Regulation of The Immune System

Introduction

• Immunity mean protection from disease and more specifically, infectious disease.

• The cells and molecules responsible for immunity constitute the immune system

• There are two types of Immunity: • Innate Immunity• Adaptive Immunity

Overview of Immune System

Innate and Adaptive Immune Responses

The inter-talk between innate immunity and acquired immunity

The immune response• Immune response: It is the response made by the host to defend itself against a

pathogen. It is described as appropriate (protective).

• Immune response must be regulated at the following level:

1. Response must be only to foreign antigen and no response to self antigen ……tolerance

2. Which type of immune response must be activated3. Response termination…… Homeostasis

ImmunologicaL Tolerance

• Tolerance is a physiologic state in which the immune system does not react destructively against components of an organism that harbors it or against antigens that are introduced into it.

• Central Tolerance

• Peripheral Tolerance

Central Tolerance through Clonal DeletionClones of cells that have receptors for self-antigens are deleted during

development but…..• If all reactive lymphocytes which are recognizing self Ag are eliminated the

repertoire is too limited!

• Not all peptides of the body are accessible in the thymus

• Some new peptides are expressed later in life.

• One TCR can see many peptides

Peripheral Tolerance– Clonal Anergy-

– Suppression of responses may occur by production of regulatory T cells

– Ignorance to some self antigens may also exist

Central and Peripheral Tolerance

(Absence ofCo-stimulation)

Central toleranceT lymphocyte

• Development of T- Lymphocytes:- develop in BM and mature in the Thymus.- Acquiring TCR and then screened by the two

selective processes: * Positive selection (MHC-restriction) * Negative selection (removing self-

intolerant)

Differentiation of thymocytes

cortex

CD4+8+

double possmall restingthymocyte

CD4-8-

double neglarge & activethymocyte

precursor thymocyte

medullaCD4+

CD8+

Single possmall, restingthymocyte

5%

negativeselection

export tothe periphery

mature naive T cells

positiveselection

apoptosis

95%

Peripheral Tolerance

1. Clonal Anergy-failure of APC to deliver a second signal

during antigen presentation (example: B7-CD28 interaction)

2.Suppression of responses may occur by production of

regulatory T cells that inhibit immune response to self-

antigen (example: TGF-, IL10 and Th1 vs. Th2 cytokines)

3.Ignorance to some self antigens may also exist

T cell activationThe Two Signal Hypothesis for T-cell Activation

Mature Dendritic

cellAPC

TH cell

CD28B7

MHC II TCR

Signal 2

Signal 1

Activated TH cell

Hypothetical mechanism of tolerance in mature T cells

CD28

RestingB-cellAPC

TH0 cell

Tolerance (anergy or apoptosis) from lack of signal 2

Signal 1

Tolerant T cell

Fas

FasL

cytokines

Apoptosis

Inhibition of proliferation &effector action

Activated T cells

NormalResponse

CD28 B7

Proliferation & differentiation

Antigen Recognitionwithout co-stimulation

Anergy

CTLA4 B7

FunctionallyUnresponsiveCTL4-B7 interaction

Fas-FasL interaction

Cytokine-mediated suppression

Activation induced

cell death

Cytokine regulation

Pathways to Peripheral Tolerance

Definition of Regulatory T cells

• Regulatory T cells (sometimes known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens

• The latest research suggests that regulatory T cells are defined by expression of the forkhead family transcription factor FOXP3 (forkhead box p3).

• They are (CD4+) helper T cell population and express high levels of the interleukin-2 receptor alpha chain (CD25).

Treg cell mediated phenomenon• Bystander suppression

– suppressive activity of Treg cells requires their prior activation through their T cell receptor

– once activated, Treg cells suppress in an antigen-nonspecific way

– Treg cells with one antigen specificity can suppress effector T cells (Teff cells) with many other distinct antigen specificities

Suppression mechanisms of Treg cells

• Treg cell influence other T cells

• Treg cell alter APCs

• T cell derived suppression molecules

T cells

DisarmedLoss of CTL effectLoss of IFN-g secretionLoss of graft rejection ability

Lin C-Y; 2002; Nature Immunol

Prevent CD8+T cells from differentiation into effector T cells but not proliferation

in vivo

Alter the differentiation of naïve CD4+T cell into IL-10/TGF- secreting T cells

• Naive CD4+T cell could differentiate into IL-10 or TGF- secreting induced Treg cells in the presence of Treg cells in invivo and in vitro study

Treg cell alter APCs• Treg cell could conjugate with dendritic cells documented by

in vivo two-photon microscopy• Treg cells could alter the dendritic cells functions in the

following ways– DC silencing

– Treg cell expansion: with the help of to TGF- the differentiation of Teff to Treg cells)

Regulatory T cells

FunctionallyUnresponsive T cell

Production of IL-10 or TGF-

RegulatoryT cell

Functions of Treg cells• Homeostatic control

– Prevent potential outgrowth of auto-reactive T cells• Damage control

– Limit the tissue injury during inflammation caused by infection/autoimmune/transplantation

• Infectious Tolerance– Stabilized tolerance during the final stage of inflammation

Concepts of B cell toleranceCenteral tolerance:

•Apoptosis

•Receptor editing……

Peripheral Tolerance•Anergy

•Apoptosis

2.Which type of immune response must be activated?

