Autoimmune Disorders

Autoimmune disorders involve the development of an adaptive immune response against one’s own cells.  This process includes T lymphocytes, B lymphocytes, and antibodies targeting the body’s own cells for destruction, leading to chronic inflammation, damage, and deterioration of affected tissues.  There are over 80 identified types of autoimmune diseases, which have been found to affect a variety of different cell types in the body.  These disorders have no cure and their etiology is unknown and likely multifactorial.  One possible mechanism is molecular mimicry, where a previous viral infection stimulates an immune response against a viral antigen that cross-reacts with self-antigens.

Many autoimmune disorders share common risk factors such as female biological sex, genetics (e.g., inheritance of certain MHC/HLA alleles), family history (especially first-degree relatives), and previous infections with Epstein-Barr Virus (EBV).  It is not clear why post-puberty females are more susceptible to autoimmune disorders, but sex hormones are thought to play a role, particularly as symptoms can lessen during pregnancy.  Additionally, the use of oral contraceptives correlates with a reduced incidence of some types of autoimmune dieases in females.

Treatments often involve immunosuppressants and anti-inflammatories to minimize damage, avoiding triggers, and managing symptoms.  These disorders are estimated to affect over 20 million Americans and more than 2 million Canadians.

*MHC = Major Histocompatibility Complex;  HLA = Human Leukocyte Antigen

Mechanism of Autoimmune Disorders

Autoimmune disorders can involve one or more hypersensitivity reactions:

1. Type II Hypersensitivity Reactions: Antibodies inappropriately bind to host cells, activating the complement system and targeting host cells for destruction.
2. Type III Hypersensitivity Reactions: Antibody-antigen complexes are deposited in regions of the body, causing vasculitis, joint pain, and renal damage.
3. Type IV Hypersensitivity Reactions: Damage is caused by cytotoxic T cells, leading to inflammation and tissue dysfunction.

Hypotheses on Causes of Autoimmune Disorders

Although autoimmune diseases are idiopathic, it is thought that they are multifactoral with many contributing elements.  One hypothesis is that genetic susceptibilities and non-genetic factors contribute to the development of an autoimmune disease.  Specific genetic susceptibilities include the inheritance of particular MHC/HLA alleles as well as levels of sex hormones.  Non-genetic, environmental factors are thought to include one or more of the following:

• a previous infection with a pathogen (e.g. EBV) invokes an immune response against viral antigens that leads to an immune response that cross-reacts with self-antigens.
• stress, shift work
• cigarette smoking, pollutants, environmental chemicals
• high intake of salt, alcohol, coffee, saturated fat, and/or red meat
• low intake of sources of vitamins and anti-oxidants (e.g., fruits and vegetables)
• vitamin D deficiencies
• sedentary lifestyle
• trauma
• microbiota composition

Common Autoimmune Diseases

 1.  Multiple Sclerosis (MS):

Multiple Sclerosis (MS) is an immune-mediated inflammatory disease that leads to the demyelination of CNS neurons, specifically the destruction of oligodendrocytes in the brain and spinal cord.  The signs and symptoms of MS often cycle through periods of remissions and exacerbations as myelin attempts to repair itself.  However, over time, the repair process cannot keep up with the damage, and lesions, or plaques of scar tissue known as sclerae, begin to accumulate, which is the origin of the disease’s name, Multiple Sclerosis.  The parenchyma of the brain shows increased levels of T lymphocytes, macrophages, microglia, and other inflammatory cells as well as pro-inflammatory cytokines.  The resulting neuron dysfunction manifests as a range of symptoms that depend on the extent of loss of function in various motor, sensory, and autonomic nerves affected by demyelination.  Lesion formation also causes the breakdown of the blood-brain barrier, allowing an influx of T lymphocytes that likely exacerbates the demyelination problem.  Furthermore, high IgG levels are noted in the cerebrospinal fluid (CSF) indicating their spread through the brain as well.

The etiology of MS is unknown, but it is believed to involve genetic susceptibility and a nongenetic trigger, such as a viral infection or low vitamin D levels.  Risk factors for MS include female biological sex, genetics (inheritance of certain MHC/HLA alleles), family history (especially first-degree relatives), previous infection with Epstein-Barr Virus (EBV), low vitamin D levels, and living in northern latitudes like Canada or northern Europe.

There are four different types of MS, each with differing progression of lesion formation, frequency of relapses, and prognosis, with individual progression varying.  MS is characterized by progressive changes or loss of motor function, sensory function, and autonomic function.  Signs and symptoms of MS can include fatigue, sensory losses (paresthesias), muscle cramping, muscle spasticity, muscle weakness, tremors, reduced coordination, bladder, bowel and/or sexual dysfunction, heat intolerance, cognitive difficulties, memory problems, blurry vision or loss of vision, depression, euphoria, aphasia (trouble speaking), seizures, and personality changes.  The onset of MS typically occurs between 15-45 years old, with an average age of 29 years in females and 31 years in males.  Globally, 2.1 million people are affected by MS.

Diagnosis of MS can involve MRI scans, evoked potential tests (measuring how fast neurons respond to stimulation), and lumbar puncture tests (to detect elevated IgG in the CSF).  Treatment for MS often includes immunosuppressants, vitamin D (carefully monitored to avoid hypervitaminosis), as well as maintaining a healthy diet, sleep patterns, exercise habits, and support groups.

