Immunological Tolerance Flashcards
What are some common autoimmune disorders?
Multiple Sclerosis
Rheumatoid Arthritis
What is immunological tolerance?
Immunological tolerance means non- responsiveness to specific antigens. (different from immune suppression)
Is tolerance antigen specific? What does this imply?
Yes. It implies the involvement of T cells and B cells
What are the two downstream paths of TGF-beta mediated T cell development?
IL-6 positive Th17 response
IL-6 negative FoxP3 response
What is central tolerance?
This is based on elimination of T cells that are reactive to antigens present in the thymus—self antigens.
Central Tolerance is based around both
positive and negative selection -> leads to
a “medium” affinity
Why is peripheral tolerance necessary?
Central tolerance will not function in some cases where the Ag is unknown to be presented (pregnancy).
What cells are involved with peripheral tolerance?
Regulator T Cells
Myeloid Derived Suppressor Cells
What is the function of regulator T cells?
They are professional T cells that are designed to impose suppression to other immune cells and are present under normal conditions.
What is the function of MDSCs?
A group of myeloid cells become potent immunoregulatory cells when exposed to inflammatory cytokines (e.g.IFN-gamma) and blocks T cell responses. Often tumor associated and only come about with inflammation or infection.
How are non-thymic self-antigen reactive cells eliminated?
AIRE is a transcription factor that is expressed mainly in the medulla of the thymus. AIRE induces expression of a wide range of genes expressed by other organs (e.g. endocrine gland). This leads to negative selection of thymocytes reactive to these self antigens.
What occurs in Autoimmune polyendocrine syndrome?
Loss of functions of AIRE gene leads to endocrine organs being destructed by antibodies and lymphocytes.
What are the mechanisms of peripheral tolerance?
Dominant Suppression (cell suppresses its activity) Cell Intrinsic Activation (become unresponsive)
What is the function of nTregs?
Mainly against self Ag
What is the function of the iTregs?
Mainly against foreign antigens
What is the function of Tr1?
Express high levels of IL-10, an immunoregulatory cytokine.
Where are the nTregs made?
Thymus
Where are the iTregs made?
Periphery
Where are the Tr1s made?
Periphery
What are Hassall’s corpuscles?
A group of thymocytes that have reactivity against self- antigens are converted into nTregs. This takes place in the structure called Hassall
What is the mutation in the disease IBEX?
FoxP3
When will iTregs form?
The cytokine milieu drives the differentiation of a naïve T cell in the presence of its antigen. For iTregs, the presence of TGF-alpha and IL-2 plays critical roles.
Presence of IL-6 is inhibitory.
What cytokine does Tr1 make?
IL-10
Are Tr1 FoxP3 positive or negative?
Negative. These cells are Foxp3 negative and imposes their suppressive function via IL-10.
What is essential for Tregs to suppress targets?
Direct cell-cell contact is essential for Tregs to suppress target cells.
What do FoxP3+ cells use for suppression?
Foxp3+ Tregs use soluble factors (TGF-beta, IL-10) to enhance their functions.
What is another molecule generated by Tregs to suppress lymphocytes?
Adenosine
What is clonal anergy and how is it caused?
Clonal anergy is a state of T cells that are unresponsive to antigenic stimulation. Anergy is induced when antigen is presented in the absence of co-stimulatory signal (CD28).
What is the function of the B7 and CD28 interaction?
Ligand of CD28 are B7.1 (CD80) and B7.2 (CD86). These co-stimulators expressed only by a limited group of cells (so called professional APCs). This limits the risk of false stimulations.
What is the function of CTLA-4?
A. CTLA-4 is expressed by T cells after activation and competes with CD28 for B7 binding and will ultimately win the contest because it has higher affinity for B7 than does CD28. CTLA4 also recruits signaling molecules that suppress TCR signaling and blocks antigen-activation.
What are some autoimmune applications of CTLA-4?
It can be used to suppress reactions in transplant patients.
