Tolerance and Autoimmunity

Dr Abdul Ghaffar

MBIM 650/720 Medical Microbiology

READING: Roitt, Brostoff and Male: Immunology, 4th ed., Chapt. 112 and 27.

IMMUNOLOGY - LECTURE SIXTEEN

TOLERANCE AND AUTOIMMUNITY

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.

Induction of tolerance to non-self

Tolerance can be induced to antigenic components on both soluble proteins and cells (tissues) by injecting these materials into animals. Induction of such a tolerance depends on a number of variables.

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 a 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-cell, 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 B cell level or T cells 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: Functionally immature cells of a clone encountering antigen undergo a programmed cell death. For example, auto-reactive T-cells are eliminated in the thymus following interaction with self antigen during their differentiation (negative selection). Recent studies have shown that a variety of antigens are expressed in thymic epithelial cell. Likewise, differentiating early B cells when they encounter self antigen, cell associated or soluble become tolerant. B cells expressing only IgM (no IgD) on their surface when exposed to antigen are more prone to tolerance induction than immune response. Clonal deletion has been shown to occur also in the periphery.

Clonal anergy: Auto-reactive T cells when exposed to antigenic peptides which do not possess co-stimulatory molecules (B7-1 or B7-2) become anergic to the antigen. 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 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 helper T-cells and hence not be activated and die out.

Receptor editing: B cells which encounter large amounts of soluble antigen, as they do in the body, and bind to this antigen with very low affinity become activated to reexpress their RAG1 and RAG2 genes. These genes cause them to undergo DNA recombination and change their specificity.

Anti-idiotype antibody: Anti-idiotype antibodies produced experimentally have been demonstrated to inhibit immune response to specific antigens. Anti-idiotype antibodies are produced during the process of tolerization and such antibodies have been demonstrated in tolerant animals. These antibodies prevent the receptor from combining with antigen.

Suppressor cells: Both low and high doses of antigen may induce suppressor T cells which can specifically suppress immune responses of both B and T cells, either directly or by production of cytkines, most importantly, TGFβ and IL10.

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.).

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.

WEB RESOURCES

Auto-immunity and thyroid disease

Medline Plus: Hashimoto's disease
Hashimoto's thyroiditis

The Grave's disease page
Medline Plus: Grave's disease
Hyperthyroidism

Medline Plus: Addison's disease

NIH/NIDDK: Addison's disease

Family Practice Notebook: Addison's disease

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 Information Box	Thyroid	Thyroglobulin, thyroid peroxidase (microsomal)	RIA, Passive, CF, hemagglutination
	Primary Myxedema	Thyroid	Cytoplasmic receptor	Immunofluorescence (IF)
	Grave's disease Information Box	Thyroid	TSH receptor	Bioassay, Competition for TSH receptor
	Pernicious anemia	Red cells	Intrinsic factor (IF), Gastric parietal cell	B-12 binding to IF immunofluorescence
	Addison's disease Information Box	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 β cells
	Insulin resistant diabetic	Systemic	Insulin receptor	Competition for receptor
	Atopic allergy	Systemic	β-adrenergic receptor	Competition for receptor
	Myasthenia gravis	Muscle	Muscle, acetyl choline receptor	Immunofluorescence, competition for receptor
	Goodpasture's syndrome	Kidney, lung	Renal and lung basement membrane	Immunofluorescence (linear staining)
	Pemphigus	Skin	Desmosomes Cadherin molecules	Immunofluorescence
	Pemphigoid	Skin	Skin basement membrane	Immunofluorescence
	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	Duct mitochondria	Immunofluorescence
	Vitiligo	Skin Joints	Melanocytes	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)

NIH/NINDS: Sjogrens's syndrome

Sjogren's syndrome (University of Washington)

Cross reactive antigens: Antigens on certain pathogens may have determinants which cross react with the 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 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: Anti-inflammatory (corticosteroid) and immunosuppressive (cyclosporin) drug therapy is the present method of treating autoimmune diseases. Future treatments may include more sophisticated methods based on modern understanding of the immune system (e.g., anti-idiotype antibodies, antigen peptides, anti-IL2 receptor antibodies, anti-CD4 antibodies, antiTCR 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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