Immune Disorders PDF

Kristelle Anne Diadio BSMLS 3B Self-antigens become recognized in conjunction IS LEC with certain MHC antigens...

Kristelle Anne Diadio BSMLS 3B Self-antigens become recognized in conjunction IS LEC with certain MHC antigens Expression of class II molecules on cells where they are not normally found may result in the MODULE 4.2 presentation of self antigens 3. Hormonal Influence - about 78% of patients with autoimmune diseases are of female gender Immune Disorders Estrogens - tend to direct the immune system in Autoimmune Diseases favor of a type 2 helper cell (Th2) response, resulting in more B-cell activation and antibody production Autoimmunity Androgens - favor a type 1 helper cell (Th1)  Autoimmunity – “horror autotoxicus,” or “fear of response with activation of CD8+ T cells self-poisoning Prolactin - a hormone that stimulates the production of breast milk in pregnant and nursing Failure of an organism to recognize its own healthy women, can stimulate both humoral and cell- tissue as self mediated immune responses Includes any immune response to the host’s own tissue, whether humoral (e.g., circulating 4. Tissue Trauma and Release of Cryptic Antigens - autoantibodies) or cellular (e.g., delayed Some self-antigens may be cryptic, or hidden within hypersensitivity) the tissues of the host Condition in which damage to organs or tissues T and B lymphocytes are shielded from these results from the presence of autoantibody or sequestered antigens and are not educated to autoreactive cells become tolerant to them  Autoimmune diseases - disorders in which immune Examples: responses are targeted toward self antigens and a. Myelin basic protein - normally sequestered by result in damage to organs and tissues in the body the blood-brain barrier (BBB) b. In the case of sperm, vasectomy can induce  Self-tolerance - ability of the immune system to autoantibody formation accept self-antigens and not initiate a response c. production of autoantibodies to the lens of the eye against them following an ocular injury 5. Microbial Infections  Etiology of Autoimmune Diseases: Molecular mimicry - refers to the fact that many 1. Self-Tolerance bacterial or viral agents contain antigens that a. Central tolerance - occurs in the primary lymphoid closely resemble the structure or amino acid organs, the thymus and the bone marrow sequence of self antigens o Negative selection: T cells that express Tcell foreign antigens may trigger immune responses receptors (TCRs) with a strong affinity for these that crossreact with similar self-antigens self-antigens are deleted by apoptosis Examples: Streptococcus pyogenes develops o Negative selection: B cells mature in the bone rheumatic fever ( production of antibodies to the M marrow, those with receptors having a strong protein and N-acetyl glucosamine components of the affinity for self-antigens are eliminated by bacteria, which crossreact with cardiac myosin, apoptosis causing damage to the heart) b. Peripheral tolerance - Anergy caused by the Bystander effect - the microorganism can induce a absence of a costimulatory signal from an antigen local inflammatory response that recruits presenting cell (APC) or binding of inhibitory leukocytes and stimulates APCs to release receptors such as CTLA-4 (a molecule that prevents cytokines that nonspecifically activate T cells T-cell activation) Superantigens - proteins that are produced by o Self-reactive B cells in the periphery can be deleted by apoptosis, be rendered anergic after various microbes that have the ability to bind to repeated stimulation with self-antigens, or both class II MHC molecules and TCRs, regardless receive inhibitory signals through receptors such of their antigen specificity as CD22 Example: staphylococcal enterotoxins that cause food 2. Genetics - Individual may have inherited a gene that poisoning and toxic shock syndrome codes for a specific MHC molecule, making him/her 6. Epigenetics more susceptible to a particular autoimmune disease 7. Interaction Between Factors (e.g. Presence of HLAB27 makes an individual at risk for having ankylosing spondylitis)  Kristelle Anne Diadio BSMLS 3B Autoimmune Diseases isoniazid, quinidine, anticonvulsants