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80 Cards in this Set
- Front
- Back
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Define tolerance:
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The specific unresponsiveness of the human immune system to its own self antigens.
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What components of immunity exhibit tolerance?
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All of them
-innate (no PRRs on self cells) -Cell mediated - Tcells -Humoral - Bcells |
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How is Tcell tolerance different from Bcell?
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Tcell tolerance is LONG lived
Bcell tolerance is short lived Bcell tolerance less complete Bcell tolerance quiescent in absence of Tcell help |
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How does the immune system avoid recognizing self?
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Well, it doesn't really; there is always the initial point where developing cells must bind self antigen on APCs in generative organs.
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What are 2 ways by which immune cells can remain tolerant?
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-Tolerance
-Ignorance |
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What is an immunogenic antigen?
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One that stimulates proliferation and differentiation of a cell upon recognition
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What is a tolerogenic antigen?
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One that causes the cell that recognizes it to become either anergic or apoptotic.
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What is a nonimmunogenic antigen?
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One that is ignored by lymphocytes even tho they bear specific receptors for it
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What are 3 factors that determine how an immune response to an antigen will develop?
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1. Nature of Ag-spcf lymphocyte
2. Nature of the antigen 3. How Ag is displayed |
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What are 3 factors that determine whether an antigen will induce tolerance?
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-Immunologic maturity of the person in whom the Ag resides
-Antigenic structure/dose -Immunosuppressive therapy |
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Who is most immunologically tolerant based on maturity?
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Elderly and neonates
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What antigenic structure and dose is most capable of being tolerated?
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-Simple structure
-Very high or very low dose |
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What does immunosuppression do to tolerance?
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Enhances it
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Are our body's self antigens normally tolerated or ignored?
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TOLERATED
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Is it possible to induce tolerance of antigens that are causing autoimmune disease?
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Yes
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Where are 2 categories of places where immune cells can see self antigen?
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1. Central (generative organs)
2. Peripheral (lymph) |
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What is central tolerance?
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The deletion of lymphs that STRONGLY recognize self antigens present in the generative organs.
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What type of selection achieves central tolerance?
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Neg selection
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What is required for neg selection?
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Pos selection - the cells do have to bind to self antigen at least a little.
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What happens to the naieve cells that survive neg selection in generative lymphoid organs?
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They go out into peripheral circulation.
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Are ALL self antigens present in the generative organs?
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No; some are just out in the periphery
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What is peripheral tolerance?
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The deletion or anergy of lymphs that recognize self Ag in peripheral tissues.
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What are the two ways that central tolerance is not complete?
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1. A small subpopulation of lymphs ESCAPE neg selection
2. Not all self peptides are present in generative organs |
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How are the cells that strongly bind self antigen during negative selection killed?
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By apoptosis of unknown mechanisms.
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What antigens are higher in concentration in the thymus; those that induce positive, or negative selection?
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Those that cause negative selection (bind strongly).
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What is the result of a defect in central tolerance?
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Many Tcells mature and exit the bone marrow, capable of binding self antigen!
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What are the earliest cells in lymphocyte maturation?
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Pro-B or Pro-T cells
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What are the 5 steps in lymphocyte maturation?
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1. Proliferation
2. Pre-B/T Ag receptor expression 3. Proliferation 4. Ag full receptor expression 5. Pos and Neg selection |
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What is the first thing expressed on a T or Bcell surface?
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HALF of the cell receptor; one chain of it.
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What happens after the expression of a pre-lymphocyte receptor during maturation?
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The cell proliferates
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Once a small clonal population of cells expressing the pre-B/T Ag receptor has expanded, what is the next step in maturation?
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Expression of the complete antigen receptor
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What are the cells in the thymus that express self peptides to achieve central tolerance?
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Thymic medullary epithelial cells
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What is the gene that regulates this expression of self antigens?
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the AIRE gene
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What is AIRE?
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Autoimmune regulator
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What disease results from mutations in the AIRE gene?
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APECED
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What is APECED?
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Autoimmune
PolyEndocrinopathy with Candidias and Ectodermal Dysplasia |
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What is the general result of AIRE mutations?
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Lack of negative selection of self-reactive Tcells in the thymus.
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What are the 3 main manifestations of the antibodies that result from APECED?