2.  Rheumatoid Arthritis:

Rheumatoid Arthritis (RA) is an autoimmune disease that targets synovial tissue, causing bilateral symmetric polyarthritis (synovitis) that often affects the hands and feet, though all joints can be affected, and it can also impact other organs such as the skin, heart, lungs, and eyes.  RA leads to joint deterioration, inflammation and pain.  The etiology of RA is unknown, making it idiopathic.  The pathogenesis of RA is thought to involve underlying genetic susceptibilities and is triggered by non-genetic stimuli, such as infections, smoking, and trauma.  T cells, B cells, autoantibodies, and neutrophils contribute to progressive damage to synovial membranes, articular cartilage, and surrounding tissues, including tendons, ligaments, bone, and blood vessels. This damage leads to pannus formation, a type of new fibrovascular or granulation tissue.
Risk factors for RA include being female, genetic inheritance of certain MHC/HLA alleles, family history (especially first-degree relatives), previous infection with Epstein-Barr Virus (EBV), cigarette smoking, vitamin D deficiency, high intake of salt, alcohol, coffee, red meat, and a sedentary lifestyle. Females are three times more at risk than males, with the average age of onset between 35-50 years old.
Signs and symptoms of RA include a gradual, insidious onset leading to joint inflammation and swelling. As the disease progresses, patients experience stiffness, pain with joint movement, limited range of motion, and joint deformity. Finger joint deformities such as Boutonniere deformities and swan-neck deformities occur due to the shortening of tendons from scarring.  Boutonniere deformity is usually noted in the fingers or toes, causing proximal or distal interphalangeal joint deformities.  An ulnar shift of all the fingers may also occur.  To make matters worse, range of motion can be limited even further due joint narrowing that occurs with damage.  This can lead to ankylosis (joint fusion/fixation) in which joints are locked in deviated positions if not treated.  Muscle spasms and pain can also occur and flare-ups are associated with anemia (e.g., iron-deficient anemia).  Individuals with RA are more prone to lung fibrosis, atherosclerosis, myocardial infarctions and stroke (cerebrovascular accidents, CVA).
Diagnosis of RA can involve various tests.  RA can be indicated by a combination of imaging results (e.g., x-ray, MRI), high erythrocyte sedimentation rates (ESR), high C-reactive protein (CRP) levels, the presence of serum Rheumatoid factor (RF) autoantibodies and anti-nuclear antibodies.  Imaging may reveal joint deterioration, and can help rule out other causes of arthralgia (joint point) and inflammation (e.g., infections).  Treatment options for RA can include heat and cold therapies, orthotics, splints, occupational and therapeutic exercises, maintaining a healthy diet and sleep habits, Disease-Modifying Antirheumatic Drugs (DMARDs), corticosteroids, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and arthroplasty, such as hip replacements.

*ESR and CRP are general markers of inflammation.

3.  Lupus (Systemic Lupus Erythematosus):

Systemic Lupus Erythematosus (SLE) also known as Lupus is an autoimmune disorder that is characterized by a large number of circulating autoantibodies against DNA, platelets, and erythrocytes.  This results in the formation of immune complexes (autoantibodies bound to self-antigens) which are deposited into connective tissues and organs, such as the kidneys, lungs, heart, brain, joints, and digestive tract.  These deposits activate the complement system and leukocytes causing tissue destruction and chronic inflammation.  Contributing to the problem, these large amounts of antigen-antibody clusters are not adequately cleared by macrophages and deposition in blood vessels causes vasculitis and the release of lysosomal enzymes and pro-inflammatory cytokines.  This phenomenon is categorized as a Type III Hypersensitivity Reaction, and is characterized by serum auto-antibodies (IgG and IgM) forming immune complexes involving host cell’s DNA, nuclei, platelets and erythrocytes (red blood cells, RBCs).

Signs and symptoms include a facial rash, specifically with erythema (redness caused by hyperemia, or increased blood flow) in a butterfly-like pattern over cheeks and nose.  The term malar rash is sometimes used as mala is Latin for cheeks or lower part of the face. The name of the disorder Systemic Lupus Erythematosus, was coined in the 13th-century in which the Latin word lupus refers to facial lesions that were thought to resemble wolf bites.  The term systemic refers to common systemic symptoms such as malaise, fatigue, and fever.  Finally, erythematosus comes from the Greek word erythros meaning red.  Rashes can occur on other sun-exposed regions as well (e.g., hands).  Although the reasons are unclear, it is known that signs and symptoms of SLE get worse with sun exposure.  It is speculated that in SLE, skin is more sensitive to UV damage, and that damaged cells trigger SLE flares, particularly skin rashes.

Furthermore, deposition of immune complexes in blood vessel walls can lead to vasculitis which can cause urticaria (hives or itchy welt/rash), pruritis (itchy skin), patchy or generalized rashes as well.  Also, within the blood, autoantibodies that bind and target platelets, RBCs and WBCs for destruction can lead to thrombocytopenia, hemolytic anemia, leukopenia, and lymphopenia, resulting in fatigue and immunosuppression. 

