L25 Autoimmune Disorders PDF

Autoimmune Disorders Suggested reading for Lecture 25: Basic Immunology, Ch. 11, pp. 226-234 MICRG 1553 Immunology Kathryn Leyva, Ph.D. Learning Objectives 1. Compare and contrast organ-specific and systemic autoimmunities 2. For each organ-specific autoimmunity, identify the...

Autoimmune Disorders Suggested reading for Lecture 25: Basic Immunology, Ch. 11, pp. 226-234 MICRG 1553 Immunology Kathryn Leyva, Ph.D. Learning Objectives 1. Compare and contrast organ-specific and systemic autoimmunities 2. For each organ-specific autoimmunity, identify the self antigen eliciting production of autoantibodies and/or autoreactive T cells & describe how these autoimmune mechanisms result in development of disease: a. Graves disease b. Myasthenia gravis c. Pernicious anemia d. Hashimoto thyroiditis e. Type 1 diabetes mellitus f. Multiple sclerosis 3. For each systemic autoimmunity, identify the autoantigens/autoantibodies produced & describe how these autoantibodies result in development of disease: a. Systemic lupus erythematous b. Rheumatoid arthritis 4. Understand the mechanism of action of the immunotherapies discussed for: a. Multiple sclerosis: fingolimod, natalizumab, and ocrelizumab b. Systemic lupus erythematous: belimumab and antifrolumab-fnia 2 c. Rheumatoid arthritis: cytokine/cytokine receptor/JAK inhibitors, abatacept, and rituximab Introduction https://drjockers.com/heal-autoimmune-disease/ https://labpedia.net/elementary-immunology/chapter-16-autoimmunity/ Categories of AI Disease  Autoimmunities are typically classified as either organ-specific or systemic: ◼ Organ-specific: Immune response directed to specific self antigens in an organ, gland, or tissue; lesion(s) & clinical symptoms are limited to that organ  Type II and/or Type IV hypersensitivity mechanisms ◼ Systemic: autoantibodies are formed against antigens common to many tissues  Often Type III hypersensitivity mechanisms; can also include Type II and/or Type IV J. Mbongue et al. Immunology 2014(5):857143 4 Autoimmune-Mediated Damage  In organ-specific autoimmunities, tissues are affected in two main ways: 1. Autoantibodies can overstimulate or block the normal function of the target tissue  Antibodies can act as agonists ▪ Graves disease  Antibodies can act as antagonists ▪ Myasthenia gravis ▪ Pernicious anemia 5 Organ Specific: Graves Disease  Autoantibodies cause overstimulation of TSHR ◼ Anti-TSHR antibodies result in unregulated activation & over-production of thyroid hormones = hyperthyroidism  Patients also may present with proptosis; inflammation of the orbit and periorbital tissues https://en.wikipedia.org/wiki/Graves%27_disease 6 TSHR = thyroid stimulating hormone receptor Organ Specific: Myasthenia Gravis (MG)  Autoantibodies block ACh from binding to AChR ◼ Anti-AChR antibodies (in the neuromuscular junction) act as competitive receptor antagonist by binding and blocking neuromuscular transmission; result is muscle weakness (ACh) (ACh)  The most frequent early sign of MG is ptosis ◼ Ultimately, autoantibodies can cause complement-mediated destruction of the muscle fibers https://courses.lumenlearning.com/microbiology/chapter/autoimmune-disorders/ 7 AChR = acetylcholine receptors Organ Specific: Pernicious Anemia  Autoantibodies block absorption of vitamin B12 ◼ Dietary vitamin B12 is absorbed when bound to intrinsic factor (IF)  IF is secreted by gastric parietal cells  IF-B12 complex is absorbed in the ileum (part of small intestine) ◼ Anti-intrinsic factor antibodies block:  IF binding to B12  IF-B12 binding to IF receptor ◼ Decreased vitamin B12 absorption = decreased erythropoiesis  Megaloblastic anemia  FYI: often see