Immuno12 &13 Tolerance & Autoimmunity

8/7/2019 Immuno12 &13 Tolerance & Autoimmunity

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Pharm-Immuno 12&13

Immunologic Tolerance &

AutoimmunityDr. Saber Hussein


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Objectives

1.Define and explain the concept of immunologictolerance

2.Categorize the conditions that influence tolerance

induction3.Know the mechanisms that induce self-tolerance

4.Know the benefits & disadvantages of tolerance


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Tolerance & Anergy

Tolerance: The acquisition of a specific nonresponsiveness to a

molecule recognized by the immune system as nonself

Tolerogen:

An otherwise immunogenic substance that, because of itschemical composition, dose, or route of introduction,induces immunologic tolerance rather than immunity

Anergy:

An absence of cell-mediated immune reaction in supposedly

sensitized animals or individuals. No allergic response to an

immunogen or allergen

In advanced cases of TB, infections withMycobacterium

tuberculosis, the tuberculin test becomes negative


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Central & peripheral

tolerance to self Ags

Central tolerance

Immature lymphocytes

specific for self Ags

may encounter these

Ags in the generative

lymphoid organs (bone

marrow & thymus) andare deleted

Peripheral tolerance

Mature self-reactive

lymphocytes may be

inactivated ordeleted

by encounter with self

antigens in peripheral

lymphoid tissues


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Consequences of the lymphocyte-Ag encounter Naive lymphocytes may be activated to proliferate and differentiate

by immunogenic antigens Tolerance is induced when tolerigenic antigens induce

functional anergy (unresponsiveness) or

apoptosis, leading to an inability of the cells to again respond to the sameAg even in an immunogenic form

Some Ags are ignored

by lymphocytes,

resulting in no

response, but the

lymphocytes arecapable of responding

to the same antigen in

an immunogenic form

Fig 9-1


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Tolerance

induction

Tolerance is a

secondary

"nothing"

response

Conditions that influence tolerance induction:

1. The immunologic maturity of an animal & its immune cells

2. The dose of Ag

3. The physico-chemical nature of the Ag

4. Immunogenicity of an Ag

5. Route of Ag administration

6. Kind of recipient


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Mechanisms that induce self-tolerance

Three principal mechanisms that induce self-tolerance:

[1] Physical elimination or clonal deletion

[2] Functional inactivation, anergy

[3] Regulated inhibition of Ag-reactive T & B cells Induction of self-tolerance can occur at three levels:

i. The T-cell level

ii. The B-cell leveliii. The T-cell-B-cell cooperative level


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T Cell Positive & Negative Selection in the Thymus

MHC-restriction is not preprogrammed into T cells

It is acquired

(a)by contact with humoral factors and

(b)by physical interaction of TCR-expressing cells

with MHC molecule-expressing cells during T-celldevelopment in the thymus

Positive and negative thymic selection is a life or

death process for the developing T cell:

Positive selection for self-MHC-restricted cells Negative selection of autoreactive T cells

Mature T cells are self-MHC-restricted and self-

tolerantbecause all thymocytes whose TCRs show

strong recognition of self Ags are eliminated


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IL-2 synthesis is controlled by

costimulatory signals CTLA-4 is a CD28

homologue that issynthesized after the

activation of T cell.

When CTLA-4ligates B7 it blocksactivation signals

that is No more IL-2is synthesizedleading to cell death


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Ags can induce any of the following:

1. Clonal abortion:1. multivalent antigen can, when given in appropriate

concentrations, cause immature B cells to abort by

preventing their further differentiation

Tolerizability ofpre-B cells is high Clonal deletion:

very strong negative signals (missing Ag; absence of TH)

can cause deletion of mature B cells

Clonal anergy: intermediate concentration of multivalent antigen allows

pre-B cells to develop into morphologically normal B

cells, with normal numbers of immunoglobulin receptors,

but renders them profoundly anergic


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T cell & B cell tolerance Because the thymus activity decreases into adulthood most T cell lines

are present after birth

The clone that dies or becomes tolerant will not or only slowly be

replaced with active T cells T cell tolerance stays for long time

B cells are made life long in the bone marrow

Later encounter with immunogenic Ag would activate the new B cells

B cell tolerance

is shorter


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Advantages & disadvantages of tolerance

