Immune System & Immune System & AutoimmunityAutoimmunity

Doctor: Raed Al AniDoctor: Raed Al Ani

Pathology2009 – 2010

AutoimmunityAutoimmunity The evidence is compelling that an immune The evidence is compelling that an immune

reaction to self-antigens (i.e., reaction to self-antigens (i.e., autoimmunity) is the cause of certain autoimmunity) is the cause of certain human diseases; a growing number of human diseases; a growing number of entities have been attributed to this process entities have been attributed to this process ..

However, in many of these disorders the However, in many of these disorders the proof is not definitive, and an important proof is not definitive, and an important thing is that the simple presence of auto-thing is that the simple presence of auto-reactive antibodies or T cells does not reactive antibodies or T cells does not equate to autoimmune disease only.equate to autoimmune disease only.

Low-affinity antibodies and T cells reactive Low-affinity antibodies and T cells reactive with self-antigens can be readily demonstrated with self-antigens can be readily demonstrated in most otherwise healthy individuals; in most otherwise healthy individuals; presumably, these antibodies and T cells are presumably, these antibodies and T cells are not pathogenic and are of little consequence. not pathogenic and are of little consequence.

Moreover, similar innocuous autoantibodies to Moreover, similar innocuous autoantibodies to self-antigens are frequently generated self-antigens are frequently generated following other forms of injury (e.g., ischemia) following other forms of injury (e.g., ischemia) and may even serve a physiologic role in the and may even serve a physiologic role in the removal of products of tissue breakdown.removal of products of tissue breakdown.

Immunological toleranceImmunological tolerance

Immunological tolerance is Immunological tolerance is unresponsiveness to an antigen that is unresponsiveness to an antigen that is induced by exposure of specific induced by exposure of specific lymphocytes to that antigen. lymphocytes to that antigen.

Self-tolerance refers to a lack of immune Self-tolerance refers to a lack of immune responsiveness to one's own tissue responsiveness to one's own tissue antigens. During the generation of billions antigens. During the generation of billions of antigen receptors in developing T and B of antigen receptors in developing T and B lymphocytes, it is not surprising that lymphocytes, it is not surprising that receptors are produced that can recognize receptors are produced that can recognize self-antigens. self-antigens.

Central toleranceCentral tolerance

This refers to deletion of self-reactive T This refers to deletion of self-reactive T and B lymphocytes during their and B lymphocytes during their maturation in central lymphoid organs maturation in central lymphoid organs (i.e., in the thymus for T cells and in the (i.e., in the thymus for T cells and in the bone marrow for B cells). bone marrow for B cells).

Any developing T cell that expresses a Any developing T cell that expresses a receptor for such a self-antigen is receptor for such a self-antigen is negatively selected (deleted by apoptosis), negatively selected (deleted by apoptosis), and the resulting peripheral T-cell pool is and the resulting peripheral T-cell pool is thereby depleted of self-reactive cells . thereby depleted of self-reactive cells .

Unfortunately, the process of deletion of Unfortunately, the process of deletion of self-reactive lymphocytes is far from self-reactive lymphocytes is far from perfect. Many self-antigens may not be perfect. Many self-antigens may not be present in the thymus, and hence T cells present in the thymus, and hence T cells bearing receptors for such autoantigens bearing receptors for such autoantigens escape into the periphery. escape into the periphery.

There is similar "slippage" in the B-cell There is similar "slippage" in the B-cell system as well, and B cells that bear system as well, and B cells that bear receptors for a variety of self-antigens, receptors for a variety of self-antigens, including thyroglobulin, collagen, and DNA, including thyroglobulin, collagen, and DNA, can be found in healthy individuals.can be found in healthy individuals.

Peripheral tolerancePeripheral tolerance

Self-reactive T cells that escape Self-reactive T cells that escape negative selection in the thymus can negative selection in the thymus can potentially wreak disturbances potentially wreak disturbances unless they are deleted or effectively unless they are deleted or effectively muzzled. muzzled.

Several mechanisms in the Several mechanisms in the peripheral tissues that silence such peripheral tissues that silence such potentially auto-reactive T cells have potentially auto-reactive T cells have been identified: been identified:

AnergyAnergy Anergy: This refers to functional inactivation (rather than Anergy: This refers to functional inactivation (rather than

death) of lymphocytes induced by encounter with antigens death) of lymphocytes induced by encounter with antigens under certain conditions.under certain conditions.

Because costimulatory molecules are not strongly expressed Because costimulatory molecules are not strongly expressed

on most normal tissues, the encounter between autoreactive on most normal tissues, the encounter between autoreactive T cells and self-antigens in tissues may result in anergy. T cells and self-antigens in tissues may result in anergy.