https://healtheappointments.com/chapter-28- vitamins-essays/ hypersegmented PMNs (shown) 8 Autoimmune-Mediated Damage  In organ-specific autoimmunities, tissues are affected in two main ways: 2. Autoantibodies and/or autoreactive T cells can cause direct cellular damage  Cellular lysis and/or inflammatory responses gradually result in the replacement of normal tissue with connective tissue (fibrosis), compromising tissue function ▪ Pernicious anemia ▪ Hashimoto thyroiditis ▪ Type 1 diabetes mellitus ▪ Multiple sclerosis 9 Organ Specific: Pernicious Anemia  Autoantibodies & CTLs cause direct cellular  Possible link to Helicobacter pylori damage to gastric parietal cells infection (molecular mimicry) ◼ Anti-parietal cell antibodies & autoreactive CTLs against H+,K+-ATPase  Killing of parietal cells  Reduced intrinsic factor production https://www.sciencedirect.com/science/article/pii/S0006497120663650 10 CTLs = cytotoxic T lymphocytes (CD8 T cells) Organ Specific: Hashimoto Thyroiditis Hashimoto  Autoantibodies & autoreactive T cells cause direct cellular damage to the thyroid gland ◼ CTLs and Th1 cells cause inflammation and damage to the thyroid; result: goiter ◼ Anti-thyroid peroxidase (TPO) and/or anti-thyroglobulin (Tg) antibodies inhibit production of iodine, activate Normal complement & induce ADCC; result: hypothyroidism thyroid Kumar et al. Robbins Basic Pathology, 8th edition 11 DTH = delayed type (Type IV) hypersensitivity ADCC = antibody-dependent cellular cytotoxicity Organ Specific: Type 1 Diabetes Mellitus (T1DM)  Autoantibodies & autoreactive T cells cause direct  Possible link to viral infections cellular damage to the pancreas (bystander T cell activation and/or molecular mimicry) ◼ DTH response is the main cytotoxic mechanism:  Effector CTLs destroy pancreatic  cells  Effector TH1 cytokines will stimulate local inflammation ◼ Several autoantibodies can be found in patients with T1DM  Abs activate complement or ADCC Modified from https://infodiabet.wordpress.com/2010/11/01/recent- research-relationship-between-enterovirus-infection-and-t1d/ 12 DTH = delayed type (Type IV) hypersensitivity ADCC = antibody-dependent cellular cytotoxicity  https://images.medicinenet.co m/images/appictures/multiple- Organ Specific: Multiple Sclerosis (MS) sclerosis-s2-definition.jpg  Autoantibodies & autoreactive T cells cause direct cellular damage to the CNS ◼ Infections &/or tissue damage may cause disruption of the BBB, resulting in ◼ release of CNS antigens and/or entry of self-reactive T cells into the CNS  CMI response: T cells & macrophages infiltrate the CNS and attack self-antigens on nerves, such as: ▪ MBP = myelin basic protein ▪ MOG = myelin oligodendrocyte glycoprotein  Humoral response: autoantibodies to MBP (or other antigens) can activate complement or induce ADCC BBB = blood brain barrier 13 CMI = cell-mediated immune CNS = central nervous system Some Immunotherapies for MS  S1P receptor modulator: ◼ Fingolimod (Gilenya®) & Ozanimod Ozanimod + Ofatumumab + (Zeposia®): S1P receptor agonists, resulting in downregulation of S1PR1 to retain lymphocytes within the lymphatic tissues  FYI: there are other S1P receptor modulators on the market for MS now too!  