Autoimmune Diseases Handout - Introduction to Clinical Medicine

Intro to Clinical Medicine Lecture (9) Autoimmune diseases Thomas G. Forsthuber, M.D., Dr. Med. Professor of Immunology, Adjunct Professor of Microbiology & Immunology (UT Health) Office: BSE 3.250B E-mail: [email protected] Office Hours: Monday...

Intro to Clinical Medicine Lecture (9) Autoimmune diseases Thomas G. Forsthuber, M.D., Dr. Med. Professor of Immunology, Adjunct Professor of Microbiology & Immunology (UT Health) Office: BSE 3.250B E-mail: [email protected] Office Hours: Monday 4:30 – 5:30 pm Immune system related diseases Autoimmune diseases Hypersensitivity disorders (allergies) Immunodeficiencies Neoplasia (leukemias, lymphomas, others)  Autoimmune Diseases Autoimmune diseases are caused by an erroneous attack of the immune system on self-tissues Important examples of autoimmune diseases are: – Rheumatoid arthritis – Multiple sclerosis – Type 1 Diabetes – Graves Disease – Myasthenia gravis For most of these diseases we do not know the cause The pathogenic mechanisms for many of these diseases are not clear However, it is believed that pathogenic antibodies or immune cells (T cells, other immune cells) cause/contribute to the immune damage Some notable facts about autoimmune diseases: Are very common (estimated 8 million people in US alone) Frequently affect young individuals Most autoimmune diseases are more frequent in women Are frequently chronic life-long diseases with high personal and socio-economic burden – For MS: $30,000/year medication, $30,000 loss in wages, at least 24 billion dollars per year total cost to USA Frequently arise spontaneously Are sometimes induced (drugs, rabies vaccine) For most autoimmune diseases there is currently no cure There are treatments for autoimmune diseases, but they have side effects Some of the current treatments and their problems Glucocorticoids (e.g. Prednisolone) – Immunosuppression, hyperglycemia, skin atrophy, bruising, muscle atrophy, osteoporosis, weight gain, glaucoma, cataracts, euphoria/psychosis Mitoxantrone – It is a cancer drug! – Nausea, vomiting, hair loss, immunosuppression, Cardiomyopathy TNF inhibitors (e.g. infliximab – remicade; adalimunab – Humira) – T cell lymphomas, opportunistic infections, Tb Interferon beta – flu like symptoms Rituximab (anti-CD20 Ab) – Cardiac arrest, acute renal failure, infections, progressive multifocal leukoencephalopathy (PML), pulmonary problems Tysabri (anti-VLA-4) – Progressive multifocal leukoencephalopathy (PML) Camphath (Alemtuzumab, anti-CD52) - Autoimmune thyroiditis Fingolimod (FTY720) – skin cancer, hemorrhagic encephalitis Some immunological facts: The immune system has the ability to respond to an almost unlimited repertoire of antigens. Therefore, it has the inherent ability to respond to self-antigens. Autoreactive B or T cells exist even in healthy humans Sometimes autoantibodies can be detected in healthy humans Some T or B cells can recognize autoantigens and could potentially attack self-tissues Autoimmunity: An immune response against self tissues Autoimmune disease: An autoimmune response that results in tissue damage.  How do autoimmune diseases arise? Molecular mimicry: Sequence homology between microbial and self proteins. Immune system responds to microbes and cross-reactive autoimmunity to self-antigens develops. – Example: Rheumatic fever, Guillain-Barre syndrome (GBS) Failure of regulatory mechanisms: Failure of tolerance, lack of regulatory T cells, lack of regulatory B cells. – mutation in Foxp3 gene leads to IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) Access to “forbidden sites”: Antigens may normally be sequestered from the immune system (e.g. in the brain, testes, anterior chamber of the eye). Inflammation may give lymphocytes access to these sites. Genetic and environmental causes