Basic Immunology
and Disorders of The Immune System
Francisco G. La Rosa, MD

IV. Autoimmune Diseases

A. Loss of Self-tolerance

B. Theories for the origen of Autoimmunity

C. Representative Autoimmune Diseases:

Systemic lupus erythematosus
Rheumatoid arthritis
Sjögren Syndrome
Systemic sclerosis
Inflammatory Myopathies
Mixed connective tissue disease

A. Loss of Self Tolerance

A defect in the central mechanism underlying self-recognition (auto-tolerance, self-tolerance) can result in autoimmune responses, that is, immune responses of an individual to antigens present in the host’s own tissue which can be mediated by humoral (circulating antibodies, immune complexes) or cellular (delayed hypersensitivity) mechanisms. Autoimmune diseases have been divided into two clinical types:

Organ-specific (e.g., thyroiditis, pernicious anemia)

Systemic (non organ-specific; e.g., systemic lupus erythematosus, SLE, rheumatoids arthritis.

B. Theories for the origen of Autoimmunity:

Several theories have been proposed to explain autoimmune responses, or the termination of self-tolerance:

a. An excess of self-reactive helper T (Th)-cell activity induced, for example, by altered forms of self-antigen or with antigen that cross-reacts with self-antigen, which might be produced by a coupling of chemicals or drugs (e.g., hydralazine) or viruses to self-antigen: the modified chemical (drug)-host or viral-host antigens would then trigger a self-reactive Th-effect and elicit autoantibody production.

b. A bypass of the lack of requisite self-reactive Th-cell activity or bypass of the need for such Th-cell activity via polyclonal B-cell activation with materials such as bacterial lipopolysaccharide, Epstein-Barr virus, or purified protein derivative (PPD) of tuberculin.

c. A deficiency of suppressor T (Ts) cells designed to down-regulate the immune response to self-antigen.

d. Release of sequestered antigen (e.g., from lens of the eye, sperm) not ordinarily available for recognition by the immune system: release might occur via such means as trauma or infection.

e. There is clearly a role for genetic factors in autoimmune disease. Most autoimmune diseases appear to be HLA associated with DR2, DR3, DR4, and DR5.

f. Autoimmune diseases tend to occur at a higher frequency in females than in males. The incidence of SLE in women is six to nine times more common in females.

B. Representative Autoimmune Diseases

Acute disseminated encephalomyelitis may occur following vaccination (e.g., rabies immunization) or viral infection (e.g., measles, influenza).

1. Pathologic examination reveals perivascular accumulation of macrophages, lymphocytes, and some neutrophils throughout the gray or white matter of the brain with variable demyelination.

2. Immunologic findings suggested that the disease represents a cell-mediated allergic response to basic protein of myelin similar to that seen in experimental allergic encephalomyelitis

Experimental allergic encephalomyelitis is the experimental model for postvaccinal and postinfectious encephalomyelitis that can be induced in animals (e.g., guinea pig) by the injection of either homologous or heterologous brain or spinal cord extracts emulsified in complete Freund’s adjuvant.

Chronic thyroiditis (Hashimoto’s thyroiditis) is a disease of the thyroid that mainly affects women in the age group between 30 and 50 years.

1. Various antibodies to thyroid-specific antigens can be demonstrated.

2. Experimental animals injected with homologous or autologous thyroid extract incorporated in complete Freund’s adjuvant develop lesions and other features similar to those seen in human disease.

Multiple sclerosis is a relapsing disease with exacerbations between periods of remission. Epidemiologic studies have revealed high-risk and low-risk areas of the world and a possible role for a transmissible agent. Evidence that susceptibility close association with HLA-DR2.

1. Inflammatory lesions (sclerotic plaques) are confined to the myelin in the central nervous system and consist of mononuclear cell infiltrates and demyelination.

2. The cause of multiple sclerosis remains unknown, but the clustering character of cases suggests an infectious agent. Of interest in this regard is the finding that patients tend to have elevated levels of antibodies to measles virus in their serum and spinal fluid; however, the exact role of measles virus is unknown. There is, in fact, evidence that other viral agents may also be involved.

Graves’ disease (thyrotoxicosis, hyperthyroidism) results from the overproduction of thyroid hormone (thyroxine).

1. Current evidence suggests that patients produce antibodies to thyrotropin receptors, which are referred to as thyroid-stimulating antibodies since they compete with thyroid stimulating hormone (thyrotropin, which is made in the pituitary) for receptor sites on the thyroid cell membrane and mimic the action of thyrotropin. The end result is overproduction of thyroid hormone and hyperthyroidism.

Guillain-Barré syndrome (acute idiopathic polyneuritis) commonly occurs after an infectious disease (e.g., measles, hepatitis) or after vaccination (e.g., influenza) and affects all age groups.