Monoclonal antibodies: ◼ Natalizumab (Tysabri®): anti-4β1 integrin that blocks extravasation of T cells across the BBB ◼ Ocrelizumab (Ocrevus®) & Ofatumumab (Kesimpta®): anti-CD20 bind to and (from E Fox et al. Neuol Clin Pract Feb 2019) mediates depletion of CD20+ cells 14 BBB = blood brain barrier Systemic Autoimmune Diseases  There is often a defect in immune regulation resulting in an immune response directed toward a broad range of target antigens, involving several organs/tissues. ◼ Rheumatoid arthritis ◼ Systemic lupus erythematosus  Systemic autoimmune diseases are often due to Type III & Type IV hypersensitivities: ◼ Deposition of immune complexes: Type III hypersensitivity ◼ T cell mediated damage: Type IV hypersensitivity  Systemic autoimmune diseases are often associated with development/presence of antinuclear antibodies = ANAs ◼ Serum antibodies can be detected using indirect fluorescent antibody (IFA) assays https://www.youtube.com/watch?v=JApDiFm9eMo 15 Systemic: Rheumatoid Arthritis (RA)  Genetic, host, and environmental factors contribute to a breakdown of tolerance to self antigens, resulting in the activation of self-reactive T and B cells that trigger synovial hypertrophy & chronic joint inflammation You don’t need to memorize these https://creakyjoints.org/symptoms/rheumatoid-arthritis-symptoms/ https://www.researchgate.net/figure/Risk-factors-responsible-for-rheumatoid-arthritis_fig3_354382535 https://en.wikipedia. org/wiki/Rheumatoid_arthritis 16 Systemic: Rheumatoid Arthritis (RA)  Autoreactive T and B cells are activated ◼ Increased TH1 & TH17 cytokines detected, along with increased macrophage inflammatory cytokines ◼ Autoantibodies form immune complexes that can deposit into the tissues, causing tissue damage Modified from Ding et al. (2023) Signal Transduction and Targeted Therapy 8(68) DOI:10.1038/s41392-023-01331-9 17 Systemic: Rheumatoid Arthritis (RA)  Common autoantibodies found in RA patients ◼ Rheumatoid factor (RF) = IgM anti-IgG antibody  Possible exposure of hidden carbohydrates on IgG (cryptic epitopes) www.ksvdl.org ◼ Anti-citrullinated peptide antibodies (ACPA)  Anti-CCP & anti-MCV antibodies  Citrullination alters the protein (altered self); stimulates an immune response 18 CCP = cyclic citrullinated peptide MCV = mutated citrullinated vimentin Some Immunotherapies for RA https://www.nature.com/articles/nrrheum.2011.145  Block the effects of proinflammatory cytokines: JAK inhibitor ◼ TNF inhibitors: bind and neutralize TNF ◼ Anakinra (Kineret®): IL-1R antagonist ◼ Tocilizumab (Actemra®): anti-IL-6R ◼ Tofacitinib (Xeljanz®): JAK1/3 inhibitor  Inhibit T cell activation: ◼ Abatacept (Orencia®): CTLA-4 fusion protein that B7 = binds B7; blocks the T cell costimulatory signal.  Deplete B cells: ◼ Rituximab (Rituxan®): anti-CD20 antibody that binds to B cells, resulting in B cell destruction (depletion). https://www.nature.com/articles/nrrheum.2011.145 19 Systemic: Systemic lupus erythematosus (SLE) You don’t need to memorize these  In SLE, genetic, hormonal, & environmental factors contribute to a breakdown of tolerance to self antigens, mainly nuclear antigens. ◼ Defective clearance of apoptotic bodies &/or release of NETs can lead to release of nuclear antigens  Stimulation of self-reactive T & B cells against these nuclear antigens results in the generation of anti-nuclear antibodies (ANAs) Modified from https://www.researchgate.net/figure/ Neutrophil-extracellular-traps-Neutrophil-extracellular- traps-NETs-are-composed-of_fig3_313671642 20 Systemic: Systemic lupus erythematosus (SLE)  Most common ANAs: anti-dsDNA & anti-Sm antibodies ◼ Antigens are components of the nucleus (FYI: Sm is a ribonucleoprotein) ◼ FYI: many other autoantibodies can be detected in patients with SLE  ANAs bind to nuclear antigens & form immune complexes ◼ Immune complexes are endocytosed by B cells and dendritic cells ◼ pDC secretion of IFN-α triggers continued ANA production https://www.hindawi.com/journals/bmri/2010/948364/ 21 ANAs = antinuclear antibodies pDC = plasmacytoid dendritic cell Systemic: Systemic lupus erythematosus (SLE)  Immune complexes deposit in the vasculature/joints, activating