Other symptoms include:  arthralgia (joint pain), joint swelling, headaches, memory loss, seizures, psychosis, possibly heart, lung, GI tract, and kidney problems.  Additionally, it is estimated that 18-36% of individuals with SLE have what is termed Raynaud’s phenomenon, which involves having periodic vasospasms in fingers and toes that cause pallor, cyanosis, and numbness or pain.  Raynaud’s phenomenon is usually triggered by cold temperatures or emotional stress.  Females and those with a family history of the condition are more likely to experience Raynaud’s phenomenon, suggesting that both sex hormones and genetics may be contributing factors.

Diagnostic test results that can indicate SLE include: low blood cell counts (erythrocytopenia, leukopenia, thrombocytopenia), LE cells (neutrophils full of nuclear material), low levels of complement plasma proteins, increased ESR, unchanged CRP levels, and the presence of autoantibodies in sera (e.g., antinuclear antibodies (ANA), anti-dsDNA antibodies, anti-Smith antibodies (which interact with small nuclear RNA antigens), and antiphospholipid antibodies.  Imaging (e.g., MRI of brain, kidney, lungs) can be helpful in detecting and assessing damage and inflammation (e.g., carditis, pericarditis, pleuritis).  Angiography can be used to assess for thrombi.  Kidney damage (e.g., glomerulonephritis) is indicated by proteinuria, polyuria, increased anemia (due to low erythropoietin, EPO production) and some forms of hypertension.  Levels of ESR are reflective of the extent of inflammation present.  The higher the ESR, the more inflammation is occurring.  Interestingly, CRP has both pro-inflammatory and anti-inflammatory properties.  CRP levels can rise with inflammation, although unlike ESR,  CRP appears to remain low in SLE unless an infection occurs.  CRP is a plasma protein produced by the liver, and can activate the complement system as well as phagocytic cells.
Risk factors for developing SLE include biological sex, with females being ten times more susceptible than males.  Other risk factors include:  genetics (e.g. specific MHC/HLA alleles), T and B cell hyperactivation, increased cytokine and neutrophil activity, virus infections (EBV), cigarette smoking, silica dust, estrogen, exposure to pesticides, and low birthweight.  Additionally, some blood pressure and heart arrhythmia medications put one at risk for SLE.

One hypothesis for the development of SLE, is that molecular mimicry between a viral antigen and a self-antigen has occurred leading to autoimmunity.  Another hypothesis proposes that SLE is caused by a defect in the steps of apoptosis, such that intracellular components are not packaged properly in apoptotic bodies for phagocytosis by macrophage.  This would lead to the chronic exposure of intracellular components to immune system cells (e.g., T cells), which could then develop an inappropriate immune response (of T cells, B cells, and antibodies) against these intracellular components (DNA, nuclear RNA, etc.).
Treatment for SLE involves immunosuppressants, anti-inflammatories, antimalarials (e.g., hydroxychloroquine), corticosteroids, disease modifying antirheumatic drugs (DMARDs), as well as a healthy diet and lifestyle.  Although it may seem strange to use antimalarials, these drugs have been found to reduce chemotaxis of both eosinophils and neutrophils, as well as impair complement and immune complex formation, all of which lessens the amount of damage and inflammation.  DMARDs can be helpful in that they have both immunosuppressive and anti-inflammatory qualities.
In Canada, it is estimated that approximately 15,000 people are affected by SLE, with 10 times more females affected than males.  The age of onset is typically between 15 and 44.
In the USA, it is estimated that 1.5 million Americans are affected and there are 5 million people estimated to be affected world-wide.

4.  Myasthenia Gravis

Myasthenia Gravis (MG) is idiopathic, as are most autoimmune diseases.  MG is characterized by the production autoantibodies to nicotinic acetylcholine receptors (AChRs) on the motor end plate of skeletal myofibers in neuromuscular junctions.  Unfortunately, once created, the attachment of autoantibodies to AChRs blocks acetylcholine (ACh) neurotransmitters from binding the acetylcholine receptors.  This leads to the inability of motor neurons to stimulate depolarization and contraction of the affected myofibers. Patients become symptomatic when many myofibers are affected and muscle weakness, fatigue, and/or flaccid (limp/floppy) paralysis develops.

Often the muscle weakness experienced fluctuates and can worsen with activity and improve after rest.  Typically, MG does not affect life span, though medical emergencies can occur if swallowing muscles are affected and aspiration and/or subsequent pneumonia occurs.  Additionally, there is a risk of neuromuscular respiratory failure if respiratory muscles are affected.  Each case varies in its severity and prognosis, though for many patients, thymectomy results in complete remission. Other treatments involve the use of cholinesterase inhibitors, immunosuppressive drugs, and plasmapheresis (removing antibodies from plasma).  Avoidance of hot weather and other stressors is recommended as they can exacerbate symptoms.

The pathogenesis of MG involves an inappropriate T and B cell mediated autoimmune disorder.   It is thought that macrophages and dendritic cells phagocytose AChRs and present AChR antigens on MHC-II molecules to Helper T cells leading to the stimulation of B lymphocytes to produce anti-AChR antibodies.  It is thought that thymus abnormalities play a role in the development in MG as thymus hyperplasia or thymoma develops in 75% of patients.  Another contributing factor in many cases of MG is the development of the autoantibodies against muscle-specific kinases (MuSK).  The MuSK enzyme is involved in the maturation and clustering of AChRs in the motor end plate.  The loss of more than 30% of AChRs leads to signs and symptoms of MG.