such as methyldopa  Signs – Increase in the amount of globulin 3. Hormones Occurrence of different autoantibodies detected in o Antibodies present: serum 1. antibodies to double-stranded DNA (dsDNA), Decreased concentration of complement in serum histones, and other nuclear components Absence of CD8+ lymphocytes 2. autoantibodies to lymphocytes, erythrocytes, Lumpy-bumpy immunoglobulin and complement platelets, phospholipids, ribosomal components, deposits in arterial walls and basement membrane and endothelium Lesions detected in biopsy (e.g. glomerular lesions) **Note: Abnormal apoptosis of certain types of cells may resulting from deposition of immune complexes occur, releasing excess amounts of cellular constituents such as DNA and ribonucleic acid (RNA)  Types of autoimmune disease:  Accumulation of IgG to dsDNA seems to be the most 1. Organ-specific - The immune response is directed to pathogenic because it forms complexes of an an antigen unique to a single organ or gland intermediate size that become deposited in the manifestations are largely limited to that organ, glomerular basement membrane (GBM) causing cell damage, overstimulation or blocking o Possible Deficiencies in Systemic Lupus the normal function of the organ Erythematosus: 2. Systemic - The response is directed towards a broad 1. defects in complement receptors on phagocytic range of target antigens and involves different tissues cells and organs 2. defects in receptors for the Fc portion of general defect in immune regulation that results in immunoglobulins hyperactive T cells and B cells 3. deficiencies of early complement components such as C1q, C2, or C4  Locations of the organ specific diseases: o Symptoms: 1. Thyroid Gland - Hashimoto’s Thyroiditis Graves’ 1. Characterized by fever, weakness, arthritis, skin Disease rashes, pleurisy, and kidney dysfunction 2. Pancreas - Type I Diabetes 2. Joint involvement (polyarthralgias or symmetric 3. Nervous System - Myasthenia Gravis arthritis) - most common in SLE patients 3. Erythematous rash (Malar Rash) - classic butterfly 4. Gastrointestinal Tract - Pernicious Anemia rash across the nose and cheeks that appears in 5. Heart - Myocardial Infarction some SLE patients ( lupus, derived from the Latin 6. Adrenal Glands - Addison’s Disease term meaning “wolf-like.”) 7. Blood - Autoimmune Hemolytic Anemia, Idiopathic 4. Nephritis (diffuse proliferative Thrombocytop Enic Purpura glomerulonephritis) - is a major cause of illness 8. Kidneys and Lungs - Goodpasture’ S Syndrome and death SYSTEMIC DISEASES (1) Systemic Lupus Erythematosus  Systemic Lupus Erythematosus – A chronic systemic inflammatory multi-organ disease marked by alternating exacerbations and remissions A connective autoimmune tissue disease that o Treatment: expresses itself as a vasculitis (inflammation of 1. Anti-malarial drug hydroxychloroquine is blood vessels), usually involving organ systems recommended for all SLE patients originate from complex interactions between 2. Monoclonal antibodies - belimumab (directed environmental factors, genetic susceptibility, and against soluble B lymphocyte stimulator [BlyS]) or abnormalities within the immune system rituximab (anti-CD20), which affect B-cell activity, o Etiology: may be used for patients who have not responded 1. Environmental factors: UV light, certain adequately to the previous treatments medications, and certain infections 2. Drugs: procainamide (used to treat abnormal Diagnosis heart rhythms), hydralazine (used for high blood pressure), and the tuberculosis drug isoniazid,  Anti-nuclear antibodies (ANA) – are autoantibodies procainamide, hydralazine, chlorpromazine, that are directed against antigens in the nuclei of mammalian cells  Kristelle Anne Diadio BSMLS 3B a heterogeneous group of antibodies that have different antigen specificities directed against include dsDNA and single stranded DNA (ssDNA), histones, nucleosomes (DNA–histone complexes), centromere proteins, and extractable nuclear antigens (ENAs) Common Anti-Nuclear Antibodies AUTOANTIBODY ANTIGEN(S) IMMUNOFLUORESCENT PATTERN PATTERN DISEASE ASSOCIATION Anti-dsDNA dsDNA Homogeneous SLE Anti-ssDNA Related to purines Not detected on routine SLE, many and