1. Examination of peripheral nerve tissue reveals a perivascular mononuclear cell infiltrate and demyelination.

2. A similar disease can be produced in experimental animals by injection of peripheral nerve extracts, or peptides derived therefrom, incorporated in complete Freund’s adjuvant. The experimental disease appears to be cell-mediated as evidenced by sensitivity of lymphocytes to nerve extracts. Anti-nerve antibodies can be detected but seem to play no role in pathogenesis.

3. The human disease has several of the same immunologic features as the experimental animal model (e.g., lymphocytes sensitive to peripheral nerve extracts, lymphokine production, and anti-nerve antibodies).

Myasthenia gravis is a chronic disease resulting from faulty neuromuscular transmission.

1. Muscle weakness and neuromuscular dysfunction result from depletion of acetylcholine receptors at the myoneural junction.

2. Injection of experimental animals with purified acetylcholine receptor incorporated in complete Freund’s adjuvant induces experimental myasthenia gravis that closely mimics human disease.

Systemic lupus erythematosus is a chronic, multiorgan disorder that predominantly affects young women of childbearing age. Multiply tissues that are involved include the skin, mucosa, blood vessels, kidney, brain, and blood.

1. The butterfly rash, an erythematosus rash that occurs over the nose and cheeks.

2. Diffuse proliferative glomerulonephritis and membranous glomerulonephritis are common manifestations.

3. Central nervous system (CNS) manifestations appear to 50% of patients and include depression, psychoses, seizures, and sensorimotor neuropathies.

4. Three primary types of antibodies to DNA (either IgG or IgM) can be detected:

a. Antibodies to single-stranded DNA (ss-DNA)

b. Antibodies to double-stranded DNA (ds-DNA).

c. Antibodies that react with both ss-DNA and ds-DNA, in addition to anti-DNA antibodies, antibodies are formed against RNA, erythrocytes, platelets, mitochondria, ribosomes, lysosomes, thromboplastin, and thrombin. Some patients demonstrate a positive test for rheumatoid factor.

Rheumatoid arthritis is a chronic inflammatory joint disease, with possible systemic involvement as well.

1. The disease affects primarily females and is associated with HLA-DR4, which may impart genetic susceptibility.

2. An unknown etiologic agent initiates a nonspecific immune response. An inflammatory joint lesion that begins in the synovial membrane can become proliferative, destroying adjacent cartilage and bone and resulting in joint deformity.

3. Rheumatoid factor. A hallmark of rheumatoid arthritis is the presence of rheumatoid factor, an immunoglobulin (mainly IgM but also IgG and IgA) produced by the B cells and plasma cells in the synovial membrane with antibody specificity for the Fc fragment of IgG.

4. The joint synovial fluid contains immune complexes consisting of rheumatoid factor IgG-complement.

Sjogren’s syndrome, also called sicca syndrome, is a chronic inflammatory disease that affects multiple systems of the body, although the primary target appears to be secretory arthritis or SLE.

1. Salivary and lacrimal glands are infiltrated with plasma cells, B cells, and T cells. Some patients show a quantitative and qualitative T-cell suppression in peripheral blood. All of these features suggest an immunologic etiology.

Hemolytic diseases that have been characterized as having an autoimmune basis include warm antibody hemolytic anemia, cold antibody hemolytic anemia, and paroxysmal cold hemoglobinuria.

Idiopathic thrombocytopenic purpura, which may be either acute or chronic, results from antibody-mediated platelet destruction. In children, it is sometimes preceded by a viral infection.

Goodpasture’s syndrome is a rare, progressive disease of the lungs and kidneys. The disease occurs in all age groups, affecting mainly young men. The prognosis is poor. IgG appears to represent an antibody specific for an antigen shared by kidney and lung basement membranes.

Pernicious anemia results from defective red blood cell maturation due to faulty absorption of vitamin B12. Normally, dietary B12 is transported across the small intestine into the body as a complex with intrinsic factor synthesized by parietal cells in gastric mucosa. In patients with pernicious anemia, the process is blocked.

1. The hallmark of the disease is the progressive destruction of stomach glands associated with loss of parietal cells which secrete intrinsic factor. This leads to failure of B12 absorption.

2. The gastric mucosa is infiltrated with mononuclear leukocytes and neutrophils.

Bullous (vesicular) diseases are chronic dermatologic problems that result when destruction of intercellular bridges (desmosomes) interferes with cohesion of the epidermis, leading to the formation of blisters.

1. Pemphigus vulgaris skin lesions, when examined by immunofluorescence, show deposition of antibody (mainly IgG) and complement components in squamous intercellular spaces.

2. Bullous pemphigoid lesions, by immunofluorescence examination, demonstrate deposition of antibody and complement along skin basement membrane. Circulating antibasement membrane antibodies can also be detected.

Polymyositis-dermatomyositis is an acute or chronic inflammatory disease of the muscle and skin.

1. Deposition of immunoglobulin and complement in the vessel walls of the skin and muscle.

2. Cellular immunity may also play a role in pathogenesis as judged from studies of cellular passive transfer and lymphokine release from lymphocytes.

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