Autoimmunity Chapter 15 PDF

6/27/2024 AUTOIMMUNITY C Chapter 15 Preamble PowerPoints are a general overview and are provided to help students take notes over the video lecture ONLY. PowerPoints DO NOT cover the details needed for the Unit exam E...

6/27/2024 AUTOIMMUNITY C Chapter 15 Preamble PowerPoints are a general overview and are provided to help students take notes over the video lecture ONLY. PowerPoints DO NOT cover the details needed for the Unit exam Each student is responsible for READING the TEXTBOOK for details to answer the UNIT OBJECTIVES Unit Objectives are your study guide (not this PowerPoint) Test questions cover the details of UNIT OBJECTIVES found only in your Textbook! 1  6/27/2024 Etiology of autoimmune diseases Immunologic tolerance Genetic and environmental factors Chapter Systemic autoimmune diseases Systemic lupus erythematosus (SLE) Overview Rheumatoid arthritis (RA) and other SARDs Granulomatosis with polyangiitis (GPA) Associated laboratory testing Organ-specific autoimmune diseases Examples and associated laboratory testing Humoral and cell-mediated immune responses directed toward self-antigens Autoimmune Cause tissue and organ damage Systemic or organ-specific Diseases Due to loss of self-tolerance Ability of the immune system to accept self- antigens and not initiate an immune response against them 2  6/27/2024 Mechanisms of Central and Peripheral Tolerance During the maturation process of T cells, the great majority of undifferentiated lymphocytes that are processed through the thymus do not survive. The process is not totally effective, however, as normal individuals do possess self-reactive lymphocytes. Autoimmunity results from complex interactions between genetic and environmental factors. Inheritance of certain genes may make some individuals more susceptible to autoimmune diseases. Exposure of genetically susceptible individuals to Genetic and Environmental endogenous and environmental factors can trigger autoimmune responses. Hormones can influence autoimmunity; women are almost three times as likely to acquire an autoimmune disease as Factors in compared to men. Development of Autoimmunity 3  6/27/2024 Genetic and Environmental Factors in Development of Autoimmunity (cont.) Tissue injury can lead to the release of cryptic antigens which can induce an autoimmune response. Microbial infections may trigger autoimmunity in several ways. Molecular mimicry - bacteria or viruses possess antigens that are like a self antigen. Epitope spreading, where the immune response to a microbe expands to activate immune responses to other antigens, including self antigens. Superantigens, which can activate numerous clones of T cells, or through certain viruses, which can cause polyclonal B cell activation. Environmental factors that can alter gene expression may also contribute to autoimmunity. Autoimmune diseases can be directed against a particular organ in the body or involve pathology throughout the body. Autoimmune More than 100 autoimmune diseases discovered Systemic diseases Diseases SLE, RA and other SARDs, GPA (continued) Organ-specific Autoimmune thyroid diseases, type 1 diabetes, celiac disease, autoimmune liver diseases, multiple sclerosis, myasthenia gravis, anti-glomerular basement membrane disease 4  6/27/2024 Systemic Lupus Erythematosus (SLE) A chronic systemic inflammatory disease that affects multiple organ systems Pathology is caused by a type III hypersensitivity reaction. Tissue damage occurs at the sites in the body where immune complexes have deposited. Patients develop numerous autoantibodies (e.g., to dsDNA and other nuclear components, lymphocytes, RBCs, platelets) Immune complexes form, triggering complement activation, chemotaxis of neutrophils, and inflammation Clinical Symptoms of SLE Joint involvement Skin rashes A classic butterfly rash across the nose and cheeks may develop. This is what is responsible for the name lupus, derived