B-Cells Flashcards
what are b-cells and their role?
- b-cells are one of specialized cells of the adaptive immune system
- they produce antibodies for a long range, distant site of infection
what are b-cell receptors (BCRs)?
- b-cell receptors are specialized proteins expressed on the surface of B cells that allow them to recognize and bind to specific antigens
- BCRs are antibodies stuck to the surface of b-cells
what is the structure of b-cell receptors?
- they have “2 arms” (antigen binding domains) and it looks like a Y, but each arm is the exact same
- the arms are composed of surface immunoglobulin (mIgM) bound to the membrane of the b-cell
- it is complexed with Ig⍺ and Igβ chains that contain ITAMS for intracellular signalling
what do b-cell receptors bind to?
- BCRs bind directly to the 3-dimensional (tertiary) structure of an antigen
–> it can be a protein, carbohydrate, lipid, nucleic acid
they do NOT require MHC = broader diversity in what they bind and how they bind
how are lymphocyte receptors so diverse?
- b-cells and t-cells don’t have receptors when they’re first produced
- lymphocyte receptors (TCRs and BCRs) are produced by random rearrangement of their DNA
- this process is celled SOMATIC RECOMBINATION
–> if changes are made to DNA of cells = change in mRNA and protein produced
only occurs in lymphocytes, most cells DNA don’t change
how does the process of somatic combination lead to diversity?
- lymphocyte receptor rearrangement is a RANDOM process which resulting in every individual generating a large and unique TCR and BCR repertoire
–> T-cell diversity takes place in thymus
–> B-cell diversity takes place in bone marrow
what are the components of BCRs?
- BCRs are made up of heavy and light chains composed of variable and constant domains
- heavy chain genes are found on chromosome 14 and contain multiple V, D, J and C exons
- light chain genes only contain V, J and C exons (not D)
- there are 2 types of light chain genes: Kappa (κ) genes and Lambda (ƛ) genes
–> each rearranged BCR expresses either κ or ƛ (never both) - BCR genes are commonly referred to as immunoglobulin (Ig) genes
how does the process of somatic combination work for t-cells and b-cells?
- receptors are encoded by variable (V), diversity (D), joining (J) and constant (C) gene segments
–> heavy chains of BCRs are encoded by V, D, J, and C segments
–> light chains are encoded by V, J and C segments - there are many possible combinations of V(D) and J
- V(D) J recombination randomly selects and joins segments from the V, D, J gene pool and connects to a constant (C) region to form a functional BCR
- lymphocytes do not express functional antigen receptors (BCRs or TCRs) until somatic recombination occurs
- this process occurs early in lymphocyte development
how does genetic polymorphism affect human immunoglobulin genes?
- the number of functional gene segments in human immunoglobulin genes can vary between individuals due to genetic polymorphism.
- this variation can influence the diversity of B-cell receptors (BCRs), which contributes to the individual’s immune response capabilities
what are the key steps to b-cell recombination?
- in the bone marrow, hematopoietic stem cells (HSC) produce pro-b cells that are committed to the b-cell lineage
- the pro-B cells then begin the process of immunoglobulin (Ig) gene recombination to form functional B-cell receptors (BCRs).
- the heavy and light chain genes are rearranged, creating unique antigen-binding sites on the BCR
- pnce the pro-B cell successfully produces a BCR, it expresses IgM (the first type of antibody). The cell is now referred to as an immature B cell
- the b-cell and BCR must pass positive and negative selection before leaving the bone marrow
- after, immature B cell then leaves the bone marrow and migrates to the spleen or lymph nodes to complete its maturation.
what is the process of B-cell receptor selection?
positive and negative selection occurs in the bone marrow
1) positive selection:
- does the BCR bind ligands/antigens? if yes = survive and mature
2) negative selection:
- does the BCR bind self-ligands? if yes = cell tries to fix the receptor through more rearrangement (if can’t fix = delete)
*this process removes self-reactive b-cells
once the BCR has passed both selection processes, it migrates to secondary lymphoid organs for SHM and affinity maturation
what is BCR somatic hypermutation (SHM)?
a physiologic process in which B-cell randomly mutates its immunoglobulin regions to produce an antibodies with greater affinity for a pathogen
- these mutations increase the diversity of the antibody pool, enabling the immune system to adapt better to various antigens.
- this process is mediated by enzymes called AID and UNG
what is affinity maturation?
a process that improves the quality of the immune response by generating B cells that produce antibodies with higher affinity for the antigen
–> B cells with higher-affinity receptors for the antigen are selected for survival
how does somatic hypermutation lead to affinity maturation?
Somatic Hypermutation (SHM) leads to affinity maturation by generating a diverse pool of B cells with varying affinities for a specific antigen
- during SHM, random point mutations are introduced into the variable regions of immunoglobulin genes at a high frequency
- as a result, it generates a diverse population of B cells with different mutations
- these mutations can lead to changes in the antigen-binding site of the B cell receptor (BCR), altering its affinity for the pathogen
–> B cells with mutations that increase their affinity for an antigen are selected and proliferate
–> B cells that have mutations leading to a lower affinity for the antigen are eliminated - the selected high-affinity B cells undergo clonal expansion, producing more B cells that can bind tightly to the pathogen, thereby improving the overall immune response
This process of selecting and expanding high-affinity B cells is known as affinity maturation.
why are high affinity b-cells important in the immune response?
high affinity b-cells produce antibodies that bind more tightly and specifically to antigens
–> the more tightly antibodies bind to an antigen, the more likely they are to target and remove it from the body
–> higher affinity increases the quality of specific antibody effector functions
how does diversity vary between T-cells and B-cells?