contribute to autoimmune diseases: Certain genes like HLA, TNF. Environmental influences such as smoking, infections, microbiome. The genetic base for autoimmune diseases: HLA (MHC) is the strongest link Autoimmune MHC Antigen Disease Class II Multiple Sclerosis HLA-DR2 Myelin peptide Rheumatoid HLA-DR1, Joint proteins Arthritis -DR4 HLA-DQ2, Gluten-derived Celiac -DQ8 peptides HLA-DQ8, Islet antigen; Type 1 Diabetes -DQ2 insulin 60% of MS patients are DR2 80-90% of RA patients are DR1 or DR4 98% of celiac patients are DQ2  Other genes that play a role in autoimmune diseases AIRE (Autoimmune regulator) – failure to present self antigens in the thymus. Leads to APS 1 (Autoimmune polyglandular syndrome). Foxp3 mutations (affects Tregs) – IPEX syndrome in humans Fas – deficiency in death receptor. Leads to ALPS (autoimmune lymphoproliferative syndrome). Polymorphisms of some genes, such as TNF or TNF receptor genes CTLA-4 – autoimmune lymphoproliferative disease. IL-7R (Interleukin-7 receptor) Environmental factors: Certain infections linked to autoimmune diseases – Campylobacter jejuni – Guillain-Barre syndrome – Group A Streptococcus pyogenes – Rheumatic fever/heart disease – EBV – Multiple sclerosis – Coxsackie B virus – Autoimmune myocarditis Gut microbiome has been linked to development of autoimmune diseases Smoking High salt diet Obesity  Classification of autoimmune diseases Organ-specific autoimmune diseases – Antibody-mediated organ-specific autoimmune diseases Grave’s disease, Myasthenia gravis, Goodpasture’s syndrome – Cell-mediated organ-specific autoimmune diseases Multiple sclerosis Type 1 diabetes Systemic autoimmune diseases – Systemic lupus erythematosus – Rheumatoid arthritis Note: Frequently both antibodies and immune cells contribute to autoimmune pathology. Diagnosis: Graves’ disease Antibody-mediated organ-specific autoimmune diseases – Grave’s disease – stimulating autoantibodies – Myasthenia gravis – blocking autoantibodies – Goodpasture’s syndrome – destructive autoantibodies Graves’ disease (Basedow) Autoimmune hyperthyroidism = autoimmune-induced overactivity of the thyroid gland Also known as diffuse toxic goiter or Basedow disease  T3 (triiodothyronine) T4 (Thyroxine) T4 is converted to T3 Ratio of T4 to T3 released in the blood is roughly 20 to 1 T3 is 3-4 times more bioactive than T4 Clinical tests measure free T4 and free T3 Hypothalamic-pituitary-thyroid (HPT) axis: Hypothalamus detects T4 -> releases TRH (thyrotropin-releasing hormone) TRH induces TSH (thyroid-stimulating hormone) by the pituitary TSH induces T3/T4 by the thyroid gland  Graves’ disease (Basedow’s disease) Stimulating autoantibodies against TSH receptor mimic the effect of TSH Result: stimulation of the thyroid gland and release of high levels of thyroid hormones Patients develop symptoms of hyperthyroidism: – enlarged thyroid, bulging eyes, heat intolerance, sweating, tremor, nervousness “Thyroid storm”: very dangerous crisis with: – high fever, severe tachycardia, extreme restlessness. –Sometimes caused by stress or infection! –Death from heart failure, MI, organ failure Diagnosis: -Thyroid hormone (Thyroxine or T4, and triiodothyronine or T3 markedly elevated. - Thyroid-stimulating hormone (TSH) suppressed -Thyroid-stimulating antibodies Treatment: Antithyroid drugs block iodine uptake and decrease hormones. Alternatively: surgery, radioiodine Myasthenia gravis (MG) Myasthenia gravis: Blocking antibodies. Production of autoantibodies against acetylcholine receptor on the motor end plates of muscles. Binding of acetylcholine is prevented. Receptor turnover may also be accelerated. Patients show progressive weakening of muscles.  