cell activation
What must B cells and Helper T cells recognise in order to interact?
B cells and Helper T cells must recognise epitopes of the same molecular complex in order to interact
What are the steps involved in B cell proligeration and differentiation?
- Naive B cells travel to the lymph node via the bloodstream and leave via the efferent lymph
- B cells that encounter antigen in the follicle form a primary focus. Some proliferating B cells migrate into the follicle to form a germinal center
- Plasma cells that migrate to the medullary cords or leave via the efferent lymphatics
- Plasma cells migrate to the bone marrow
What happens to B cells in the germinal centre?
Sustained B cell proliferation and differentiation.
What happens in size to the germinal centre with an immune response and once the infection clears?
Grows in size with immune response,
disappears when infection cleared
What B cell survives in the germinal centre?
Survival of B cell that has a high affinity for the
antigen
What is the goal of affinity maturation?
Production of high affinity antibodies = more
efficient
What is the affinity like for antibodies produced early during primary immune response?
Abs produced early during primary (1st) immune response
have lower affinity (weak binding) for antigen
What happens to affinity as you move later in the first immune response/2nd immune response?
Later 1st immune response/ 2nd immune responses =>
production of high affinity antibodies
What process increases affinity of antibodies over the immune response?
Achieved through process of Somatic Hypermutation
What signals are needed for affinity maturation?
Affinity maturation needs signals from helper T cells
What is somatic hypermutation?
Process of introducing mutations in the variable region of
Immunoglobulins (rearranged VDJ/VJ)
What is somatic hypermutation initiated by?
Initiated by enzyme AID expressed in Germinal centre B cells only.
What do higher affinity antibodies do to proliferation of B cells?
Higher affinity antibodies => stronger cell signalling; faster
proliferation of B cells => advantage over low affinity B cells
What is the effect on Ag recognition by somatic hypermutation?
-Somatic mutations in Ig V genes lead to selection of high-affinity B cells
Where is somatic hypermutation localised in?
Somatic hypermutation is localised in rearranged VDJ or
VJ (corresponding to variable region)
What are B cells with high affinity selected for?
B cells with high affinity Ag receptors are selected
to survive
What do B cells with low affinity fail to do?
B cells with low affinity Ag receptors may fail to
survive
Where is competition for Ag recognition and what zone is this?
Competition for Ag recognition on follicular
dendritic cells in the germinal centres ( light zone)
What is there preferential selection of in affinity maturation?
Preferential selection of B cells with high affinity Ag
receptors during immune responses- those that
have successfully presented to TfH cells, and
received survival signals.
What are the steps invovlved in B cell selection in germinal centers?
- B cell activation by protein antigen and helper T cells
- B cells with somatically mutated Ig V genes and Igs with varying affinities for antigen
- B cells encounter antigen on follicular dendritic cells(FDC) and present antigen to TFH cells
- B cells with high affinity antigen receptors preferentially recognise antigen on FDCs, interact with TFH cells and are selected to survive
What type of proteins are antibodies?
Tetrameric proteins
What is the structure of antibodies?
2 identical heavy chains
2 identical light chains
What are the chains in antibodies held together by?
held together by disulphide bonds
What is the structure of heavy chain in antibodies?
- 3-4 constant domains
- 1 Variable domain
What is the structure of light chain in antibodies?
-1 Constant domain
-1 Variable domain
What is the difference in variable domains between different immunoglobulins?
amino acid sequence varies highly
between different immunoglobulins
What domains make up the antigen binding site?
Variable domain of heavy and light chain
What is the function of antibodies?
Binding to extracellular microbes and toxins
-Neutralisation
-Elimination via
–Opsonisation which increases phagocytosis
-Complement activation
–Opsonisation
–Lysis
What is isotype switching?
Its where B cells become capable to produce Abs of different classes but without changing specificity(respond to the same Ag)
In isotype switching, what does IgM switch to?
IgG, IgA, IgE
In isotype switching what does IgG switch to?
IgA, IgE
What does isotype switching in antibodies give the ability to perform?
ability to perform different effector functions
What can isotype switching in antibodies deal better with?
Can deal better with pathogens
What does isotype switch need signals from?
- isotype switch needs signals from helper T cells
What does isotype switching not alter?
-Isotype switching does not alter specificity for Ag
-Isotype switching does not alter the light chain
How do T cells help with Ab isotype switch?
- CD40L on T cell interacts with CD40 on activated B
cells - Cytokines produced by T cell
What does the cytokine IFN-gamma isotype switch to?
=> switch to IgG1, IgG3
What does the cytokine IL-4 isotype switch to?
IL-4 => switch to IgE
What does the cytokine TGF-beta, IL-5 isotype switch to?
TGF-beta, IL-5 => switch to IgA
What are the steps in DNA rearrangement in isotype switching?
- Initiated by AID at switch regions
- Removal of entire intervening DNA
sequences between switch regions - Ligation of the original switch region and
new switch region
What are the steps involved in B cell selection in germinal centers?
- Activation of B cells and migration into germinal center
- B cell proliferation
- Somatic mutation and affinity maturation; isotype switching
- Exit of high affinity antibody-secretinig memory and B cells
What is the effector function of the Fab region of antibodies?
Fab - bind and neutralise/block entry of Ags
What is the effector function of Fc portion of antibodies?
Fc portion- complement activation, interaction with other cells with Fc receptors e.g. macrophages
What are the steps involved in hypervariable regions and antigen binding?
- Amino acid (aa) residues in hypervariable
regions make contact with aa residues in the the
antigen - Binding of diverse antigens by antibodies is
mainly due to hypervariable regions of VH and VL - The rest of the variable region forms a
framework => keeps hypervariable regions in
position to interact with the antigen
What are the steps involved in clonal selection?
- Lymphocyte clones specific for ~10^7-10^9 antigens
- Present before exposure to antigen
- In the presence of Infection, Antigens are
recognised by lymphocyte clone with the specific
antigen receptor for that antigen
=> expansion of antigen-specific clone
=> generation of Abs specific for that Ag only
How many gene segments is the variable region in heavy chain encoded by?
VH encoded in 3 gene segments (V, D, J)
How many gene segments is the variable region in light chain encoded by?
VL encoded in 2 gene segments (V, J)
What does gene segment recombination lead to?
Gene segment recombination => Ab diversity
What is gene segment recombination?
Gene segment recombination = random arrangement
of gene segments in different combinations
When does gene segment rearrangement take place?
Gene segments rearrangements (VDJ/VJ) take place
during B cell development in bone marrow
What is produced after the first successful VDJ rearrangement?
Heavy chain produced
What is produced after the second successful VDJ rearrangement?
Light chain produced
What do mature naive B cells express?
Mature naïve B cells express full IgM/antigen
receptor
In somatic DNA rearrangement what is each segment that needs to be joined flanked by?
Each segment to be joined is flanked by
Recombination signal sequence (RSS)
Where does RAG-1 recombinase cut DNA at?
RAG-1 recombinase cuts DNA at precise
location- endonuclease
What are pseudogenes?
Genes that aren’t functional
What does junctional diversity increase?
increases the number of Ab
generated
How does junctional diversity work?
Introduction and deletion of nucleotides at the
junction between different segments ( ie V, J, D)