pyrimidines screen other diseases Anti-histone Different classes of Homogeneous Drug-induced histones SLE, other diseases Anti-DNP DNA–histone Homogeneous SLE, drug- complex induced SLE (nucleosomes) Anti-Sm Extractable nuclear Coarse speckled Diagnostic for antigen (uridinerich SLE RNA component) Patterns: Anti-RNP Proteins complexed Coarse speckled SLE, mixed a. Homogenous - characterized by uniform staining of with small nuclear connective RNA tissue diseases the entire nucleus in interphase (nondividing) cells Anti–SS-A/Ro Proteins complexed Finely speckled SLE, Sjögren’s and of the condensed chromosomal region in to RNA syndrome, others metaphase cells Anti–SS-B/La Phosphoprotein Finely speckled SLE, Sjögren’s b. Speckled - characterized by discrete, fluorescent complexed to RNA syndrome, polymerase others specks throughout the nuclei of interphase cells Anti-nucleolar RNA polymerase, Prominent staining of SLE, systemic o The speckled group is divided into three fibrillarin, PM-1 nucleoli (can be sclerosis smooth, clumpy, or subgroups depending on whether the specks are speckled) dense fine, tiny/fine, or large/coarse Anti–Scl-70 DNA topoisomerase Compound pattern with Systemic I speckling sclerosis, c. Centromere - Numerous discrete speckles are seen scleroderma in the nuclei of interphase cells and the chromatin Anti–Jo-1 Histidyl-tRNA Fine cytoplasmic Polymyositis synthetase speckling of dividing cells Anti- CENP-A/B/C in the Discrete speckled CREST o Most cells have 46 speckles, representing the centromere chromosome syndrome centromeres (limited number of chromosomes cutaneous d. Nucleolar - Prominent staining of the nucleoli systemic sclerosis) within the nuclei of interphase cells DSF70/LEDGF Lens epithelium Dense fine speckled Usually e. Discrete Nuclear Dot - This group is characterized derived growth indicates factor/transcription absence of by the presence of 1 to 6 or 6 to 20 discrete nuclear co-activator p75 SARDs dots per cell, depending on the subgroup CREST = calcinosis cutis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia; DNP = deoxyribonucleoprotein; dsDNA = double-stranded DNA; RNA = ribonucleic acid; RNP = ribonucleoprotein; Common immunofluorescence antinuclear antibodies SARDs = systemic autoimmune rheumatic diseases; SLE = systemic lupus patterns associated with specific diseases erythematosus; ssDNA = single-stranded DNA ANA Pattern Antigen Associated diseases Speckled ENA, RNP, Sm, Ro/SSA, SLE, MCTD, Systemic La/SSB, Scl-70, Jo-1, sclerosis, Sjögren's  Methods of ANA Detection: ribosomal-P syndrome, PM 1. Indirect Immunofluorescence (IIF) - Fluorescent Homogenous dsDNA, Histones SLE, Drug-induced SLE antinuclear antibody (FANA) testing been the most widely used and accepted test because it is highly sensitive, detects a wide range Peripheral (rim) RNP, Sm, Ro/SSA SLE, Systemic sclerosis of antibodies, and is inexpensive and easy to perform Nucleolar Anti-PM-Scl, anti-RNA Systemic sclerosis, PM polymerase I-III, anti-U3- RNP, To RNP Centromere CENP A-E Limited systemic sclerosis  Kristelle Anne Diadio BSMLS 3B 2. Immunofluorescence Using Crithidia luciliae - One 2. Swelling of the soft tissue around 3 or more joints particularly sensitive assay for dsDNA is an IIF test 3. Swelling of the proximal interphalangeal, using a hemoflagellate organism called Crithidia metacarpophalangeal, or wrist joints luciliae as the substrate 4. Symmetric arthritis This trypanosome has a circular organelle called a 5. Nodules over the bones kinetoplast that is composed mainly of dsDNA 6. Positive test for rheumatoid factor (RF) (Sensitive assay for anti-dsDNA) 7. Radiographic evidence of erosions in the joints of A positive test is indicated by a brightly stained the hands, the wrists, or both. o Treatment: 1. NSAIDs - salicylates (aspirin) and ibuprofen 2. Disease-modifying anti-rheumatic drugs (DMARDs) - most notably Methotrexate 3. Agents that act against TNF-α - monoclonal antibodies to (1) TNF-α (e.g., infliximab, (2) Anti-Phospholipids Antibodies adalimumab, certolizumab, golimumab) and (2)  Anti-Phospholipids Antibodies – a heterogeneous TNF-α receptors fused to an IgG molecule group of antibodies that bind to phospholipids alone (etanercept) or