from the Latin term meaning “wolflike”. Renal involvement Neurologic symptoms Anemia, leukopenia, thrombocytopenia Others 5  6/27/2024 Laboratory Tests to Diagnose SLE The first clue in the mystery of lupus was the discovery of the LE cell by Malcolm Hargraves in 1948. The LE cell is a neutrophil that has engulfed the antibody-coated nucleus of another neutrophil, mainly in vitro. Next was the discovery that SLE is associated with more than 25 autoantibodies. The large number of possible autoantibodies reflects a generalized dysregulation of the immune system in SLE. Laboratory Tests to Diagnose SLE CBC Urinalysis CRP/ESR Elevated during flare-ups Complement quantitation C3 levels can be decreased during inflammation. ANAs When SLE is suspected, the first test typically done is a screening test for antinuclear antibodies (ANA). 6  6/27/2024 Directed against antigens in cell nuclei Antinuclear Present in more than 95% of lupus patients Antibodies Include: Anti-ds DNA (lupus-specific) (ANAs) Anti-ss DNA Anti-histones and nucleosomes Antibodies to centromere or nucleolar components Anti-ENA (e.g., anti-Sm, anti-RNP, anti- SS-A, anti-SS-B) Laboratory Tests to Diagnose SLE Fluorescent antinuclear antibody (FANA) testing is the most widely used and accepted test, because it detects a wide range of antibodies and is positive in about 95 percent of patients with SLE. https://www.youtube.com/watch?v=QzCQV RL8vRk 7  6/27/2024 Fluorescent ANA (FANA) Test Principle Incubate patient serum with Hep-2 cells fixed Incubate onto microscope slide. Wash and Wash and incubate with fluorescein-labeled incubate anti-human IgG. Wash and Wash and view slides under fluorescent view microscope. Immunofluorescence Using Crithidia luciliae ◦ An IIF using C. luciliae as the substrate ◦ Contains a circular organelle called a kinetoplast (rich in dsDNA) ◦ Used to detect antibodies to dsDNA and determine dsDNA antibody titers 8  6/27/2024 ENA Ouchterlony Test Immunodiffusion test detects antibodies to specific ENA. Patient serum or controls in outer wells react with ENA antigens in center well. In this example, patient A has antibody to Sm. Anti-Sm is diagnostic for SLE Other Assays for ANA ELISA testing is ELISA testing has also quantitative, is less come into wider use for subjective, and lends detection of: itself well to automation. anti–ds-DNA antihistone antibodies anti–SS-A and anti–SS-B. 9  6/27/2024 Found in about 60% of lupus patients Associated with deep vein and arterial thrombosis Phospholipid Increased risk of recurrent pregnancy loss Antibodies Can cause false-positive results in nontreponemal tests for syphilis Example: the lupus anticoagulant (produces prolonged APTT and PT) Rheumatoid Arthritis (RA) Chronic arthritis of the peripheral joints that can progress to joint deformity and disability About 25% of patients have osteoporosis. Some patients also develop: Subcutaneous nodules Pericarditis Interstitial lung disease Vasculitis 10  6/27/2024 Pathology and Treatment of RA Inflammation destroys the bone and cartilage. TNF-a plays a key role in the process. Overly active osteoclasts absorb the bone. Autoantibodies combine with antigens to form immune complexes. Treatment: NSAIDs Disease-modifying anti-rheumatic drugs (DMARDs) Biologic agents that target TNF-a Autoantibody (usually IgM) that reacts with Fc portion Rheumatoid of IgG factor Found in approximately 80% of patients with RA; not specific for RA Laboratory Autoantibody directed against cyclic citrullinated Anti-CCP peptide (peptide containing a modified arginine) Highly specific for RA Testing for ANAs RA ESR, CRP, C’ 11  6/27/2024 Other Systemic Autoimmune Rheumatic Diseases (SARDs) Sjögren’s Systemic sclerosis Mixed connective Inflammatory syndrome (SSc) tissue disease myopathies Dry eyes and Fibrosis and Overlap of Polymyositis and mouth; SS-A and vasculitis limited dermatomyositis SS-B antibodies affecting skin, cutaneous SSc Progressive joints, other and other muscle organs; includes SARDs; anti-U1- weakness; many CREST syndrome; RNP ANAs many ANAs Rare autoimmune disease involving inflammation of small- to medium-sized blood vessels and respiratory tract Progresses to more systemic disease involving other organs (e.g., kidneys, joints, skin) Granulomatosis With Polyangiitis Most patients have antibodies to (Wegner’s neutrophil cytoplasmic antigens such as proteinase 3. Granulomatosis) Neutrophil activation results in damage to vascular endothelium and a Th1 response. 