Overview of Autoimmune Diseases and Their Mechanisms

What is the estimated number of Americans affected by autoimmune diseases?

Approximately 20 million Americans.

How are autoimmune diseases characterized in terms of their progression?

They are usually chronic and irreversible.

What is the defect that underlies autoimmune diseases?

A defect in mechanisms of recognition and definition of 'self'.

Who first conceptualized the idea of immune tolerance?

Sir Peter Medawar.

What is immune tolerance?

The ability to not regard body tissues as foreign, i.e., to ignore MHC antigens.

When does immune tolerance typically occur?

During neonatal development.

What is one mechanism that leads to B cell tolerance?

Lack of help from T cells.

What happens to immature B cells in the bone marrow related to B cell tolerance?

They are deleted.

What are the two signals required for B cell activation?

B cells need two signals to respond; lack of the second signal results in cell death.

What are the two mechanisms involved in T cell tolerance?

Central tolerance and peripheral tolerance.

What occurs during central tolerance in T cells?

Elimination of self-reactive T cells before they leave the thymus.

What is the role of apoptosis in central tolerance?

It induces apoptosis in T cells that do not show a correct interaction with human cellular antigens linked to MHC.

What is peripheral tolerance in T cells characterized by?

Sequestered antigens and anergic T cells that inhibit further activation.

What is the significance of CD28 expression in T cell activation?

T cells expressing CD28 are more likely to react with antigen-presenting cells (APCs).

What happens to T cells expressing Fas ligand?

They are deleted.

What are some common symptoms of autoimmune diseases?

Elevated serum gamma-globulin levels, diverse autoantibodies, depressed serum complement, and lesions from immune complexes.

What can cause excess T-helper activity in autoimmune diseases?

Altered self-antigens, molecular mimicry, and cross-reactivity with foreign antigens.

Which viral infection is associated with rheumatoid arthritis due to molecular mimicry?

Epstein-Barr virus (EBV).

What is a consequence of T suppressor cell (Ts) deficiency?

It leads to a failure to down-regulate the immune response to self antigens.

What is an example of a sequestered antigen that can trigger an autoimmune response?

Antigens from the lens of the eye or from sperm.

What factors may trigger the release of autoimmune diseases?

Trauma or infection.

What is a common genetic predisposition associated with autoimmune diseases?

HLA antigens.

At what age group do most autoimmune diseases typically appear?

20-40 years old.

Which gender is more frequently affected by rheumatoid arthritis (RA)?

Women, with a ratio of 3:1 compared to men.

Which autoimmune disease is more common in men than women?

Ankylosing spondylitis, with a ratio of 9:1.

What percentage of patients with autoimmune thyroiditis also suffer from pernicious anemia?

10%.

What percentage of patients with Sjogren's syndrome also suffer from rheumatoid arthritis?

50%.

What are the two types of immune responses involved in autoimmune diseases?

Antibody (Ab) and T cell responses.

What is the primary antibody associated with rheumatoid arthritis?

IgG, specifically rheumatoid factor.

What is the pathophysiological mechanism of rheumatoid arthritis?

Chronic inflammation of the synovial membrane leading to the formation of pannus.

What are the diagnostic criteria for rheumatoid arthritis according to the American Rheumatism Association?

Presence of four or more of seven features including morning stiffness, arthritis in multiple joints, and positive rheumatoid factor.

What are some common symptoms of rheumatoid arthritis?

Weight loss, malaise, fever, fatigue, and weakness.

Which organs can be affected by rheumatoid arthritis besides joints?

Cardiovascular (pericarditis), pulmonary (nodules, interstitial fibrosis), liver (hepatitis), eyes (dryness), and skin (nodules and ulcers).

What are some treatment options for rheumatoid arthritis?

Exercise, diet, NSAIDs, steroids, TNF blocking agents, and DMARDs.

What is the mechanism of action for Actemra in RA treatment?

IL-6 receptor inhibitor.

What does Xeljanz inhibit in the treatment of RA?

Janus kinase (JAK) pathways associated with chronic inflammation.

How does methotrexate help in treating rheumatoid arthritis?

It increases anti-inflammatory adenosine levels.

What is the role of joint replacement in rheumatoid arthritis treatment?

It is a surgical option for severe cases.