Diagnosis can involve testing for presence of autoantibodies (i.e., anti-AChR, anti-MuSK, and anti-muscle antibodies) in serum.  Often imaging (e.g., MRI or CT scans) is used to identify any possible thymic enlargements (including thymomas) and rule out any other tumors or causes.  Nerve conduction and stimulation studies are used to rule out neural disorders. Additionally, single fiber electromyography (SFEMG) recording abnormalities can indicate MG.

The underlying mechanism of MG is characterized as a Type II Hypersensitivity Reaction, in which an inappropriate immune reaction develops against the host’s cells.

In the case of MG, the muscles most often affected are in the eyes, eyelids, and face.  The resulting signs and symptoms therefore include: muscle weakness, fatigue, flaccid paralysis, particularly affecting eyes, eyelids, and face, frequently causing double vision, blurred vision, and unilateral or bilateral ptosis (droopy eyelids) as well as photophobia.  MG can also cause dysarthria, dysphagia, difficulty chewing, and slurred speech.  As mentioned above, swallowing difficulties can present risks for aspiration.  At times individuals experience weakness in arms, legs and feet as well as foot drop.

Risk factors for developing MG include the genetic inheritance of certain MHC/HLA (major histocompatibility complex, Human Leukocytes Antigen) alleles as well as thymus abnormalities.  Females are greater at risk for developing MG than males, with the mean age of onset being 28 years for females and 42 years for males.  However older adult males (50+ yrs) are susceptible to the development of MG as well.  The reason for differences in risk factors due to biological sex is unclear.

Pregnancy is risk factor, in that the autoantibodies involved are small IgGs that can cross the placental barrier.  This means that babies born to a birth parent that has anti-AChR antibodies, will have an increased risk of developing neonatal MG.  Treatments during pregnancy that lower the autoantibody serum levels minimize the chance of neonatal MG developing and treatments continue after-birth for both the birth parent and infant.  Most often when it does occur, neonatal MG is transient, possibly due to the short IgG half-life of 10-21 days.

5.  Hashimoto’s Thyroiditis:

Hashimoto’s thyroiditis is an autoimmune disease that leads to the destruction of the thyroid gland resulting in reduced thyroid hormone production, a condition termed hypothyroidism. This disease was first reported by Japanese surgeon, Hakaru Hashimoto in 1912. Hypothyroidism leads to fatigue, weight gain, feeling cold, slowed movements, lack of energy, memory loss, deafness, joint pains and muscle cramps. Other symptoms include dry skin, bradycardia, constipation, cold intolerance, decreased sweating, hair loss, thick and brittle nails, menstrual irregularities, and the development of a goiter (enlargement of the thyroid gland).
The underlying mechanism of Hashimoto’s thyroiditis is depicted by a Type III Hypersensitivity Reaction in which auto-antibodies against cells of the thyroid gland leads to destruction and loss of functioning thyroid cells.
Diagnostic testing can involve blood tests assessing the levels of thyroid-stimulating hormone (TSH), thyroid hormones (T4 and T3), and thyroid autoantibodies (e.g., anti-TPO and anti-thyroglobulin), as well as complete blood counts. Ultrasound may be used to assess the thyroid gland size and the presence of any thyroid nodules. Fine needle biopsies of any suspicious nodules are examined to exclude malignancies and treat those if necessary.  Thyroid biopsies in cases of Hashimoto’s thyroiditis often reveal a high concentration of lymphocytes, atrophy of the thyroid parenchyma (thyrocyte depletion) and fibrosis.
Risk factors for the development of Hashimoto’s thyroiditis include genetics (e.g., specific MHC/HLA alleles), family history, other autoimmune diseases (e.g., pernicious anemia, adrenal insufficiency, celiac disease, type I diabetes mellitus), anticancer medications, possibly excess dietary iodine (usually in the form of table salt) and vitamin D deficiency. Age and biological sex are also risk factors and incidence rates are 10-15 times higher in adult females. Age of onset is typically between 30-50 years old in females and 40-65 years old in males.
Of concern, are reports that the increases in TSH and decreases in T4 that are observed with Hashimoto’s thyroiditis, correlate with higher total cholesterol, higher triglycerides, higher LDL, and lower HDL. This serum lipid profile increases the likelihood of developing coronary artery disease. It is therefore important to diagnose and treat Hashimoto’s thyroiditis as early as possible.
Treatment of Hashimoto’s thyroiditis primarily involve supplemental thyroid hormone. Treatments can also include the removal of any malignant thyroid nodules and thyroid surgery to alleviate obstructive problems as well as cosmetic issues associated with large goiters. Prevention of extreme hypothyroidism is important as that can lead to myxedema coma which has a high mortality rate. Older females can be susceptible to the development of myxedema coma.

6. Graves Disease:

Graves disease is an autoimmune disease which is named after Robert Graves who described this disease in 1835.  Graves disease causes hyperthyroidism due to the creation of auto-antibodies that bind to thyroid stimulating hormone receptors (TSHRs) on thyroid gland cells (thyrocytes) and stimulate the production of thyroid hormone (T4 and T3).  The auto-antibodies in Graves disease are therefore termed Thyroid Stimulating Immunoglobulins (TSIs).  This type of inappropriate immune mechanism is categorized as a Type II Hypersensitivity Reaction as auto-antibodies are binding to thyroid cells (thyrocytes).  Graves disease is unlike other autoimmune diseases in that cells are inappropriately stimulated rather that destroyed.

