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INFECTIOUS DISEASE

BACTERIOLOGY IMMUNOLOGY MYCOLOGY PARASITOLOGY VIROLOGY

VIDEO LECTURE

 

IMMUNOLOGY - CHAPTER   SIXTEEN 

TOLERANCE AND AUTOIMMUNITY 

Dr Abdul Ghaffar and Dr Prakash Nagarkatti
 

 

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Logo image Jeffrey Nelson, Rush University, Chicago, Illinois  and The MicrobeLibrary
Last major update July 2010

TEACHING OBJECTIVES
 Understand the concept and significance of tolerance
Know the factors which determine induction of tolerance
Understand the mechanism of tolerance induction
Understand the concepts of autoimmunity and disease
Know the features of major autoimmune diseases
Know the theories on etiology of autoimmune disease

TOLERANCE 

Introduction

Tolerance refers to the specific immunological non-reactivity to an antigen resulting from a previous exposure to the same antigen. While the most important form of tolerance is non-reactivity to self antigens, it is possible to induce tolerance to non-self antigens. When an antigen induces tolerance, it is termed tolerogen.

 

Tolerance to self antigens

We normally do not mount a strong immune response against our own (self) antigens, a phenomenon called self-tolerance. When the immune system recognizes a self antigen and mounts a strong response against it, autoimmune disease develops. Nonetheless, the immune system has to recognize self-MHC to mount a response against a foreign antigen. Thus, the immune system is constantly challenged to discriminate self vs non-self and mediate the right response.

 

Induction of tolerance to non-self

Tolerance can also be induced to non-self (foreign) antigens by modifying the antigen, by injecting the antigen through specific routes such as oral, administering the antigen when the immune system is developing, etc. Certain bacteria and viruses have devised clever ways to induce tolerance so that the host does not kill these microbes. Ex: Patients with lepromatous type of leprosy do not mount an immune response against Mycobacterium leprae.

 

Tolerance to tissues and cells

Tolerance to tissue and cell antigens can be induced by injection of hemopoietic (stem) cells in neonatal or severely immunocompromised (by lethal irradiation or drug treatment) animals. Also, grafting of allogeneic bone marrow or thymus in early life results in tolerance to the donor type cells and tissues. Such animals are known as chimeras. These findings are of significant practical application in bone marrow grafting.


 

Tolerance to soluble antigens

A state of tolerance to a variety of T-dependent and T-independent antigens has been achieved in various experimental models. Based on these observations it is clear that a number of factors determine whether an antigen will stimulate an immune response or tolerance (Table 1).

 

Table 1

Factors that determine induction of immune response or tolerance following challenge with antigen

Factors that affect response to Ag

Favor immune response

Favor tolerance

Physical form of antigen

Large, aggregated, complex molecules;

Soluble, aggregate-free, relatively smaller, less complex molecules, Ag not processed by APC or processed by cell without class II MHC

Route of Ag administration

Sub-cutaneous or intramuscular

Oral or sometimes intravenous

Dose of antigen

Optimal dose

Very large (or sometime very small) dose

Age of responding animal

Older and immunologically mature

Newborn (mice), immunologically immature

Differentiation state of cells

Fully differentiated cells; memory T and memory B cells

Relatively undifferentiated: B cells with only IgM (no IgD), T cells (e.g. cells in thymic cortex)

 

Immunologic features of tolerance

Tolerance is different from non-specific immunosuppression and immunodeficiency. It is an active antigen-dependent process in response to the antigen. Like immune response, tolerance is specific and like immunological memory, it can exist in T-cells, B cells or both and like immunological memory, tolerance at the T cell level is longer lasting than tolerance at the B cell level.

Induction of tolerance in T cells is easier and requires relatively smaller amounts of tolerogen than tolerance in B cells. Maintenance of immunological tolerance requires persistence of antigen. Tolerance can be broken naturally (as in autoimmune diseases) or artificially (as shown in experimental animals, by x-irradiation, certain drug treatments and by exposure to cross reactive antigens).

Tolerance may be induced to all epitopes or only some epitopes on an antigen and tolerance to a single antigen may exist at the B cell level or T cell level or at both levels.


