Pathology 2009 – Immune System & 2010

Autoimmunity
Doctor: Raed Al Ani

Autoimmunity

The evidence is compelling that an immune reaction to self-antigens (i.e., autoimmunity) is the cause of certain human diseases; a growing number of entities have been attributed to this process . However, in many of these disorders the proof is not definitive, and an important thing is that the simple presence of auto-reactive antibodies or T cells does not equate to autoimmune disease only.

Low-affinity antibodies and T cells reactive with self-antigens can be readily demonstrated in most otherwise healthy individuals; presumably, these antibodies and T cells are not pathogenic and are of little consequence. Moreover, similar innocuous autoantibodies to self-antigens are frequently generated following other forms of injury (e.g., ischemia) and may even serve a physiologic role in the removal of products of tissue breakdown.

Immunological tolerance

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

Central tolerance

This refers to deletion of self-reactive T and B lymphocytes during their maturation in central lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells). Any developing T cell that expresses a receptor for such a self-antigen is negatively selected (deleted by apoptosis), and the resulting peripheral T-cell pool is thereby depleted of self-reactive cells .

Unfortunately, the process of deletion of selfreactive lymphocytes is far from perfect. Many self-antigens may not be present in the thymus, and hence T cells bearing receptors for such autoantigens escape into the periphery. There is similar "slippage" in the B-cell system as well, and B cells that bear receptors for a variety of self-antigens, including thyroglobulin, collagen, and DNA, can be found in healthy individuals.

Peripheral tolerance

Self-reactive T cells that escape negative selection in the thymus can potentially wreak disturbances unless they are deleted or effectively muzzled. Several mechanisms in the peripheral tissues that silence such potentially autoreactive T cells have been identified:

Anergy

Anergy: This refers to functional inactivation (rather than death) of lymphocytes induced by encounter with antigens under certain conditions. Because costimulatory molecules are not strongly expressed on most normal tissues, the encounter between autoreactive T cells and self-antigens in tissues may result in anergy. B cells can also become anergic if they encounter antigen in the absence of specific helper T cells.Suppression by regulatory T cells. The responses of T lymphocytes to self-antigens may be actively suppressed by regulatory T cells.

Factors affecting tolerance: role Factors affecting tolerance: role of antigen of antigen
Factors which affect response
Physical form of antigen Antigen processing Route of injection Dose of antigen

Favor immune response
Large, aggregated, complex molecules properly processed Subcutaneous or intra-muscular Optimal dose

Favor tolerance
soluble, aggregate-free, simple small molecules improperly processed Oral or, sometimes, intravenous Very large or very small dose

Factors affecting Factors affecting tolerance: tolerance: role of antigen role of antigen
Factors which affect response
Age of responding animal Differentiation state of cells

Favor immune response
Adult, immunologically mature Fully differentiated, Memory

Favor tolerance
Newborn (mice) Immunologically immature Undifferentiated B cell with only IgM, T cells in the thymic cortex

Theories & Hypothesis of Autoimmunity

Autoimmune diseases range from those in which
1- Specific immune responses are directed against one particular organ or cell type and result in localized tissue damage. 2- Multisystem diseases characterized by lesions in many organs and associated with multiple autoantibodies or cellmediated reactions against numerous self-antigens. In the systemic diseases, the lesions affect principally the connective tissue and blood vessels of the various organs involved.

Autoimmune diseases (AIDs) may be classified as organspecific or systemic (nonorgan-specific). There is a spectrum of AIDs including some that exhibit ‫هدد دددددد ددد ددددددد‬ intermediate features.
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Theories:
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1. Cryptic Antigen 2- By-pass Theory (a) . 3- By-pass Theory (b) 4- By-pass Theory (c) 5. Genetic Defects. 6- Regulatory T-cells (a) 7- Danger Theory.

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Somatic Mutation Hypothesis Polyclonal Activation Hypothesis

Hypothesis:

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Mechanisms of Autoimmunity
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Unfortunately, there are no simple answers to this question, and we still do not understand the underlying causes of most human autoimmune diseases. We referred to gene mutations that compromise one or another pathway of selftolerance and cause pathologic autoimmunity. These single-gene mutations are extremely informative, and they help to establish the biologic significance of the various pathways of self-tolerance. The breakdown of self-tolerance and the development of autoimmunity are probably related to the inheritance of various susceptibility genes and changes in tissues, often induced by infections or injury, that alter the display and recognition of selfantigens

Role of Genetic Factors in Autoimmunity
There is abundant evidence that genes play an important role in the development of autoimmune diseases.  Autoimmune diseases have a tendency to run in families, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins.  Several autoimmune diseases are linked with the HLA locus. The frequency of a disease in an individual with a particular HLA allele, compared to individuals who do not inherit that allele, is called the relative risk  Despite enormous interest in this area, so far most of the associations are with chromosomal segments, and the actual genes have not been identified with certainty.

Role of Infections and Tissue Injury

Molecular Mimicry

Viruses and other microbes, particularly certain bacteria such as streptococci and Klebsiella organisms, may share cross-reacting epitopes with self-antigens, such that responses to the microbial antigen may attack self-tissues. This phenomenon is called molecular mimicry. It is the probable cause of a few diseases, the best example being rheumatic heart disease, in which an immune response against streptococci cross-reacts with cardiac antigens. It is not known if more subtle mimicry plays a role in other autoimmune diseases.

