Immunologic tolerance and regulation of immune response Flashcards
Regulation of the immune response
Adaptive immunity is a sophisticated defense system
Excessive or deficient responses might lead to severe consequences like autoimmunity or immunodeficiency
Tolerance
Lack of response to a specific antigen
Induced by prior exposure to a specific antigen under specific circumstances
Directed mainly to self-antigens
Self does not equal non-self
Self reactive cells are bound to happen, so we need to stop them from generating a response etc
Central tolerance
Immature self reactive lymphocytes in production sites (thymus, bursa, or bone marrow)
Either Delete (identify and delete)
Or
Alter their specificity (B cell only) (bc if T cells are self reactive its eliminated; if B cell is, it gets a second chance to change- if still have a reaction = deletion)
Peripheral tolerance
Mature lymphocytes that react to self-antigens in peripheral sites (lymph nodes, spleen)
Anergy, deletion, or suppressed by T reg cells
Central T cell Tolerance: Positive selection
Recognition of self-MHC molecules = survival
Requirements for functional T cells
If they don’t bind self MHC at all they are destroyed
Central T cell Tolerance: Negative selection
Receptors bind to strongly to self-antigens die by apoptosis
Autoimmune regulator (AIRE)
If bind too strongly they are destroyed
Autoimmune regulator
Transcription regulator active in medullary thymic epithelial cells
Thymic epithelial cells can express genes form other tissues
Leads to the expression of genes for a number of tissue-restricted antigens (TRAs).
Ag not normally found in Thymus but can be found in other parts of body
Provokes the elimination of corresponding self-reactive thymocytes
Regulatory T cells (Treg)
CD4+, CD25+, Foxp3+
nTreg (natural) formed in the thymus and is the majority
iTreg (induced) formed in secondary lymphoid organs, especially the intestine
Secretes IL-10, TGF-B
Inhibition of T cell repsonses
Inhibition of other cells
Peripheral T cell Tolerance
Normal T cell response: DC and T cell had B7/CD28 and TCR = effector and memory T cells
Anergy: functional unresponsiveness
Suppression: Block in activation
Deletion: apoptosis
Clonal anergy
Clonal Anergy
Lack of co-stimulation or inhibitory receptor engagement
-activation of tyrosine kinases and phospholipase C, increase intracellular Ca, increase IkB that inhibits NF-kB
inhibit activation of main transcription factor needed for cytokine production
- decrease cytokine production (IL-2)
IL-2 is needed for proliferation, eventually non-responsive= anergy
Recognition of self antigen, signaling block or engagement of inhibitory receptors, unresponsive (anergic) T cell
Suppression by Treg cels
Express CTLA-4 - block or remove B7 molecules made by APCs and make these APCs incapable of providing costimulation via CD28 and activating T cells
Blocking activation by interferring
CTLA-4 blocks and removes B7 leads to lack of costimulation leads to T cell unresponsiveness
Regulatory cytokines (IL-10, TGF-B) that inhibit the activation of lymphocytes, dendritic cells, and macrophages
High levels of expression of the IL-2 receptor
-bind and consume this T cell growth factor, thus reducing its availability for responding T cells
Interleukin-10
Immunoregulatory cytokine
Inhibits both innate and adaptive immune response
Transforming Growth factor-B
Regulates T cell activation
Regulated B cell function
Other cells
Regulates macrophages
Central B cell tolerance
High-avidity self antigen recognition: Self antigen binds self reactive B cell
Apoptosis-deletion
Receptor editing:expression of new Ig light chain
Non self reactive B cell
Low-avidity self antigen recognition
Self antigen
reduced receptor expression, signaling
Anergic B cell
Central B cell tolerance Receptor editing
Reactivate RAG genes, resume immunoglobulin light chain gene recombination, and express a new Ig light chain with different antigen specificity
If editing fails deletion by apoptosis occur (similar to T cell negative selection)
Low avidity antigens (usually soluble proteins) - B cells survive with reduced receptor expression and become anergic
Peripheral B cell tolerance
Lack of co-stimulation (same as T cells)- wont be activated
- no Th cells or APCs means no Ab production
- PAMPs and TLR in B-cells
Somatic mutations: self reactive B cells can still develop in secondary lymphoid organs
If encounter self Ag in environment that doesnt activate innate immunity, which provides many costimulatory molecules and helps DCs and APCs to become activated, should not respond to- should have this in healthy normal tissue
So no costimulation is enough of a signal not to activate
Factors affecting Tolerance and immunogenicity: Antigen concentration
Antigen concentration
High- too many TCRs occupied (signals you are engaging with an Ag in an exaggerated manner) leads to apoptosis (- selection)
Can induce immune paralysis (wont respond)
Antigen probably bypass APCs and reach the Th cell receptors directly
No costimulation= anergy
Low/intermediate- moderate TCRs occupied -> thymocyte proliferation -> + selection
Too high or too low will induce tolerance
Factors affecting Tolerance and immunogenicity: Avidity model
Very low avidity interaction between T-cell and peptide-MHC will lead to death by neglect
Low/intermediate-avidity interaction will positively select thymocytes
High-avidity interaction will lead to clonal deletion
Factors affecting Tolerance and immunogenicity: favors immune stimulation
Antigen presence: short lived
Portal of entry: subcutaneous; intradermal
Adjuvants: presence: stimulated Th cells
APCs: Mature Dcs: high levels of costimulators
Factors affecting Tolerance and immunogenicity: favors tolerance
Antigen presence: prolonged
Portal of entry: intravenous; mucosal; presence in primary lymphoid organs
Adjuvants: absence: lack of costimulation
APCs: immature DCs: low levels of costimulators
Antigen regulation of Immune responses
Adaptive immune responses are antigen driven
- increase Ag = immune response is prolonged
- decrease Ag = immune response stops
APCs:
- langerhans cells -T cell response
- Follicular DC - B cell response
- DC1 - Th1
- DC2 - Th2
IgG suppress the production of both IgM and IgG
IgM suppress only the synthesis of IgM
Energy cost to produce a lot is high- so want a lot, but need to be smart about it
Inhibitory receptors on B cells
It is critically important to limit and terminate a response
CD32b (FcyRIIb) expressed on B cells
-block signal transduction, prevents B cell activation and triggers apoptosis
Neuroendocrine regulation of immunity
Stress and immune system
Shipping fever
Autonomic nervous system: epinephrin, norepinephrine, acetylcholine
Hypothalamic-pituitaty adrenal cortical axis
-glucocorticoids
