Pathogenesis And Treatment of Autoimmune Diseases Notes

Types And Examples Of Autoimmune Diseases

Autoimmune diseases are a group of chronic inflammatory diseases in which it is demonstrated that the immune response to a self-antigen caused the specific pathologic changes in the disease.

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In other words, it is essential to confirm autoantibody pathogenicity for the pathologic changes in a particular autoimmune disease. This is because the phenomenon of autoimmunity may also be present in other pathologic conditions having inflammation or tissue damage.

Therefore, for a disease to be included under ‘autoimmune diseases’, it should fulfil certain laboratory and clinical criteria of presumptive evidence.

Criteria and presumptive evidence of immunologic pathogenesis in autoimmune diseases:

This group includes three conditions having overlapping clinical features of progressive skeletal muscle weakness: polymyositis, dermatomyositis and inclusion body myositis, but distinctive age at presentation and some other features.

1. Organ-specific (Localised) diseases:

• In these, the specific autoantibodies react against a target organ or tissue and cause its damage.
• The tissues frequently affected are endocrine glands ( for example, Thyroid, pancreatic islets of Langerhans, adrenal cortex), alimentary tract, blood cells, etc.
• A peculiar feature of organ-specific autoimmune diseases is the tendency to overlap and produce another syndrome during the disease.

2. Organ non-specific (Systemic) diseases:

• These are diseases in which pathologic lesions are produced in multiple diverse organs and tissues by several autoantibodies which react with antigens in many tissues and thus cause systemic lesions.
• Based on this, a list of common autoimmune diseases is presented. Some of the systemic autoimmune diseases (marked with an asterisk.

Autoimmune diseases:

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is the classical example of systemic autoimmune disease due to abundant autoimmune manifestations caused by several autoantibodies due to generalized hyperreactivity of the humoral immune response. The disease derives its name ‘lupus’ from the

Latin word meaning ‘wolf’ since initially this disease was believed to affect skin only and eat away skin like a wolf.

However, now 2 forms of lupus erythematosus are described:

1. Systemic or disseminated form: This is characterized by acute and chronic inflammatory lesions widely scattered in the body and there is the presence of various nuclear and cytoplasmic autoantibodies in the plasma. The disease characteristically involves kidneys, joints, skin, serosal surfaces, blood vessels, and central nervous system.
2. The discoid form is characterized: By chronic and localized skin lesions involving the bridge of the nose and adjacent cheeks without any systemic manifestations. Rarely, discoid form may develop into disseminated form.

Etiology And Pathogenesis

The exact etiology of SLE is not known. However, abnormal genetic predisposition and interaction with the environment.

Factors result in abnormal immune responses which generate autoantibodies and immune complexes:

• Genetic factors Genetic predisposition to develop autoantibodies to nuclear and cytoplasmic antigens in SLE is due to the immunoregulatory function of class II HLA genes and early components of complement. These are HLA-D2,3,8; genetic defect in C1q, C2, C4.
• Environmental factors Various other factors express the genetic susceptibility of an individual to develop clinical disease.
• These factors are:
  • Certain drugs, for example, Penicillamine D
  • Certain viral infections, for example, EBV infection
  • Certain hormones (for female gender predisposition) for example, Oestrogen, and
  • UV light.

There is polyclonal activation of B cells and associated hypergammaglobulinaemia. Autoantibodies against the nucleus or its components are demonstrable in plasma in almost all cases of SLE.

Some of the important autoantibodies against the nucleus and different nuclear antigens are as under:

• Antinuclear antibodies (ANA):  These are the antibodies against a common nuclear antigen that includes DNA as well as RNA. These are demonstrable in about 98% of cases and are used as screening tests.
• Antibodies to double-stranded DNA (anti-dsDNA): This is the most specific for SLE, especially in high titers, and is present in 70% of cases.
• Anti-Smith antibodies (anti-Sm): These antibodies appear against the Smith antigen which is part of ribonucleoproteins. It is also specific for SLE but is seen in about 25% of cases.
• Other autoantibodies:  Besides the above, several other antibody tests lack specificity for SLE.
• These are as follows:
• Anti-ribonucleoproteins (anti-RNP) are seen in 40% of cases of SLE but seen more often in Sjögren’s syndrome.
• Anti-Ro antibodies or anti-Sjögren-related syndrome (anti-SS-A) are not specific for SLE and are seen in about 30% of cases; they are often associated with Sicca syndrome.
• The anti-histone antibody, which is an antibody against histone associated with DNA in chromatin, is seen particularly in cases of drug-induced lupus than in SLE.
• Antiphospholipid antibody (APLA) or lupus anticoagulant is a test for thrombotic complications in cases of SLE.
• Anti-ribosomal P antibody is an antibody against the protein in ribosomes and is seen in CNS lupus.
• The anti-neuronal antibody is seen in 60% of cases of CNS lesions of SLE.

Mechanism Of Autoantibody Formation

Following immunologic mechanisms leading to the formation of multiple autoantibodies in SLE:

• Activation of innate immunity i.e. role of dendritic cells and monocytes/macrophages.
• Lowered and abnormal activation pathways of adaptive immunity cells i.e. mature T and B cells.
• Ineffective regulatory immune cells (CD4+ and CD8+ T cells, B cells).
• Impaired clearance of apoptotic cells and immune complexes.