It is unclear what triggers the development of Graves Disease.  One hypothesis is that Graves disease is caused by molecular mimicry in which an infecting viral or bacterial antigen initiates an immune response that cross-reacts with TSHR.  A second hypothesis is that acute stress induces immune system hyperactivity.  A third hypothesis is that a previously hidden self-antigen(s) is/are exposed to the immune system which then initiates an immune response.

Signs and symptoms of Graves disease include hyperthyroidism leading to an enlarged thyroid gland (goiter), increased basal metabolic rate, sweating, weight loss, increased bowel motility, tachycardia, tachypnea, tremors, and restlessness.  Graves disease can also cause fatigue, osteoporosis, back pain, dyspnea, easy bruising, and renal problems.  The ophthalmology that can occur, causes eyes to “bulge”, and leads to difficulty moving eyes, dry eyes, blurred vision, double vision, and/or low tolerance of bright lights (photophobia).  Prolonged hyperthyroidism can lead to bone breaks due to osteoporosis, cardiac hypertrophy, congestive heart failure, and blindness.

Diagnostic tests for Graves disease include blood tests to assess the levels of TSH, T3, T4, and TSIs.  In Graves disease, prior to treatment, autoantibodies (TSIs) are present and the levels of thyroid hormones (T3 and T4) are typically high.  Without treatment, TSH levels are usually low, and other anti-thyroid antibodies may also be present.  Often complete blood cell counts are performed as are imaging (e.g., ultrasound, CT, or MRI) coupled with biopsies to assess the thyroid and rule out other diseases.  Graves disease causes the thyroid to become infiltrated with lymphocytes and anti-TSHR antibodies.

Treatment most often involves the delivery of radioactive iodine which preferentially localizes to the thyroid gland due to the gland’s ability to rapidly sequester iodine for use in building thyroid hormones.  Radioiodine therapy is used to reduce an enlarged thyroid gland, with the goal of totally eliminating the thyroid gland and then supplying the patient with supplemental thyroid hormone at required levels.  Instead of radioiodine therapy, other options include thyroidectomy (surgical removal of the thyroid gland) and anti-thyroid medications.  After the thyroid gland is eliminated, supplemental thyroid hormone delivery is a required lifelong treatment in order to maintain homeostasis and normalize bodily functions.

Treatment for Graves disease is important as severe thyrotoxicosis (i.e., thyroid storm) can occur leading to tachycardia, nausea, fever, high systolic blood pressure, confusion, fainting, reduced consciousness, coma, heart failure and death.

Unfortunately, thyroidectomy does not improve ophthalmopathy.  Therefore, medications such as anti-inflammatories are used to reduce Graves ophthalmopathy particularly if optic nerve compression is occurring which can lead to blindness if not treated.

Risk factors for the development of Grave’s include genetics (e.g., specific MHC/HLA alleles), family history, other autoimmune diseases such as pernicious anemia, rheumatoid arthritis, SLE, Addison disease (adrenal cortisol and aldosterone insufficiency), celiac disease, type I diabetes mellitus.

Age and biological sex are also risk factors and incidence rates are 7-8 times higher in adult females in comparison to adult males.  Age of onset for both sexes is typically between 20-40 years old.  Other risk factors include trauma or surgery of the thyroid gland. Selenium deficiencies as well as cigarette smoking have been found to exacerbate signs and symptoms.

7.  Rheumatic Fever and Rheumatic Heart Disease:

Acute Rheumatic Fever (ARF) is an autoimmune inflammatory disease that can develop after a group A beta hemolytic Streptococcus pyogenes infection, most often an upper respiratory (pharyngeal) infection, such as some forms of Strep throat.  At times this preceding streptococcal infection occurs in the skin rather than the throat.  The initial throat or skin infection is often termed rheumatic fever (RF), with ARF referring to the subsequent autoimmune disease that affects the heart, joints, skin, and central nervous system (CNS). Prior to the development of penicillin, RF was the 2nd leading cause of death in children and adolescents in the USA, with 1st being tuberculosis.

The underlying mechanism of ARF involves developing due to molecular mimicry, in which antibodies and T cells produced to target the infecting bacteria and cross-react with self antigens.  As with many other autoimmune diseases, ARF is a T and B cell mediated immune response in which host cells are attacked in a Type II Hypersensitivity Reaction.  The M protein on specific strains of Streptococcus mimic endogenous membrane proteins in the heart, skin and connective tissues.   T cells and antibodies (e.g., antistreptolysin O, ASO and antistreptococcal DNAse B, ADB) are able to clear the bacterial infection, but go on to target collagen and myosin proteins, affecting heart, brain, skin, joints.  This gives rise to clinical manifestations indicative of ARF.

The preceding strep throat infection gives rise to a sore throat, malaise, fever.  If not treated with antibiotic promptly there is a risk that sequelae of the autoimmune ARF can develop.  It should be noted that only specific strains of streptococcus bacteria (e.g., Group A beta hemolytic Streptococcus pyogenes) present a risk of RF and ARF developing.

