Autoimmune Diseases Betsy Kirchner CNP The Cleveland Clinic
Disclosures (financial) No relevant disclosures
Learning Objectives Explain the pathophysiology of autoimmune disease Discuss safe administration of biotherapies used to treat autoimmune disease
Outline Basics of Immunology Physical/innate/adaptive Immunopathology Autoimmune disease RA model Infusion Issues
Basics of Immunology
Basics of Immunology Physical Barriers Innate Macrophages Complement proteins Natural Killer Cells Adaptive Humoral (B Cells and Antibodies) Cell-mediated (T Cells and Cytokines)
Basics of Immunology Human blood 55% plasma - the fluid part of the blood with ions, proteins and other substances dissolved in it. 45% cellular elements ~95% red blood cells (erythrocytes) ~5% platelets <1% white blood cells (leukocytes)
Basics of Immunology 5 major types of leukocytes Neutrophils leave the blood to go to tissues where infection or inflammation is developing. Eosinophils attack organisms that are too big to be eaten by a single phagocyte. Basophils do not attack and swallow invading cells; they release chemicals that help the body s allergic response to a pathogen. Monocytes are cells released into the blood from the bone marrow. When they get to a particular site in an organism they may change into macrophages that engulf and destroy invading pathogens. Lymphocytes are the fifth group of white blood cells; they are divided into three categories: NK cells, B cells, T cells
Basics of Immunology Normal Immune System 3 branches (ignore 2) Everywhere (ignore everywhere but blood) 5 types of WBC (ignore 4) 3 types of lymphocytes (ignore 1) Why??? Autoimmune disease: 2 key components B-cells T-Cells
Basics of Immunology: The Adaptive Immune System Antibodies and B Cells Antibodies are proteins 5 kinds: IgG (75%) IgA IgD IgE IgM All antibodies are made by B cells Antibodies prevent infections from getting into cells; they cannot enter a cell to neutralize a threat
Basics of Immunology: The Adaptive Immune System 3 types of T Cells Cytotoxic lymphocytes (CTLs, killer ) Makes contact with target and triggers it to commit suicide Virus-infected cells Helper T cells Secrete cytokines (eg IL-6, IFN-g) Regulatory T cells???
Immunopathology
Immunopathology Basics Rheumatoid Arthritis
Autoimmune Diseases > 150 Rheumatology Dermatology Gastroenterology Neurology Endocrinology Hepatology Ophthalmology Others
Autoimmune Disease Immunopathology Failure of autoantibodies and T cells to recognize own cells Autoantibodies and T cells launch attack against own cells
Immunopathology: Pathogenesis of RA Systemic inflammation and tissue specific destruction Genetically susceptible host Antigenically triggered? T cells/macrophages/fibroblastic cells Cytokine driven
Immunopathology: Etiopathogenesis of Rheumatoid Arthritis Autoreactivity Genetics Environment Plasma cells Rheumatoid factor Autoantibodies Innate Immunity Adaptive Immunity Dendritic cells T Self-antigens FLS = fibroblast-like synoviocyte;; MMP = matrix metalloproteinase;; Mφ = macrophage. Activates T cells Activates (MS, autoimmune hepatitis Hashimoto s CD4 & CD8) Adapted from Choy EHS, Panayi GS, N Engl J Med. 2001;;344:907-916;; Smolen JS, Steiner G. Nat Rev Drug Discov. 2003;;2;;473-488. T Macrophages (Crohn s) B T PC T MΦ Activates B B cells (autoimmune hepatitis Grave s disease)) T MΦ FLS Inflammation Joint damage Cytokines MMPs PC FLS
Immunopathology: Mechanisms of Joint Damage in RA Multiple factors contribute to the joint damage associated with RA, including 1 Activated T cells and macrophages 2,3 B cells, autoantibodies and immune complexes 4 Circulating cytokines (TNF-α, IL-1, IL-6, IL- 17) 5-7 Others 1 Andersson AK, et al. Arthritis Res Ther. 2008;;10:204;; 2 Brennan EM, et al. Arthritis Rheum. 2002;;46:31-41;; 3 Beech JT, et al. Arthritis Res Ther. 2006;;8:R168;; 4 Petkova SB, et al. J Exp Med. 2006;;203:275-280;; 5 Zwerina J, et al. Proc Natl Acad Sci, USA. 2007;;104:11742-11747;; 6 Yoshitake F, et al. J Biol Chem. 2008;;283:11535-11540;; 7 Joosten LAB, et al. Arthritis Rheum. 2008;;58:98-108.