 

Mechanism of tolerance induction

The exact mechanism of induction and maintenance of tolerance is not fully understood. Experimental data, however, point to several possibilities.

Clonal deletion
T and B lymphocytes during development come across self antigens and such cells undergo clonal deletion through a process known as apoptosis or programmed cell death. For example, T cells that develop in the thymus first express neither CD4 nor CD8. Such cells next acquire both CD4 and CD8 called double-positive cells and express low levels of
αβ TCR. Such cells undergo positive selection after interacting with class I or class II MHC molecules expressed on cortical epithelium. During this process, cells with low affinity for MHC are positively selected. Unselected cells die by apoptosis, a process called "death by neglect". Next, the cells loose either CD4 or CD8. Such T cells then encounter self-peptides presented by self MHC molecules expressed on dendritic cells. Those T cells with high affinity receptors for MHC + self-peptide undergo clonal deletion also called negative selection through induction of apoptosis. Any disturbance in this process can lead to escape of auto-reactive T-cells that can trigger autoimmune disease. Likewise, differentiating early B cells when they encounter self-antigen, cell associated or soluble, undergo deletion. Thus, clonal deletion plays a key role in ensuring tolerance to self antigen.


Peripheral tolerance
The clonal deletion is not a fool proof system and often T and B cells fail to undergo deletion and therefore such cells can potentially cause autoimmune disease once they reach the peripheral lymphoid organs. Thus, the immune system has devised several additional check points so that tolerance can be maintained.

Activation-induced cell death
T cells upon activation not only produce cytokines or carryout their effector functions but also die through programmed cell death or apoptosis. In this process, the death receptor (Fas) and its ligand (FasL) play a crucial role. Thus, normal T cells express Fas but not FasL. Upon activation, T cells express FasL which binds to Fas and triggers apoptosis by activation of caspase-8. The importance of Fas and FasL is clearly demonstrated by the observation that mice with mutations in Fas (lpr mutation) or FasL (gld mutation) develop severe lymphoproliferative and autoimmune disease and die within 6 months while normal mice live up to 2 years. Similar mutations in these apoptotic genes in humans leads to a lymphoproliferative disease called autoimmune lymphoproliferative syndrome (ALPS).


Clonal anergy
 Auto-reactive T cells when exposed to antigenic peptides on antigen presenting cells (APC) that do not possess the co-stimulatory molecules CD80 (B7-1) or CD86 (B7-2) become anergic (nonresponsive) to the antigen. Also, while activation of T cells through CD28 triggers IL-2 production, activation of CTLA4 leads to inhibition of IL-2 production and anergy. Also, B cells when exposed to large amounts of soluble antigen down-regulate their surface IgM and become anergic. These cells also up-regulate the Fas molecules on their surface. An interaction of these B cells with Fas-ligand bearing T cells results in their death via apoptosis.

Clonal ignorance
T cells reactive to self-antigen not represented in the thymus will mature and migrate to the periphery, but they may never encounter the appropriate antigen because it is sequestered in inaccessible tissues. Such cells may die out for lack of stimulus. Auto-reactive B cells, that escape deletion, may not find the antigen or the specific T-cell help and thus not be activated and die out.

Anti-idiotype antibody
These are antibodies that are produced against the specific idiotypes of other antibodies. Anti-idiotypic antibodies are produced during the process of tolerization and have been demonstrated in tolerant animals. These antibodies may prevent the B cell receptor from interacting with the antigen.


Regulatory T cells (Formerly called suppressor cells)
Recently, a distinct population of T cells has been discovered called regulatory T cells. Regulatory T cells come in many flavors, but the most well characterized include those that express CD4+ and CD25+. Because activated normal CD4 T cells also express CD25, it was difficult to distinguish regulatory T cells and activated T cells. The latest research suggests that regulatory T cells are defined by expression of the forkhead family transcription factor Foxp3. Expression of Foxp3 is required for regulatory T cell development and function. The precise mechanism/s through which regulatory T cells suppress other T cell function is not clear. One of the mechanisms include the production of immunosuppressive cytokines such as TGF-
β and IL-10. Genetic mutations in Foxp3 in humans leads to development of a severe and rapidly fatal autoimmune disorder known as Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome. This disease provides the most striking evidence that regulatory T cells play a critical role in preventing autoimmune disease.
 