12  6/27/2024 Anti-Neutrophil Cytoplasmic Antibodies (ANCA) Produced against proteins in neutrophil granules Strongly associated with syndromes involving vascular inflammation Detected by IIF on ethanol-fixed leukocytes Patient serum incubated with microscope slide containing ethanol-fixed leukocytes. Wash and add FITC-labeled anti-IgG conjugate. Wash and view fluorescence in neutrophils under fluorescent microscope. ELISA and chemiluminescent assays are also available. ANCA Patterns in IIF Method Cytoplasmic (c-ANCA) Pattern Perinuclear (p-ANCA) Pattern Perinuclear fluorescence Cytoplasmic fluorescence (Smooth Appearance) (Grainy appearance) 13  6/27/2024 C ORGAN SPECIFIC AUTOIMMUNE DISEASES Autoimmune Thyroid Diseases (AITDs) Thyroid hormone synthesis is carefully regulated by endocrine feedback loop. Autoantibodies produced in AITDs can lead to decreased or increased production of thyroid hormones. 14  6/27/2024 Hashimoto’s Thyroiditis Immune destruction of the thyroid gland produces hypothyroidism. Symptoms include fatigue, dry skin, weight gain, brittle hair, formation of a goiter. Laboratory results: Normal or high TSH Low free T4 Anti-TPO Anti-Tg Graves’ Disease An AITD characterized by hyperthyroidism Symptoms: nervousness, weight loss, rapid heartbeat, goiter, exophthalmos TRAbs produced. Low TSH and high FT4; antibodies to TPO and Tg may be produced. 15  6/27/2024 Laboratory Diagnosis of AITD Disease TSH Level Free T4 Autoantibodies Hashimoto’s Normal or Anti-thyroglobulin Decreased thyroiditis elevated Anti-thyroid peroxidase Thyroid-stimulating hormone Decreased or receptor antibodies (TRAbs) Graves disease Elevated undetectable Anti-thyroglobulin Anti-thyroid peroxidase (TPO) Endocrine disorder characterized by hyperglycemia Type 1 destruction of b cells in pancreas results in insulin deficiency Long-term effects Type 1 Cardiovascular disease, kidney dysfunction, nerve damage, blindness, infections Diabetes Laboratory results Mellitus (T1D) Increased glucose blood level Elevated HbA1c Autoantibodies to GAD and IA-2, ICA 16  6/27/2024 Affects small intestine and other organs Triggered by gluten Autoantibodies form in HLA-DQ2- or HLA-DQ8- positive people to: Gliadin (a component of gluten) and DGPs Tissue transglutaminase (tTG) [IgA]* Celiac Disease Endomysium (EMA) Symptoms Diarrhea, abdominal pain and bloating, others Treatment: follow a gluten-free diet * = Screening test of choice Immune-mediated liver diseases that can lead to end- stage liver failure if untreated Clinical features: elevated liver enzymes, fatigue, nausea and vomiting, abdominal pain, itchy skin, jaundice Autoimmune hepatitis (AIH) Autoimmune Hepatocytes targeted Liver Diseases AIH-1- Positive for SMA, ANAs AIH-2- Positive for LKM-1 or LC-1 antibodies Primary biliary cholangitis (PBC) Destruction of intrahepatic bile ducts; cholestasis Majority of patients produce mitochondrial Abs (AMAs). 