Important regulatory decisions determine thebranch of the immune system to be activated, the intensity of the response, and its duration..

Cytokines•Involved in initiating immune response •Involved in turning off immune response•Some serve as direct effector molecules (e.g., TNFa)

cytokines of Th1 and Th2 CellsTh1cell

Th2cell

Macrophage B cell

IFNγ

Activates

IL-4 IL-5

IL-10

Activates

Inhibits productionInhibits proliferation

Mast cell Eosinophil

Antibodies (including IgE)

Th1 versus Th2 BalanceDisease Th1 Th2

Experimental Cure Progression

Leishmaniasis

Experimental autoimmune Progression Preventionencephalomyelitis

Tuberculosis Cure/Prevention Progression

Atopy Prevention? Progression

Type 1 Diabetes (NOD) Progression Prevention

3.Homeostasis of Immune System

3.Homeostasis of Immune System

Immune response to foreign antigens are self limited and wane as antigens are eliminated returning the immune system to its basal resting state

During the immune response:•Antiapoptic proteins…….BCL family•Co –stimulator Survival signals•Cytokines

Apoptosis

3.Homeostasis of Immune System

• CTLA-4 may also act as a terminator for immune response

• Fas-Fas ligand

3.Homeostasis of Immune System• Regulation by Antibody• Antibody exerts feedback inhibition on its own production. • There are two explanations for antibody-mediated

suppression.1. Circulating antibody competes with antigen-reactive B cells

for antigen inhibiting the clonal expansion of the B cells.2. Binding of antigen-antibody complexes by Fc receptors on B

cells reduces signaling by the B-cell-receptor complex.

• Vaccine production

3.Homeostasis of Immune System• Network hypothesis• Another means of regulation that has been proposed is the

idiotypic network hypothesis(idiotypes reflect the antigen binding specificity of any particular antibody molecule). This theory suggests that the idiotypic determinants of antibody molecules are so unique that they appear foreign to the immune system and are, therefore, antigenic. Thus, production of antibody in response to antigen leads to the production of anti-antibody in response, and anti-anti-antibody and so on. Eventually, however, the level of [anti]n-antibody is not sufficient to induce another round and the cascade ends

Factors Affecting Tolerance Induction

A. Age: Young immunologically immature animals show tolerance antigen exposure.

1. Immature B cells lack surface IgD and fail to resynthesize IgM receptors after capping.2. Antigen is poorly localized and presented in immature animals

B. Route of exposure: i.v. or oral exposure favors tolerance. S.c. or intradermal favors immunity. Intramuscular favors Th2.

C. Dose of antigen: High doses favor tolerance; however, repeated low doses can also cause tolerance

D. Associated antigens: Coupling of antigens to self Ig or self cells

enhances tolerogenicity. 1. Coupling nucleosides to self carriers can prevent anti-DNA in

genetically autoimmune mice.

• Tolerance can be broken– New clones of T and B cells appear in the absence of

antigen– Viral infection can create a cytokine milieu to turn on

quiescent (anergic) cells– New epitopes are introduced by viral modification

Inappropriate Immune Response

Failure to regulate the immune response:1- Hypersensitivity (exaggerated)2- Immune tolerance (no response)3- Autoimmunity (to self)4- Immune deficiency (absent or functionally defective host

defense).

Inappropriate Immune Response

• Hypersensitivity reactions:Harmful immune responses that produce tissue injury andmay cause serious diseases.The antigen itself may not be harmful.Four types:Allergy (type I): The most serious (IgE- mediated).Type II: IgG- mediated Serum sickness, Arthus reaction (type III)- IgG mediated).Delayed type (type IV)- Specific T cells-mediated).

Inappropriate Immune Response• Autoimmunity:- Specific immunity to self antigens.- Initiated by responses involving T cells.- T cells help to initiate a harmful Ab response.- It is not known what triggers autoimmunity.- Strong association bet. infection & autoimmunity- Susceptibility to autoimmunity is controlled by

environmental & genetic factors.- MHC class II more than MHC class I.

• Some examples of autoimmune diseases• Multiple sclerosis• Myasthenia Gravis• Coeliac disease• Psoriasis• Crohn’s disease• Lupus erythematosus• Rheumatoid Arthritis

Immune deficiency

• Primary (Genetically determined):Early in life (6-24 months).Rare, can be adaptive or innate.Eg thymic hypoplasia (DiGeorge syndrome)

• Secondary (Acquired)Malnutrition, infection, cancer, renal disease,

sarcoidosis, ageing, chemotherapy, autoimmunity.

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