Know the difference between cross reactivity and cross presentation
Cross reactivity is when an antibody that has been made in response to an antigen binds to another antigen and an example of that is rheumatic fever when antibodies produced against streptococcus also reacts with myocardial antigens.
Cross presentation is when an intracellular pathogen peptides are presented in MHC 1 and 2 by the APC cells
What can antibodies bind to
Pretty much anything
What function does B cells exhibit when they mature
They express antibodies IgM and IgD which can be found in the serum
Flowchart of B cells and their role in humoral immunity
When B cell encounters an antigen or when it is activated by a CD4 cells, it undergoes proliferation to become the following type of cells
1. Some make IgM antibodies, those are on the surface and those are the easiest to make
2. Some B cells undergo isotope switching and make IgG antibodies
3. Then there are B cells that are associated with high affinity maturation
4. Some B cells form memory cells
Where does B cell activation occur
Wherever there are B cells so primarily in the lymphoid organs
3. Lymph nodes
What are the functions of spleen
It has two major functions that are hematologic function and immunologic function. Just like any lymphoid organs it is encapuslated and divided by trbeculae. The immunologic function is observed in the white pulp whereas the hematologic function is observed in the red pulp.
Histology of spleen.
What is in the white pulp zone
1. B cell zone
2. T cell zone
4. Germline centers
5. Marginal zone
What makes spleen different from a lymph node
Spleen and lymph nodes have a lot of things common between them in terms of imunologic function. However, what makes spleen unique is the fact that there is a marginal zone all around the spleen that plays a role in developing immune response to certain infections. If spleen is taken out of someone they are more susceptible to such infections whereas if a lymph node is taken out that patient still exhibit complete immunological function
How does antigen get to a B cell (we talk here in term of spleen)
Blood flows through the marginal zone where some of the B cells are. The blood is trapped by B cells in the marginal zone. The blood has macrophages. Macrophages carry the antigen to the follicle and show it to B cells
What is unique about antigen presentation to B cells by macrophages
It is important to know that macrophages dont display the antigens on MHC rather they only hold the pathogen in place which allows the B cells to come and "beat up" the pathogen to collect the antigens and develop an adaptive immune reponse
How is BCR activated
1. Ligation of BCR
2. Accessory molecules are p's at ITAMs by Sck
3. Syk (analogous to adapter protein ZAP70) comes along and binds to the phosphate groups
4. Then it goes from Btk to BLNK to PLCgamma
5. PLCgamma makes IP3 and DAG
Where was the first immunodeficiency recorded in this mechanism
In Btk, these patients could not signal throug BCR
Does B cells need coreceptors?
No. But they do have coreceptors, those coreceptors can enhance their activity
What is this coreceptor
It is a complement receptor, more specifically it is a complement receptor 2, CR2
What happens when the B cells get activated through the BCR
1. They undergo clonal expansion
2. They prepare the antigen for antigen presentation, since they are APCs
3. Some of the B cells immediately start making IgMs
4. Express B7-1/2
5. Migrate towards T cells
Explain the sequence of events after B cell activation
1. T cells migrate towards B cells, B cells migrate towards T cells, they meet at a point called the follicular focus, this is where the intital burst of antibodies come from. These cells immediately start making IgM.
There are 3 key events that happen: B cells present the antigen to the T cell to reactivate it, T cell expressed CD40 L and cytokines such as IL-4, this leads to the production of antibodies.
2. Some of the B cells and T cells migrate back to the lymph node or spleen and form the germinal center where they make specialized antibodies. T cells now are called Tfh cells, follicular helper T cells.
Steps in antigen presentation and activation by the B cells
1. Antigen that has activated the B cell is internalized, processed and presented in MHC to the T cell
2. The T cell previously have been activated by a dendritic cell so it expressed CD40L. It also makes cytokines such as IL-4 to specify the development of B cell and activates B cell by CD40-CD40L interaction
What happens to B cells after the T cell activation
1. B cells undergo clonal expansion and rapidly proliferate.
2. They undergo isotype switching and start making specialized antibodies via somatic hypermutation and Affinity maturation
3. Plasma cells and memory B cells differentiation takes place
What part of this process is impaired in patients who do not have any CD4 cells such as in AIDS patients
In order for B cells to start pumping out antibodies this CD4 interaction is absolutely necessary. In AIDS patients antibody production is impaired
Define isotype switching and somatic hypermutation
Isotype switching is the genomic rearrangment that results in the production of different kind of Ig
Somatic hypemutation is when we introduce point mutations in the hypervariable region of the Ab genes
What is the idea of genomic rearrangment in a mature B cell
A mature B cell already have the VDJ segments sorted out. In order to make a different antibody it picks the constant region chain (purple in the diagram) that it wants and the rest of the DNA is looped and thrown away.
For example if this cell wants to make IgE antibody, it will take out the Cmeu, Cgamma regions all the way and incorporate the Cepsilon region. Once it makes the switch it cant make a switch backwards, but it can make it forwards.
Know the difference in these 2 processes
How do B cells know what antibody to make
They know what antibody to make from the cytokines that are released by the Tfh cells
Explain the idea of affinity maturation
1. When we make a switch from IgM to maybe IgG there are less binding sites on the antibody, it has a lower affidity. Hence to compensate for this B cells in the germinal centers have to make a new library of antibodies by introducing point mutations in the hypervariable region. The antibody that has a higher affinity for the antigen is selected. This is done by the help of Follicular Dendritic Cells and Tfh cells. B cells that make the higher affinity antibody keep getting CD40 signals from the Tfh cells and they undergo positive selection and proliferate. However B cells that have lower affinity antibodies stop receiving signals from Tfh cells and they undergo clonal deletion
What is a disease associated with this process
Hyper IgM syndrome where the B cells are unable to switch antibodies and hence they keep making IgM. The concentration of IgM increases dramtically in the sera. There are 2 types of hyper IgM syndrome
Type 1 is when there is nothing wrong with the B cells but in the T cells they are missing CD154, which is the CD40 L.
Type 2 is when there is a mutation in the gene coding for the enzyme AID (Activated Induced Cytadine Deaminase) which is requried to introduce point mutations in the hypervariable region of Ig.
Clinical symptoms for both of the types of hyper IgM syndrome are similar
What are the 2 types of B cells that survive after an immune response and where are they found
Plasma cells and memory B cells, plasma cells reside in the bone marrow whereas the memory B cells can either stay in the tissues or they can go into the organs
What factors helps to maintain immune homeostasis
1. Ig half life decreases as their concentration in the sera increases
2. FCgamma receptors on B cells are inhibitory receptors. Their ligand is an antibody bound to a microbe (which suggests that there in enough antibody in the blood). The receptos bind to these microbe attached antibodies and turn on the activity of phosphatases which inhibit the kinase activity on the ITAMs of BCR.
What are the other types of B cells and why are they needed
In a T cell mediated immune response, it is restrcited to peptide antigens since that is the only thing that T cells can see on MHC. Hence there are 2 types of B cells that can detect other antigens such as lipoproteins, LPS etc. These B cells are Marginal B cells (they are present on the margins of the spleen) and B-1 B cells in the peritoneal cavity. When they encounter an antigen they start pumping out IgM antibodies
What is the name of the B cells that interact with T cells
Follicular B cells
How do these B cells identify PAMPs
They have receptors that detect Repeating Identical Patterns. So the same antigen like LPS can activate TLRs on macrophages and the receptors on these B cells. There is little somatic hypermutation, little plasma cells and little memory B cells