Autoimmunity CHAPTER 20 with active MS contains activated T lymphocytes, which infiltrate the brain tissue and cause characteristic inflamma- tory lesions, destroying the myelin. Since myelin functions to insulate the nerve fibers, a breakdown in the myelin sheath leads to numerous neurologic dysfunctions Epidemiological studies indicate that Ms is most com mon in the Northern hemisphere and, interestingly, in the United States. Populations who live north of the 37th parallel dence of 11 who live south of the 37th parallel show a prevalence of 57-78 per 100,000 And individuals from south of the 37th parallel who move north assume a new risk if the move occurs before 15 years of age. These provocative data suggest that there is an environmental component of the risk of con- tracting MS. This is not the entire story, however, since genetic influences also are important. While the average per son in the united states has about one chance in 1000 of FIGURE 20-6 Characteristic"butterfly" rash over the cheeks of a developing MS, close relatives of people with MS, such as young girl with systemic lupus erythematosus /From L. Steinman, children or siblings, have 1 chance in 50 to 100 of developing 1993ScAm.2693)80J MS. The identical twin of a person with ms has a 1 in 3 chance of developing the disease. These data point strongly to the genetic component of the disease. And, as is described small blood vessels, a type III hypersensitive reaction devel in the Clinical Focus of this chapter, MS affects women two ops. The complexes activate the complement system and to three times more frequently than men generate membrane-attack complexes and complement split well understood. However, there are some suggestions that in vasculitis and glomerulonephritis l, resulting infection by certain viruses may predispose a person to MS Excessive complement activation in patients with seve Certainly some viruses can cause demyelinating diseases, and SLE produces elevated serum levels of the complement split it is tempting to speculate that virus infection plays a signifi products C3a and C5a, which may be three to four times cant role in MS, but at present there is no definitive data higher than normal. C5a induces increased expression of the Implicating a particular virus type 3 complement receptor(CR3)on neutrophils, facilitat ing neutrophil aggregation and attachment to the vascular Rheumatoid Arthritis Attacks joints endothelium As neutrophils attach to small blood vessels, the Rheumatoid arthritis is a common autoimmune disorder number of circulating neutrophils declines(neutropenia)and most often affecting women from 40 to 60 years old.The various occlusions of the small blood vessels develop(vasculi- major symptom is chronic inflammation of the joints tis). These occlusion can lead to widespread tissue damage although the hematologic, cardiovascular, and respirator Laboratory diagnosis of SLE focuses on the characteristic systems are also frequently affected. Many individuals with antinuclear antibodies, which are directed against double- rheumatoid arthritis produce a group of auto-antibodies stranded or single-stranded DNA, nucleoprotein, histones, called rheumatoid factors that are reactive with determi- and nucleolar RNA. Indirect immunofluorescent staining nants in the Fc region of IgG. The classic rheumatoid factor with serum from SLE patients produces various characteris- is an IgM antibody with that reactivity. Such auto-antibodies tic nucleus-staining patterns bind to normal circulating IgG, forming IgM-lgG complexes that are deposited in the joints. These immune complexe Multiple Sclerosis Attacks the Central activate the complement cascade resulting in a type Ill Nervous system hypersensitive reaction, which leads to chronic inflammation Multiple sclerosis(MS) is the most common cause of neuro. of the joints logic disability associated with disease in Western countries The symptoms may be mild, such as numbness in the limbs, Animal Models for Autoimmune or severe, such as paralysis or loss of vision. Most people wi MS are diagnosed between the ages of 20 and 40 Individuals Diseases with this disease produce autoreactive T cells that participate in the formation of inflammatory lesions along the myelin Animal models for autoimmune diseases have contributed heath of nerve fibers. The cerebrospinal fluid of patients valuable insights into the mechanism of autoimmunity, tosmall blood vessels, a type III hypersensitive reaction devel￾ops. The complexes activate the complement system and generate membrane-attack complexes and complement split products that damage the wall of the blood vessel, resulting in vasculitis and glomerulonephritis. Excessive complement activation in patients with severe SLE produces elevated serum levels of the complement split products C3a and C5a, which may be three to four times higher than normal. C5a induces increased expression of the type 3 complement receptor (CR3) on neutrophils, facilitat￾ing neutrophil aggregation and attachment to the vascular endothelium. As neutrophils attach to small blood vessels, the number of circulating neutrophils declines (neutropenia) and various occlusions of the small blood vessels develop (vasculi￾tis). These occlusions can lead to widespread tissue damage. Laboratory diagnosis of SLE focuses on the characteristic antinuclear antibodies, which are directed against double￾stranded or single-stranded DNA, nucleoprotein, histones, and nucleolar RNA. Indirect immunofluorescent staining with serum from SLE patients produces various characteris￾tic nucleus-staining patterns. Multiple Sclerosis Attacks the Central Nervous System Multiple sclerosis (MS) is the most common cause of neuro￾logic disability associated with disease in Western countries. The symptoms may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision. Most people with MS are diagnosed between the ages of 20 and 40. Individuals with this disease produce autoreactive T cells that participate in the formation of inflammatory lesions along the myelin sheath of nerve fibers. The cerebrospinal fluid of patients with active MS contains activated T lymphocytes, which infiltrate the brain tissue and cause characteristic inflamma￾tory lesions, destroying the myelin. Since myelin functions to insulate the nerve fibers, a breakdown in the myelin sheath leads to numerous neurologic dysfunctions. Epidemiological studies indicate that MS is most com￾mon in the Northern hemisphere and, interestingly, in the United States. Populations who live north of the 37th parallel have a prevalence of 110–140 cases per 100,000, while those who live south of the 37th parallel show a prevalence of 57–78 per 100,000. And individuals from south of the 37th parallel who move north assume a new risk if the move occurs before 15 years of age. These provocative data suggest that there is an environmental component of the risk of con￾tracting MS. This is not the entire story, however, since genetic influences also are important. While the average per￾son in the United States has about one chance in 1000 of developing MS, close relatives of people with MS, such as children or siblings, have 1 chance in 50 to 100 of developing MS. The identical twin of a person with MS has a 1 in 3 chance of developing the disease. These data point strongly to the genetic component of the disease. And, as is described in the Clinical Focus of this chapter, MS affects women two to three times more frequently than men. The cause of MS, like most autoimmune diseases, is not well understood. However, there are some suggestions that infection by certain viruses may predispose a person to MS. Certainly some viruses can cause demyelinating diseases, and it is tempting to speculate that virus infection plays a signifi￾cant role in MS, but at present there is no definitive data implicating a particular virus. Rheumatoid Arthritis Attacks Joints Rheumatoid arthritis is a common autoimmune disorder, most often affecting women from 40 to 60 years old. The major symptom is chronic inflammation of the joints, although the hematologic, cardiovascular, and respiratory systems are also frequently affected. Many individuals with rheumatoid arthritis produce a group of auto-antibodies called rheumatoid factors that are reactive with determi￾nants in the Fc region of IgG. The classic rheumatoid factor is an IgM antibody with that reactivity. Such auto-antibodies bind to normal circulating IgG, forming IgM-IgG complexes that are deposited in the joints. These immune complexes can activate the complement cascade, resulting in a type III hypersensitive reaction, which leads to chronic inflammation of the joints. Animal Models for Autoimmune Diseases Animal models for autoimmune diseases have contributed valuable insights into the mechanism of autoimmunity, to Autoimmunity CHAPTER 20 467 FIGURE 20-6 Characteristic “butterfly” rash over the cheeks of a young girl with systemic lupus erythematosus. [From L. Steinman, 1993, Sci. Am. 269(3):80.]