The Adaptive Immune system (1) Flashcards
why do we need an adaptive immune system
The adaptive immune system has the capacity to learn from and remember specific pathogens. it can then protect long-lasting protection against infection.
INNATE VS ADAPTIVE IMMUNE RESPONSE
The innate immune system Immediately prevents the spread of movement of foreign pathogens.
The adaptive immune response is slower. it is specific to every single pathogen that we encounter.
Adaptive immunity is orchestrated by lymphocytes.
The adaptive immune response is meant to only attack non-self pathogens which can some times lead to error which is when the autoimmune disease develops.
Recognition of lymphocyte subsets
Lymphocytes originate from a pluripotent/multipotent stem cell in the nine marrow.
All lymphocytes are derived from a common lymphoid progenitor cell and from this cell there we have B, T, NK cell.
It’s normally difficult to differentiate lymphocytes under a microscope. but now we can actually differentiate them by the unique protein that they express on their cell surface.
Lymphocytes cell surface proteins
All B cells, apart from terminally differentiated plasma cells express a protein on their surface called CD19 (cluster of differentiation).
In contrast, T cells do not express this protein but they do all express another protein called CD3. T cells can then be further subdivided into 2 major subsets based on whether they express CD4 (which makes them T helper cells) or CD8 (making them cytotoxic T cells).
T cell differentiation
T cell precursors originate in the bone marrow and they migrate to the thymus where they undergo maturation into either CD4 or CD8 T cell.
The CD4 T helper cells can be further subdivided according to the cytokines that they produce and therefore the function that they impact. We have Th1, Th2, Th17 and Treg (regulatory T cells).
B and T cell development
Both B and T cell development take place in a specialised microenvironment.
B cell maturation is guided entirely by stromal cells in the bone marrow. T cell maturation is driven by interactions with stromal cells but in specific compartments of the cortex and the medulla of the thymus.
Comparison of B cell and T cell development
B cells are produced throughout life in the bone marrow.. approximately 50 million new B cells are produced every day. At any one time, there are about 1 billion B cells undergoing maturation.
In contrast, T cells are produced in the thymus which involutes after puberty. This significantly reduces the capacity of adults to produce new T cells but the thymus does retain some cortical medullary tissues and T cells can be derived from extrathymic sites in adulthood like the liver and the intestine.
The life expectancy of naive B cells is approximately 5 days. In contrast, Naive T cells have a very long life span that can probably be measure in yrs rather than days.
There are approximately half a billion T cells circulating in the average human being at any one given time and both B and T cells display a vast diversity of antigen receptors on their surface and this is the basics of the adaptive immune response.
Lymphocyte stages of development
B cells.
They originate from a common lymphoid progenitor in the bone marrow. The first evidence of commitment to becoming a B cell is the emergence of a pro B cell which has undergone genetic rearrangements of its diversity (D) and joining (J) segments. They are then followed further differentiation steps towards pre B cell, large and small and the first expression of a pre B cell receptor on the surface of the cells.
Immature B cells then undergo a process of negative and positive selection and only those B cells that are positively selected and avoid negative selection are finally released into the peripheral blood.
failure at either of these steps leads to apoptosis or programmed cell death
Lymphocyte stages of development
T cells.
The T cell precursors migrate to the thymus where they undergo 4 different stages of DN (double negative) differentiation and this signifies that these cells express neither CD4 nor CD8.
DN4 cells express a pre T cell receptor on their surface and then transiently go through an immature single positive phase (wither CD4 or CD8) before becoming double-positive for both of the antigens. These cells like immature B cells undergo both positive and negative selection before being released into the peripheral blood as eitherCD4 or CD8 T cells.
Common stages of B and T cell development
1st phase: generation of an antigen receptor
The generation of each unique antigen receptor through genetic rearrangement of the V (variable), D (diversity) and J (joining)segments.
2nd phase: refinement of the antigen receptor repertor
The receptor is first challenged with self-antigen and only those cells that recognise self are selected for further development. This is a process called POSITIVE SELECTION. those receptors that bind too strongly to self-antigen are deleted through a process called NEGATIVE SELECTION.
3rd phase: involves an encounter with a foreign antigen. this phase takes place in the secondary lymphoid tissues in the lymph nodes or the spleen and results in the clonal selection and expansion of individual B cells or T cells. This ultimately leads to the development of effector and memory lymphocytes.
Summary (1.1)
B cells and T cells are the lymphocyte components of the adaptive immune system
Their critical function is to produce immunological memory
B cells and T cells begin life in the bone marrow – T cells complete their development in the thymus
All lymphocyte development is guided by interactions with stromal cells in the bone marrow
All undergo both positive and negative selection
There are many subsets of T cells but the most important are CD4+ Thelper and CD8+ Tcytotoxic
B cell Antigens
B cells operate at the interphase of both innate and adaptive immune system. This is because B cells are capable of recognising native antigen and in some instances, they can produce a full immunological response against the pathogen without the need for T cell help.