Myasthenia gravis (MG) Clinical picture: – Progressive muscle weakness Difficulty chewing, swallowing, talking (slurred speech), Weakness of the eye muscles = double vision Drooping eyelids Difficulty breathing Weakness of body muscles = difficulty holding up arms – Muscle wasting may occur after years – Remitting-relapsing disease course – Important complication: Myasthenic crisis (respiratory failure due to MG, aspiration pneumonia) Diagnosis: – clinical picture, – nerve stimulation test (evoked muscle action potential), – anticholinesterase (edrophonium) test = weakness gets better after injection and lasts for couple of minutes – Thymoma on chest CT (~15% of patients) Treatment: – Oral anticholinesterase inhibitor (Pyridostigmine) – Plasmapheresis – Thymectomy – Immunosuppression Severe exacerbation of MG Myasthenic crisis: – Insufficient medication – Respiratory distress – Dysphagia – Weakness – Better with acetylcholinesterase inhibitor (edrophonium) Cholinergic crisis: – Not enough medication – Abdominal cramps – Diarrhea, nausea vomiting – Worse with edrophonium – Worse with acetylcholinesterase inhibitor Clinical signs: – Weak facial muscles, expressionless, – Inability to support head which will fall onto chest, slack jaw, limp body – Gag reflex often absent, patient at risk for aspiration – Inability to cough leads to pneumonia A 45-year old man presents to the ER with massive hemoptysis, respiratory failure, and acute renal failure. The patient deteriorates quickly and dies overnight. Autopsy shows extensive bleeding into the lungs.  Immunofluorescence and H&E pathology Diagnosis: Goodpasture’s syndrome Caused by “destructive” autoantibodies  Goodpasture’s syndrome (Earnest Goodpasture 1919) Clinical picture: Disease may be present years before patients seek medical attention!! The disease affects lungs and kidneys and symptoms are accordingly: Lungs: – Coughing up of blood (hemoptysis) – Shortness of breath Kidneys: Rapidly progressive glomerulonephritis – Hematuria – Edema – High blood pressure – Proteinuria Diagnosis: Kidney biopsy, anti-glomerular basement membrane antibodies (anti-GMB antibodies), anti-alveolar antibodies Treatment: immunosuppressive drugs (glucocorticoids, cyclosporine) Goodpasture’s Syndrome Goodpasture’s Syndrome: Autoantibodies specific for basement membrane antigens bind to kidney glomeruli and lung alveoli and activate complement which leads to inflammation and tissue damage. IgG and C3b found in basement membranes.  What is the suspected diagnosis? You are at a UTSA football game. All of a sudden there is a lot of commotion around a young boy who seemingly is disoriented, has slurred speech, and shows noticeably deep but regular breaths. You notice that the boy smells funny (you cannot really place the smell, but it is a bit fruity, like an old apple). It turns out that this child had been extremely thirsty for weeks, urinated frequently, was tired, and did not feel well for the last day or two. The child is dehydrated by the “back of the hand” test. Cell-mediated organ specific autoimmune diseases Insulin-dependent diabetes mellitus (IDDM, Type 1 diabetes) Hashimoto’s thyroiditis Multiple sclerosis How did the old doctors diagnose the condition in this boy?? The “urine wheel” Type 1 diabetes mellitus Diabetes mellitus (Greek, diabeinein = “syphon, passing through”, excessive urination; mellitus = Latin for honey = urine tastes sweet) Frequently young children T lymphocyte mediated autoimmune attack destroys pancreatic Langerhans islet cells that produce insulin (beta cells of the islets). Insulin is required to regulate glucose uptake into cells. Lack of insulin results in hyperglycemia in the blood, decreased protein synthesis, and acidosis. First insulin treatment in 1922!!! In the absence of insulin, the body will act as if it is starving and make ketones (ketone bodies) in the liver from fatty acids which then can be used as fuel for cell metabolism. The ketones are acidic and increase the osmolarity of the blood. Blood ph drops (acidosis). Glucose spills into the urine and takes water with it (= dehydration!). To balance the water loss and keep perfusing organs water goes from cells into the blood, which impairs cell function. Untreated, this leads to diabetic ketoacidosis, coma, and death due to brain edema.  