What autoimmune disease is characterized by the presence of antinuclear antibodies?

Systemic lupus erythematosus (SLE).

What is the primary target of antibodies in myasthenia gravis?

Acetylcholine receptors.

What is the primary affected tissue in Hashimoto's thyroiditis?

Thyroid tissue.

What is the primary affected tissue in Graves' disease?

Thyroid tissue.

What is systemic lupus erythematosus (SLE)?

An autoimmune disease characterized by a variety of symptoms including a butterfly rash on the face, affecting primarily young women.

What are the genetic associations with SLE?

HLA-DR2 and HLA-DR3 are associated with SLE, with HLA-DR3 also linked to Sjogren's syndrome.

What is the hallmark symptom of SLE?

A butterfly rash on the nose and cheeks.

What general symptoms are associated with SLE?

Weight loss, fever, malaise, and lethargy.

What laboratory findings are common in SLE patients?

Decreased T cells, immunoglobulins (Igs), complement levels, and the presence of antinuclear antibodies (ANA).

What causes the immune system's exposure to normally sequestered antigens in SLE?

A defect in apoptosis leading to increased cell death and failed clearance.

How does the prognosis differ between SLE patients with isolated skin/musculoskeletal involvement versus those with renal or CNS involvement?

Patients with isolated skin and musculoskeletal involvement have higher survival rates than those with renal and CNS disease.

What are some American College of Rheumatology (ACR) criteria for diagnosing SLE?

Criteria include arthritis, renal involvement (proteinuria, cellular casts), hematologic disease (leukopenia, thrombocytopenia), and immunologic disorders.

What treatments are available for mild SLE?

NSAIDs and sunscreen to reduce skin rash.

What is the cornerstone treatment for SLE?

Hydroxychloroquine, an anti-malarial derivative.

What are some disease-modifying antirheumatic drugs (DMARDs) used in SLE treatment?

Benlysta (biologic DMARD), Azathioprine, and Methotrexate.

What is Sjogren's syndrome?

An autoimmune disease affecting exocrine glands, particularly the lacrimal and salivary glands, leading to dry eyes, mouth, and vagina.

What is the typical demographic for Sjogren's syndrome?

Primarily affects women aged 40-50 years.

What are some viral triggers suggested for Sjogren's syndrome?

EBV, human T cell leukemia virus, and hepatitis C.

What autoantibodies are associated with Sjogren's syndrome?

ANA and rheumatoid factor; 50% of patients also have rheumatoid arthritis.

What treatments are available for Sjogren's syndrome?

Restasis (artificial tears), pilocarpine (for dry mouth), good dental hygiene, and vaginal lubricants.

What are the complications of untreated Sjogren's syndrome?

Non-Hodgkin's lymphoma and primary biliary cirrhosis.

What is Guillain-Barre syndrome?

An autoimmune condition that often follows a viral infection, characterized by progressive muscle weakness and possible paralysis.

What are common triggers for Guillain-Barre syndrome?

Viral infections (like measles and hepatitis) and bacterial infections (such as Campylobacter jejuni).

What is the typical treatment for Guillain-Barre syndrome?

Plasmapheresis and intravenous immunoglobulin (IVIG).

What factors are associated with a poor prognosis in Guillain-Barre syndrome?

Rapid progression of symptoms, advanced age, prolonged ventilation, and severe reduction of action potentials on neuromuscular testing.

What is the expected recovery rate for Guillain-Barre syndrome?

Full recovery may be expected in 50%-95% of cases within 6-10 months.

What is multiple sclerosis (MS)?

A relapsing neuromuscular disease characterized by motor weakness, impaired vision, and mental aberrations.

What role do myelin-reactive T cells play in MS?

They adhere to and penetrate the blood-brain barrier, potentially being activated by cytokines from brain microglia.

How do microglia contribute to multiple sclerosis?

Microglia participate in the destruction of CNS myelin.

What is the consequence of demyelination in MS?

It leads to the formation of plaques in the brain and spinal cord, disrupting information transmission in the CNS.

Which part of the brain is commonly affected by MS?

The cerebellum, responsible for balance and fine motor coordination.

What percentage of MS patients experience spinal lesions?

Up to 75% of patients.

What are some risk factors for developing MS?