- t-cells are more diverse @ start
- b-cells less diverse @ start but progressively get more diverse
- b-cells purposely introduce mutations so daughter cells look different, but t-cells have identical daughter cells
where does SHM and affinity maturation take place?
- both SHM and affinity maturation happen in germinal centres of secondary lymphoid tissues, such as the spleen and lymph nodes
- DARK ZONE
what are germinal centres?
- germinal centres form in the lymph nodes 6 days after primary infection or immunization
- they are only present if we’re actively forming an immune response
- germinal centres are the focus of proliferating b-cells and specialized helper t-cells (Tfh)
what are the components of germinal centres?
there are 2 areas:
- dark zone = B-cell clonal expansion and somatic hypermutation
- light zone = affinity maturation and selection for highest affinity BCRs
the light zone also has follicular dendritic cells that trap antigens long-term to support B-cell affinity maturation, and to maintain the structure of germinal centres
how do B cells compete in the germinal center, and what determines their survival?
within the germinal center, there are not enough antigens for all B cells to survive, so they compete.
- dividing b-cells with point mutations compete for binding to antigens presented by follicular dendritic cells in the light zone.
–> favourable mutations allow the b-cell to bind strongly to the antigen = get signals to remain activated
–> disadvantaged mutations mean the b-cell can’t bind antigen = won’t get any more activating signals = eliminated
This process ensures that only high-affinity B cells survive, contributing to affinity maturation.
why is the secondary immune response faster than primary?
- somatic recombination and affinity maturation contribute to increased sequence diversity, which expands the b-cell receptor repertoire
- throughout our lifetime, we respond to various pathognes
- as the immune response develops, antibodies generated have progressively higher affinity for the pathogen due to affinity maturation
- after the primary immune response, some B cells differentiate into memory B cells, which persist long-term = these memory cells retain the highest-affinity BCRs (antibodies) for the pathogen
therefore, memory cells with high-affinity BCRs enable the secondary immune response to be more efficient and faster than the primary response.
what are the main b-cell types of the adaptive immune system?
- conventional b-cells (B2) = have diverse BCRs which rely on t-cell for activation
- plasma cells = activated b-cells that produce antibodies (the Ig molecule released has exactly the same specificity of the membrane-bound BCR)
- unconventional b-cells (B1) = less diverse BCRs which are less dependent on t-cell for activation
how are b-cells activated?
- they require 3 signals
- most of the time receive them from helper t-cells
- sometimes get signals from the innate immune response
*multiple signals are required for control because you don’t want accidental response, particularly because b-cell response is potent
how is b-cell activation similar to t-cell activation?
- they both require 3 signals
what are 2 pathways of b-cell activation?
1) t-cell dependent B-cell activation (more common)
2) t-cell independent activation of b-cells (less common)
what are the steps to t-cell dependent B-cell activation
1) the b-cell receptor (BCR) binds directly to its matching, specific antigen
2) CD40 on b-cells binds co-stimulatory molecule on helper t-cell (CD40L)
- there is also MHC class II binding to t-cell for recognition*
3) helper cell releases cytokines to enable b-cell differentiation, proliferation and survival of the b-cell
what are the steps to t-cell independent activation of b-cells
this pathway primarily occurs with multivalent antigens, which are antigens that carry alot of antigens in one spot
- multiple BCRs bind the same pathogen to create receptor clustering, which strengthens BCR signalling
- PRRs bind to the antigen, triggering additional signalling pathways inside the b-cell
- the combined 2 signals lead to activation and proliferation of the b-cell
what is the entire process of t-cell dependent b-cell activation?
1) activation of CD4+ helper cell
- a free antigen enters the lymph node directly or is presented by APCs on MHC class II
- naive CD4+ T cells in the T-cell zone sample the antigens presented by APCs and if the CD4+ T cell’s TCR matches the antigen-MHC complex, the T cell becomes activated and differentiates into TFH cells
2) activation of b-cell
- at the same time, a naive B cell with a BCR encounters their matching antigen (either directly or presented by follicular dendritic cells) and becomes partially activated (SIGNAL 1)
- the B cell processes the antigen and presents it on MHC class II molecules.
- activated TFH cells migrate and b-cell meet at the border zone of the lymph node to interact and meet
- the TFH cell’s TCR binds the antigen presented on the MHC class II of the b-cell, forming a synapse (CD4+ requires MHC class II to bind)
- the TFH cell produces CD40L, which binds to CD40 on the b-cell (SIGNAL 2)
- the TFH cell releases cytokines to promote b-cell activation, proliferation and differentiation into plasma cells (SIGNAL 3)
