Under normal circumstances immune system will not destroy self antigens. Autoimmunity can be defined...

Under normal circumstances immune system will not destroy self antigens.

Autoimmunity can be defined as breakdown of mechanisms responsible for self tolerance and induction of an immune response against components of the self.

In numerous autoimmune diseases it is well recognized that products of the immune system cause damage to the self.

Tolerance to self antigens:

*Tolerance is non-reactivity 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.

* Thus, the immune system is constantly challenged to discriminate self vs non-self and mediate the right response.

*Tolerance is an active antigen dependent process in response to the antigen.

*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

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

Like immunological memory >>

1) it can exist in T-cells, B cells or both

2) 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 either:

o naturally (as in autoimmune diseases) or

o artificially (as shown in experimental animals, by x-irradiation, certain drug treatments & by exposure to cross reactive antigens).

Tolerance may be induced to all epitopes or only some epitopes on an antigen

Tolerance to a single antigen may exist at B cell level or T cells level or at both levels.

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

o Clonal deletion

o Peripheral tolerance

o Activation-induced cell death

o Clonal anergy

o Clonal ignorance

o Anti-idiotype antibody

o Regulatory T cells

The two main mechanisms of preventing B cells from reacting against self antigens are clonal deletion and clonal anergy.

The environment in the bone marrow where B cells develop is usually sterile and devoid of foreign antigens. Therefore the only antigen that developing B cells could encounter is self-antigen.

If immature B cells, expressing IgM but not IgD on their surface, recognise antigen through their IgM they undergo one of two fates:

1) Clonal deletion:

In which the developing B cell recognising self antigen is induced to die by apoptosis and obviously will not develop into a mature B cell.

2) Clonal anergy:

Alternatively the developing B cell may be rendered unresponsive, and will then be unable to respond to its particular 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.

1. Positive and negative selection:

T cells recognise antigen in an MHC-restricted manner. Some of the TcR binds to MHC and some binds to the peptide.

Because the rearrangement of TcR genes is random, T cells can be produced with 4 potential types of TcR specificity:

1. Foreign antigenic peptide + self-MHC.

2. Self-antigenic peptide + self-MHC.

3. Foreign antigenic peptide + foreign MHC.

4. Self-antigenic peptide + foreign MHC.

Only cells with pattern 1 will be useful at recognising antigens derived from pathogens.

Pattern 2 cells are potentially damaging and could cause an immune response against the body’s own antigens.

Cells that can only recognise antigen in association with foreign MHC (patterns 3 and 4) will be useless in that individual.

Therefore during T cell development there is the requirement:

1) to select T cells that are self-MHC restricted (positive selection) and

2) to prevent the production of T cells with specificity for self-antigenic peptide and self-MHC (negative selection).

Self tolerance in T cells

Self tolerance in T cells

2. Clonal anergy:

Auto-reactive T cells when exposed to antigenic peptides on APCs that do not possess the co-stimulatory molecule 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.

Self tolerance in T cells

Peripheral tolerance:

The clonal deletion is not a fool proof system and often T and B cells fail to undergo deletion; 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 to maintain tolerance. These include:

o Clonal anergy

o Active regulation

o Clonal ignorance

Clonal ignorance:

T cells reactive to self-antigen not represented in the thymus will mature and migrate to the periphery.

• These cells are quite capable of making a response but are unaware of the presence of their auto-antigen. This arises for 2 reasons:

1) The antigen may simply be present in too low concentration. Since all lymphocytes have a threshold for receptor occupancy which is required to trigger a response then very low concentrations of antigen will not be sensed.

2) Some antigens are sequestered from the immune system in locations which are not freely exposed to surveillance (termed immunologically privileged sites such as the eye, CNS and testis).

Such cells may die out for lack of stimulus.

Likewise, 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.

Activation-induced cell death:

T cells upon activation not only produce cytokines or carry out their effector functions but also die through 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 or FasL 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).

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 may prevent the B cell receptor from interacting with the antigen.

Regulatory T cells (Formerly called suppressor cells):

The most well characterized T regs include those that express CD4+ and CD25+.

Because activated normal CD4 T cells also express CD25, it was difficult to distinguish T regs and activated T cells.

The latest research suggests that regulatory T cells are defined by expression of Foxp3 (a transcription factor), which is required for their development and function.

The precise mechanism/s through which T regs 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.

A-Clonal deletion:

B-Activation-induced cell death:

C-Clonal anergy:

D-Anti-idiotype antibody:

E-Regulatory T cells (Formerly called suppressor cells):

*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.

*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.

*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).

*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.

*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.

*These are antibodies that are produced against the specific idiotypes (an idiotype is a shared characteristic between a group of immunoglobulin or T cell receptor (TCR) molecules based upon the antigen binding specificity and therefore structure of their variable region) of other antibodies.

*These antibodies may prevent the B cell receptor from interacting with the antigen.

*Regulatory T cells 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.

11stst classificatioclassificationn

22ndnd classificationclassification

33rdrd classificationclassification

Organ specific (IDDM)

Humoral-associated (SLE)

Type II hypersensitivity (ARF)

Systemic (Scleroderma, SLE)

Cell-mediated (IDDM)

Type III hypersensitivity(SLE)

Type IV hypersensitivity(IDDM)

A Group of 60 to 80 chronic inflammatory diseases with genetic predisposition and environmental modulation

Prevalence of 5% to 8% in US

Prevalence is greater for females than males

•75% of cases•4th largest disease class in women

There is an Autoimmune reaction present

Have to be sure it is not secondary to tissue damage

It is always an unknown cause of the process

SYSTEMIC

Systemic Lupus Erythematosus (SLE) (III)

ORGAN SPECIFIC A

utoimmune Hemolytic Anemia (AIHA) (II)

Acquired Rheumatic Fever (ARF) (II)

Graves' disease (II)

Hashimoto's disease (II & IV)

Multiple sclerosis (MS) (IV)

Destruction of erythrocytes by autoantibodies (II)

50% of all hemolytic cases.

