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Retno Murwanti, DVM, MSc, PhD.! Dept. of Pharmacology and Clinical Pharmacy! Faculty of Pharmacy! Universitas Gadjah Mada! 2013


Immunologic Tolerance


Immunologic Tolerance
!Antigens that induce tolerance are
called tolerogens, or tolerogenic antigens, to distinguish them from immunogens, which generate immunity. !

!Tolerance to self antigens, also

Immunologic tolerance is dened as unresponsiveness to an antigen that is induced by previous exposure to that antigen.

called self-tolerance, is a fundamental property of the normal immune system. !

!Failure of self-tolerance results in

immune reactions against self (autologous) antigens, called autoimmunity, and the diseases they cause are called autoimmune diseases. !

!Elucidating the mechanisms of selftolerance is the key to understanding the pathogenesis of autoimmunity.

General Features of Immunologic Tolerance

Normal individuals are tolerant of their own (self) antigens because the lymphocytes that recognize self antigens are killed or inactivated or the specicity of these lymphocytes is changed! Tolerance results from the recognition of antigens by specic lymphocytes.! Self-tolerance may be induced in immature self-reactive lymphocytes in the generative lymphoid organs (central tolerance) or in mature lymphocytes in peripheral sites (peripheral tolerance)! Central tolerance occurs during the maturation of lymphocytes in the central (generative) lymphoid organs, where all developing lymphocytes pass through a stage at which encounter with antigen may lead to cell death or replacement of a self-reactive antigen receptor with a new one.

General Features of Immunologic Tolerance

Peripheral tolerance occurs when, as a consequence of recognizing self antigens, mature lymphocytes become incapable of responding to that antigen, or are induced to die by apoptosis, or mature T cells are actively suppressed by regulatory T cells! Whether lymphocytes that recognize antigens become activated or tolerant is determined by the properties of the antigens, the state of maturation of the antigen-specic lymphocytes, and the types of stimuli received when these lymphocytes encounter self antigens! Some self antigens may be ignored by the immune system! Foreign antigens in the absence of costimulatory signals may inhibit immune responses by inducing tolerance in specic lymphocytes.! The induction of immunologic tolerance may be exploited as a therapeutic approach for preventing harmful immune responses.

T Lymphocyte Tolerance
Tolerance in CD4+ helper T lymphocytes is an effective way of preventing immune responses to protein antigens because helper T cells are necessary inducers of both cell-mediated and humoral immune responses to proteins.! Immunologists have also developed experimental models for studying tolerance in CD4+ T cells that have proved to be quite informative. ! Many of the therapeutic strategies that are being developed to induce tolerance to transplants and autoantigens are targeted to these T cells.

Tolerance in T Cells

Central Tolerance in T Cells

During their maturation in the thymus, many immature T cells that recognize antigens with high avidity are deleted and some of the surviving cells in the CD4+ lineage develop into regulatory T cells ! Some self-reactive CD4+ T cells that see self antigens in the thymus are not deleted but instead differentiate into regulatory T cells specic for these antigens

Central T Cell Tolerance

Recognition of self antigens by immature T cells in the thymus may lead to death of the cells (negative selection, or deletion) or the development of regulatory T cells that enter peripheral tissues.

Peripheral Tolerance in T Cells

Peripheral tolerance is the mechanism by which mature T cells that recognize self antigens in peripheral tissues are rendered incapable of subsequently responding to these antigens. ! Peripheral tolerance mechanisms may be responsible for T cell tolerance to tissue-specic self antigens, especially those that are not abundant in the thymus. The same mechanisms may induce unresponsiveness to tolerogenic forms of foreign antigens. ! The mechanisms of peripheral tolerance are anergy (functional unresponsiveness), suppression, and deletion (cell death)

Mechanisms of peripheral T cell tolerance.

The signals involved in a normal immune response (A) and the three major mechanisms of peripheral T cell tolerance (B) !

Mechanisms of T cell anergy.

" T cell responses are induced when the cells recognise an antigen presented by a professional antigen-presenting cell (APC) and activating receptors on the T cells recognise costimulators on the APCs! " If the T cell recognises a self antigen without costimulation, the T cell becomes unresponsive to the antigen because of a block in signaling from the TCR complex or engagement of inhibitory receptors ! " The signaling block may be the result of recruitment of phosphatases to the TCR complex or the activation of ubiquitin ligases that degrade signaling proteins. ! " The T cell remains viable but is unable to respond to the self antigen. DC, dendritic cel

Regulatory T Cell!
Regulatory T cells are generated by self antigen recognition in the thymus (natural regulatory cells) and by antigen recognition in peripheral lymphoid organs (inducible or adaptive regulatory cells). ! The development and survival of these regulatory T cells require IL-2 and the transcription factor FoxP3. ! In peripheral tissues, regulatory T cells suppress the activation and effector functions of other, self-reactive and potentially pathogenic lymphocytes.

