Pharm-Immuno 12&13

Immunologic Tolerance & Autoimmunity

Dr. Saber Hussein

Objectives1.Define and explain the concept of immunologic

tolerance

2.Categorize the conditions that influence tolerance induction

3.Know the mechanisms that induce self-tolerance

4.Know the benefits & disadvantages of tolerance

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 its

chemical 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 with Mycobacterium tuberculosis, the tuberculin test becomes negative

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) and are deleted

• Peripheral tolerance – Mature self-reactive

lymphocytes may be inactivated or deleted by encounter with self antigens in peripheral lymphoid tissues

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 same

Ag even in an immunogenic form

• Some Ags are ignoredby lymphocytes, resulting in no response, but the lymphocytes are capable of responding to the same antigen in an immunogenic form

Fig 9-1

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

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 level

iii. The T-cell-B-cell cooperative level

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-cell development 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-tolerant because all thymocytes whose TCRs show strong recognition of self Ags are eliminated

IL-2 synthesis is controlled by costimulatory signals

• CTLA-4 is a CD28 homologue that is synthesized after the activation of T cell.

• When CTLA-4 ligates B7 it blocks activation signals – that is No more IL-2

is synthesized leading to cell death

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 of pre-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

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

Advantages & disadvantages of tolerance

• Advantages 1. Self-tolerance is essential for the function of the immune

system

2. Tolerance to foreign tissue grafts

3. Gene therapy

4. Control of damaging immune responses such as:i. Hypersensitivity

ii. Autoimmune diseases

• Disadvantages

1. Tolerance to certain foreign antigens that cause disease such as bacterial infections

2. Tolerance to some self-antigens associated with cancer

Autoimmunity/Objectives• Define autoimmunity• Know the multiple etiologies for autoimmune disease

and 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 the preventive approaches to specifically eliminate the causes

Autoimmunity, definition, mechanism• Autoimmunity:

– The immune response of the body with

• antibodies or • cell-mediated

immunity – to self-tissues or

antigens, • resulting in

pathological consequences and

• autoimmune disease

Etiologies of autoimmune diseases• Genetic factors:

– Involvement of genetics is evidenced by the fact that monozygotic twins, 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 are

sequestered from the lymphoid system. Examples:

• Lens and uveal proteins of the eye• Spermatozoa.

– Accidents might end the sequestration of such Ags leading to autoimmunity

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-Ab production

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 of presenting their Ag to TH They become APC

Mechanisms of bypassing the absence of TH cells

1. 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 disease

4. Bacteria and EBV can act as adjuvant leading to polyclonal activation and autoimmune response

Postulated mechanisms of autoimmunity

• In this proposed model of an organ-specific T cell-mediated auto-immune disease, various genetic loci may confer susceptibility 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

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)

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 of CTLA-4-B7 interactions,

the T cell fails to respond and is rendered incapable of responding even if the antigen is subsequently presented by costimulator-expressing APCs

Fig 9-5

Activation-induced death of T cells

1. T cells respond to Ag presented by normal APCs by – secreting IL-2, – expressing anti-apoptotic proteins,

and – undergoing proliferation and

differentiation. 2. Restimulation of recently activated T

cells by Ag leads to: – coexpression of Fas and FasL, – engagement of Fas, and – apoptotic death of the T cells– FasL on one T cell may engage Fas

either • on a neighboring cell or • on the same cell

3. Fas-independent activation-induced cell death of immature T cell results from expression of intracellular pro-apoptotic proteins because of – Ag recognition by T cells without

costimulation or– innate immunity

Fig9-61

2

3

Death R.

T cell-mediated suppression of immune

responses

• In a normal response, T cells recognize Ag and proliferate and differentiate into effector cells

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

differentiation of the naive T cells into TH1 effectors that produce IFN-γ and activate macrophages in the effector phase of the response

• Some T cells may differentiate into regulatory cells in the peripheral tissues or the thymus

• Regulatory cells inhibit the activation and differentiation of naive T cells– by contact-dependent mechanisms, or – they may secrete cytokines that

inhibit the effector phase of T cell responses

Fig9-7

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 antigens

stimulate T cell-mediated immune responses?

Fig 9-8

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 bone marrow is

• killed by apoptosis or

• Receptor editing:– changes its antigen receptor by making a new light chain with

different specificity

Fig9-9

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

Autoimmune disease association with alleles of MHC locus

Several lines of evidence support such association:• Family and linkage studies show that individuals who inherit

particular HLA alleles are more likely to develop some autoimmune diseases than individuals lacking these alleles ("relative risk").

• Selected examples of HLA disease associations are listed. For instance, individuals who have the HLA-B27 allele are 90 to 100 times more likely to develop the disease ankylosing spondylitis than B27-negative individuals; other diseases show varying degrees of association with other HLA alleles.

• Breeding studies in animals have shown that the incidence of some autoimmune diseases correlates strongly with the inheritance of particular MHC alleles (e.g., insulin-dependent [type 1] diabetes mellitus with the mouse class II allele called I-Ag7).

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

Ankylosing spondylitis

• Progressive deformity due to ankylosing spondylitis over a period of 26 years

Association of autoimmune diseases with alleles of the MHC locus

MHC II allele

Fig9-11

Skin disease characterized by groups of itching blisters

The roles of some

non-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

Mechanisms by which microbes

may promote auto-

immunity

A. Normally, encounter of mature T cells with self Ags presented by resting APCs results in peripheral tolerance by anergy or deletion

B. Microbes may activate the APCs to express costimulators; and when these APCs present self Ags, the specific T cells are activated rather than rendered tolerant.

C. Some microbial Ags may cross-react with self antigens (mimicry) • Therefore, immune responses initiated by the microbes may become

directed at self cells and tissues • Molecular mimicry applies to T cells and self-reactive B cells

Fig.9-13

Autoimmune diseases1. Antibody-mediated autoimmunity

1. Autoimmune hemolytic anemia2. Myasthenia gravis3. Graves' disease

2. Immune complex-mediated autoimmunity1. Systemic lupus erythematosus (SLE)

3. T-Cell-mediated autoimmunity:1. Multiple sclerosis2. Type I diabetes mellitus3. Hashimoto's thyroiditis

4. Antibody- & T-cell-mediated autoimmune disease

1. Rheumatoid arthritis

Myasthenia gravis

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 contain

rheumatoid factor and normal IgG, which attract PMN causing inflammation

• In active disease the patients have – low titers of complement and – high titers of rheumatoid factor