Advantages1. Self-tolerance is essential for the function of the immune

system

2. Tolerance to foreign tissue grafts

3. Gene therapy4. Control of damaging immune responses such as:

i. Hypersensitivity

ii. Autoimmune diseases

Disadvantages1. Tolerance to certain foreign antigens that cause disease such

as bacterial infections

2. Tolerance to some self-antigens associated with cancer


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Autoimmunity/Objectives Define autoimmunity

Know the multiple etiologies for autoimmune diseaseand the central role of helper T cells

Describe

cell-mediated autoimmunity leading to autoimmune

disease antibody-mediated autoimmunity leading to

autoimmune disease

List other factors that may lead to autoimmune

disease Discuss some of the approaches used in the

treatment of autoimmune diseases; appreciate thepreventive approaches to specifically eliminate the

causes


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Autoimmunity, definition, mechanism

Autoimmunity:

The immuneresponse of the

body with

antibodies or

cell-mediatedimmunity

to self-tissues or

antigens,

resulting inpathological

consequences

and

autoimmune

disease


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Etiologies of autoimmune diseases Genetic factors:

Involvement of genetics is evidenced by the fact that monozygotictwins, dizygotic twins and family members have increased

predisposition for certain diseases. Such inheritance is polygenic.

Examples:

SLE (anti-dsDNA Abs)

Type 1 diabetes (>14 genes are involved)

HLA genes are associated with several autoimmune diseases

Environmental factors:

They trigger autoimmune diseases. There are Ags that aresequestered from the lymphoid system. Examples:

Lens and uveal proteins of the eye

Spermatozoa.

Accidents might end the sequestration of such Ags leading toautoimmunity


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Tolerance Autoimmunity1. Absence of TH cells:

Low dose of Ag T-cell

tolerance

B cells are not affected

but because TH is

lacking No auto-Abproduction

2. Control by Ts

3. Absence of MHC II on

potential target cells

1. Bypass of TH absence

leads to autoimmunity

2. Impairment of Ts can

lead to autoimmune

response as result of

primary

immunodeficiency or

anti-Ts Abs

3. Gaining the ability ofpresenting their Ag to

TH They become

APC


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Mechanisms of bypassing the

absence of TH cells1. Provision of an altered determinant capable

of activating TH cells

2.

Polyclonal activation of B cells3. Bacterial & viral infections:

Streptococcal infections elicit Ab that cross-reacts with normal tissue of the heart

leading to autoimmune disease4. Bacteria and EBV can act as adjuvant leading

to polyclonal activation and autoimmuneresponse


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Postulated mechanisms of autoimmunity

In this proposed model of an

organ-specific T cell-mediatedauto-immune disease, variousgenetic loci may confersusceptibility to autoimmunity,

probably by influencing the

maintenance of self-tolerance Environmental triggers, such as

infections and

other inflammatory stimuli

promote the influx of lymphocytes

into tissues and

the activation of self-reactive T cells,

resulting in tissue injury

Fig 9-3


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Central T cell tolerance

Negative selection, or deletion Strong recognition of self antigens by immature T cells in the

thymus may lead to death of the cells

Development of regulatory T cells that enter peripheral tissues

May result from self-antigen recognition in the thymus

Fig 9-4 (CD4 & DC8)


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T cell

anergy

An antigen presented by costimulator-expressing antigen-presenting cells (APCs) induces a normal T cell response.

If the T cell recognizes antigen without costimulation, or

in the presence ofCTLA-4-B7 interactions,

the T cell fails to respond and is rendered incapable of respondingeven if the antigen is subsequently presented by costimulator-

expressing APCs

Fig 9-5


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Activation-induced

death of T cells

1. T cells respond to Ag presented bynormal APCs by

secreting IL-2,

expressing anti-apoptotic proteins,

and undergoing proliferation and

differentiation.

2. Restimulation ofrecently activated Tcells by Ag leads to:

coexpression ofFas and FasL,

engagement of Fas, and apoptotic death of the T cells

FasL on one T cell may engage Faseither

on a neighboring cell or

on the same cell

3. Fas-independent activation-induced celldeath ofimmature T cell results fromexpression of intracellularpro-apoptoticproteinsbecause of

Ag recognition by T cells withoutcostimulation or

innate immunity

Fig9-61

2

3

Death R.