However, for the majority of antigens, B cells need to interact with T cells in other to become fully activated. The two different classes of antigen, therefore, are described as thymus independent (T dependent) to thymus-dependent antigens.
T independent antigens are classically polysaccharide lipid or nucleic acids and are characterised by repeating motifs. these repeating motifs allow the B cell receptor to be cross-linked on the surface of the B cell but the majority of antigens are proteins and are therefore T dependent antigens as they do not contain repeating epitopes which prevent them from being crosslinked spontaneously on the surface of the B cell.
T cell-independent responses
As T independent antigen are independent antigens, they allow for the B cell receptor cross-linking and therefore aggregation of the B cell receptor on the surface of the B cell. This provides an activation signal. However, these B cells still require a 2nd activation signal or co-stimulatory signal in order to become fully activated. This is often provided by toll-like receptor antigen engagement which reinforces the assertion that the B cells link the innate immune system to the adaptive immune system.
Naive B cell express both IgM and IgD on their surface. following activation with T independent antigens, these B cells can most commonly secrete IgM antibodies. They are not capable of class switching because this process is absolutely requiring T cell help.
Although T independent antigens can drive naive B cell response, this response is short-lived and does not produce immunological memory.
Antigen recognition by B cells vs T cells
- Both B and T cells produce a diverse array of antigen receptors by V(D)J recombination
- The B cell receptor (BCR) consists of 2 HC (heavy chains) and 2 LC (light chains) making a classic Y shaped antigen receptor expressed on their surface. (can be found on the membrane and also secreted as Immunoglobulin)
This B cell receptor can also be secreted as antibody.
-T cell receptor (TCR) consists of just 2 chains (ALpha and Beta chain heterodimer) (can be found in membrane form only)
- Antigen engagement of both the BCR and TCR results in cell signalling which is regulated by the B cell co-receptor complex and the CD3 complex respectively.
- Both signal by associating with signaling complex in membrane:
Ig-a and Ig-b for B cells; CD3 complex for T cells
- B cells can bind intact protein antigen in solution
- T cells bind peptides displayed on the surface of another cell - an “antigen presenting cell” (dendritic cell, macrophage, or B cell) - in the context of MHC I or MHC II molecules.
MHS (Major histocompatibility molecules)
T-independent and T-dependent B cell activation
T-independent and T-dependent B cell activation follow a 2 signal activation model. T dependent B cell activation also requires multiple signals but typically this will involve 3 cognate Ligan receptor interactions.
B cell-T cell interactions
For the vast majority of antigens, B cell needs the help of T cell in order to produce an effective immune response.
B cells and T cells have evolved an array of reciprocal ligand receptor expression which allows them to interact with each other and some of the most important ones are shown in the image and they include;
- CD40 on the B cell
- CD40 ligand on the T cell
- CD80 and CD86 on the B cells
- CD28 on the T cell
*Both B and T cells recognise antigen but they do not usually recognise the same epitope.
B cells recognise native antigen whereas T cells can only see processed antigen which is presented ot them in the context of the MHC molecules.
T-dependent B cell response
They require 3 signals in order to become fully activated. The first signal occurs following antigen binding to the B cell receptor.
The antigen is internalised and then processed into peptides in the lysosomes prior to being bind to MHC class II molecules.
MHC class II antigen complexes are then shuttled to the cell membrane where they are displayed on the cell surface. A CD4 positive T helper cell with a receptor that is able to recognise the presented peptide antigen provides the first activation signal to the T cell.
CD80 and or CD86 on the surface of the B cell binds to CD28 on the surface of the cognate T cell. This provides the 2nd signal to the T cell for activation and results in increased T cell activation and the upregulation of CD40 ligand on the surface.
This in turn binds to CD40 on the B cell surface creating the B cell 2nd signal for activation.
The T cell also increases its production of cytokines which further activate the B cell through a 3rd signal. The B cell will then proliferate and undergo a process called somatic hypermutation to improve the affinity of the B cell receptor for antigen.
Ultimately, this leads to the production of immunoglobulin secreting plasma cells and or memory B cells.
Primary and Secondary Antibody Responses
The ultimate aim of the adaptive immune system is to be able to respond in a specific way to a vast array of different antigens.
The principal advantage of the adaptive immune response is that it creates immunological memory which enables the host organism to react more quickly and more effectively to repeat infection.
The development of immunological memory in a population leads to the concept of herd immunity and this slows or even prevents the spread of the infectious agent. However, for herd immunity to be effective, approximately 60% of the population needs to have been vaccinated or infected or recovered from a pathogen.
