Immune Regulation & Tolerance Flashcards
Antigen Effects
Generation of an immune response depends on the dose, timing, and nature of the antigen.
- Presence of antigen / controlled antigen removal by immune system
- Antigen concentration / dose
- Very large doses of Ag = tolerance
- Very, very low doses of Ag = fail to reach threshold for activation
- Antigen route
- Ag given by subcutaneous or intradermal injection tend to induce more active response
- Ag given IV, PO, or inhaled has increased chance of an altered or tolerogenic response
Cytokine Effects
Cytokines have a profound impact on regulation of the immune response.
Forms an extracellular communication network between cells.
- IFN-α/β
- Produced during viral infection
- Increases class I MHC
- NK cell activation
- Indirectly promotes TH1 pathway through NK cell and macrophage cytokines.
- IL-4
- Promotes TH2 pathway
- Promotes Ab production by B cells
- High [TGF-β] with low IL-6 and IL-23
- Production of TREG cells
Immune Development Effects
Immune system more likely to be tolerized during prenatal and neonatal periods than in adults.
Antibody Effects
Pre-existing IgG antibodies inhibits production of Ab with similar reactivity.
- High affinity IgG antibodies compete with B cells for Ag.
-
Anti-idiotype network model
- Anti-antibodies (Ab-2) can arise in later stages of an immune response to foreign Ag
- Ab-2 can recognize variable regions on Ab-1 elicited previously
- Ab-2 = anti-diotypes
- Variable regions on Ab-1 = idiotypes
FcγRIIB-1
Receptors
Cross-linking of FcγRIIB-1 receptors on naïve B-cells by IgG inhibits activation.
Prevents low affinity IgM from being produced if high affinity IgG is already being made by other B-cells with similar reactivities.
APC Effects
Characteristics of cell or APC presenting Ag to naïve celsl can impact whether response robust or tolerogenic.
MHC and B7 expression varies by cell type and activation.
Stimulation of PRRs by PAMPs and DAMPs increases expression of MHC & B7 shifting towards a more active response.
B-cell
Down Regulatory Receptors
-
CD22
- Found on mature B cells and some immature B cells
- Inhibitory receptor for BCR signaling
- Prevents overactivation of the immune system and development of autoimmune diseases
-
FcγRIIB-1 receptors
- Cross-linking by IgG on naive B-cells inhibits activation.
CTLA-4
Both CD-28 and CTLA-4 found on T-cells.
- CD-28:B7 delivers secondary activating signal to T-cell.
- CTLA-4:B7 delivers inhibitory signal causing anergy.
- Regulation of both CD-28 and CTLA-4 on mature primed T-cells important in control of auto-reactive T-cells.
Selective Cell Migration
Immune regulation involves the spatial and temporal recruitment of different cell types.
Occurs through differential expression of chemokines and cellular adhesion molecules.
Ex.
- Innate immunity
- TH1, TH2, TH17 cells express different combinations of chemokine receptors and are recruited in different circumstances.
Neuroendocrine Regulation
There is extensive communication between the immune system and the neuroendocrine system.
- Innervation of primary and secondary lymphoid organs by ANS.
- Many hormones exert direct & indirect effects on the immune system.
-
Stress responses
- Corticosteroids → immunosuppresive
- Endorphins → either immunosuppresive or immunostimulatory
-
IL-1 and IL-6
- Induce production ACTH → corticosteroid release
- Inhibition of TH1 cytokine production
- Promotes induction of TGF-β
- Increase body temp
- Suppresses appetite
- Enhance duration of slow-wave sleep
- Growth hormone
- Prolactin
- Thyroxine
-
Stress responses
Genetic Impact
on
Immune Response
Possible genetic impact on individual susceptibility to infection, allergy, and autoimmunity.
Proposed mechanisms:
-
MHC haplotype impacts
- Peptide presentation
- Thymic education
-
Non-MHC genes in the MHC region
- HLA locus encodes > 100 genes including
- complement components (C4, C2, factor B)
- cytokines (TNF-α)
- compnents of Ag processing and presentation (TAP)
- heat shock proteins
- HLA locus encodes > 100 genes including
- Genes outside of MHC
Immunogenic Tolerance
The ACQUIRED inability of an individual to respond to a particular antigen.
- Ag specific
- Induced following T/B cell exposure to Ag
- Tolerogen = Ag in which tolerance was induced
Ignorance
Immune system doesn’t react to the antigen because it doesn’t “see” the antigen.
Throught to be a mechanism of autommune avoidance.
Factors Promoting Tolerance
- High doses of Ag
- Persistent of Ag in the host
- IV or PO administration
- Absence of adjuvants
- Substances added to increase the body’s response
- Ex. aluminum gels or salts in vaccines
- Low levels of costimulators
Characteristics of Tolerance
- Shows Ag specificity
- Shows memory
- Is not merely the absence of immunity
- Can be induced more readily in immnature than in mature lymphocytes
- Can be broken