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T cell-mediated

suppression of immune

responses

In a normal response, T cellsrecognize Ag and proliferate anddifferentiate into effector cells

A typical TH1 response APCs secrete IL-12, which stimulates

differentiation of the naive T cells intoTH1 effectors that produce IFN- andactivate macrophages in the effectorphase of the response

Some T cells may differentiate intoregulatory cells in the peripheraltissues or the thymus

Regulatory cells inhibit the

activation and differentiation ofnaive T cells

by contact-dependent mechanisms, or

they may secrete cytokines thatinhibit the effector phase of T cellresponses

Fig9-7


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Tolerance or activation? Features of protein antigens that influence the choice between T

cell tolerance and activation

Why the self antigens induce tolerance and microbial antigensstimulate T cell-mediated immune responses?

Fig 9-8


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Negative selection and receptor editing in

immature B lymphocytes

An immature B cell that strongly recognizes self antigens

E

.g. a multivalent self Ag with several epitopes in the bonemarrow is

killedby apoptosis or

Receptor editing:

changes its antigen receptor by making a new light chain with

different specificity

Fig9-9


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Peripheral

tolerance in

B cells

A. A mature B cell that recognizes a self Ag without T cell help is

functionally inactivated & becomes incapable of responding to

that Ag

B. B cells that are partially activated by recognition of self Ags

without T cell help may be excluded from lymphoid follicles and

may die by apoptosis because they are deprived of survival

stimuli

Fig9-10


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Autoimmune disease association with alleles of MHC locus

Several lines of evidence support such association:

Family and linkage studies show that individuals who inheritparticular HLA alleles are more likely to develop someautoimmune diseases than individuals lacking these alleles ("relativerisk").

Selected examples of HLA disease associations are listed. For

instance, individuals who have the HLA-B27 allele are 90

to100

times more likely to develop the disease ankylosing spondylitisthan B27-negative individuals; other diseases show varying degreesof association with other HLA alleles.

Breeding studies in animals have shown that the incidence of someautoimmune diseases correlates strongly with the inheritance of

particular MHC alleles (e.g., insulin-dependent [type 1] diabetesmellitus with the mouse class II allele called I-Ag7).

Genome scanning studies have also revealed the association of MHCwith autoimmune diseases in humans and mice (e.g., HLA-DR andtype 1 diabetes in humans). See next, Fig9-11:


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Ankylosing spondylitis Progressive deformity due to ankylosing

spondylitis over a period of 26 years


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Association of autoimmune diseases with alleles of the

MHC locus

MHC IIallele

Fig9-11

Skin disease characterized by

groups of itching blisters


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The roles

of somenon-MHC

genes in

auto-

immunity

Some genes other than MHC genes may contribute to the

development of autoimmune diseases.

Lpr = Mouse mutation "lymphoproliferation"

gld = "generalized lymphoproliferative disease

AICD, activation-induced cell death

ALPS, autoimmune lymphoproliferative syndrome

AutoImmuneRegulator

polyEndocrine

Fig9-12


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Mechanisms

by which

microbesmay promote

auto-

immunityA. Normally, encounter of mature T cells with self Ags presented by

resting APCs results in peripheral tolerance by anergy ordeletion

B. Microbes may activate the APCs to express costimulators; and

when these APCs present self Ags, the specific T cells are activatedrather than rendered tolerant.

C. Some microbial Ags may cross-react with self antigens (mimicry)

Therefore, immune responses initiated by the microbes may becomedirected at self cells and tissues

Molecular mimicry applies to T cells and self-reactive B cells

Fig.9-13


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Autoimmune diseases1. Antibody-mediated autoimmunity

1. Autoimmune hemolytic anemia2. Myasthenia gravis

3. Graves' disease

2. Immune complex-mediated autoimmunity

1. Systemic lupus erythematosus (SLE)3. T-Cell-mediated autoimmunity:

1. Multiple sclerosis

2. Type I diabetes mellitus

3. Hashimoto's thyroiditis4. Antibody- & T-cell-mediated autoimmune

disease1. Rheumatoid arthritis


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Myasthenia

gravis


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Rheumatoid Arthritis

Chronic, inflammatory joint disease. Serum and synovial fluid of patients contain

Rheumatoid factor

IgM and IgG antibodies bound to Fc fragment of

normal IgG

Synovial membranes and blood vessels containrheumatoid factor and normal IgG, which attractPMN causing inflammation

In active disease the patients have

low titers of complement and

high titers of rheumatoid factor

Immuno12 &13 Tolerance & Autoimmunity

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