phospholipids complexed with protein o Diagnosis: are especially associated with deep-vein and 1. Manual agglutination tests using charcoal or latex arterial thrombosis and with recurrent pregnancy particles coated with IgG loss 2. ELISA 3. CLIA (Chemiluminescence immunoassays) (3) Rheumatoid Arthritis 4. Nephelometric methods  Rheumatoid Arthritis – characterized as a chronic, (4) Other Systemic Autoimmune Rheumatic symmetric, and erosive arthritis of the peripheral joints that can also affect multiple organs such as the Diseases (SARDs) heart and the lungs (a) Sjogren’s Syndrome inflammatory process that results in the  Sjogren’s Syndrome – characterized by chronic destruction of bone and cartilage inflammation of the exocrine glands, most notably rheumatoid joints show an increase in cells lining the ocular and salivary glands the synovial membrane and formation of a pannus This produces symptoms of dry eyes and a dry  TNF-α – stimulates the production of other cytokines mouth, also known as “sicca syndrome.” and facilitating the transport of white blood cells o Two groups: (WBCs) to the affected areas 1. Primary Sjögren’s syndrome - occurs in the  Local bone erosion (it may lead to osteoporosis) – absence of other diseases osteoclasts become overly activated in the 2. Secondary Sjögren’s syndrome - occurs in patients inflammatory environment of the joints who also have other diseases, most commonly SLE  TNF-α, in conjunction with other cytokines and a or rheumatoid arthritis molecule called RANKL (receptor activator of nuclear o Sicca Complex/Syndrome: factor kappa-B ligand) induces the differentiation of 1. Keratoconjunctivitis sicca - dry eye syndrome osteoclasts and inhibits bone formation 2. Xerostomia - dry mouth syndrome  Most common cause of death: cardiovascular disease  positive RF and ANAs, exhibiting a fine speckled pattern o Antibodies present: of fluorescence that is indicative of anti–SSA/Ro and/or 1. Rheumatoid Factor (RF) - antibody that is most anti–SSB/La often of the immunoglobulin m (IgM) class and is  The presence of antibodies to SS-A/Ro is one directed against the Fc portion of IgG component for the classification of primary Sjögren’s 2. Antibodies to cyclic citrullinated proteins (anti- syndrome cyclic citrullinated peptide antibody [anti-CCP or ACPA]) - Death of granulocytes and macrophages (b) Scleroderma triggers production of citrullinated proteins 3. Antibodies can react with citrulline-containing  Scleroderma – characterized by excessive fibrosis and components of the matrix, including filaggrin, vascular abnormalities that affect the skin and joints keratin, fibrinogen, and vimentin and progress over time to involve internal organs, o Diagnosis (at least 4 for 6 weeks): most commonly the esophagus, lower 1. Morning stiffness around the joints lasting at least gastrointestinal tract, lungs, heart, and kidneys 1 hour  Kristelle Anne Diadio BSMLS 3B  Antibodies to neutrophil cytoplasmic antigens: (c) Crest Syndrome antibody is directed against an enzyme in neutrophils called PR3 o Crest Syndrome:  Binding of PR3 antibodies to the PR3 antigen: 1. Calcinosis cutis activation of the neutrophils, which adhere to 2. Raynaud’s phenomenon, endothelial cells lining the blood vessels 3. Esophageal dysmotility 4. Sclerodactyly  Chronic infections: elease of the proinflammatory cytokine TNF-α, which stimulates neutrophils and 5. Telangiectasia results in migration of the PR3 antigen from the  Crest Syndrome – Milder form of scleroderma granules to the neutrophil membrane Marker is centromere antibody  S. aureus may induce molecular mimicry: contains peptides that bear similarity to the proteinase 3 (PR3) (d) Mixed connective tissue disease (MCTD) autoantigen  Mixed connective tissue disease (MCTD) – overlap  A key diagnostic aid: positive antineutrophil syndrome with clinical features of SLE, polymyositis, cytoplasmic antibody (ANCA) test result, specifically and RA antibody to proteinase 3 (e) Inflammatory Myopathies (IMs) (6) (Anti-neutrophil cytoplasmic antibodies )  Inflammatory Myopathies (IMs) – chronic ANCA inflammation of the skeletal muscles (“myositis”) and  (Anti-neutrophil cytoplasmic antibodies) ANCA – are progressive