Immunology for the Rheumatologist PDF

Immunology for the Rheumatologist Alan L. Epstein, MD Clinical Professor of Medicine Univ. of Penn. School of Medicine  Learning Objectives We spend much of our time as rheumatologists dealing with the immune system gone awry. We rarely study the normal function of the immune syst...

Immunology for the Rheumatologist Alan L. Epstein, MD Clinical Professor of Medicine Univ. of Penn. School of Medicine  Learning Objectives We spend much of our time as rheumatologists dealing with the immune system gone awry. We rarely study the normal function of the immune system. Why is it important to have an understanding of immunology? Abnormal immune responses are the cause of many of our inflammatory diseases with serious morbidity and mortality. Antibodies are in widespread use to treat immunologic diseases. Understanding immunology helps us to better understand the diseases that we treat and their current therapies. It also prepares us for advances in understanding the immune mechanisms of inflammatory and autoimmune diseases and therapeutic options for these diseases in the future. 1) Review the innate immune system 2) Discuss acute gout as an example of a disease driven by aberrant innate immune function 3) Review the adaptive immune system 4) Discuss the details of T-cell function 5) Discuss the immunopathogenesis of rheumatoid arthritis 6) Review the treatment of rheumatoid arthritis from an immunologic perspective  Disclosures Speakers’ Bureau: Abbvie, Amgen, BMS, Celgene, Crescendo, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, Quest, Sanofi- Regeneron Role of the immune system Defense against infection Surveillance against tumors Recognizes and reacts against foreign proteins and tissues How do perturbations in the normal immune system result in disease? How can we modulate the immune response to help our patients?  Components of the Immune System Physical Barriers-part of innate immune system – Skin – Epithelial membranes Innate Immune System – “Non-specific” response – Involves both immune & non-immune cells – Immediate response – Response = inflammation cytokines/chemokines & co-stimulatory molecules Adaptive Immune System – Specific recognition – Immune cells only (T-, B-cells) – Delayed response – Response = clonal expansion & effector cytokine secretion – Memory  Mechanisms of inflammation Compare and contrast gout and rheumatoid arthritis  Two arms of the immune system Innate (acute) Immunity: First response—12+ hours Gout is an example of this response Adaptive (acquired) immunity Takes time to develop RA is an example of this response  Cells of the Immune System (Leukocytes) Innate response Adaptive response Eosinophil Macrophage Dendritic cell (IL-5 (APC) (APC) producers) NK cell Tc lymphocyte Neutrophil (CD8+) (ADCC) (Phagocytosis, Degranulation) B lymphocyte Basophil Th lymphocyte (CD4+) Dendritic cell (Histamine (APC) Release) Adapted from Goldsby, Kindt, Osborne and Kuby, Immunology 5th Ed. 2003 p25  Two Arms of the Immune System: Innate and Adaptive Immunity Prevent infections Antibodies block infections and eliminate microbes Eliminate microbes T lymphocytes eradicate intracellular microbes Innate Immunity: General features Initial response to microbes Recognizes structures shared by classes of microbes Receptors encoded in germline, limited diversity Consists of epithelial barriers, phagocytes (neutrophils, monocytes and macrophages), NK cells, dendritic cells Complement system Cytokines + chemokines such as TNFα, IL-1, IL-6, IL-10, IFNγ All defenses without MEMORY  Danger Is All Around Us Physical Damage – Tissue injury – Cell death Chemical Insults – Environmental toxins – Self-inflicted toxins Infection – Bacteria – Viruses – Parasites – Fungi  Sensing Danger/Danger Signals a.k.a. “pathogen-associated molecular patterns” “danger-associated molecular patterns” Unique microbial structures – Bacterial cell wall components (LPS, PGN) – Microbial proteins (flagellin, zymosan, toxins) Nucleic acids – Double stranded RNA – CpG DNA – Viral and Microbial RNA Necrotic cell ATP Uric acid Hyaluronan fragments Cytochrome c Pattern Recognition Molecules (PRMs) Toll-like Receptors (TLRs) NOD-like Receptors (NLRs) inflammation RIG-I-like Receptors (RLRs) Pentraxins Complement cascade Collectins opsonization Ficollins C-type lectins phagocytosis Scavenger receptors  Recognition of pathogens by Toll-like receptors Bacteria Yeast Viruses Protozoa Host All Gram -ve Gram +-ve Mycobacteria Uropath All RSV All T. cruzi. bacteria LPS PGN lipoproteins CpG Flagellin Zymosan protein poly-C ssRNA GPI anchors Hsp60 lipoproteins GIPLs FN frags TLR-4/4 TLR-2/6 TLR-6/1 TLR-9/? TLR-5/? TLR11 TLR-2/? TLR-4/4 TLR-3/? TLR-7/8 TLR-2/? TLR-4/4 MyD88 NFĸB JNK p38 TLRs mediate innate immune response Found on macrophages, neutrophils, and dendritic cells Recognize distinct pathogen-associated molecular patterns conserved in microbes, eg, lipopolysacharides, lipoproteins,viral ds-RNA  TLR Signalling Kawai et al. Nature Immunology. 11(5) 373-384. 2010 Macrophage Function Macrophage Function COMPLEMENT-3 distinct ways to activate all lead to C3b Both Classical and Alternative Complement Pathways Coat Microbe With C3b Classical Complement Pathway is Triggered by Antibodies Binding to Foreign Cells Classical and Alternative Complement Pathways Cause Inflammation, Opsonization, and Cytolysis  The Membrane Attack Complex C5a C5 70-100 Å C9 C9 C9 C9 C9 C9 C9 C9C9 C9C9 C6 C5b C7 C8 Functions of NK Cells