Cross-Reactivity

. The display of tissue antigens may be altered by infections and other triggers. Local tissue injury for any reason may lead to the release of selfantigens and autoimmune responses.  At present there is no evidence that clearly implicates any microbe in the causation of human autoimmune diseases.  The activation of such autoreactive T cells is called "epitope spreading" because the immune response "spreads" to epitopes that were not recognized initially.

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of protean manifestations and variable behavior. Clinically, it is an unpredictable, remitting and relapsing disease of acute or insidious onset that may involve virtually any organ in the body; however, it affects principally the skin, kidneys, serosal membranes, joints, and heart. Immunologically, the disease is associated with an enormous array of autoantibodies, classically including antinuclear antibodies (ANAs).

The clinical presentation of SLE is so variable and it has so many overlaps with other autoimmune diseases (rheumatoid arthritis, polymyositis, and others) that it has been necessary to develop diagnostic criteria for SLE . The diagnosis is established if a patient demonstrates four or more of the criteria during any interval of observation.

SLE is a systemic autoimmune disease caused by autoantibodies produced against numerous self-antigens and the formation of immune complexes. The major autoantibodies, and the ones responsible for the formation of circulating immune complexes, are directed against nuclear antigens. Other autoantibodies react with erythrocytes, platelets, and various complexes of phospholipids with proteins. Disease manifestations include nephritis, skin lesions and arthritis (caused by the deposition of immune complexes), and hematologic and neurologic abnormalities.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease affecting many tissues but principally attacking the joints to produce a nonsuppurative proliferative synovitis that frequently progresses to destroy articular cartilage and underlying bone with resulting disabling arthritis. When extra-articular involvement develops-for example, of the skin, heart, blood vessels, muscles, and lungs-RA may resemble SLE or scleroderma. The peak incidence is in the second to fourth decades of life, but no age is immune. Morphology will be considered first, as a background to a discussion of pathogenesis

broad spectrum of morphologic alterations is seen in RA; the most severe occur in the joints. RA typically presents as symmetric arthritis, principally affecting the small joints of the hands and feet, ankles, knees, wrists, elbows, and shoulders. Typically, the proximal interphalangeal and metacarpophalangeal joints are affected, but distal interphalangeal joints are spared. Axial involvement, when it occurs, is limited to the upper cervical spine; similarly, hip joint involvement is extremely uncommon.

The subarticular bone may also be attacked and eroded. Eventually the pannus fills the joint space, and subsequent fibrosis and calcification may cause permanent ankylosis. The radiographic hallmarks are joint effusions and juxta-articular osteopenia with erosions and narrowing of the joint space and loss of articular cartilage.

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

Sjögren Syndrome

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

Etiology and Pathogenesis
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Several lines of evidence suggest that Sjögren syndrome is an autoimmune disease in which the ductal epithelial cells of the exocrine glands are the primary target. Nevertheless, there is also systemic B-cell hyperactivity, as evidenced by the presence of ANAs and RF (even in the absence of associated RA. Most patients with primary Sjögren syndrome have autoantibodies to the RNP antigens SS-A (Ro) and SS-B ( these antibodies are also present in some SLE patients and are therefore not diagnostic for Sjögren syndrome)

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Involved tissues show an intense lymphocyte (primarily activated CD4+ T cells) and plasmacell infiltrate, occasionally forming lymphoid follicles with germinal centers. There is associated destruction of the native architecture Lacrimal gland destruction results in a lack of tears, leading to drying of the corneal epithelium, with subsequent inflammation, erosion, and ulceration (keratoconjunctivitis).

Similar changes may occur in the oral mucosa as a result of loss of salivary gland output, giving rise to mucosal atrophy, with inflammatory fissuring and ulceration (xerostomia). Dryness and crusting of the nose may lead to ulcerations and even perforation of the nasal septum. When the respiratory passages are involved, secondary laryngitis, bronchitis, and pneumonitis may appear. Approximately 25% of the patients (especially those with anti-SS-A antibodies) develop extraglandular disease affecting the CNS, skin, kidneys, and muscles.

Example of an Autoimmune Disease: Multiple Sclerosis (MS) Degenerative disease of the myelin sheath
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Myelin sheath damage is initiated by increased migration of autoreactive T cells across the BBB, leading to inflammation and formation of hardened scar tissue (“sclerotic plaques”) in various areas of the CNS Demyelination 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

This remark on the previous slide

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Multiple Sclerosis: Genes and Environment
Genetic predisposition:  Familial recurrence rate of about 20%  Mostly seen in patients of northern European background Environmental Factors:  Reported links to infection with measles, mumps, rubella, Epstein-Barr virus  Molecular mimicry between Epstein-Barr virus and myelin basic protein (MBP) provides basis for immune response; cross-reaction between virus and myelin results in demyelination

Multiple Sclerosis: Signs & Symptoms
 Blindness  Partial

or complete paralysis  Impaired speech, swallowing, coordination  Erectile dysfunction, incontinence  Stiffness of muscles  Short-term memory problems

• not all MS patients will experience these symptoms •Different area(s) of CNS affected - accounts for symptom heterogeneity among MS patients ‫هدد دددددد ددد ددددددد‬ ‫دددد ددد‬
This remark on the previous slide

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