muscle weakness autoantibodies that are produced against proteins that are present in the neutrophil granules  Two examples of IM: 1. Polymyositis (PM) - Degeneration/inflammation of Indirect Immunofluorescence Testing (ANCAs) skeletal muscles manifested by muscle weakness of  Ethanol-fixed leukocytes - used as substrate unknown etiology Ethanol treatment permeabilizes the granule Anti-Jo-1 membranes, allowing for migration of the contents 2. Dermatomyositis (DM) - differs from PM in that DM o Procedure: can present in children and adults 1. Patient serum is incubated with a microscope slide characterized by the presence of a skin rash in containing ethanol-fixed leukocytes addition to muscle involvement 2. Following incubation, the slide is washed to remove unbound serum, and an anti-human IgG, o Antibodies present in IMs: fluorescein isothiocyanate (FITC)-labeled 1. associated and found in other SARDs (e.g., SS- conjugate, is added A/Ro, SS-B/La, PM-Scl, snRNPs) 3. Following a second and wash step, the slide is 2. myositis-specific, including antibodies to tRNA viewed under a fluorescent microscope for antisynthetases and Anti-Jo-1 (Most common) staining of the neutrophils (5) Granulomatosis with polyangiitis (GPA) Anti-Neutrophil Cytoplasmic Antibodies (ANCAs)  Granulomatosis with polyangiitis (GPA) – formerly PATTERN ON INDIRECT APPEARANCE AUTOANTIGENS ASSOCIATED IMMUNOFLUORESCENCE DISEASES WITH ETHANOL-FIXED known as Wegener’s granulomatosis or WG LEUKOCYTES rare autoimmune disease involving inflammation c-ANCA Diffuse, granular PR3 antigen Granulomatosis with staining in the polyangiitis (GPA; of the small- to medium-sized blood vessels, or cytoplasm of the Wegener’s neutrophils, granulomatosis) vasculitis fading toward the localized inflammation of the upper and lower outer edges of the cells respiratory tract p-ANCA Fluorescence Positively charged  Microscopic  General Symptom: fever, malaise, arthralgias, anorexia, surrounding the lobes of the antigens, including polyangiitis (MPA) and weight loss neutrophil nuclei, myeloperoxidase  Eosinophilic blending them (MPO) granulomatosis o Symptoms of the upper airway: together with polyangiitis (EGPA; Churg 1. persistent rhinorrhea (“runny nose”) Strauss 2. rhinitis syndrome) c-ANCA = cytoplasmic anti-neutrophil cytoplasmic antibody; p-ANCA = 3. sinusitis perinuclear anti-neutrophil cytoplasmic antibody 4. oral or nasal ulcers 5. gingivitis  Kristelle Anne Diadio BSMLS 3B  Cells present: activated T and B cells (with T cells Systemic Autoimmune Diseases predominating), macrophages, and plasma cells in DISEASE TARGET CELLS ASSOCIATED thyroid gland AND TISSUES AUTOANTIBODIES  thyroid gland destruction is mediated primarily by CD8+ Systemic lupus Multiple cells and  Anti-nuclear erythematosus organs throughout the antibodies (ANAs) cytotoxic T cells (SLE) body, including the skin, (e.g., antidsDNA,  produce antibodies to Tg and TPO (able to fix joints, kidneys, brain, anti-Sm) complement) heart, lungs  Phospholipid antibodies  produce antibodies against the TSH receptor ( prevent  Antibody to RBCs binding of TSH)  Antibody to platelets  Injury to the thyroid gland and inhibition of its function  Antibody to lymphocytes result in the symptoms associated with  Antibody to HYPOTHYROIDISM ribosomal components  Antibody to endothelium  Rheumatoid factor Rheumatoid Joints, bone; other  Anti-CCP (cyclic arthritis (RA) tissues in some case citrullinated protein)  Rheumatoid factor  ANAs Sjögren’s Eyes, mouth ANAs, rheumatoid factor, syndrome anti-salivary duct antibodies, anti-lacrimal gland antibodies Systemic sclerosis Connective tissue ANAs: anti-Scl-70, anti- centromere antibody o Signs and symptoms: Polymyositis/ Muscles, skin ANAs (e.g., anti-Jo-1) 1. dry skin Dermatomyositis 2. Decreased sweating Granulomatosis Upper respiratory  Anti-neutrophil 3. Puffy face with edematous eyelids with polyangiitis system, lungs, blood cytoplasmic (Wegener’s vessels antibodies (ANCA); c- 4. Pallor with a yellow tinge granulomatosis) ANCA pattern 5. Weight gain  Rheumatoid factor 6. Fatigue  ANAs 7. Dry and Brittle Hair ORGAN DISEASES (b) Grave’s Disease (1) Thyroid Hormones  Grave’s Disease - Most common cause of o Mechanism: hyperthyroidism (0.5 % of the population) 1. Hypothalamus release TRH Most prevalent autoimmune disorder in the US 2. TRH acts on the pituitary today 3. Pituitary release TSH Manifested as thyrotoxicosis, hyperthyroidism due 4. TSH, in turn, binds to receptors on the thyroid to diffuse enlarged goiter gland, causing thyroglobulin to be broken down Distribution: common in women (10 to 1), into secretable T3 and T4 common in ages between 20 and 50  WHERE DOES THE PROBLEM START? presence of o Antibodies present: autoantibodies to components of the thyroid gland 1. Thyroid stimulating hormone receptor antibodies interferes with this process and causes under- or (TRAbs) - type responsible for the hyperthyroidism overactivity of the gland seen in Graves’ disease are called thyroid- stimulating immunoglobulins (TSIs) (a) Hashimoto’s Disease 2. Thyroid-blocking antibodies (TBAbs)  Hashimoto’s Disease - Also known as chronic 3. Anti-Tg and anti-TPO lymphocytic thyroiditis  Patient symptoms may vary from hyperthyroidism to Most common form of thyroiditis euthyroidism (the state of normal thyroid function) to Characterized by a slow progression to hypothyroidism, which may confound the patient’s hypothyroidism (Patients also produce thyroid- diagnosis specific autoantibodies and cytotoxic T cells) o Signs and symptoms: Autoantibodies and sensitized Th cells specific for 1. Nervousness thyroid antigens cause destruction of thyroid gland 2. Insomnia and depression Women are 5 to 10 times more likely to develop 3. Weight loss Common in females 35-55 years 4. Heat intolerance  Kristelle Anne Diadio BSMLS 3B 5. Sweating  Antibodies to islet cells have traditionally been detected 6. Rapid heartbeat by IIF 7. Palpitations o Antibodies present: 8. Breathlessness 1. Antibodies to insulinoma antigen 2 (IA-2 or 9. Fatigue ICA512)* 10. Cardiac dysrhythmias 2. Antibodiesto IA-2βA (phogrin) 11. Exopthalmus 3. Anti-insulinand anti-proinsulin antibodies 4. Antibodies to zinc transporter 8 (ZnT8) 5. Anti-glutamic acid decarboxylase (GAD)* 6. Islet cell antibodies (ICAs)* o Treatment: 1. Multiple Daily Injections of Insulin 2. Transplantation of whole pancreas or pancreatic beta islet cells 3. Use of stem cells (3) Nervous System (a) Myasthenia Gravis  Myasthenia Gravis - Characterized by muscular weakness, fatigue, and the presence of anti- acetylcholine receptor (anti-AChR) autoantibodies Action of auto-antibodies: blocking, binding, and Typical Laboratory Findings in Autoimmune Thyroid modulating Diseases Patient produces auto-antibodies that bind the DISEASE TSH LEVEL FREE T4 AUTOANTIBODIES acetylcholine receptors on the motor end-plates of (FT4) LEVEL Hashimoto’s Normal or Decreased  Anti-thyroglobulin muscles, blocking the normal binding of thyroiditis elevated  Anti-thyroid acetylcholine and also inducing complement peroxidase (TPO) mediated lysis of the cells Graves’ Decreased or Elevated  Thyroid-stimulating o The result is a progressive weakening of the disease undetectable hormone receptor antibodies (TRAbs) skeletal muscles  Anti-thyroglobulin o Other antibodies:  Anti-thyroid 1. Antibodies against muscle-specific kinase (MuSK) peroxidase (TPO) - inhibit development of the neuromuscular junction and in the clustering of AChRs on the (2) Pancreas muscle cell membrane  Type I Diabetes Mellitus - insulin-dependent 2. Antibodies against LRP4 - inhibit the the activation diabetes or juvenile-onset diabetes of MuSK is a chronic autoimmune directed against 3. Antibodies to titin - a major protein in striated specialized insulinproducing cells (beta cells) that muscles are located in spherical clusters, called the islets of o Signs and Symptoms: Langerhans, scattered throughout the pancreas 1. Early signs are drooping of the eyelids(ptosis), Destroys beta cells, resulting in decreased double vision (diplopia) and the inability to retract production of insulin and consequently increased the corners of the mouth, often resulting in a levels of blood glucose snarling appearance Most people with T1D carry the HLA-DR3 or DR4 2. Other symptoms may include difficulty in speaking, gene, and there is an increased risk when both of chewing, and swallowing, and inability to maintain these