Mechanisms of Action ! of Regulatory T Cells

Regulatory T cells suppress immune responses at multiple steps-at the induction of T cell activation in lymphoid organs as well as the effector phase of these responses in tissues. Although several mechanisms of suppression have been described, the two that are supported by the most data involve inhibitory cytokines and a contactmediated effect on APCs.! Regulatory T cells produce IL-10 and TGF-# both of which inhibit immune responses.! Regulatory T cells inhibit the ability of APCs to stimulate T cells.

Regulatory T cells

a subset of CD4+ T cells whose function is to suppress immune responses and maintain selftolerance.

B Lymphocyte Tolerance

Tolerance in B lymphocytes is necessary for maintaining unresponsiveness to thymus-independent self antigens, such as polysaccharides and lipids. ! B cell tolerance also plays a role in preventing antibody responses to protein antigens. ! Experimental studies have revealed multiple mechanisms by which encounter with self antigens may abort B cell maturation and activation.

Central tolerance in B cells

Immature B cells that recognise self antigens in the bone marrow with high avidity die by apoptosis or change the specicity of their antigen receptors.! Weak recognition of self antigens in the bone marrow may lead to anergy (functional inactivation) of the B cells

Peripheral tolerance in B cells.

B cells that encounter self antigens in peripheral tissues become anergic or die by apoptosis. In some situations, recognition of self antigens may trigger inhibitory receptors that prevent B cell activation.!

Tolerance Induced By Foreign Protein Antigens

Foreign antigens may be administered in ways that preferentially induce tolerance rather than immune responses.! Understanding how to induce tolerance by antigen administration is the key to developing antigen-specic tolerance as a treatment strategy for immunologic diseases. !

In general, protein antigens administered subcutaneously or intradermally with adjuvants favor immunity, whereas high doses of antigens administered systemically without adjuvants tend to induce tolerance. ! Reason : adjuvants stimulate innate immune responses and the expression of costimulators on APCs, and in the absence of these second signals, T cells that recognize the antigen may become anergic or die or may differentiate into regulatory cells. ! Many other features of antigens, and how they are administered, may inuence the balance between immunity and tolerance! The oral administration of a protein antigen often leads to suppression of systemic humoral and cell-mediated immune responses to immunization with the same antigen (oral tolerance)! Some systemic infections (e.g., with viruses) may initiate an immune response, but the response is impaired before the virus is cleared, resulting in a state of persistent infection. In this situation, virus-specic T cell clones are present but do not respond normally and are unable to eradicate the infection.

T cells can directly inhibit the activation of CD8 T cells or suppress CD4 helper cells that re required for full CD8+ responses (see Chapter 9). CD8+ T cells that are exposed to hig oncentrations of self antigens may also undergo apoptotic cell death.

Factors That Determine Tolerogenicity of Self Antigens Factors That the Determine the Immunogenicity


Tolerogenicity of Protein Antigens

Features That Favor Stimulation of Immune Responses Short-lived (eliminated by immune response) Subcutaneous, intradermal; absence from generative organs Antigens with adjuvants: stimulate helper T cells High levels of costimulators

Table 14-2. Factors That Determine the Immunogenicity and Tolerogenicity of Protein Antigens Features That Favor Tolerance Prolonged Intravenous, mucosal; presence in generative organs Antigens without adjuvants: nonimmunogenic or tolerogenic Low levels of costimulators and cytokines

Factor Persistence Portal of entry; location Presence of adjuvants Properties of antigenpresenting cells

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Autoimmunity ?
The state of adaptive immune system responsiveness to self antigens that occurs when mechanisms of self- tolerance fail

Early 1900s Paul Erlich :! horor autotoxicus! Immune -mediated inammatory disease

How self tolerance fail?


How self-reactive lymphocyte are activated?

Concepts in autoimmunity
Autoimmunity results from a failure of the mechanisms of selftolerance in T or B cells, which may lead to an imbalance between lymphocyte activation and control mechanisms.! Loss of self-tolerance may result if self-reactive lymphocytes are not deleted or inactivated during or after their maturation and if APCs are activated so that self antigens are presented to the immune system in an immunogenic manner.! Autoimmune diseases may be either systemic or organ specic, depending on the distribution of the autoantigens that are recognized.! Systemic (SLE), Organ specic (MS, diabetes type 1, Myasthenia gravis)! The major factors that contribute to the development of autoimmunity are genetic susceptibility and environmental triggers

