25.2: Systemic Autoimmune Disorders

Learning Objectives

• List the ways antibodies contribute to the pathogenesis of myasthenia gravis
• Explain why rheumatoid arthritis is considered a type III hypersensitivity
• Describe the symptoms of systemic lupus erythematosus and explain why they affect so many different parts of the body

Systemic Autoimmune Diseases

Whereas organ-specific autoimmune diseases target specific organs or tissues, systemic autoimmune diseases are more generalized, targeting multiple organs or tissues throughout the body. Examples of systemic autoimmune diseases include multiple sclerosis, myasthenia gravis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.

Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune central nervous system disease that affects the brain and spinal cord. Lesions in multiple locations within the central nervous system are a hallmark of multiple sclerosis and are caused by infiltration of immune cells across the blood-brain barrier. The immune cells include T cells that promote inflammation, demyelination, and neuron degeneration, all of which disrupt neuronal signaling. Symptoms of MS include visual disturbances; muscle weakness; difficulty with coordination and balance; sensations such as numbness, prickling, or “pins and needles”; and cognitive and memory problems.

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Myasthenia Gravis

Autoantibodies directed against acetylcholine receptors (AChRs) in the synaptic cleft of neuromuscular junctions lead to myasthenia gravis (Figure \(\PageIndex{4}\)). Anti-AChR antibodies are high-affinity IgGs and their synthesis requires activated CD4 T cells to interact with and stimulate B cells. Once produced, the anti-AChR antibodies affect neuromuscular transmission by at least three mechanisms:

• Complement binding and activation at the neuromuscular junction
• Accelerated AChR endocytosis of molecules cross-linked by antibodies
• Functional AChR blocking, which prevents normal acetylcholine attachment to, and activation of, AChR

Regardless of the mechanism, the effect of anti-AChR is extreme muscle weakness and potentially death through respiratory arrest in severe cases.

Figure \(\PageIndex{4}\): Myasthenia gravis and impaired muscle contraction. (a) Normal release of the neurotransmitter acetylcholine stimulates muscle contraction. (b) In myasthenia gravis, autoantibodies block the receptors for acetylcholine (AChr) on muscle cells, resulting in paralysis.

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Psoriasis

Psoriasis is a skin disease that causes itchy or sore patches of thick, red skin with silvery scales on elbows, knees, scalp, back, face, palms, feet, and sometimes other areas. Some individuals with psoriasis also get a form of arthritis called psoriatic arthritis, in which the joints can become inflamed. Psoriasis results from the complex interplay between keratinocytes, dendritic cells, and T cells, and the cytokines produced by these various cells. In a process called cell turnover, skin cells that grow deep in the skin rise to the surface. Normally, this process takes a month. In psoriasis, as a result of cytokine activation, cell turnover happens in just a few days. The thick inflamed patches of skin that are characteristic of psoriasis develop because the skin cells rise too fast.

Rheumatoid Arthritis

The most common chronic inflammatory joint disease is rheumatoid arthritis (RA) (Figure \(\PageIndex{5}\)) and it is still a major medical challenge because of unsolved questions related to the environmental and genetic causes of the disease. RA involves type III hypersensitivity reactions and the activation of CD4 T cells, resulting in chronic release of the inflammatory cytokines IL-1, IL-6, and tumor necrosis factor-α (TNF-α). The activated CD4 T cells also stimulate the production of rheumatoid factor (RF) antibodies and anticyclic citrullinated peptide antibodies (anti-CCP) that form immune complexes. Increased levels of acute-phase proteins, such as C-reactive protein (CRP), are also produced as part of the inflammatory process and participate in complement fixation with the antibodies on the immune complexes. The formation of immune complexes and reaction to the immune factors cause an inflammatory process in joints, particularly in the hands, feet, and legs. Diagnosis of RA is based on elevated levels of RF, anti-CCP, quantitative CRP, and the erythrocyte sedimentation rate (ESR) (modified Westergren). In addition, radiographs, ultrasound, or magnetic resonance imaging scans can identify joint damage, such as erosions, a loss of bone within the joint, and narrowing of joint space.

Figure \(\PageIndex{5}\): The radiograph (left) and photograph (right) show damage to the hands typical of rheumatoid arthritis. (credit right: modification of work by “handarmdoc”/Flickr)

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Systemic Lupus Erythematosus

The damage and pathology of systemic lupus erythematosus (SLE) is caused by type III hypersensitivity reactions. Autoantibodies produced in SLE are directed against nuclear and cytoplasmic proteins. Anti-nuclear antibodies (ANAs) are present in more than 95% of patients with SLE,⁴ with additional autoantibodies including anti-double–stranded DNA (ds-DNA) and anti-Sm antibodies (antibodies to small nuclear ribonucleoprotein). Anti-ds-DNA and anti-Sm antibodies are unique to patients with SLE; thus, their presence is included in the classification criteria of SLE. Cellular interaction with autoantibodies leads to nuclear and cellular destruction, with components released after cell death leading to the formation of immune complexes.

