Chapter 5: Autoimmune Diseases Flashcards
Why are systemic autoimmune diseases often referred to as collagen vascular diseases or connective tissue diseases?
Because in systemic autoimmune disease the lesions that are formed primarly affect the connective tissues and blood vessels of involved organs.
What is the definition of self-tolerance?
The lack of immune responsiveness to one’s own tissue antigens.
What two mechanisms are there to control a self-reactivity?
Central and peripheral tolerance
How is controlled that T cells don’t react to selfantigens?
This proces is called deletion or negative selection. Thymic APCs present self protein antigens to immature T cells, every T cell that binds and reacts with the APC undergoes apoptosis.
Which protein stimulates the expression of some peripheral tissue-restricted self antigens an is therefore critical for negative selection?
A protein called AIRE (autoimmune regulator).
In the bone marrow this process of negative selection also occurs for B cells. But what is different in this process?
Some B cells may die by apoptosis if they bind to self antigens with high affinity, but some self-reactive B cells survive and undergo another round of rearrangement of antigen receptor genes. This way, the B cell creates a new receptor that is no longer self-reactive. This is called receptor editing.
Why is central tolerance not enough? Why do we need peripheral tolerance?
Not all self antigens are present in the thymus or bone marrow, and
hence lymphocytes bearing receptors for such autoantigens escape into the periphery. Self-reactive lymphocytes
that escape negative selection can inflict tissue injury unless
they are eliminated or muzzled in the peripheral tissues.
What is anergy?
Functional inactivation of lymphocytes that is induced by encounter with antigens under certain conditions.
When does a T cell become anergic?
A T cell needs two signals for activation. If the costimulatory signals are not delivered or if an inhibitory receptor is engaged (instead of the costimulatory receptor), than the cell becomes anergic. APCs presenting self antigens have low levels of costimulatory molecules or none at all and therefore selfantigen presenting cells mostly lead to anergy of the T cells.
How is anergy succeeded in B cells?
When a mature B cell encounters self antigen in peripheral tissues, especially in the absence of specific helper T cells, these B cells become unable to respond to the antigen.
What’s the importance of regulatory T cells during peripheral tolerance?
They have inhibitory activity and may be mediated in part by the secretion of immunosuppressive cytokines such as IL-10 and TGF-β. They also express CTLA-4, which may bind to B7 molecules on APCs and reduce
their ability to activate T cells via CD28.
T cells that recognize self antigens may receive signals that promote their death by apoptosis. What is postulated about T cells recognizing self antigens?
If T cells recognize self antigens,
they upregulate a pro-apoptotic member of the Bcl-2
family called Bim, which triggers apoptosis by the mitochondrial pathway.
Just read.
Another mechanism of
apoptosis involves the death receptor Fas (a member of
the TNF receptor family), which can be engaged by its
ligand coexpressed on the same or neighboring cells.
The importance of this pathway of self-tolerance is illustrated by the discovery that FAS mutations are responsible for an autoimmune disease called the autoimmune
lymphoproliferative syndrome (ALPS), characterized by
lymphadenopathy and production of autoantibodies.
Some self antigens are hidden (sequestered) from the immune system, because the tissues in which these antigens are located do not communicate with the blood
and lymph. What can result from this?
Normally, these antigens fail to elicit immune respons and therefore are ignored by the immune system. If the antigens are released from these tissues, for example, as
a consequence of trauma or infection, the result may be
an immune response that leads to prolonged tissue
inflammation and injury
What parts of the body are immune-priviliged sites (sites where antigens can be found that don’t initate immune respons)?
In testis, eye and brain.
Breakdown of self-tolerance and development of autoimmunity is a result from combined effects. What are these effects?
Susceptibility genes and environmental factors (infections, tissue injury)
There is abundant evidence that inherited genes
play a role in the development of autoimmune diseases. What evidence is there?
-Autoimmune diseases have a tendency to run in families, and there is a greater incidence of the same disease
in monozygotic than in dizygotic twins.
- Several autoimmune disease are linked to the HLA-locus.
-GWAS and linkage studies in families are revealing many genetic polymorphisms that are associated with different autoimmune
diseases. Some of these genetic variants are
disease-specific, but many of the associations are seen in multiple disorders, suggesting that they affect general
mechanisms of immune regulation and self-tolerance.