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-Endocrine gland problems
-Liver problems -Skin problems |
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Where do thymocytes enter the thymus?
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At the corticomedullary junction
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Where do thymocytes go initially in the thymus?
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To the cortex
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What type of thymocytes are found in the subcapsular region and cortex?
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Double negative immature thymocytes
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What type of thymocytes are found in the corticomedullary region?
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Double positive immature thymocytes
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What type of thymocytes are found in the medulla?
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Mature single positive thymocytes
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Where does negative selection occur in the thymus?
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In the medulla
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What is required for a NORMAL response of a Tcell to a specific antigen in peripheral lymph organs?
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-MHC presentation of Ag
-B7 costimulation of CD28 |
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What will happen if a Tcell in a peripheral lymphoid organ recognizes Ag on an APC that lacks B7?
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The Tcell will go into a state of anergy.
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What if that anergic Tcell is REstimulated with an APC presenting the same Ag, but now has B7?
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It will remain anergic and nonresponsive.
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What will happen if a peripheral APC presents Ag and has B7, but now the Tcell is expressing CTLA4 instead of CD28?
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It will induce an unchangeable state of anergy.
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What is the reason for a Tcell expressing CTLA4 instead of CD28?
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We don't know.
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In what state will Tcells be if APCs in the periphery have high levels of B7?
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Tcells will express CD28
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In what state will Tcells be if APCs in the periphery have low levels of B7?
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Tcells will express CTLA4
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What is the alternative way to achieve periphal tolerance besides anergy?
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Tcell deletion
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One more thing about anergy; what stimulates high levels of B7?
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IFN-y
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ok back to Tcell deletion
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ok
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What are two types of proteins expressed on Tcells that deal with cell death?
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1. Death receptors
2. Apoptotic proteins |
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If a CD4+ Thelper cell is repeatedly activated by self antigens, what will result?
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Expression of Fas on some of the clones, and FasL on others
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What is the result of Fas/FasL upregulation?
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Cellular apoptosis
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What proteins increase in surface expression in response to Antigen recognition?
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Pro-apoptotic
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What proteins increase in surface expression in response to 2nd signal activation?
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Anti-apoptotic
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So what happens if the 2nd costimulatory signal is missing?
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Only pro-apoptotic proteins are expressed so the Tcell undergoes apoptosis.
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What are the 3 ways by which peripheral tolerance is achieved?
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1. Anergy
2. Deletion 3. Tsuppression |
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What cells achieve T cell suppression?
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Tregulatory cells
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Where do Tregs develop?
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In the thymus
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How do Tregs develop in the thymus?
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By recognition of self antigen by immature double pos thymocytes (in the corticomedullary area)
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Why do Tregs develop?
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Because of their TCR-MHC avidity
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How do Tregs work?
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They blunt the activation of mature Tcells by contactdependent or independent mechanisms.
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What is the Contact-dependent pathway for Treg suppression of Tcell activation?
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Binding of the Treg to the Tmature cell induces inhibitory signaling, maybe CTLA-4
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What is the contact-independent pathway for Treg suppression of Tmature activation?
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The Treg cells secrete high levels of TGFb and IL-10, which inhibits Tcell activation.
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Are tolerogenic self antigens present in generative organs?
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Yes
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Are tolerogenic self antigens presented along with second signals?
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No; as a result it leads to Tcell anergy or apoptosis.
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How long do tolerogenic antigens persist in the generative organs?
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Throughout life
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Why would we want tolerogenic self antigens to persist for life?
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Because it's the REPEATED stimulation of Tcells with self antigens that induces deletion.
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Are immunogenic, foreign antigens present in generative organs?
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No
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Where are immunogenic, foreign antigens concentrated?
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In peripheral lymphoid organs.
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Are immunogenic, foreign antigens presented with second signals?
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Yes
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Why is it good that immunogenic, foreign antigens are presented with 2nd signals?
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It promotes lymphocyte survival and activation!
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How long do immunogenic, foreign antigens persist?
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Usually short lived - you want the immune system to eliminate them!
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What type of antigen results in clonal DELETION of Bcells?
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Surface antigen
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What type of antigen results in clonal ANERGY of Bcells?
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Soluble antigen
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What type of antigen results in clonal IGNORANCE of Bcells?
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Low concentrations of soluble antigen.
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