Because autoantibodies in SLE can target a wide variety of cells, symptoms of SLE can occur in many body locations. However, the most common symptoms include fatigue, fever with no other cause, hair loss, and a sunlight-sensitive "butterfly" or wolf-mask (lupus) rash that is found in about 50% of people with SLE (Figure \(\PageIndex{6}\)). The rash is most often seen over the cheeks and bridge of the nose, but can be widespread. Other symptoms may appear depending on affected areas. The joints may be affected, leading to arthritis of the fingers, hands, wrists, and knees. Effects on the brain and nervous system can lead to headaches, numbness, tingling, seizures, vision problems, and personality changes. There may also be abdominal pain, nausea, vomiting, arrhythmias, shortness of breath, and blood in the sputum. Effects on the skin can lead to additional areas of skin lesions, and vasoconstriction can cause color changes in the fingers when they are cold (Raynaud phenomenon). Effects on the kidneys can lead to edema in the legs and weight gain. A diagnosis of SLE depends on identification of four of 11 of the most common symptoms and confirmed production of an array of autoantibodies unique to SLE. A positive test for ANAs alone is not diagnostic.

Figure \(\PageIndex{6}\): (a) Systemic lupus erythematosus is characterized by autoimmunity to the individual’s own DNA and/or proteins. (b) This patient is presenting with a butterfly rash, one of the characteristic signs of lupus. (credit a: modification of work by Mikael Häggström; credit b: modification of work by Shrestha D, Dhakal AK, Shiva RK, Shakya A, Shah SC, Shakya H) 

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Table \(\PageIndex{1}\) summarizes the causes, signs, and symptoms of select autoimmune diseases.

Table \(\PageIndex{1}\): Select Autoimmune Diseases

Disease	Cause	Signs and Symptoms
Addison disease	Destruction of adrenal gland cells by cytotoxic T cells	Weakness, nausea, hypotension, fatigue; adrenal crisis with severe pain in abdomen, lower back, and legs; circulatory system collapse, kidney failure
Celiac disease	Antibodies to gluten become autoantibodies that target cells of the small intestine	Severe diarrhea, abdominal pain, anemia, malnutrition
Diabetes mellitus (type I)	Cytotoxic T-cell destruction of the insulin-producing β cells of the pancreas	Hyperglycemia, extreme increase in thirst and urination, weight loss, extreme fatigue
Graves disease	Autoantibodies target thyroid-stimulating hormone receptors, resulting in overstimulation of the thyroid	Hyperthyroidism with rapid and irregular heartbeat, heat intolerance, weight loss, goiter, exophthalmia
Hashimoto thyroiditis	Thyroid gland is attacked by cytotoxic T cells, lymphocytes, macrophages, and autoantibodies	Thyroiditis with goiter, cold intolerance, muscle weakness, painful and stiff joints, depression, memory loss
Multiple sclerosis (MS)	Cytotoxic T-cell destruction of the myelin sheath surrounding nerve axons in the central nervous system	Visual disturbances, muscle weakness, impaired coordination and balance, numbness, prickling or “pins and needles” sensations, impaired cognitive function and memory
Myasthenia gravis	Autoantibodies directed against acetylcholine receptors within the neuromuscular junction	Extreme muscle weakness eventually leading to fatal respiratory arrest
Psoriasis	Cytokine activation of keratinocytes causes rapid and excessive epidermal cell turnover	Itchy or sore patches of thick, red skin with silvery scales; commonly affects elbows, knees, scalp, back, face, palms, feet
Rheumatoid arthritis	Autoantibodies, immune complexes, complement activation, phagocytes, and T cells damage membranes and bone in joints	Joint inflammation, pain and disfigurement, chronic systemic inflammation
Systemic lupus erythematosus (SLE)	Autoantibodies directed against nuclear and cytoplasmic molecules form immune complexes that deposit in tissues. Phagocytic cells and complement activation cause tissue damage and inflammation	Fatigue, fever, joint pain and swelling, hair loss, anemia, clotting, a sunlight-sensitive "butterfly" rash, skin lesions, photosensitivity, decreased kidney function, memory loss, confusion, depression

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Key Concepts and Summary

• Systemic autoimmune diseases include multiple sclerosis, myasthenia gravis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.
• Treatments for autoimmune diseases generally involve anti-inflammatory and immunosuppressive drugs.

Footnotes

1. 4 C.C. Mok, C.S. Lau. “Pathogenesis of Systemic Lupus Erythematosus.” Journal of Clinical Pathology 56 no. 7 (2003):481—490.