B cells can also become anergic if they encounter antigen in B cells can also become anergic if they encounter antigen in the absence of specific helper T cells.Suppression by the absence of specific helper T cells.Suppression by regulatory T cells.regulatory T cells.

The responses of T lymphocytes to self-antigens may be The responses of T lymphocytes to self-antigens may be actively suppressed by regulatory T cells. actively suppressed by regulatory T cells.

Favor toleranceFavor toleranceFavor immune Favor immune responseresponse

Factors which Factors which affect responseaffect response

Factors affecting tolerance: role Factors affecting tolerance: role of antigenof antigen

Factors affecting tolerance: role Factors affecting tolerance: role of antigenof antigen

Very large or very Very large or very small dosesmall dose

Optimal doseOptimal doseDose of antigenDose of antigen

Physical form of antigen

Large, aggregated, complex molecules

soluble, aggregate-free, simple small molecules

Antigen processing properly processed improperly processed

Route of injection Subcutaneous or intra-muscular

Oral or, sometimes, intravenous

Favor toleranceFavor toleranceFavor immune Favor immune responseresponse

Factors which Factors which affect responseaffect response

Factors affecting Factors affecting tolerance:tolerance:

role of antigenrole of antigen

Factors affecting Factors affecting tolerance:tolerance:

role of antigenrole of antigen

Age of responding animal

Adult, immunologically mature

Newborn (mice)Immunologically immature

Differentiation state of cells

Fully differentiated, Memory

Undifferentiated B cell with only IgM, T cells in the thymic cortex

Theories & Hypothesis of Theories & Hypothesis of AutoimmunityAutoimmunity

Autoimmune diseases range from those Autoimmune diseases range from those in whichin which

1- Specific immune responses are 1- Specific immune responses are directed against one particular directed against one particular organ or cell type and result in organ or cell type and result in localized tissue damage.localized tissue damage.

2- Multisystem diseases 2- Multisystem diseases characterized by lesions in many characterized by lesions in many organs and associated with organs and associated with multiple autoantibodies or cell-multiple autoantibodies or cell-mediated reactions against mediated reactions against numerous self-antigens.numerous self-antigens.

In the systemic diseases, the In the systemic diseases, the lesions affect principally the lesions affect principally the connective tissue and blood connective tissue and blood vessels of the various organs vessels of the various organs involved. involved.

Autoimmune diseases (AIDs) may be classified as organ-specific or systemic (non-organ-specific). There is a spectrum of AIDs including

some that exhibit intermediate features. ذي مالحظه على الساليد اللي ه

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Theories: Theories: 1. Cryptic Antigen 1. Cryptic Antigen 2- By-pass Theory (a) .2- By-pass Theory (a) . 3- By-pass3- By-pass Theory (b) Theory (b) 4- By-pass4- By-pass Theory (c) Theory (c) 5. Genetic Defects.5. Genetic Defects. 6- Regulatory T-cells (a)6- Regulatory T-cells (a) 7- Danger Theory.7- Danger Theory.

Hypothesis:Hypothesis: Somatic Mutation HypothesisSomatic Mutation Hypothesis Polyclonal Activation HypothesisPolyclonal Activation Hypothesis

Mechanisms of Mechanisms of AutoimmunityAutoimmunity

Unfortunately, there are no simple Unfortunately, there are no simple

answers to this question, and we still do answers to this question, and we still do not understand the underlying causes of not understand the underlying causes of most human autoimmune diseases. most human autoimmune diseases.

We referred to gene mutations that We referred to gene mutations that compromise one or another pathway of compromise one or another pathway of self-tolerance and cause pathologic self-tolerance and cause pathologic autoimmunity.autoimmunity.

These single-gene mutations are extremely These single-gene mutations are extremely informative, and they help to establish the informative, and they help to establish the biologic significance of the various biologic significance of the various pathways of self-tolerance. pathways of self-tolerance.

The breakdown of self-tolerance and the The breakdown of self-tolerance and the development of autoimmunity are probably development of autoimmunity are probably related to the inheritance of various related to the inheritance of various susceptibility genes and changes in susceptibility genes and changes in tissues, often induced by infections or tissues, often induced by infections or injury, that alter the display and injury, that alter the display and recognition of self-antigensrecognition of self-antigens

Role of Genetic Factors in Role of Genetic Factors in AutoimmunityAutoimmunity

TThere is abundant evidence that genes play an here is abundant evidence that genes play an important role in the development of autoimmune important role in the development of autoimmune diseases. diseases.