genes are present support of the trunk, the neck, or the head o Laboratory Diagnosis: o Treatment: 1. a fasting glucose greater than 126 mg/dL on more 1. Anti-cholinesterase - main therapy than one occasion(normal value is lower than 100 2. Thymectomy mg/dL) 3. Plasmapheresis - remove the autoantibodies or 2. a random plasma glucose level of 200 mg/dL or intravenous immunoglobulin (whose mechanism more with classic symptoms of diabetes of action is unknown 3. an oral glucose tolerance test of 200 mg/dL or 4. Monoclonal antibodies: rituximab more in a 2- hour sample with a 75 g glucose load 4. a hemoglobin A1c value (HbA1c) greater than 6.5%  Kristelle Anne Diadio BSMLS 3B (b) Multiple Sclerosis 2. Anti-intrinsic factor (anti-IF) - More specific for pernicious anemia  Multiple Sclerosis - characterized by the formation of  Parietal cells of the stomach secrete IF which will form a lesions called plaques in the white matter of the protective complex with Vit. B12 brain and spinal cord, resulting in the progressive Upon reaching the ileum, complex attaches to destruction of the myelin sheath of axons receptors, B12 is released from IF and absorption Antibody binds to the myelin membrane and may takes place initiate the immune response, stimulating o Functions of vitamin B12: macrophages and specialized phagocytes called 1. Keeps the healthy function of our brains and microglial cells nervous system The Th1 cytokines IL-1, TNF-α, and IFN-γ are 2. Helps form our red blood cells believed to be central to the pathogenesis of the 3. Helps form our genetic material (DNA and RNA) disease, promoting changes in the endothelial cells 4. Helps balance levels of homocysteine in the blood that facilitate adherence of activated T cells and o Mechanism: their migration across the blood–brain barrier 1. Binding of the auto-antibody to intrinsic factor  Theorized that the inflammatory response is triggered blocks the intrinsic factor–mediated absorption of by molecular mimicry vitamin B12  EBV, measles, HSV, VZV, Rubella, influenza C, HHV-6 2. In the absence of sufficient vitamin B12, which is  Characterized by visual disturbances, weakness in the necessary for proper hematopoiesis, the number extremities, locomotor incoordination, and sensory of functional mature red blood cells decreases abnormalities below normal o Signs and Symptoms: 1. visual disturbances (b) Celiac Disease 2. weakness in the extremities 3. locomotor incoordination, dizziness, facial palsy  Celiac Disease - autoimmune disease affecting the 4. sensory abnormalities small intestine and other organs 5. Flashes of light seen on eye movement  Dietary gluten - triggers the development of Celiac o Diagnosis: Disease 1. Isoelectric focusing with immunoblotting - Gluten contains gliadin → Giadin - resistant to producing two or more distinct bands (oligoclonal digestive enzymes in the stomach, pancreas and bands) on protein electrophoresis that are not small intestine seen in the serum  undigested gliadin is able to pass through the epithelial 2. IgG index - a calculated ratio of cerebral spinal barrier of the intestine and triggers an inappropriate fluid (CSF) IgG/albumin ÷ serum IgG/albumin immune response 3. patients produce antibody directed against a  The gliadin peptides that are picked up by the APC are myelin basic protein peptide presented to antigen-specific CD4+ T cells, which 4. Other antibodies directed against components of produce cytokines that activate CD8+ T cells oligodendrocytes and against myelin membranes.  B cells are stimulated to produce antibodies to the o Treatment: deamidated gliadin peptides (DGPs), tTG, and 1. Ocrelizumab - binds to CD20 and depletes mature endomysium B cells from the blood Endomysium - a layer of connective tissue 2. Natalizumab - directed against an adhesion surrounding the intestinal muscles molecule of lymphocytes, preventing them from o Symptoms: binding to endothelial cells and crossing the 1. present with diarrhea blood–brain barrier 2. abdominal distention 3. Stem cell transplantation 3. failure to thrive 4. vomiting 5. irritability 6. anorexia (4) Gastrointestinal Tract 7. constipation o Treatment: (a) Pernicious Anemia 1. Elimination of gluten from the diet  