Regulation of the immune response

 

Regulation of the immune response

´ Immune response like all other biological systems in subject to control mechanism

´ This mechanism restore the immune system to a resting state when responsiveness to a given antigen is no longer required

 ´ Factor affecting the intensity of an immune response

1.  The dose

2.  Nature of antigen

3.  Form and route of administration of the antigen

4.  Presence and absence of adjuvant

5.  Antigen presenting cell

6.  Genetic background of individual

7.  History of previous exposure to the antigen in question

• An effective immune response removes antigen from the system completely

Repeated antigen exposure is required to maintain T and B-cell proliferation, and during an effective immune response there is often a dramatic expansion of specifically reactive effector cells.

ü At the end of an immune response, reduced antigen exposure results in a reduced expression of IL-2 and its receptor leading to apoptosis of antigen-specific T-cells

ü Majority of antigen-specific T-cells therefore die at the end of an immune response leaving a minor population of long-lived T-cells and B-cells to survive and give rise to the memory population.

ü Tolerance is failure to respond to that antigen upon subsequent challenge with same antigen

1.    Different antigens elicit different kinds of immune response:

 Intracellular organisms e.g. bacteria, parasites, viruses induce a cell mediated immune response (T-cells, NKC & MQ)

´ Intracellular antigens may not be cleared effectively leading a sustained immune response

´ The pathological consequence is auto-immunity and hypersentivity

´ Extracellular organisms-in extracellular fluids and soluble antigens induce a humoral response

 2. Large dose of adjuvant can cause induce tolerance

´ Very large doses of antigen often result in specific T and sometimes B-cell tolerance. Independent polysaccharide antigens have been shown to generate tolerance in B-cells after administration in high doses.

3. Antigen  route of administration

´ Antigens administered subcutaneously or intradermal evokes an active immune response

´ Antigen given intravenously, orally or as an aerosol may cause tolerance e.g. Lymphocytic choriomeningitis virus (LCMV)-antigen

´ Mice primed subcutaneously with a peptide in incomplete Freund’s adjuvant develop immunity to LCMV.

´  However, when the same peptide/ag is repeatedly injected intraperitoneally, the animal becomes tolerized and cannot clear the virus

4. Antigen presenting cell (APC)

ü The nature of APC initially presenting the antigen may determine whether immune responsiveness or tolerance

ü Effective activation of T-cells require the expression of MHC on the surface of APC

ü Therefore presentation by dendritic cells or MQ express high levels of MHC Class II molecules in addition to co-stimulatory molecules results in highly effective T-cell

ü e.g. a new-born mice injected with spleen cells failed to develop a  CTL response to the male antigen. However,  dendritic cells are injected with new-born mice, a good specific CTL response develops.

5. Adjuvant

´ May facilitate immune response by inducing the expression of high levels of MHC and co-stimulatory molecules of APC.

´ e.g. Ability to activate Langerhans cells, leads to migration of these skin dendritic cells to the local draining lymph nodes where effective T-cell activation occur.

6. Immunoglobulins

´ Administration of IgM antibody titre together with an antigen specifically enhances the immune response to that antigen whereas IgG antibody suppresses the response.

´ The clinical consequence is that certain vaccines (mumps and measles) are not given to infants before one year because levels of maternal IgG remain high for atleast 6 months after birth and the presence of such passively acquired IgG at the time of vaccination would result in development of an inadequate immune response in the baby

´ Results in feedback inhibition of further production of the same antibody.

´  This feedback inhibition operates by simple removal of residual antigen hence limiting the stimulus, levels of circulating antigen, decline sharply following appearance of antibody in circulation as would be expected.

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7. Regulatory T Cells (Tregs): Prevent overactive immune responses by:

 Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells,

 Maintaining Immune Homeostasis: Tregs help to prevent the immune system from overreacting and causing damage to the body-.

maintain tolerance to self-antigens, and prevent autoimmune disease  Prevent the immune system from attacking its own tissues,

Suppressing Immune Responses: Tregs suppress the activity of other immune cells, including effector T cells, B cells, and dendritic cells.

the maturation and function of APCs, which are important for initiating immune responses.

Secretion of Immunoregulatory Cytokines: Tregs release cytokines, signaling molecules that can suppress the activity of other immune cells. E.g. IL-10, TGF-β, and IL-35, and also by consuming IL-2 and inducing cell death

8. Idiotypic Interactions

´ Individual T-cell receptors and immunoglobulin are immunogenic by virtue of diverse unique sequences within the variable region known as idiotypes.

´ Antibodies formed against these antigen binding sites are called anti-idiotypic antibodies and can influence the outcome of an immune response

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9 . Immune Checkpoints: These are regulatory pathways that control immune responses. E.g., the PD-1/PD-L1 pathway is a mechanism that limits the immune response to prevent damage to healthy tissues, but it can also be hijacked by cancer cells to avoid detection