Autoimmune diseases have a tendency to run in Autoimmune diseases have a tendency to run in families, and there is a greater incidence of the same families, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins.disease in monozygotic than in dizygotic twins.

Several autoimmune diseases are linked with the Several autoimmune diseases are linked with the HLA HLA locus.locus. The frequency of a disease in an individual with The frequency of a disease in an individual with a particular HLA allele, compared to individuals who a particular HLA allele, compared to individuals who do not inherit that allele, is called the do not inherit that allele, is called the relative riskrelative risk

Despite enormous interest in this area, so far most of Despite enormous interest in this area, so far most of the associations are with chromosomal segments, and the associations are with chromosomal segments, and the actual genes have not been identified with the actual genes have not been identified with certainty. certainty.

Role of Infections and Tissue Role of Infections and Tissue InjuryInjury

Molecular MimicryMolecular Mimicry Viruses and other microbes, particularly certain Viruses and other microbes, particularly certain

bacteria such as streptococci and bacteria such as streptococci and KlebsiellaKlebsiella organisms, may share cross-reacting epitopes organisms, may share cross-reacting epitopes with self-antigens, such that responses to the with self-antigens, such that responses to the microbial antigen may attack self-tissues. microbial antigen may attack self-tissues.

This phenomenon is called This phenomenon is called molecular mimicry.molecular mimicry. It It is the probable cause of a few diseases, the best is the probable cause of a few diseases, the best example being rheumatic heart disease, in which example being rheumatic heart disease, in which anan immune response against streptococci cross-immune response against streptococci cross-reacts with cardiac antigens. It is not known if reacts with cardiac antigens. It is not known if more subtle mimicry plays a role in other more subtle mimicry plays a role in other autoimmune diseases.autoimmune diseases.

Cross-ReactivityCross-Reactivity

. The display of tissue antigens may be altered . The display of tissue antigens may be altered by infections and other triggers. Local tissue by infections and other triggers. Local tissue injury for any reason may lead to the release injury for any reason may lead to the release of self-antigens and autoimmune responses. of self-antigens and autoimmune responses.

At present there is no evidence that clearly At present there is no evidence that clearly implicates any microbe in the causation of implicates any microbe in the causation of human autoimmune diseases.human autoimmune diseases.

The activation of such autoreactive T cells is The activation of such autoreactive T cells is called "epitope spreading" because the called "epitope spreading" because the immune response "spreads" to epitopes that immune response "spreads" to epitopes that were not recognized initially. were not recognized initially.

Systemic Lupus Systemic Lupus ErythematosusErythematosus

Systemic lupus erythematosus (SLE) is a Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of protean multisystem autoimmune disease of protean manifestations and variable behavior. manifestations and variable behavior.

Clinically, it is an unpredictable, remitting and Clinically, it is an unpredictable, remitting and relapsing disease of acute or insidious onset relapsing disease of acute or insidious onset that may involve virtually any organ in the that may involve virtually any organ in the body; however, it affects principally the skin, body; however, it affects principally the skin, kidneys, serosal membranes, joints, and heart. kidneys, serosal membranes, joints, and heart.

Immunologically, the disease is associated Immunologically, the disease is associated with an enormous array of autoantibodies, with an enormous array of autoantibodies, classically including antinuclear antibodies classically including antinuclear antibodies (ANAs). (ANAs).

The clinical presentation of SLE is so The clinical presentation of SLE is so variable and it has so many overlaps variable and it has so many overlaps with other autoimmune diseases with other autoimmune diseases (rheumatoid arthritis, polymyositis, (rheumatoid arthritis, polymyositis, and others) that it has been necessary and others) that it has been necessary to develop diagnostic criteria for SLE .to develop diagnostic criteria for SLE .

The diagnosis is established if a The diagnosis is established if a patient demonstrates four or more of patient demonstrates four or more of the criteria during any interval of the criteria during any interval of observation. observation.

SLE is a systemic autoimmune SLE is a systemic autoimmune disease caused by autoantibodies disease caused by autoantibodies produced against numerous self-produced against numerous self-antigens and the formation of antigens and the formation of immune complexes.immune complexes.

The major autoantibodies, and the The major autoantibodies, and the ones responsible for the formation ones responsible for the formation of circulating immune complexes, of circulating immune complexes, are directed against nuclear are directed against nuclear antigens. antigens.

Other autoantibodies react with Other autoantibodies react with erythrocytes, platelets, and various erythrocytes, platelets, and various complexes of phospholipids with complexes of phospholipids with proteins.proteins.