Type 1 diabetes mellitus Clinical picture: – Classical triad: increased thirst (polydipsia), increased urination (polyuria), and increased appetite (polyphagia) but loss of weight. – Fatique Diagnosis: – Glucose enhanced in blood and urine Fasting glucose > 125 mg/dL Blood glucose > 200 mg/dL two hours after 75 g oral glucose Random glucose > 200 mg/dL Note: HbA1c is a way to test long-term glucose levels – Glucose tolerance test Treatment: Insulin! Complications: – Coma and death (Diabetic ketoacidotic coma, hypoglycemic coma) – Small vascular disease (diabetic retinopathy, diabetic neuropathy, diabetic nephropathy) – Large vascular disease (Coronary artery disease, stroke, peripheral vascular disease = diabetic foot) Insulitis in T1D Normal Islet Insulitis Insulin pens Insulin pumps  Blood glucose monitors A 23-year old female college student presents to family physician after Thanksgiving holidays with chronic fatigue, cold intolerance, excessive sleepiness, muscle cramps, and constipation.  Most common cause of primary hypothyroidism in USA (note: most common cause of Hashimoto’s thyroiditis hypothyroidism worldwide is iodine deficiency!!!) Inflammation and infiltration of thyroid by T cells and macrophages. DTH type reaction. Antibodies may also contribute. Typical presentation is goiter and signs of hypothyroidism Initially goiter – later atrophy Pain can occur but is not typical Destruction of thyroid will lead eventually to hypothyroidism. Symptoms: Hypothyroidism – cold intolerance, hoarse voice, decreased sweating, depression, memory loss, sleepiness, fatigue, hair loss, bradycardia, Diagnosis: measure thyroid hormone levels (elevated TSH, low T4), anti-thyroglobulin antibodies, anti-thyroid peroxidase antibodies, thyroid ultrasound, fine needle biopsy with histology Treat by giving thyroid hormone Often misdiagnosed initially as depression Normal RAIU Enhanced RAIU = hyperthyroiditis Graves disease Decreased RAIU = Hypothyroiditis Hashimoto thyroiditis de Quervains thyroiditis = subacute granulomatious thyroiditis RAIU = Radioactive iodine uptake  Patient presentation You are seeing a young woman, mother of two children, at the office. She has been having tingling sensations in her left arm and left face over the last week or so. What brings her to the office is that she had pain in her right eye, and blurry vision since last night, and now she cannot see anymore with this eye. Multiple Sclerosis (MS) CLINICAL PICTURE: Recurrent episodes of neurologic deficits Wide range of symptoms Young adults, women to men 2:1 Relapses are typical Disease duration frequently 20+ years Several forms of MS: – 85% remitting-relapsing MS – Primary progressive MS – Secondary progressive MS MRI scan of the brain  MS is much more frequent north of the equator Multiple Sclerosis (MS) PATHOLOGY: Characteristic are multiple foci of demyelination of the white matter of the CNS Lesions are sharply circumscribed regions of gray discoloration (plaques) Firm consistency (“sclerosis”) Frequently inflammatory infiltrates along lateral ventricles or vessels  MS converts from relapsing-remitting to progressive disease Diagnosis of MS Magnetic resonance imaging (MRI) Clinical picture Cerebrospinal fluid shows oligoclonal bands of immunoglobulins Decreased activity on visual evoked potentials and somatosensory evoked potentials Anti-myelin antibodies (anti-MBP and anti-MOG antibodies) McDonald criteria for objective diagnosis of MS: combination of MRI, oligoclonal bands in CSF, abnormal evoked potentials Treatment of MS: – Immunosuppressive