Termination of tolerance
Experimentally induced tolerance can be terminated by prolonged absence of exposure to the tolerogen, by treatments which severely damage the immune system (x-irradiation) or by immunization with cross reactive antigens. These observations are of significance in the conceptualization of autoimmune diseases.
 

 

 

AUTOIMMUNITY 

Definition

Autoimmunity can be defined as breakdown of mechanisms responsible for self tolerance and induction of an immune response against components of the self. Such an immune response may not always be harmful (e.g., anti-idiotype antibodies). However, in numerous autoimmune diseases it is well recognized that products of the immune system cause damage to the self.

Effector mechanisms in autoimmune diseases

Both antibodies and effector T cells can be involved in the damage in autoimmune diseases.

General classification

Autoimmune diseases are generally classified on the basis of the organ or tissue involved. These diseases may fall in an organ-specific category in which the immune response is directed against antigen(s) associated with the target organ being damaged or a non-organ-specific category in which the antibody is directed against an antigen not associated with the target organ (Table 2). The antigen involved in most autoimmune diseases is evident from the name of the disease (Table 2).

Genetic predisposition for autoimmunity

Studies in mice and observations in humans suggest a genetic predisposition for autoimmune diseases. Association between certain HLA types and autoimmune diseases has been noted (HLA: B8, B27, DR2, DR3, DR4, DR5 etc.).

 

addison.jpg (429353 bytes)  Figure 1  Hyperpigmentation of buccal mucosa in Addison's disease  Bristol Biomedical Archive. Used with permission

goodpasture.jpg (429313 bytes)  Figure 2  Immunofluorescent stain of immunoglobulin G (IgG) showing linear pattern in Goodpasture's
syndrome Bristol Biomedical Archive. Used with permission

pemphingus.jpg (442197 bytes) Figure 3  Pemphigus vulgaris - immunofluorescence  Bristol Biomedical Archive. Used with permission

pemphigoid.jpg (356796 bytes) Figure 4  Mucous membrane pemphigoid - immunofluorescence  Bristol Biomedical Archive. Used with permission

 

 

sjogren.jpg (247868 bytes)  Figure 5 Parotid enlargement in Sjogren's syndrome Bristol Biomedical Archive. Used with permission

vitil1.jpg (324404 bytes) vitil2.jpg (332689 bytes)  Figure 6  Depigmentation in vitiligo Bristol Biomedical Archive. Used with permission

Etiology of autoimmunity disease

The exact etiology of autoimmune diseases is not known. However, various theories have been offered. These include sequestered antigen, escape of auto-reactive clones, loss of suppressor cells, cross reactive antigens including exogenous antigens (pathogens) and altered self antigens (chemical and viral infections).

Sequestered antigen
Lymphoid cells may not be exposed to some self antigens during their differentiation, because they may be late-developing antigens or may be confined to specialized organs (e.g., testes, brain, eye, etc.). A release of antigens from these organs resulting from accidental traumatic injury or surgery can result in the stimulation of an immune response and initiation of an autoimmune disease.

Escape of auto-reactive clones
The negative selection in the thymus may not be fully functional to eliminate self reactive cells. Not all self antigens may be represented in the thymus or certain antigens may not be properly processed and presented.

Lack of regulatory T cells
There are fewer regulatory T-cells in many autoimmune diseases.
 

Table 2
Spectrum of autoimmune diseases, target organs and diagnostic tests

 

 

Disease

Organ

Antibody to

Diagnostic Test

 Organ-Specific

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Non-organ Specific

 

Hashimoto's thyroiditis

Thyroid Thyroglobulin, thyroid peroxidase (microsomal)

RIA, Passive, CF, hemagglutination

Primary Myxedema

Thyroid

Cytoplasmic TSH receptor

Immunofluorescence (IF)
Graves' disease Thyroid  

Bioassay, Competition for TSH receptor

Pernicious anemia Red cells Intrinsic factor (IF), Gastric parietal cell B-12 binding to IF  immunofluorescence
Addison's disease
(Fig 1)
Adrenal Adrenal cells Immunofluorescence