Disease manifestations include Disease manifestations include nephritis, skin lesions and arthritis nephritis, skin lesions and arthritis (caused by the deposition of immune (caused by the deposition of immune complexes), and hematologic and complexes), and hematologic and neurologic abnormalities.neurologic abnormalities.

Rheumatoid ArthritisRheumatoid Arthritis Rheumatoid arthritis (RA) is a systemic, chronic Rheumatoid arthritis (RA) is a systemic, chronic

inflammatory disease affecting many tissues but inflammatory disease affecting many tissues but principally attacking the joints to produce a principally attacking the joints to produce a nonsuppurative proliferative synovitis that frequently nonsuppurative proliferative synovitis that frequently progresses to destroy articular cartilage and progresses to destroy articular cartilage and underlying bone with resulting disabling arthritis. underlying bone with resulting disabling arthritis.

When extra-articular involvement develops-for When extra-articular involvement develops-for example, of the skin, heart, blood vessels, muscles, example, of the skin, heart, blood vessels, muscles, and lungs-RA may resemble SLE or scleroderma.and lungs-RA may resemble SLE or scleroderma.

The peak incidence is in the second to fourth decades The peak incidence is in the second to fourth decades of life, but no age is immune. Morphology will be of life, but no age is immune. Morphology will be considered first, as a background to a discussion of considered first, as a background to a discussion of pathogenesispathogenesis

broad spectrum of morphologic alterations broad spectrum of morphologic alterations is seen in RA; the most severe occur in the is seen in RA; the most severe occur in the joints. RA typically presents as joints. RA typically presents as symmetric symmetric arthritis, principally affecting the small arthritis, principally affecting the small jointsjoints of the hands and feet, ankles, knees, of the hands and feet, ankles, knees, wrists, elbows, and shoulders.wrists, elbows, and shoulders.

Typically, the proximal interphalangeal and Typically, the proximal interphalangeal and metacarpophalangeal joints are affected, metacarpophalangeal joints are affected, but distal interphalangeal joints are spared. but distal interphalangeal joints are spared. Axial involvement, when it occurs, is limited Axial involvement, when it occurs, is limited to the upper cervical spine; similarly, hip to the upper cervical spine; similarly, hip joint involvement is extremely uncommon. joint involvement is extremely uncommon.

The subarticular bone may also be attacked and The subarticular bone may also be attacked and eroded. Eventually the pannus fills the joint eroded. Eventually the pannus fills the joint space, and subsequent space, and subsequent fibrosis and fibrosis and calcificationcalcification may cause permanent may cause permanent ankylosis.ankylosis.

The radiographic hallmarks are joint effusions The radiographic hallmarks are joint effusions and juxta-articular osteopenia with erosions and and juxta-articular osteopenia with erosions and narrowing of the joint space and loss of articular narrowing of the joint space and loss of articular cartilage.cartilage.

Destruction of tendons, ligaments, and joint capsules produces the characteristic Destruction of tendons, ligaments, and joint capsules produces the characteristic deformities, including radial deviation of the wrist, ulnar deviation of the deformities, including radial deviation of the wrist, ulnar deviation of the fingers, and flexion-hyperextension abnormalities of the fingers.fingers, and flexion-hyperextension abnormalities of the fingers.

Sjögren SyndromeSjögren Syndrome It is a clinicopathologic entity characterized It is a clinicopathologic entity characterized

by dry eyes (by dry eyes (keratoconjunctivitis siccakeratoconjunctivitis sicca) and ) and dry mouth (dry mouth (xerostomiaxerostomia), resulting from ), resulting from immune-mediated destruction of the immune-mediated destruction of the lacrimal and salivary glands.lacrimal and salivary glands.1- Primary form :It occurs as an isolated 1- Primary form :It occurs as an isolated disorder , also known as the disorder , also known as the sicca syndrome.sicca syndrome.2- Secondary form or more often in 2- Secondary form or more often in association with another autoimmune association with another autoimmune disease . Among the associated disorders, disease . Among the associated disorders, RA is the most common, but some patients RA is the most common, but some patients have SLE, polymyositis, systemic sclerosis, have SLE, polymyositis, systemic sclerosis, vasculitis, or thyroiditis. vasculitis, or thyroiditis.

Etiology and Etiology and PathogenesisPathogenesis

Several lines of evidence suggest that Sjögren Several lines of evidence suggest that Sjögren syndrome is an autoimmune disease in which the syndrome is an autoimmune disease in which the ductal epithelial cells of the exocrine glands are ductal epithelial cells of the exocrine glands are the primary target.the primary target.