Usually >40 years old (acquired).

Types

• Warm (37C) mediated by IgG.• Cold (32C) mediated by IgM.

Causes of Warm

• Idiopathic in 50% of cases• Diseases

• Chronic lymphocytic leukemia• Systemic lupus erythematosus

• Drugs• Penicillin, methyldopa, quinidine

Target tissue:• Erythrocyte surface molecules (surface antigen)

Symptoms

• Fatigue, pallor, SOB, tachycardia, jaundice, splenomegalyL

aboratory diagnosis• Coombs’ test

• Direct (bound) and Indirect (free)• Elevated reticulocyte count

Treatment

• Prednisone• Splenectomy• Immunosuppressive agents

Non-suppurative sequelae following pharyngitis by Streptococcus pyogenes (Group A Streptococcus / GAS)

2 to 3 weeks following pharyngitis

Female to male ratio of 1:1

Incidence of 0.5% to 3% (rare in developed Countries)

Target tissue:• Streptococcal M protein, cardiac muscle antigens (surface

antigens)

Highest incidence/prevalence between 6 and 20 years

• Rare >30 yearsC

haracterized by• Painful polymigratory arthritis• Carditis

Effector mechanism

• Antibodies to GAS cross reacting to antigens of heart and joints (molecular mimicry)

Laboratory diagnosis

• Anti-streptolysin-O (ASO)• Anti-DNaseB

Most common cause of hyperthyroidism (thyrotoxicosis)

• Incidence of 50-80 cases / 100,000 population / year• Female to male ratio of 8:1• Also called diffuse thyrotoxic goiter or overactive thyroid

Effector mechanisms involve auto-reactive B and T cells against

• Thyroid stimulating hormone (TSH) receptor (Thyrotropin receptor)

• Thyroid peroxidase / Thyroperoxidase (TPO)

Target tissue:• TSH surface receptor (thyrotropin receptor antibody)

Symptoms

• Fatigue, heat intolerance, weight loss, anxiety, restlessness, insomnia, ophthalmopathy

Laboratory diagnosis

• Free T3 (triiodothyronine) and T4 (thyroxine) serum levels• Thyroid stimulating hormone (TSH)• Thyroid stimulating hormone (TSH / Thyrotropin) receptor

antibodyT

reatment• Anti-thyroid drugs

• Methimazole (Tapazole)• Thyroidectomy

Alternative names

• Chronic lymphocytic thyroiditis• Autoimmune thyroiditis

Female to male ratio of 12:1

Effector mechanisms (II & IV)

• Autoantibodies and CD4 THl cells specific for• Thyroglobulin• Thyroid peroxidase • Thyroid cells ( follicles)

• Inhibits iodine uptake and production of • T3 and T4

Most common cause of hypothyroidism.

Target tissue:• Thyroglobulin (Extracellular matrix antigen)

Symptoms

• Fatigue, cold intolerance, weight gain, depression, enlarged gland

Laboratory diagnosis

• T3,T4 and TSH serum levels• Autoantibodies to

• Thyroid peroxidase (TPO)• Thyroglobulin

Treatment

• Replacement therapy (Levothyroxine)

Chronic unpredictable disease of CNS with four possible clinical courses

Characterized by patches of demyelination and inflammation of myelin sheath

Prevalence higher in Northern Hemisphere

• North of 37th parallel (125 cases /100,000)• South of 37th parallel (70 cases /100,000)

Female to male ratio of 2:1

Target tissue:• Myelin proteins (several)

Effector mechanisms

• Myelin basic protein is primary autoantigen for CD4 TH1 cells

Radiology diagnosis

• MRI for detecting demyelinating lesions (plaques)

•Laboratory diagnosis

• High resolution protein electrophoresis for• Oligoclonal bands in CSF(

http://www.medclip.com/index.php?page=videos&section=view&vid_id=106267)

Chronic, multi-system inflammatory disease with protean manifestations and remitting course

Clinical manifestationsMusculoskeletal (joint and muscle pain)Dermatological (malar rash)Renal (glomerulonephritis)

Female to male ratio of 9:1

Target Tissue: (systemic)• Nucleic acids, chromosomal proteins

Etiology is unknown

• Genetics(3-10 fold in identical twins), race, hormones (estrogen), environment & drugs (etanercipt & infleximab)

Effector mechanisms

• Autoantibodies to many autoantigens• Most common autoantibody is to ds-DNA• Immune complex deposition on basement membranes with

complement activation and inflammation

Laboratory diagnosis

• Anti-nuclear antibody (ANA)• IFA (indirect fluorescent antibody) assay using HEp-2 cells• Homogeneous pattern and titer > 1:160

• Anti ds-DNA• IFA assay using Crithidia lucilliae (sens.66-95 & spec.75-100)

• C3 level

Release of sequestered antigen

• Multiple sclerosis

Molecular mimicry

• Rheumatic feverI

nappropriate expression of MHC class II molecules ( bystander activation)

• IDDM

Polyclonal activation of B cells (epitope spread)

• Systemic lupus erythematosus