The signs and symptoms of ARF develop 2-4 weeks after a strep infection and can include:

• Joints: Painful joints (arthralgia), manifesting as migrating polyarthritis affecting the knees, ankles, elbows, and wrists occurs due to auto-immune destruction of joint tissue. Most often no permanent damage is observed, with pain and inflammation subsiding within 4-6 weeks. Treatment is symptomatic and often involves NSAIDs and rest.
• Skin:  Erythema marginatum (non-itchy, painless reddish rash which can form rings) can appear due to destruction of subcutaneous connective tissues.  More rarely, subcutaneous nodules appear on the skin above prominent tendons and bony prominences.  Skin appears to heal completely in weeks to months.
• CNS: Sydenham chorea can occur due to the basal nuclei being affected by antibodies that cross-react with basal nuclei proteins.  Also termed, St. Vitus’ dance, Sydenham’s chorea can occur and involves involuntary rapid and uncoordinated movements of the arms, hands, feet, and face.  This phenomenon is given the name chorea from the Greek word for dance and can resemble writhing or drunken-like movements.  Most often Sydenham’s chorea affects young females and is usually temporary, resolving within 3-6 months.

• The most serious effect of ARF is myocarditis, which can lead to permanent damage. Myocarditis can manifest as arrhythmias (e.g., atrial fibrillation) and the development of Aschoff bodies within the myocardium.  Aschoff bodies are the sites of initial degeneration and replacement by granulomatous tissue, and finally fibrotic Aschoff nodules. Additionally, damage to heart valves, possible involving infectious vegetations and insufficiency is common particularly in the mitral valve.  Valvular damage can lead to heart murmurs and regurgitation which can reduce cardiac output.  Inflammatory effusions can lead to pericarditis, friction rub, orthopnea, and dyspnea.  Individuals experiencing carditis can present with tachycardia, rales, edema, and shortness of breath.  Heart damage can lead to congestive heart failure (CHF).  Treatment involves heart valve replacement or repair if necessary, coupled with medicine for CHF (e.g., ACE inhibitors, diuretics, beta blockers, digoxin).

Rheumatic Heart Disease is a condition that develops in adulthood after childhood episode(s) of rheumatic fever that have caused long-term damage to the heart.   It is estimated that approximately 60% of RF will develop into RHD. RHD can lead to congestive heart failure, endocarditis, and strokes (cerebrovascular accidents, CVAs).

The incidence rates of acute rheumatic fever (ARF) have declined significantly in N. America and Europe over the last 50 years due to improved sanitation, socioeconomic conditions and antibiotic treatments. Thankfully, this has led to declining numbers of RHD as well.

However, in developing nations, it is currently estimated that ARF has led to approximate 35 million people affected with rheumatic heart disease,

Preventative measure of Rheumatic Fever include: prompt antibiotic treatment of streptococcal respiratory infections (e.g., Strep throat) which eliminates the bacteria more quickly, reducing the chances of the development of an adaptive immune response that may produce T cells and autoantibodies that target self antigens for destruction.  Vaccine development is underway.

Risk Factors for the development of ARF and RHD include:  group A beta hemolytic streptococcal (GAS) infection that is not treated with antibiotics; genetic susceptibility, malnutrition, and lack of sanitation.

Diagnostic tests involve blood tests for specific anti-streptococcal antibodies (ASO and ADB) as well as ruling out other infections.  Rapid antigen tests on throat swabs can be helpful in identifying infecting agent.  Non-specific tests (e.g., erythrocyte sedimentation rate, ESR, and C-reactive proteins, CRP) can be used to monitor disease activity as high levels of both correlate with the extent of inflammation and infection.  Imaging (e.g., x-ray, ultrasound) and electrocardiography (ECG) is very helpful in assessing cardiac involvement.  Often criteria for diagnosis can involve confirmation of preceding GAS infection, in addition to signs of carditis (imaging and/or ECG), polyarthritis, chorea, erythema marginatum, and/or subcutaneous nodules.

8.  Pernicious Anemia:

Pernicious Anemia is an autoimmune disease with an ominous name, in that ‘pernicious’ means deadly.  The name dates from a time before treatments had been discovered.  Pernicious anemia involves an inappropriate adaptive immune response that destroys gastric parietal cells.  Parietal cells have several important roles, one of which is to produce intrinsic factor (IF) glycoprotein which is required for vitamin B₁₂ absorption.  Normally IF is produced in the gastric mucosa by parietal cells, enters the intestinal lumen to bind the vitamin B₁₂ that has been both released from food and produced by intestinal microorganisms.  Once bound, IF then facilitates the absorption of vitamin B₁₂ by intestinal cells in the terminal ileum. Other non-autoimmune conditions that impair IF production are gastrectomy, as well as folic acid deficiency.

The underlying mechanism in pernicious anemia is a Type III Hypersensitivity Reaction in which auto-antibodies against gastric parietal cells, lead to decreased production of intrinsic factor and vitamin B₁₂ absorption.  This is problematic as the individual then has insufficient serum levels of vitamin B₁₂ which is necessary for mitosis.