Mechanisms associated with autoimmune reactions

Autoimmunity results from a failure of the mechanisms of self-tolerance in T or B cells, which may lead to an imbalance between lymphocyte activation and control mechanisms.! ! Some of the general mechanisms that are associated with autoimmune reactions are the following:! ! Defects in deletion (negative selection) of T or B cells or receptor editing in B cells during the maturation of these cells in the generative lymphoid organs! ! Defective numbers and functions of regulatory T lymphocytes! ! Defective apoptosis of mature self-reactive lymphocytes! ! Inadequate function of inhibitory receptors! ! Activation of APCs, which overcomes regulatory mechanisms and results in excessive T cell activation

Pathogenesis of autoimmunity

Mechanisms of chronicity of autoimmune diseases

Autoimmune diseases tend to be chronic, progressive, and selfperpetuating

T cells and autoimmunity

Genetic Basis of Autoimmunity

HLA-associated disease! Non-HLA associated disease! Single genes abnormality

HLA-associated disease
Individuals inherit multiple genetic polymorphisms - contribute to disease susceptibility - these genes act with environmental factors to cause the diseases! HLA : MHC molecules expressed on the surface of human cells! Among the genes that are associated with autoimmunity, the strongest associations are with MHC genes.! WHY? class II MHC molecules are involved in the selection and
activation of CD4+ T cells, and CD4+ T cells regulate both humoral and cell-mediated immune responses to protein antigens.!

HLA-associated disease : Rheumatoid arthritis, Type 1 diabetes, Multiple schlerosis, Sistemic Lupus Erythematosus, Ankylosing spondylitis, Celiac disease

Non-HLA associated disease

Many of the polymorphisms associated with various autoimmune diseases are in genes that inuence the development and regulation of immune responses. ! Different polymorphisms may either protect against disease development or increase the incidence of the disease. ! Example of Genes involved : PTPN22,NOD2l,Insulin,CD25, IL-23 receptor (IL-23R), andATG16.

Single-Gene Abnormalities
The known genes contribute to the established mechanisms of central tolerance (AIRE), generation of regulatory T cells (FoxP3, IL-2, IL-2R), anergy and the function of regulatory T cells (CTLA-4), and peripheral deletion of T and B lymphocytes (Fas, FasL)

Role of infection in Autoimmunity


Infections may predispose to autoimmunity by several mechanisms:! enhanced expression of costimulators in tissues ! cross-reactions between microbial antigens and self antigens. ! Some infections may protect individuals from autoimmunity, by unknown mechanisms.

Role of infections in the development of autoimmunity

Other Factors in Autoimmunity

Anatomic alterations in tissues, caused by inammation (possibly secondary to infections), ischemic injury or trauma, may lead to the exposure of self antigens that are normally concealed from the immune system. ! Hormonal inuences play a role in some autoimmune diseases.

Systemic Lupus Erythematosus

Prototypic Immune Complex-Mediated Disease! a chronic, remitting and relapsing, multisystem autoimmune disease that affects predominantly women, with an incidence of 1 in 700 among women between the ages of 20 and 60 years. ! The principal clinical manifestations : rashes, arthritis, and glomerulonephritis, but hemolytic anemia, thrombocytopenia, and CNS involvement are also common.! Many different autoantibodies are found in patients with SLE. The most frequent are antinuclear, particularly anti-DNA, antibodies; others include antibodies against ribonucleoproteins, histones, and nucleolar antigens. ! Immune complexes formed from these autoantibodies and their specic antigens are responsible for glomerulonephritis, arthritis, and vasculitis involving small arteries throughout the body. Hemolytic anemia and thrombocytopenia are due to autoantibodies against erythrocytes and platelets, respectively. ! The principal diagnostic test for the disease is the presence of antinuclear antibodies; antibodies against double-stranded native DNA are specic for SLE.

Systemic Lupus Erythematosus

Two recent observations are leading to new hypotheses of the pathogenesis of SLE. ! First, studies in patients have revealed that blood cells show a striking molecular signature (pattern of gene expression) that indicates exposure to IFN-$, a type I interferon that is produced mainly by plasmacytoid dendritic cells. Some studies have shown that plasmacytoid dendritic cells from SLE patients also produce abnormally large amounts of IFN-$. ! Second, studies in animal models have shown that Toll-like receptors (TLRs) that recognize DNA and RNA, notably the DNA-recognizing TLR9, play an important role in the activation of B cells specic for self nuclear antigens.

A model for the pathogenesis of SLE

New Therapies for SLE

Clinical trials are under way to test the efcacy of anti-IFN-$ antibodies ! Inhibition of TLR signals are being considered. ! Depleting B cells by use of an antibody against the B cell surface protein CD20. ! An antibody that blocks the B cell growth factor BAFF is now approved for the treatment of SLE.