HLA-DRB1, decreased vitamin D/sunlight exposure, and prior infection with measles or reactivation of EBV.

What is the prognosis for untreated MS patients?

Approximately 30% develop physical disability within 25 years.

What factors are associated with a poor prognosis in MS?

Higher incidence of spinal cord lesions and being male with rapidly progressive disease.

What treatments are commonly used for MS?

Methotrexate, azathioprine, immunomodulators like interferon beta-1 alpha and beta, dalfampridine, alemtuzumab, and fingolimod.

What new treatment hope is being investigated for MS?

Clemastine, a second-generation antihistamine shown to re-myelinate nerves in a mouse model, currently in Phase II clinical trials.

What is myasthenia gravis?

An autoimmune disease characterized by the depletion of acetylcholine receptors at the myoneural junction.

What initiates symptoms in myasthenia gravis?

Symptoms begin when 30% of acetylcholine receptors are non-functional.

What are common symptoms of myasthenia gravis?

Muscle weakness and fatigue, with pronounced ptosis in males.

What is the typical progression of muscle weakness in myasthenia gravis?

It typically starts in the eyes and face, then spreads to the trunk.

What percentage of myasthenia gravis patients have an enlarged thymus or thymic tumor?

60-80% of patients.

What treatments are available for myasthenia gravis?

Anticholinesterases, azathioprine, and other immunomodulators.

What is the prognosis for patients with myasthenia gravis?

Fewer than 5% of patients die from the disease, but late onset is associated with poorer outcomes.

What may be required for some myasthenia gravis patients?

Thymus removal may be necessary.

What antibodies are present in 80-90% of myasthenia gravis patients?

Antibodies against acetylcholine receptors.

What is Hashimoto's thyroiditis and who is more commonly affected?

Hashimoto's thyroiditis is an autoimmune thyroiditis that is familial and more common in females.

At what age does Hashimoto's thyroiditis typically occur?

Usually occurs in middle age, around 40-50 years.

What genetic component is associated with Hashimoto's thyroiditis?

Inheritance of HLA-DR5.

What are some common symptoms of Hashimoto's thyroiditis?

Symptoms include weight gain, slow pulse, thinning hair, hoarse voice, and potential sleep apnea due to pressure on the trachea.

What antibodies are typically seen in Hashimoto's thyroiditis?

Anti-thyroid peroxidase and anti-thyroglobulin antibodies.

What other autoimmune conditions may be associated with Hashimoto's thyroiditis?

Rheumatoid arthritis (RA), insulin-dependent diabetes mellitus (IDDM), and systemic lupus erythematosus (SLE).

How is Hashimoto's thyroiditis diagnosed?

Diagnosis may involve finding decreased T4 and T3 circulating levels, ultrasonogram revealing nodules, and histology through needle biopsy of the thyroid.

What are some complications associated with the therapy for Hashimoto's thyroiditis?

Complications may include osteoporosis, bone density loss, increased heart rate, and thickening that may lead to arrhythmia.

What is Graves' disease and who is more commonly affected?

Graves' disease is an autoimmune condition that is familial and more common in females, typically seen in the 20-40 age group.

What are the clinical signs of Graves' disease?

Clinical signs include weight loss, tremor, rapid pulse, and exophthalmos.

What genetic components are associated with Graves' disease?

Inheritance of HLA-DR4 and a gene for CTLA-4, which down-regulates overactive T cells.

What infection may predispose someone to Graves' disease?

Infection by bacteria such as Yersinia enterocolitica.

What is the pathophysiology of Graves' disease?

Antibodies continuously stimulate the receptor, increasing thyroid epithelial cell numbers and production of thyroxine (T4) and its active form T3, while inhibiting TSH release.

What ocular symptoms are associated with Graves' disease?

Exophthalmos, caused by peripheral monocytes converting into fibroblasts in eye tissue and the release of inflammatory cytokines.

What treatments are available for Hashimoto's thyroiditis?

Levothyroxine (Synthroid) to replace thyroid hormone, and avoidance of antacids and iron-containing multivitamins for at least 4 hours after ingestion.

What treatments are available for Graves' disease?

Ocular lubricants for dryness, radioactive iodine to shrink the thyroid, and thioamides to block thyroid stimulation.