Specifically, both vitamin B₁₂ and folic acid are required for thymidine synthase.  Thymidine is a nucleotide required for DNA synthesis, and pernicious anemia (and lack of vitamin B₁₂) leads to an inadequate supply of the pyrimidine thymidine, resulting in problems in cells that undergo rapid cell division (mitosis).

Erythropoiesis is negatively affected and erythrocyte precursors experience asynchronous maturation of the cytoplasm (which does not depend on DNA) and the nucleus (which does depend on DNA), resulting in cells that become large and are known as megaloblasts that are arrested in nuclear division.  This leads to low levels of mature red blood cells and anemia which is defined as low ability to carry oxygen in the blood.  WBC and platelet production is also negatively impacted with turnover rates slowed.

Signs and symptoms of pernicious anemia are insidious in onset and involve the development of megaloblastic anemia (characterized by large immature RBCs), fatigue, sore tongue, and paresthesia.

Risk factors for developing Pernicious Anemia include age (40-70 years), genetic predisposition (e.g., inheritance of specific MHC/HLA alleles), family history, and the presence of other autoimmune diseases due to similar individual susceptibilities.  Interestingly while in Northern Europe, there are higher incidence rates in adult females, in the USA, there are no differences in rates reported between the sexes.

Diagnostic tests include blood tests that may reveal low levels of many serum components (vitamin B12, folate, normal RBCs, and hemoglobin) and high levels of IF antibodies and other anti-parietal cell antibodies.  Additionally, blood smears may reveal large RBCs, specifically a type of macrocyte called megaloblast as they exhibit impaired DNA synthesis.  Blood smears also may reveal abnormal WBCs (e.g., hyper-segmented neutrophils with 6+ lobed nuclei).

In these cases, diagnostic tests aim to investigate the cause of vitamin B12 deficiency as other non-autoimmune causes can be responsible, such malnutrition, specifically lack of meat, fish, eggs, and/or dairy products in diet.  A gastrectomy as well as certain medications, can put a person at risk for vitamin B12 deficiencies.  In these cases, that are not autoimmune in nature, a person may develop what would be termed vitamin B12 deficiency anemia which has similar signs and symptoms as pernicious anemia.  Confirmation of pernicious anemia as a diagnosis occurs when high levels of IF antibodies and other anti-parietal cell antibodies are found.

Potential complications of Pernicious Anemia can occur.  As mentioned, with pernicious anemia, the autoimmune-mediated destruction of gastric parietal cells leads to decrease in production of intrinsic factor.  Without intrinsic factor, intestinal cells can’t absorb vitamin B₁₂ which is required for mitosis, which especially affects production levels of cells that normally divide rapidly (e.g. RBCs, WBCs).  Without treatment, complications can develop, including congestive heart failure and neurologic symptoms (paresthesias, weakness, clumsiness).   Additionally, if not treated, gastric atrophy occurs and individuals are 2-3 times more susceptible to the development of gastric carcinoma.  Treatment early is advisable and can reverse gastric atrophy.

Summary of Above Text in Point Form:

• Autoimmune Disorders
  • Definition:
    • Development of an adaptive immune response against one’s own cells
    • Involves T lymphyocytes, B lymphocytes and antibodies targeting one’s own cells for destruction, leading to chronic inflammation and damage as well as deterioration of the tissues that are affected.
    • Over 80 types of autoimmune diseases have been identified
    • Can affect any cell in the body.
    • No cure,
    • Idiopathic, Etiology is unknown and likely multifactorial; possibly molecular mimicry is involved in which a previous viral infection stimulates an immune response that cross-reacts and is triggered by viral non-self antigens that closely resemble self antigens.
    • Many autoimmune disorders have the same risk factors:
    • Risk Factors: biological sex female, genetics (inheritance of certain MHC/HLA alleles), family history (especially first-degree family members = children or siblings), previous infection with EBV
    • It is not clear why post-puberty females are more susceptible to autoimmune diseases.  It is thought that sex hormones may play a role, particularly as signs and symptoms can lessen during pregnancy.  Additionally use of oral contraceptives correlate with reduced incidence in females.
    • Treatment can involve immunosuppressants to minimize damage, avoidence of triggers, and management of signs and symptoms.
    • Estimated to affect over 20 million Americans and more than 2 million Canadians
    • Risk factors include: female biological sex, genetics (e.g., inherited MHC alleles)
  • Mechanism:
    • Autoimmune Disorders can involve one or more hypersensitivity reactions, specfically
      • Type II Hypersenstivity Reactions in which antibodies inappropriately bind to host cells, activating the complement system targetting host cells for destruction.
      • Type III Hypersensitivity Reactions in which antibody-antigen complexes are deposited in regions of the body, often blood vessel walls causing vasculitis, joints causing pain and the glomeruli causing renal damage.
      • Type IV Hypersensitivity Reactions in which damage is caused by cyotoxic T cells.
    • Antibodies target and destroy cells.
    • Causes inflammation and tissue dysfunction.
  • Hypotheses on Causes:
    • Previous infection with a pathogen similar to self-antigens.
    • Immune response against the pathogen leads to cross-reactivity with self-antigens.