complement, and leading to tissue damage. ◼ Leads to vascular disease, kidney disease, arthritis, skin rashes, etc  FYI: Symptoms will vary among patients https://www.eurekaselect.com/article/87070 22  Biologic Immunotherapy for SLE  Belimumab (Benlysta®): anti-BLyS  Anifrolumab-fnia ◼ BLyS = B Lymphocyte Stimulator; BLyS (Saphnelo®): anti- is a B cell growth factor IFNAR1  Without BLyS, B cells undergo ◼ Binds to IFNAR1 apoptosis with high specificity and affinity to block the activity of type 1 IFNs Modified from: https://www.creativebiolabs.net/ anifrolumab-overview.htm G Dennis (2011) Clinical Pharmacology & Therapeutics 91(1): 143-149z 23 IFNAR1=subunit 1 of the type 1 interferon receptor https://www.youtube.com/watch?v=8pLz1X2_FRw&t=34s IFN-1 = type 1 interferon Summary: Organ-specific autoimmune diseases resulting from autoantibodies that overstimulate or block normal function Disease Self-antigen Auto- Immune Outcome of Immune Immunotherapies antibodies response Response Graves disease Thyroid- Anti-TSHR Type II Unregulated activation None discussed stimulating antibodies response and overproduction of hormone (TSH) (stimulating hormones → receptor antibodies) hyperthyroidism; some patients have proptosis Myasthenia Acetylcholine Anti-AChR Type II Inhibition of None discussed gravis receptors antibodies response neuromuscular (blocking transmission; ptosis antibodies) common Pernicious Intrinsic factor Anti-IF Type II Decreased uptake of None discussed anemia (IF) on gastric antibodies response vitamin B12 leading to a parietal cells (blocking megaloblastic anemia antibodies) 24 Summary: Organ-specific autoimmune diseases resulting from direct cellular damage Disease Self-antigen Autoantibodies/ Immune Outcome of Immune Immunotherapies Autoreactive T cells response Response Pernicious H+, K+-ATPase on Anti-parietal cell Type II and IV Destruction of gastric None discussed anemia parietal cells (main) antibodies & responses parietal cells, resulting in autoreactive CTLs reduced IF secretion against H+, K+-ATPase Hashimoto Thyroid peroxidase Anti-thyroid peroxidase Type II and Type Decreased uptake of iodine None discussed thyroiditis & thyroglobulin antibodies, anti- IV responses and destruction of thyroid (main) thyroglobulin antibodies, gland → hypothyroidism; & autoreactive CTLs CMI response → goiter against thyroid cells Type 1 Antigens on Several autoantibodies Type IV response Tissue destruction → None discussed diabetes pancreatic β cells (did not cover them) & (main); can have decreased insulin secretion mellitus autoreactive CTLs a Type II against antigens on response pancreatic β cells Multiple myelin basic protein Anti-MBP antibodies & Type IV response Myelin destruction → Know the mechanisms of sclerosis (main) autoreactive CTLs (main); can have abnormal nerve conduction action of fingolimod, 25 against MBP a Type II and neurologic deficits natalizumab, and response ocrelizumab (see slide 14) Summary: Systemic autoimmune diseases Disease Self-antigen Autoantibodies Immune Outcome of IR Immunotherapy response Systemic lupus dsDNA and Sm Anti-dsDNA and Type III response Skin rashes, arthritis, Know the mechanism of erythematosus antigen (a nuclear anti-Sm antibodies (primarily) glomerulonephritis, action of belimumab and protein) (main) hemolytic anemia, anifrolumab-fnia (see thrombocytopenia, slide 19) vascular disease Rheumatoid IgG, citrullinated Rheumatoid Type III responses Joint inflammation and Know the mechanisms arthritis peptides (CCP, factor, Anti-CCP, (primarily); can destruction; other of action of the MCV) anti-MCV have Type IV anomalies occur immunotherapies antibodies (main) responses discussed (slide 23) 26