Tolerance and Autoimmunity Flashcards
Where do the most self tolerance sensitive stages of lymphocyte maturation occur and why? What form of tolerance is this known as?
Central lymphoid organs thymus (T cells) and bone marrow (B cells) have high concentrations of self antigens to present to immature lymphocytes. This is known as central tolerance
What is the principal mechanism of central tolerance?
Apoptotic cell death (clonal deletion) of self reactive lymphocytes
In central tolerance, immature lymphocytes with high affinity receptors for self antigens are deleted. What is this process called?
Negative selection
The autoimmune regulator (AIRE) gene encodes a protein that stimulates expression of endocrine self antigens in thymic epithelial cells. If there is a mutation in the AIRE gene, what disease results?
Failure of negative selection leads to immune mediated injury to multiple endocrine organs (autoimmune polyendocrine syndrome)
Where does peripheral tolerance occur? What mechanisms mediate peripheral tolerance?
Peripheral tolerance occurs outside the thymus/bone marrow and results from triggering of antigen receptor in the absence of costimulation or repeated self ag stimulation
What are the two requirements for CD4+ helper T cell activation?
- T cell receptor (TCR) must bind to major histocompatibility complex class II (MHC-II) with the antigen peptide
- T cell CD28 must bind to antigen-presenting cell (APC) B7 molecule for costimulation
What happens when peptide antigens are presented to CD4+ T cells by APCs deficient in costimulators? Why is this important to self tolerance?
Anergy or unresponsiveness. Clonal anergy refers to unresponsiveness of self reactive T cells and is an important mechanism of peripheral self tolerance
Anergic T cells are defined as those that fail to produce which growth factor?
IL-2
What differentiates clonal ignorance from clonal anergy?
In clonal ignorance, self reactive T cells ignore self antigens but are still functional. Clonal anergy results in permanent antigen nonresponsiveness
Which T cell coreceptor delivers inhibitory signals when it interacts with B7?
Cytotoxic T lymphocyte antigen 4 (CTLA4) (either lack of costimulation or interaction of CTLA4-B7 at the same time as antigen results in T cell anergy
Repeated stimulation of CD4+ T cells by antigen results in the coexpression of which receptor and ligand for activation-induced cell death?
Fas/FasL (which activate the caspase cascade via caspase 8)
What lineage of cell may also induce T cell tolerance?
Regulatory T cells (exact type unknown) are also though to play a role in tolerance.
Central B cell tolerance is most likely to occur with a central antigen of what structure? Name two examples of these self antigens?
Multivalent antigens that can bind and cross link many receptors on each specific B cell
- Membrane molecules, DNA
- Polysaccharides
What is the process by which immature B cells that encounter self antigen in bone marrow acquire new antigen specificity for their B cell receptors?
Receptor editing allows B cells to ignore self ags
What is the fate of mature B cells that recognize self ag in peripheral tissue in the absence of specific helper T cells?
Anergy with exclusion from lymphoid follicles
What happens when IgG produced by B cells forms complexes with antigen and binds to their own Fc receptors
Inhibitory feedback
What are the major factors that contribute to the development of autoimmunity?
Genetic susceptibility, environmental factors (mainly bacteria, viruses), hormonal factors (majority occur in women)
Which family of genes is most strongly associated with autoimmunity?
Human leukocyte antigen (HLA) genes
What is epitope spreading?
When autoimmune reactions against a self ag cause release of other self ags from damaged tissue, resulting in an immune response to those antigens and exacerbation of disease
Define molecular mimicry:
Ags of a microbe induce production of abs that cross react with self ags
How might inflammation, ischemic injury or trauma lead to autoimmunity?
Exposure to self ags that are normally concealed from immune system
What are the examples of anatomically sequestered ags?
Intraocular proteins, sperm proteins, CNS proteins such as myelin
Which autoimmune diseases are due to abs against receptors?
Myasthenia gravis, Graves disease, Lambert-Eaton myasthenic syndrome
What is an example of a T cell mediated autoimmune disease?
Multiple sclerosis, insulin dependent diabetes mellitus, celiac disease (even through autoantibodies are found)