• Common Autoimmune Diseases:
  1. Multiple Sclerosis (MS)
     • • • Autoimmune-mediated inflammatory disease.
         • Leads to demyelination of CNS neurons, specifically the destruction of oligodendrocytes in the brain and spinal cord.
         • Signs and symptoms often cycle through remissions and exacerbations as myelin attempts to repair itself.
         • Over time, the repair process cannot keep up with the damage, leading to accumulation of lesions (plaques of scar tissue known as sclerae).
         • The name “Multiple Sclerosis” derives from these multiple areas of scarring.
         • Increased levels of T lymphocytes, macrophages, microglia, and other inflammatory cells, as well as pro-inflammatory cytokines, are present in the brain parenchyma.
         • Neuron dysfunction causes symptoms depending on the extent of loss of function in motor, sensory, and autonomic nerves affected by demyelination.
         • Lesion formation causes breakdown of the blood-brain barrier, allowing an influx of T lymphocytes, exacerbating demyelination.
         • High IgG levels noted in cerebrospinal fluid (CSF).
       • Etiology and Risk Factors:
         • Etiology is unknown; believed to involve genetic susceptibility and a nongenetic trigger (e.g., viral infection, low vitamin D levels).
         • Risk factors:
         • Female biological sex
         • Genetics (inheritance of certain MHC/HLA alleles)
         • Family history (especially first-degree relatives)
         • Previous infection with Epstein-Barr Virus (EBV)
         • Low vitamin D levels
         • Living in northern latitudes (e.g., Canada, northern Europe)
       • Types and Symptoms:
         • Four different types of MS, each with differing progression of lesion formation, frequency of relapses, and prognosis.
         • Characterized by progressive changes or loss of motor function, sensory function, and autonomic function.
         • Signs and symptoms:
           • Fatigue
           • Sensory losses (paresthesias)
           • Muscle cramping and spasticity
           • Muscle weakness and tremors
           • Reduced coordination
           • Bladder, bowel, and/or sexual dysfunction
           • Heat intolerance
           • Cognitive difficulties and memory problems
           • Blurry vision or loss of vision
           • Depression and euphoria
           • Aphasia (trouble speaking)
           • Seizures
           • Personality changes
           • Onset typically between 15-45 years old, with an average age of 29 years in females and 31 years in males.
             Globally, 2.1 million people are affected by MS.
       • Onset typically between 15-45 years old, with an average age of 29 years in females and 31 years in males.
       • Globally, 2.1 million people are affected by MS.
         • Diagnosis:
           • MRI scans
           • Evoked potential tests (measuring how fast neurons respond to stimulation)
           • Lumbar puncture tests (detecting elevated IgG in CSF)
         • Treatment:
           • Immunosuppressants
           • Vitamin D (carefully monitored to avoid hypervitaminosis)
           • Maintaining a healthy diet, sleep patterns, and exercise habits
           • Support groups
  2. Rheumatoid Arthritis (RA)
     1. • Autoimmune disease targeting synovial tissue.
        • Causes bilateral symmetric polyarthritis (synovitis) often affecting hands and feet, but can affect other joints and organs (skin, heart, lungs, eyes).
        • Leads to joint deterioration, inflammation, and pain.
        • Etiology is unknown, making it idiopathic.
        • Pathogenesis involves genetic susceptibilities and non-genetic triggers (e.g., infections, smoking, trauma).
        • T cells, B cells, autoantibodies, and neutrophils contribute to damage to synovial membranes, articular cartilage, and surrounding tissues.
        • Pannus formation occurs (new fibrovascular or granulation tissue).
        Risk Factors
        • Female biological sex
        • Genetic inheritance of certain MHC/HLA alleles
        • Family history (especially first-degree relatives)
        • Previous infection with Epstein-Barr Virus (EBV)
        • Cigarette smoking
        • Vitamin D deficiency
        • High intake of salt, alcohol, coffee, red meat
        • Sedentary lifestyle
        • Females are three times more at risk than males
        • Average age of onset: 35-50 years old
        Signs and Symptoms
        • Gradual, insidious onset leading to joint inflammation and swelling
        • Stiffness and pain with joint movement
        • Limited range of motion
        • Joint deformity (e.g., Boutonniere deformities, swan-neck deformities)
        • Shortening of tendons from scarring
        • Proximal or distal interphalangeal joint deformities in fingers or toes
        • Ulnar shift of fingers
        • Joint narrowing and ankylosis (joint fusion/fixation)
        • Muscle spasms and pain
        • Flare-ups associated with anemia (e.g., iron-deficient anemia)
        • Increased risk of lung fibrosis, atherosclerosis, myocardial infarctions, and stroke (cerebrovascular accidents, CVA)
        Diagnosis
        • Imaging (e.g., x-ray, MRI) revealing joint deterioration
        • High erythrocyte sedimentation rates (ESR)
        • High C-reactive protein (CRP) levels
        • Presence of serum Rheumatoid factor (RF) autoantibodies and anti-nuclear antibodies
        • Imaging helps rule out other causes of arthralgia and inflammation (e.g., infections)
        Treatment Options
        • Heat and cold therapies
        • Orthotics and splints
        • Occupational and therapeutic exercises
        • Maintaining a healthy diet and sleep habits
        • Disease-Modifying Antirheumatic Drugs (DMARDs)
        • Corticosteroids
        • Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
        • Arthroplasty (e.g., hip replacements)
        *ESR and CRP are general markers of inflammation.