Tolerance and Auto-Immunity Flashcards
Self tolerance
Failure to react against own cells and their components/products
Antigen receptor rearrangement in adaptive immune cells (B and T cells) can result in what?
Some cells recognize self-epitopes, creating potential for auto-reactivity
These self-reactive cells need to be dealt with so they don’t cause autoimmune disease
Immune system balance
Key to functional immune system
Too much reactivity: autoimmune disease, chronic inflammation
Too much tolerance: immunodeficiency, persistent/overwhelming infection
Negative selection
Thymic destruction of self-reactive T cells: strong TCR signaling in response to self-antigen results in apoptosis
Immunologically privileged sites
Tissues that have barriers that normally prevent immune cells from entering
Brain, eye, testes, uterus
AIRE
Autoimmune regulator
Enables central tolerance to tissue-restricted antigens
Under control of AIRE protein, thymic medullary cells express tissue-specific proteins, deleting tissue-reactive T cells
Transcription factor expressed by T regulatory cells
FoxP3
CD4 T cells with strong reactivity to self can become what type of T cells?
T regulatory cells
Function of T regulatory cells
Suppression of peripheral immune responses
Mechanisms of T regulatory suppression
Production of immunosuppressive cytokines
Outcompete effector T cells for IL2, inhibiting their expansion
Interfere with ability of antigen presenting cells to provide activating signals
Peripheral (outside of bone marrow and thymus) mechanisms to control self-reactive T cells
Apoptosis, anergy, regulation
Anergy of T cells
Functional unresponsiveness: diminished ability to divide, produce cytokines, kill target cells
Induced by APCs presenting self-antigen to T cells in absence of inflammation through T cell receptor only, causing anergic tolerance of self-reactive T cells
Tolerance failure of B cells
Auto-antibodies, those directed against self, can result in autoimmune disease
Central tolerance mechanisms of B cells
Death of self-reactive cells
Induction of anergy
Receptor editing: B cell continues light chain rearrangement, producing new BCR
Peripheral tolerance mechanisms of B cells
Induced to die
Become anergic in spleen
B cells that have undergone somatic hypermutation can be tested for auto-reactivity again: those that remain self-reactive undergo apoptosis
Tolerance is more easily induced under what conditions?
Induced during neonatal stage
Oral intake of substance
Examples of tolerance
Tolerance to fetus in pregnancy
Oral tolerance
Tolerance to innocuous foreign substances (dyes, detergents, etc.)
Autoimmune disease is caused by failure of what?
Self-tolerance
Examples of autoimmune diseases
Psoriasis Rheumatoid arthritis Grave's disease Lupus Crohn's disease Multiple sclerosis Type 1 diabetes
Autoimmune disease: incidence
Common, and increasing
What types of cells mediate autoimmune diseases?
B and T cells
Are autoimmune diseases systemic, or organ specific?
Some are systemic (lupus, rheumatoid arthritis)
Some are organ-specific (Crohn’s disease, multiple sclerosis, type 1 diabetes)
Many autoimmune diseases are linked to what gene?
HLA (human leukocyte antigen, encodes MHC)
What gender are autoimmune diseases more common in?
Women
Can environmental factors play a role in autoimmune disease?
Yes- food (gluten, etc.), stress, toxins (smoking, etc.), infection
Do immune alterations and symptoms of autoimmune disease happen at the same time?
No- early environmental exposure can trigger events that later lead to autoimmune disease
How can tissues that are normally protected become targets of autoimmune disease?
Damage to tissues that are normally protected can cause the release of self-antigens
Molecular mimicry and autoimmune disease
Epitopes found in a pathogen can be same as or very similar to self-epitopes
Results in production of cross-reactive antibodies or activation of auto-reactive T cells
Perpetuation and amplification of autoimmune disease
Breach of tolerance leads to more inflammation and self-antigen exposure
Treatment of autoimmune disease
Immunosuppression
Newer treatment: monoclonal antibody therapy (deplete immune cells or block pathologic cytokines)
