"Recurrence of autoreactive antigen-specific CD4+ T cells in
autoimmune diabetes after pancreas transplantation
CD4+ T cells specific for the diabetes-associated autoantigen GAD65
were analyzed using peripheral blood samples after pancreas
transplantation in subjects with T1D with clinical evidence of
recurrent autoimmune diabetes. Comparisons of TCR clonotypes by cDNA
sequencing revealed that identical T cells were present in the
circulation, separated by long time intervals, consistent with a
persistent memory response associated with recurrent autoimmunity."
Which cell and receptors are responsible for identifying the new
pancreas as foreign with the CD4 cells? What is alloreactivity?
Describe the cascade of events leading to the recurrence of
T cells, with their T-cell receptors (TCR's) recognize the "not me" MHC on the transplanted pancreas. Alloreactivity is the ability of the immune system to react to cells that are from another human, based on the "not me" Major Histocompatibility Complexes. When the TCR binds the "not me" MHC, there is a conformational change and the CD3 protein on the T cell is phosphorylated, activating the T cell. The activation of that cell triggers a cascade of cytokines, with many cells being alerted by the signals of the first, and continuing to alert more. The CD4 T cells release more cytokines and the CD8 cells activate and release granzymes and perforin.
After an immune response the body saves a few samples of the cell that can make the antigen, just in case that antigen should show up again. They are memory T cell. I think that's the "persistent memory response" they are talking about. The autoimmunity response as I understand it can't be against the pancreas, because it is allo not auto. So perhaps the stimulation of the new antigens on the pancreas creates a flood of a new type of antibodies that reacts with some "me" antigens. Or perhaps the drugs given to the patient that reduce the immune response to the introduced alien pancreas also cause an imbalance in the remainder of the immune system that induces the autoimmune action. Or perhaps something else entirely.
?? This is a tough question from where I sit at this moment.
2. What is the main function of CD4 cells? What co-stimulatory
protein is necessary for naïve T-cell activation? Please explain or
draw the Th1 response including cells, proteins, B-cell type and
cytokines involved and the ultimate result of this cascade of events.
The main function of CD4 cells is to make antibody. Naive T cells get activated when they encounter two or more signals from an antigen processing cell, ie a macrophage or dendritic cell. They are primed for specific duties messages via cytokines that they bind, IL-4 leads to the Th2 response and IL-12 to the Th1 response. In a Th1 response, the DC or m/ encounters a bacteria or virus in tissue, and the TLR (toll like receptor) on the DC or m/ binds it. Once bound, the invader is phagocytosed and digested by a lysosome, and particles of the invader are installed on MHC type I and II and inserted into the DC or m/ membrane. The DC or m/ also makes CD-86 (a warning costimulator on its membrane) and IL-12 (a cytokine messenger that is released). The DC or m/ then transports the processed invader in the form of MHC plus peptide to the lymph node, where it looks for a T cell that "recognizes" (ie has a TCR that matches) its antigen. When a T cell recognizes and binds the antigen, and is activated by the CD-86 and oriented by the IL-12, it makes four cytokines: IFNgamma, TNPalpha, GM-CSF, and IL-2. Interferon gamma causes B cells to class switch to IgG, m/ and DC's increase ROS production and phagocytosis, and CD8 cells divide and make more perforin and granzymes. Tissue Necrosis Factor alpha causes m/ and DC to make more ROS and kill, and also activates neutrophils and increases inflammation to bring them to the site (increases gut leakage, adhesion molecules, etc). Granulocyte Macrophage Colony Stimulating Factor causes all granulocytes and the immune stem cells to be fruitful and multiply. And Interleukin-12 increases cell division of T-cells and other immune cells.
3. How do CTLs cells kill bacteria? How are caspases activated? What
do MHCI responding cells release in response to an infected cell?
Cytotoxic T Lymphocytes, aka CD8 cells, kill cells by perforin and granzymes. First they poke a hole in the invader's cell membrane using the perforin, and then they send in the granzymes to digest it from the inside out. One of the proteins cleaved by granzymes is caspase, which is activated by cleavage and induces apoptosis.
When an MHC1 cell is infected, (that's almost any cell in the body, and the infection is usually viral if it's being presented on MHC1), a T cell sits on its MHC and says "are you me" (no) and "are you dangerous" (yes if CD86 is expressed, matches T cell's CD28) and is activated. If the T cell is a CD4 it makes cytokines (Th1 response, discussed above) and if it's CD8 is makes perforin and granzymes and kills the infected cell, even though it is a "me" cell, because it is infected.
4. List the cells involved with the innate immune response. Which
cells contain PRRs? Where do Professional APCs come from?
First, what's a PRR?
Professional APC's are from the myelitic lineage, which comes from a CD34 stem cell. Monocytes differentiate into macrophages and dendritic cells in the tissue.
all are myelitic lineage and have TLR's
5. In the Th1 response, what causes the B-cell to undergo a class
change? What if there was no TLR to bind to an antigen? What
response, if any, would the body have?
Interferon gamma is what causes the B cell --> IgG.
If there were no TLR, the NK's would still respond to cells without enough MHC. What else?
6. What enzyme is necessary for somatic hypermutation of B-cells in
the spleen? When does anergy take place?
Somatic hypermutation is the process of B cells changing an antibody by just one amino acid (a point mutation) to increase binding affinity. The glorious part is that the B cell changes its DNA to code for future B cell progeny to manufacture the improved antibody. The enzyme required is a reverse transcriptase.
Anergy takes place when a T cell recognizes antigen in an MHC molecule and does not get the second signal, ie CD86 to say "danger".
7. Receptors on mast cells share the common ß subunit (FcRß) which
contains an immunoreceptor tyrosine-based activation motif and
transduces the signals of these receptors' aggregation. What would
happen to the immune response in a person with a mutated ß subunit?
Hard to say. Depends on what the mutation was (function could get better or worse). The function of the Fc receptors on mast cells, since they are mostly Fcepsilon, is to bind IgE antibodies which causes the release of histamine from its granules. If function got "better" the mast cells could activate and degranulate too easily and cause terrible allergies. If function got "worse" the person might not be able to use their mast cells and be infested with parasites or worms.
8. How many series 2 HLA receptors do you have in your body? Which
cells end up being stimulated by these receptors?
9. What is the purpose of IL-13? What does it do and who does it come
from in response to what? Tell the story of IL-13.