Premature onset menopause

Ovary Steroid producing cells Immunofluorescence

Male infertility

Sperm Spermatozoa

Agglutination, Immunofluorescence

Insulin dependent juvenile diabetes

Pancreas Pancreatic islet beta cells  

Insulin resistant diabetic 

Systemic Insulin receptor

Competition for receptor

Atopic allergy  Systemic

beta-adrenergic receptor

Competition for receptor 
Myasthenia graves Muscle

Muscle, acetyl choline receptor 

Immunofluorescence, competition for receptor 

Goodpasture's syndrome

Kidney, lung

Renal and lung basement membrane Immunofluorescence (linear staining) (Fig. 2)
Pemphigus Skin Desmosomes Immunofluorescence (Fig 3)
Pemphigoid Skin

Skin basement membrane

Immunofluorescence (Fig 4)
Phacogenic uveitis Lens Lens protein  
AI hemolytic anemia Red cells Platelet Red cells Passive hemagglutination

Direct Coomb's test

Idiopathic thrombocytopenia

  Platelet Immunofluorescence

Primary biliary cirrhosis

Liver Mitochondria Immunofluorescence

Idiopathic neutropenia

Neutrophils

 

Neutrophils Immunofluorescence
Ulcerative colitis Colon

Colon lipopolysaccharide

Immunofluorescence
Sjogren's syndrome

Secretory glands 
(Fig 5)

Duct mitochondria Immunofluorescence
Vitiligo

Skin Joints

Melanocytes (fig 6) Immunofluorescence
Rheumatoid arthritis Skin, kidney, joints etc IgG IgG-latex agglutination

Systemic lupus erythematosus

joints, etc.

 

DNA, RNA, nucleoproteins

 RNA-, DNA-latex agglutination, IF (granular in kidney)

 

     

Diseases are listed from the most organ-specific (top) to the least specific (bottom)

 

Cross reactive antigens
Antigens on certain pathogens may have determinants which cross react with self antigens and an immune response against these determinants may lead to effector cell or antibodies against tissue antigens. Post streptococcal nephritis and carditis, anticardiolipin antibodies during syphilis and association between Klebsiella and ankylosing spondylitis are examples of such cross reactivity.

Diagnosis

Diagnosis of autoimmune diseases is based on symptoms and detection of antibodies (and/or very early T cells) reactive against antigens of tissues and cells involved. Antibodies against cell/tissue associated antigens are detected by immunofluorescence. Antibodies against soluble antigens are normally detected ELISA or radioimmunoassay (see table above). In some cases, a biological /biochemical assay may be used (e.g., Graves diseases, pernicious anemia).

Treatment

The goals of treatment of autoimmune disorders are to reduce symptoms and control the autoimmune response while maintaining the body's ability to fight infections. Treatments vary widely and depend on the specific disease and symptoms: Anti-inflammatory (corticosteroid) and immunosuppressive drug therapy (such as cyclophosphamide, azathioprine, cyclosporine ) is the present method of treating autoimmune diseases. Extensive research is being carried out to develop innovative treatments which include: anti-TNF alpha therapy against arthritis, feeding antigen orally to trigger tolerance, anti-idiotype antibodies, antigen peptides, anti-IL2 receptor antibodies, anti-CD4 antibodies, anti-TCR antibodies, etc.

Models of autoimmune diseases

There are a number of experimental and natural animal models for the study of autoimmune diseases. The experimental models include experimental auto-allergic encephalitis, experimental thyroiditis, adjuvant induced arthritis, etc.

Naturally occurring models of autoimmune diseases include hemolytic anemia in NZB mice, systemic lupus erythematosus in NZB/NZW (BW), BXSB and MRL mice and diabetes in obese mice.

 

 

 
 

You should know:

Possible mechanisms of tolerance induction to self.

Role of antigen and host components in tolerance induction.

Different autoimmune diseases and organs/antigens involved in these conditions.

Type of immunologic tests normally used to diagnose different autoimmune diseases.

Possible etiology of autoimmune diseases and the major experimental models.

 

  

 

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