Pernicious Anemia - An autoimmune disease 2. Alternative treatments, such as the use of accompanied by cobalamin deficiency, megaloblastic recombinant enzymes to digest the toxic gliadin anemia, and neuropathy o Autoantibodies: 1. Anti-parietal cell (APC) autoantibodies  Kristelle Anne Diadio BSMLS 3B (5) Liver 21-Hydroxylase and 17α-hydroxylase are two autoantigens that have been identified as reactive (a) Autoimmune Hepatitis (AIH) with adrenocortical autoantibodies  Autoimmune Hepatitis (AIH) - formerly known as Low cortisol and low aldosterone chronic active hepatitis the autoimmune process targets the hepatocytes Organ-Specific Autoimmune Diseases  Two types of AIH can be differentiated on the basis of DISEASE TARGET CELLS ASSOCIATED AUTOANTIBODIES AND TISSUES its autoantibody specificity: referred to as AIH-1 and Addison’s disease Adrenal glands Antibody to adrenal cells AIH-2 Autoimmune Red blood cells Antibody to RBCs  Hepatitis C infection - causes AIH, through molecular hemolytic anemia Autoimmune (RBCs) Liver  AIH-1—smooth muscle mimicry and cross-reactivity between their epitopes hepatitis (AIH) antibodies; antinuclear and liver antigens antibodies (ANAs)  AIH-2—anti-liver kidney  Interface hepatitis - typical of AIH and is microsomal antibody (anti-LKM- characterized by an infiltrate of lymphocytes, plasma 1); anti-liver cytosol type 1 antibody (anti-LC-1) cells, and histiocytes surrounding dying hepatocytes Autoimmune Platelets Anti-platelet antibody o Common Laboratory Findings: thrombocytopenic purpura 1. elevated levels of the liver enzymes aspartate Celiac disease Small intestine  Anti-transglutaminase (tTG) aminotransferase (AST) and alanine and other  Antibodies to deamidated organs gliadin peptides (DGPs) aminotransferase (ALT)  Endomysial antibodies 2. increases in serum bilirubin and alkaline Anti-glomerular Kidneys, lungs Antibody to an antigen in the renal phosphatase basement and pulmonary basement membranes membrane disease (Goodpasture’s AIH-1 AIH-2 syndrome) patients are characteristically  antibodies against LKM 1, anti- Graves’ disease Thyroid gland  Thyroid-stimulating hormone positive for smooth muscle liver kidney microsomal receptor antibodies (TRAbs) antibody (antiLKM-1): directed  Anti-thyroglobulin antibodies (SMAs) or ANA against cytochrome P450 2D6  Anti-thyroid peroxidase (TPO)  against LC-1 (anti-liver cytosol Hashimoto’s Thyroid gland  Anti-thyroglobulin type 1 antibody) thyroiditis  Anti-thyroid peroxidase (TPO) Multiple sclerosis Myelin sheath Antibodies to myelin basic protein The SMAs are directed against of nerves actin and other components of Myasthenia gravis Nerve-muscle  Antibodies to acetylcholine the cytoskeleton synapses receptors (AChR)  Anti–muscle-specific kinase (MuSK) (b) Primary Biliary Cholangitis (PBC)  Antibody to the lipoprotein LRP4  Primary Biliary Cholangitis (PBC) - formerly known as Pernicious anemia Stomach Parietal cell antibody, intrinsic factor antibody primary biliary cirrhosis Poststreptococcal Kidneys Streptococcal antibodies that cross- autoimmune disease that involves progressive glomerulonephritis Primary biliary Intrahepatic react with kidney tissue Anti-mitochondrial antibodies (AMA) destruction of the intrahepatic bile ducts cholangitis bile ducts destruction leads to chronic cholestasis, Rheumatic fever Heart Streptococcal antibodies that cross- react with cardiac tissue inflammation of the portal vein in the liver, and Type 1 diabetes Pancreas  Anti-insulin accumulation of scar tissue that can ultimately lead mellitus  Islet cell antibodies  Anti–IA-2 and anti–IA-2βA to cirrhosis and liver failure.  Antibody to glutamic acid  Standard initial therapy for PBC: Ursodeoxycholic acid phosphatase (GAD) (UDCA) - a bile acid that helps move bile through the liver (6) Heart  Idiopathic Dilated Cardiomyopathy (IDCM) - evidence suggests that autoimmune reactions (autoantibodies) against certain myocyte antigens can contribute in causing cardiac dysfunction and heart failure, playing a pivotal role in its initiation and/or progression (7) Adrenal Glands  Addison’s Disease- aka Nontuberculous chronic adrenocortical insufficiency; caused by circulating autoantibodies to adrenal cortex cells