17  6/27/2024 Multiple Sclerosis (MS) ◦ This autoimmune disorder involves inflammation and destruction of the central nervous system. ◦ Most patients produce antibodies against myelin basic protein. ◦ Plaques form in white matter of the brain and spinal cord, causing destruction of the myelin sheath of axons. Symptoms include visual disturbances, weakness in limbs, dizziness, and sensory abnormalities. Multiple Sclerosis Laboratory findings (MS) Lesions seen on magnetic resonance (continued) imaging (MRI) Increased immunoglobulins in spinal fluid and increased IgG index Oligoclonal bands on protein electrophoresis of CSF 18  6/27/2024 Myasthenia Gravis Affects neuromuscular junction, resulting in weak skeletal muscles Most patients have antibodies to acetylcholine receptors (ACHR) Block binding of ACH to its receptor and transmission of nerve impulses that activate muscles Myasthenia Gravis Other symptoms may include difficulty in speaking, chewing, and swallowing and inability to maintain support of the trunk, the neck, or the head. If respiratory muscle weakness occurs, it can be life threatening. MG is often associated with the presence of other autoimmune diseases, such as SLE, RA, pernicious anemia, and thyroiditis. MG is also associated several HLA antigen abnormalities. Approximately 80–85 percent of patients have antibody to ACH receptors; this appears to be the main contributor to the pathogenesis of the disease. 19  6/27/2024 Laboratory Testing for MG RIA is used to detect antibody, based on assays that block the binding of receptors by anti-ACH receptor (ACHR) antibody. A radio-labeled snake venom called α-bungarotoxin is used to irreversibly bind to ACHRs. Precipitation of receptors caused by combination with antibody is then measured. A quick Immunostick ELISA has also been developed for testing Formerly known as Goodpasture’s syndrome Patients produce autoantibodies to basement membranes lining the renal glomeruli and lung alveoli (specifically directed against the alpha-3 chain of type IV collagen). Immune complexes bind to basement membranes, Anti- attract complement, and cause damage by type II hypersensitivity. Glomerular Syndrome can progress to renal failure and respiratory problems (cough, shortness of breath, hemoptysis). Basement Antibodies to GBM found in most patients. Membrane Detected by IIF on frozen kidney sections or ELISA for antibody to a-3 subunit Disease Tissue-bound anti-GBM detected by direct immunofluorescence on kidney biopsy sections; produces a smooth, linear, ribbon-like fluorescence along the GBM 20  6/27/2024 Summary Autoimmunity results from loss of central or peripheral tolerance. Exposure to environmental factors (e.g., infections, tissue injury) may trigger development of autoimmune disease in genetically susceptible individuals. Systemic autoimmune diseases include SLE, RA, and GPA. Most patients with rheumatic autoimmune diseases such as lupus produce antinuclear antibodies (ANAs). The gold standard in ANA testing is an IIF using Hep-2 cells. * Major patterns of fluorescence are homogenous, speckled, nuclear dot, nucleolar, and centromere. *These patterns are produced by specific types of ANAs. Summary (continued_2) Rheumatoid factor is an autoantibody directed against the Fc portion of IgG, which is found in most RA patients and in many patients with other rheumatic autoimmune diseases. Anti-neutrophil cytoplasmic antibodies (ANCAs): *These are associated with autoimmune syndromes involving vasculitis, such as GPA. *They produce either a cytoplasmic pattern (c-ANCA; seen in GPA) or perinuclear pattern (p-ANCA) of fluorescence in an IIF using ethanol-fixed leukocytes. 21  6/27/2024 Summary (continued_3) Organ-specific autoimmune diseases and their characteristic autoantibodies include: Autoimmune Disease Characteristic Autoantibody Anti-glomerular basement membrane disease GBM Autoimmune hepatitis Smooth muscle Celiac disease tTG, gliadin peptides, endomysium Graves’ disease TSH receptor Hashimoto’s thyroiditis TPO, Tg Multiple sclerosis myelin basic membrane Myasthenia gravis acetylcholine receptors Primary biliary cholangitis mitochondria Type 1 diabetes pancreatic islet cells, IA-2, GAD Postamble READ the TEXTBOOK for the details to answer the UNIT OBJECTIVES. USE THE UNIT OBJECTIVES AS A STUDY GUIDE All test questions come from detailed material found in the TEXTBOOK (Not this PowerPoint) and relate back to the Unit Objectives 22