Nevertheless, there is also systemic B-cell Nevertheless, there is also systemic B-cell hyperactivity, as evidenced by the presence of hyperactivity, as evidenced by the presence of ANAs and RF (even in the absence of associated ANAs and RF (even in the absence of associated RA.RA.

Most patients with primary Sjögren syndrome Most patients with primary Sjögren syndrome have autoantibodies to the RNP antigens SS-A have autoantibodies to the RNP antigens SS-A (Ro) and SS-B ( these antibodies are also present (Ro) and SS-B ( these antibodies are also present in some SLE patients and are therefore not in some SLE patients and are therefore not diagnostic for Sjögren syndrome) diagnostic for Sjögren syndrome)

Involved tissues show an intense Involved tissues show an intense lymphocyte (primarily activated CD4+ T lymphocyte (primarily activated CD4+ T cells) and plasma-cell infiltrate, occasionally cells) and plasma-cell infiltrate, occasionally forming lymphoid follicles with germinal forming lymphoid follicles with germinal centers. centers.

There is associated destruction of the native There is associated destruction of the native architecture architecture

Lacrimal gland destruction results in a lack Lacrimal gland destruction results in a lack of tears, leading to drying of the corneal of tears, leading to drying of the corneal epithelium, with subsequent inflammation, epithelium, with subsequent inflammation, erosion, and ulceration erosion, and ulceration ((keratoconjunctivitiskeratoconjunctivitis). ).

Similar changes may occur in the oral mucosa as Similar changes may occur in the oral mucosa as a result of loss of salivary gland output, giving a result of loss of salivary gland output, giving rise to mucosal atrophy, with inflammatory rise to mucosal atrophy, with inflammatory fissuring and ulceration (fissuring and ulceration (xerostomiaxerostomia). ).

Dryness and crusting of the nose may lead to Dryness and crusting of the nose may lead to ulcerations and even perforation of the nasal ulcerations and even perforation of the nasal septum.septum.

When the respiratory passages are involved, When the respiratory passages are involved, secondary laryngitis, bronchitis, and pneumonitis secondary laryngitis, bronchitis, and pneumonitis may appear. Approximately 25% of the patients may appear. Approximately 25% of the patients (especially those with anti-SS-A antibodies) (especially those with anti-SS-A antibodies) develop extraglandular disease affecting the develop extraglandular disease affecting the CNS, skin, kidneys, and muscles. CNS, skin, kidneys, and muscles.

Example of an Autoimmune Example of an Autoimmune Disease: Multiple Sclerosis Disease: Multiple Sclerosis

(MS)(MS) Degenerative disease of the myelin sheathDegenerative disease of the myelin sheath Myelin sheath damage is initiated by increased migration Myelin sheath damage is initiated by increased migration

of autoreactive T cells across the BBB, leading to of autoreactive T cells across the BBB, leading to inflammation and formation of hardened scar tissue inflammation and formation of hardened scar tissue (“sclerotic plaques”) in various areas of the CNS(“sclerotic plaques”) in various areas of the CNS

Demyelination along the axons disrupts nerve conductionDemyelination along the axons disrupts nerve conduction

Saladin, 2005

• Canadians have one of the highest rates of multiple sclerosis in the

world. •MS is the most common neurological

disease affecting young adults in Canada

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Multiple Sclerosis: Multiple Sclerosis: Genes and EnvironmentGenes and Environment

Genetic predisposition: Genetic predisposition: Familial recurrence rate of about 20%Familial recurrence rate of about 20% Mostly seen in patients of northern European Mostly seen in patients of northern European

backgroundbackground

Environmental Factors:Environmental Factors: Reported links to infection with measles, mumps, Reported links to infection with measles, mumps,

rubella, Epstein-Barr virusrubella, Epstein-Barr virus Molecular mimicry between Epstein-Barr virus and Molecular mimicry between Epstein-Barr virus and

myelin basic protein (MBP) provides basis for immune myelin basic protein (MBP) provides basis for immune response; cross-reaction between virus and myelin response; cross-reaction between virus and myelin results in demyelinationresults in demyelination

Multiple Sclerosis: Signs & Multiple Sclerosis: Signs & SymptomsSymptoms

BlindnessBlindness Partial or complete paralysisPartial or complete paralysis Impaired speech, swallowing, Impaired speech, swallowing,

coordinationcoordination Erectile dysfunction, Erectile dysfunction,

incontinence incontinence Stiffness of musclesStiffness of muscles Short-term memory problemsShort-term memory problems

• not all MS patients will experience these symptoms•Different area(s) of CNS

affected - accounts for symptom heterogeneity among

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