drugs – glucocorticoids – Cytotoxic drugs – Mitoxantrone (a cancer drug) – Immunomodulatory drugs Interferon beta Copaxone (polypeptide mix) Tysabri (anti-VLA-4 antibody) First oral drug: Fingolimod (Gilenya)  Patient presentation Young woman presents to your office with this rash. She also complains about pain in the elbows and knees. Systemic autoimmune diseases: Systemic lupus erythematosus (SLE): Autoantibodies to DNA, RBC, histones. Circulating immune complexes. Frequently females. Typical facial “butterfly” skin rash. Rheumatoid arthritis: Chronic inflammatory disease of small and large joints. Often other tissues such as skin and heart are affected too.  Systemic lupus erythematosus (SLE) Clinical presentation: – Unspecific symptoms such as fever, malaise, joint pain, muscle pain (myalgias), fatigue – Patients frequently first seek medical help for the joint pains! – Butterfly rash of the face – Skin lesions (discoid lupus) = thick, red, scaly patch – Anemia!! = low red blood cells and platelets – Frequent infections – Kidney problems!!! = hematuria, proteinuria, Membranous glomerulonephritis Can lead to renal failure – Neurological problems = seizures, psychosis Different types of Lupus erythematosus: – Systemic lupus erythematosus (SLE) – whole body involved, bad! – Discoid lupus erythematosus – skin only, much better prognosis – Drug-induced lupus erythematosus (typically induced by procainamide, hydralazine, quinidine. Discontinuing drug cures. SLE  SLE Diagnosis: – Antinuclear antibodies (ANA) – Anti-double stranded DNA antibodies (anti-dsDNA) – Antiphospholipid antibodies (lupus anticoagulant -> thrombosis) – Low complement levels – Impaired renal function – Anemia – SLE diagnostic criteria = Butterfly rash, photosensitivity, arthritis, ulcers, proteinuria, hemolytic anemia, ANA, Treatment: – Corticosteroids, Immunosuppressants – Belimumab (BLys inhibitor, inhibits B cell activation) – Cytotoxic drugs (Cyclophosphamide) 1950: most patients died within 5 years Today: 90% of patients live > 10 years SLE diagnostics Antinuclear antibodies (ANA) with Hep-2 Crithidia kinetoplasts stain cells. “rim pattern” = typical for SLE positive for anti-dsDNA Ab Detects: Histones, ssDNA, dsDNA, (Crithidia are similar to ribonucleoprotein Trichomonas)  Rheumatoid arthritis (RA) Rheumatoid arthritis is a systemic autoimmune disease because it can involve other tissues beyond the joints – Skin – subcutaneous nodules – Heart – pericarditis – Eye – keratoconjunctivitis sicca (dry eyes) – Lungs – Fibrosis, pleuritis – Kidney – amyloidosis Arthritis: Polyarthritis involving predominantly inflammation of small joints Ultimately severe deformities  RA – Clinical picture Specific symptoms: – Morning stiffness > 1 hour – Painful swollen joints, typically small joints of the hands and feet – Subcutaneous nodules – Later symmetric arthritis – Rheumatoid factor (RF) positive RF is an antibody (IgM, IgG, or IgA type) against the Fc portion of IgG antibodies. Function is not entirely clear. Note: RF can also be found in other conditions (endocarditis, malaria, syphilis, sarcoidosis, SLE) High titer RF is associated with more severe disease – Joint erosion by radiology – Anti-Cyclic Citrullinated Peptide antibody (anti-CCP) Nonspecific symptoms – Malaise – Fever – Muscle aches – Anemia Treatment: anti-inflammatory drugs, physical therapy, rarely surgery, Swan neck deformity: Fingers: 3 bones called “phalanges”. Joints are called “interphalangeal joints (or IP). Distal IP is at the end of finger (DIP), proximal is in the middle of finger (PIP). Swan neck deformity: conditions that loosen the proximal interphalangeal joint and allow it to hyperextend.  Rheumatoid arthritis (RA) X-ray of RA MCP joint MCP = metacarpophalangeal joints (the “knuckle” between hand and finger) Inflamed synovium Subcutaneous rheumatic nodule