Why is regulation of the immune system important?
- over-responsiveness (autoimmunity)
- under-responsiveness (immunodeficiency)
What is immunological tolerance, and what are the general mechanisms by which it is accomplished?
Unresponsiveness to a specific antigen.
- Elimination of reactive cells
- Neutralization of reactive cells
- Generation of suppressive cells
What are the mechanisms of T-cell tolerance?
- Negative selection
- Regulatory T cells
- Clonal anergy
- Activation inhibition
What is negative selection in T cells?
In thymus, TF AIRE triggers the expression of tissue-specific antigens → deletion of autoreactive T cells before they can reach the periphery and cause autoimmunity
What is AIRE?
Thymic transcription factor that triggers the expression of tissue-specific antigens (e.g., insulin), allowing deletion of reactive T cells before they can reach the periphery and cause autoimmunity.
Defective AIRE expression leads to a severe autoimmune disease known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, or APECED.
What are Tregs?
Regulatory T cells (Tregs) are CD4+/CD25+ T cells reactive to self antigen because of TF FoxP3.
Canonical Tregs are generated during thymic selection, possibly because their TCRs possess a strong affinity for self- peptide presented in class II MHC.
To prevent autoimmunity, individual Tregs patrol the body’s tissues, scanning antigen presenting cells (APCs) for expression of their specific self-Ag. If Tregs locate their cognate self-Ag, they will remain with the APC and prevent the activation of potentially autoreactive effector T cells.
How do Tregs perform immune suppression?
- Production of suppressive cytokines (IL-10 and TGFβ)
- Deprivation of T cell proliferative cytokines (IL-2 “sponging”)
- APC killing
- (granzymeA/B → dendritic cell → death)
- Stripping of co-stimulatory molecules from APCs (removal of CD28)
What is clonal anergy?
self-Ag not expressed in the thymus → autoreactive T cell not eliminated by negative selection → solution: clonal anergy
APCs must express the co-stimulatory molecule B7 (ligand for CD28) for T-cell activation to occur. T cells bearing TCRs that recognize Ag (including self-Ag) but do not receive B7 become anergic and cannot be activated by later encounters with the antigen.
What is inhibition of T-cell activation?
Given the importance of B7-CD28 co-stimulation in T cell activation, T-cell responses can be regulated by interfering with co-stimulatory signaling.
Activation → CTLA4 expressed on the T cell surface → CTLA4 binds to APC B7 w/ affinity > CD28 → T-cell activation and proliferation limited
CTLA4-related drugs are used clinically to modulate T cell responses.
What are the mechanisms of B-cell tolerance?
- Clonal deletion
- B-cell anergy
- Functional deletion
- Suppression of activation
What is clonal deletion?
Clonal deletion occurs in the bone marrow to immature B lymphocytes.
Cells express BCRs (essentially, surface IgM) that bind to self-Ag expressed in the marrow → inhibitory signals → cells retained in marrow
A self-reactive immature B cell may edit its receptor via rearrangements to generate a new, non-autoreactive BCR. If successful, maturation continues; if not, apoptosis.
What is B-cell anergy?
A method of B-cell tolerance.
Immature B cells encounter soluble, monovalent (non-crosslinking) self-Ag → autoreactive cells become anergic → cells express IgD at the surface but NOT a functional IgM BCR → cells enter circulation, but brief lifespan
What is functional deletion of B cells?
A method of B-cell tolerance caused by loss of T-cell help for a T-dependent antigen.
CD4+ Helper T cells are essential to B cells: activation, proliferation, affinity maturation, Ig isotype switching, and the determination of whether to become an antibody-secreting plasma cell or memory B cell.
What is suppression by existing antibodies?
Naïve B cells express the inhibitory receptor FcγRIIB1, which delivers a signal to prevent B-cell activation when a secondary response is already underway.
ex) hemolytic disease of the newborn
What is hemolytic disease in the newborn?
Pregnant, Rh- women w/ Rh+ fetuses may generate anti-Rh Abs during subsequent pregnancies, destroying fetal erythrocytes.
Prevented by RhoGAM.
How does antigen immunogenicity influence immunity?
- Strong immunogen → immunity
- Weak immunogen → tolerance
- Relative immunogenicity: protein antigens >> polysaccharides > lipids and nucleic acids
Protein Ags can induce both a humoral (antibody) and cell mediated (T cell) response. Other biomolecules can be recognized by B cells but cannot be presented to T cells.
What are some immunogenic factors that influence immunity?