The immunologic tissue injury in SLE may be type II or type III:

1. Type II hypersensitivity is characterized by the formation of autoantibodies against blood cells (red blood cells, platelets, leucocytes) and results in haematologic derangement in SLE.
2. Type III hypersensitivity is responsible for most lesions in SLE and is characterized by antigen-antibody complex (commonly DNA-anti-DNA antibody; sometimes Ig-anti-Ig antibody complex) which is deposited at sites such as renal glomeruli, walls of small blood vessels, etc.

Immunofluorescence Patterns Of Anas:

These autoantibodies against the nucleus or its components are demonstrated by immunofluorescence tests on blood which may show 4 types of patterns of ANAs :

• Homogeneous or diffuse nuclear staining, reflecting antibodies to chromatin, histones, and ds-DNA.
• Peripheral staining as a rim is indicative of antibodies to ds-DNA.
• The speckled staining pattern is most common and reflects antibodies to components other than DNA (i.e. Anti-Sm and others)
• The nucleolar pattern indicates antibodies against RNA (anti-RNP-antibodies).

Le Cell Phenomenon:

This was the first diagnostic laboratory test described for SLE. The test is based on the principle that ANAs cannot penetrate intact cells and thus cell nuclei should be exposed to bind them with the ANAs.

• The binding of the exposed nucleus with ANAs results in a homogeneous mass of nuclear chromatin material which is called LE body or hematoxylin body.
• LE cell is a phagocytic leucocyte, commonly a polymorphonuclear neutrophil, and sometimes a monocyte, which engulfs the homogeneous nuclear material of the injured cell.
• For a demonstration of the LE cell phenomenon in vitro, the blood sample is traumatized to expose the nuclei of blood leucocytes to ANAs.

This results in the binding of denatured and damaged nuclei with ANAs. The ANA-coated denatured nucleus is chemotactic for phagocytic cells.

• If this mass is engulfed by a neutrophil, displacing the nucleus of the neutrophil to the rim of the cell, it is called an LE cell.
• If the mass, more often an intact lymphocyte, is phagocytosed by a monocyte, it is called a Tart cell.

LE cell test is positive in 70% of cases of SLE while newer and more sensitive immunofluorescence tests for autoantibodies listed above are positive in a higher percentage of cases of SLE.

Besides, a few other autoimmune or non-autoimmune conditions may also show positive LE tests for example, Rheumatoid arthritis, lupoid hepatitis, penicillin sensitivity, etc.

Morphologic Features:

The manifestations of SLE are widespread in different visceral organs and as erythematous cutaneous eruptions.

The principal lesions are renal, vascular, cutaneous, and cardiac; other organs and tissues involved are serosal linings (pleuritis, pericarditis), joints (synovitis), spleen (vasculitis), liver (portal triads), lungs (interstitial pneumonitis, fibrosing alveolitis), CNS (vasculitis) and in the blood (autoimmune hemolytic anemia, thrombocytopenia). Lupus nephritis is.

• Histologically: The characteristic lesion in SLE is fibrinoid necrosis which may be seen in the connective tissue, beneath the endothelium in small blood vessels, under the mesothelial lining of pleura and pericardium, under the endothelium in the endocardium, or under the synovial lining
  cells of joints.

Summarises the morphology of lesions in different organs and tissues in SLE.

Clinical Features:

SLE is a multisystem disease and thus a wide variety of clinical features may be present. The severity of the disease varies from mild to intermittent to severe and fulminant.

• Usually targeted organs are the musculoskeletal system, skin, kidneys, nervous system, lungs, heart and blood vessels, GI system, and hematopoietic system.
• Fatigue and myalgia are present in most cases throughout the course of the disease. A severe form of illness occurs with fever, weight loss, anemia, and organ-related manifestations.
• The disease usually runs a long course of flare-ups and remissions; renal failure is the most frequent cause of death.

Scleroderma (Systemic Sclerosis) :

Just like SLE, scleroderma was initially described as a skin disease characterized by progressive fibrosis.

But now, 2 main types are recognized:

1. Diffuse scleroderma in which the skin shows widespread involvement and may progress to involve visceral structures.
2. CREST syndrome is characterized by Calcinosis (C), Raynaud’s phenomenon (R), Esophageal hypomotility (E), Sclerodactyly (S), and Telangiectasia (T).

Etiology And Pathogenesis:

There is the role of following 2 factors in its etiology:

• Susceptibility genes as seen in the occurrence of disease in families and in twins.
• Certain environmental factors for example  CMV infection, and the role of common shared environmental exposure of certain agents as seen by the prevalence of disease in some geographic locations.
• Antinuclear antibodies are detected in the majority of cases of systemic sclerosis. Immunologic derangements have been implicated in the pathogenesis of lesions in systemic sclerosis which finally cause activation of fibroblasts.
• The immune mechanisms leading to the stimulation of fibroblasts act in the following ways:
• Production of cytokines such as by TGF-β and IL-13 by activated CD4+ T cells helper T cells stimulates the release of factors for collagen and extracellular matrix.

Morphology of major lesions in SLE:

Endothelial cell injury due to cytotoxic damage to endothelium from autoantibodies or antigen-antibody complexes. This results in aggregation and activation of platelets which increases vascular permeability and stimulates fibroblastic proliferation.