Immunology 5- B lymphocytes Flashcards
What does an absence of T cells and B cells result in
SCID babies- unable to fight infections- due to being unable to carry out recombination.
Describe adaptive immunity
Improves the efficacy of the innate immune response
Focuses a response on the site of infection and the organism responsible
Has memory
Needs time to develop
On first encounter (primary response), takes days to develop
On repeat infections (secondary response), is faster and stronger
Describe the differences in specificity between the innate and adaptive immune systems
Although both are specific, the adaptive immune system has a higher degree of specificity
Explain why we heat up vaccines
Denature antibodies which recognise the 3-D structure of antigen. TCR recognises 2D linear region of antigen.
Describe the 2 different types of adaptive immune response
HUMORAL CELL-MEDIATED
B cells T cells
Antibodies Cytokines, Killing
Describe B lymphocytes
- white blood cells
- derived from hematopoietic stem cells
- effector cells of humoral immunity
- secrete antibodies
- memory B cells (ready to prevent repeat infections)
Describe the antigen-independent phase of B cell maturation
B cell generation and
maturation occurs in
bone marrow in the
absence of antigen
The B-cell lineage is derived from lymphoid progenitor cells that differentiate from haematopoietic stem cells
.• Migrate into the circulation (blood, lymphatic
system) and into lymphoid tissues
- Mature B cells are specific for a particular antigen
- Specificity resides in the B cell receptor (BCR) for antigen
Describe the organization of the different cells involved in the B cell maturation pathway
In adult bone marrow, B-cell development follows a radially organised pathway in which the least developed cells are close to the endosteal (inner) surface of the bone and the more mature cells are concentrated in the central marrow space.
Where do immature B cells exist the bone marrow
Via the sinusoids and migrate to the periphery, typically to the spleen or lymph nodes. Their development in the bone marrow depends on a variety of growth factors contributed by bone marrow stromal cells.
Describe the clonal selection of B cells
Each lymphocyte bears a single, unique receptor
Interaction between a foreign molecule and that receptor leads to activation
Differentiated effector cells of that lineage will bear the same receptor
Self specific receptors are deleted early in development
Do immature B cells in the bone marrow possess a B cell receptor
Yes
What can the stages of B cell maturation in the bone marrow be defined by
The rearrangement status of the Ig heavy and light chain genes.
Explain what is meant by negative selection
Due to the recombination processes involved in B-cell development that gives rise to extensive receptor diversity, by chance some BCRs will recognise self antigens. Cells that express these receptors will need to be killed or switched off. This selection process results in a pool of immature B cells that do not become challenged with self antigen, a condition called tolerance.
Describe the BCR receptor
BCR have a unique binding site which bind to a portion of the antigen called antigenic determinant or epitope
- is made before the cell ever encounters antigen
- is present in thousands of identical copies on the surface of the B lymphocyte
Describe the structure of the BCR
Transmembrane protein complex
composed of mIg and di-sulfate
linked heterodimers, Iga, Igb
Iga/Igb heterodimers contain
immunoglobulin-fold structure
The cytoplasmic tail of mIg is too
short to signal
The cytoplasmic tails of Iga/Igb
long enough to interact with
intracellular signalling molecules
Contain ITAM domains
Receptors cluster on binding to antigen- which triggers a series of downstream reactions.
Why do we need antigen receptor diversity
We are exposed to an incredibly large amount of different microbes and other antigenic determinants – no predicting which ones
Immune system must be able to respond to them all.
But - the adaptive immune system is exquisitely specific
To respond to all these different antigens, we need to have a very large pool of cells with specific receptors that can recognise these huge array of antigens
1010 different antibody molecules can be generated
Each antibody is produced by a B lymphocyte expressing a specific BCR
This would be impossible if 1 gene per antibody: We only have 25,000 genes total for all functions
How is antigen receptor diversity achieved
Diversity generated through a piece of genetic sleight of hand!
Functional genes for antigen receptors do not exist until they are generated during lymphocyte development
Each BCR receptor chain (kappa, lambda and heavy chain genes) is encoded by separate multigene families on different chromosomes
V,D and J segments are present in multiple copies- germline diversity
During B cell maturation these gene segments are rearranged and brought together. VD and VDJ segments can recombine in multiple combinations- combinatorial diversity.
Junctional diversity- junctions are formed between gene segments (joining of V segment to DJ segment) which involved DNA cleavage, followed by addition and subtraction of nucleotides to create a viable joint- sequence of amino acids in putative binding site can change- a major chemical structural change.
Multiple combinations of light and heavy chains are possible. In principle, any heavy chain can associate with any light chain.
This process is called Immunoglobulin gene rearrangement
Immunoglobulin gene rearrangement generates the diversity of the lymphocyte repertoire
Explain how Heavy chain gene rearrangement is different to light chain rearrangement
The mechanism of heavy chain synthesis is very similar to that of light chain synthesis except that three segments, rather than two, due to the CDR segment are required for the assembly of the Vh exon and that multiple Ch exons are present and functional in the heavy chain locus. The constant region is also achieved by alternate splicing in heavy chain synthesis.
Describe light chain synthesis
In the germline of humans, approximately 35 different V kappa genes are found on the kappa locus of chromosome 2. Each V kappa gene encodes the N-terminal. Downstream of the V kappa region are 5 J kappa exons. After a long intron the kappa locus ends in one C kappa exon that encodes the constant region of the kappa light chain.
In early B cell lineage a V kappa exon is selected and, after a process of DNA rearrangement involving the V(D)J recombinase it joins it to a J segment. The intervening DNA is deleted by looping it and cleaving it for ultimate degradation. A primary RNA transcript is made.
Splicing occurs to bring the selected V kappa, J kappa exons together with the C kappa exon. Splicing removed the intervening DNA sequences (other J segments). Introns are also removed
Kappa polypeptide synthesised on RER.
Describe the synthesis of the heavy chain
Approximately 50 Vh, 25Dh and 6Jh segments are present in the heavy chain locus on chromosome 14 in the human genome. The diversity segment, like the J segment, encodes amino acids in the hypervariable region of the heavy chain.
First, D and J segments are joined ( the intervening DNA is cut and looped out). Then, a V segment joins to the combined DJ segment to form the complete Vh exon. ( loss of intervening DNA). Transcription gives rise to a primary RNA transcript containing the VDJ region, remaining J segments and Cmu and Cdelta segments.
After RNA processing the introns and C delta sequences are removed to generate a mRNA, which on translation yields a mu heavy chain.
Describe the V(D)J recombinase complex
Critically contains the proteins Rag1 and Rag2 – deficiency of these = scid
What is a consequence of self tolerance and productive gene rearrangement
Mature B cells are created from immature B cells (expressing both IgD and IgM).
Explain why further tolerance induction is required in the periphery
Not all self antigens present in the bone marrow.
Why does gene rearrangement need to be tightly regulated
Do not want recombination all the time- would lead to tumour growth-oncogenes.