Immunopathology: T Cells & B Cells in RA
Immunopathology: T Cell Types in RA Naïve CD4+ T cell TH1 Cell-mediated Immunity Thy CD4+ IL-12 IL-6, IL-23 TH17 Autoimmunity Thymocyte IL-4 TGF-β Treg Suppression TH, T helper cells Treg, regulatory T cells TH2 Humoral Immunity Adapted from Iwakura, et al. J Clin Invest. 2006;;116:1218-1222.
Immunopathology: B Cells in RA Production of autoantibodies 1 Release of cytokines and chemokines, including IL- 6, IL-10, and others Antigen presentation to T cells 1 Deposition of immune-complexes in the rheumatoid synovium 1 Induction of tissue damage by anti-cyclic citrullinated peptide (CCP) autoantibodies 2 1 McInnes IB, et al. Nature Rev Immunol. 2007;;7:429-442;; 2 Kuhn KA,et al. J Clin Invest. 2006;;116:961-973
Cytokines in RA APC B cells Dendritic cells Macrophages IL- 4 IL- 6 IL- 10 T- Cell Pannus IL- 6, TNFα, IFNγ, IL- 10 IL- 2 IL- 23 IFNγ MΦ TNFα IL- 17 TNFα, IL- 1, IL- 6, RANKL metalloproteinases OC Articular cartilage RF, anti- CCP B T APC B Cells FLS Erosions of bone and cartilage PC Immune complexes Complement fixation C Adapted from S molen and Steiner. Nature Rev Drug Discovery. 2003; 2; 473-488; Choy a nd P anayi. N E ngl J Med. 2001; 344:907.
Safe Administration of IV Treatments for Autoimmune Disease
What Is Being Infused? What is a biologic? A medical product developed using proteins from living cells Many steps: Identify/Isolate human DNA sequence Select a vector/insert gene into the host genome Modification of cells à recombinant technology EXACT DNA SEQUENCE & TYPE OF HOST CELL USED WILL SIGNIFICANTLY INFLUENCE THE CHARACTERISTICS OF THE PRODUCT
What Is Being Infused? Chinna, M Overview of Biological Products FDA Webinar 6/17/13
What Is Being Infused? Small changes in production Significant changes in behavior of cells & changes in the protein Alterations in the three-dimensional structure of the protein Quantity of acid-base variants & glycosylation Impact safety & effectiveness of biologic
What Is Being Infused? What is a biologic? Major targets are cytokines, B cells, and costimulation molecules
Who is Being Infused? Adults Children Screened for latent infections No acute infections Comorbidities controlled to an acceptable degree Vaccines up to date
Why Are We Infusing? To slow down or block specific components of the immune system To halt the progression of damage Antigen Presenting Cell T-cell Macrophage B-Cell Synovium
When Are We Infusing? Varies Daily Weekly Monthly Twice yearly
How Are We Infusing? Very carefully According to protocols Infusion Reactions Premedication Flushing, headache, nausea, rash/hives, elevated temperature, hypotension, hypertension, swelling, shortness of breath, wheezing Education of patients
Example reaction algorithm
Learning Objectives Explain the pathophysiology of autoimmune disease Discuss safe administration of biotherapies used to treat autoimmune disease
Autoimmune Diseases