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Overview of the Immune System and Memory B-Cell Activity in RA 2017

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Overview of the Immune System and Memory B-Cell Activity in RA 2017 2017 Arizona United Rheumatology Alliance Annual Meeting Overview of the Immune System and Memory B-cell Activity in RA Gregg J. Silverman, MD Professor of Medicine and Pathology Director, Laboratory of B-cell Immunobiology NYU School of Medicine New York, NY Learning Objectives • Discuss how the layers of the immune system are assembled and interconnected. • Briefly review the ancient innate system, components and properties. • Discuss the special abilities of the adaptive immune system. • Review B lymphogenesis. • Discuss how antigenic selection molds the B cell repertoire. • Brief overview of the immunology of Rheumatoid Arthritis and associated ectopic lymphoid tissue and GCs. • Discuss the effect of therapy on disease-associated B cell memory and circulating ACPA. Organization of the Immune System Anatomical and Bad outer world Low Physiological Barriers stomach pH Lysozyome in tears and saliva Ciliary Innate Immunity clearance Host defense peptides NLR’s TLR’s Dendritic cells Complement Adaptive Immunity T cells Intact skin Neutrophils B cells 0-4 hours 4-96 hours Late > 96 hours Synchronous Functioning: Features of the Innate and Adaptive Immune Systems1,2 INNATE ADAPTIVE . Rapid . Delayed . Antigen-nonspecific . Antigen-specific pathogen recognition pathogen recognition . Activates the adaptive . Confers long-lasting immune system immunity Macrophage T cell Dendritic cell IL-1β B cell TNF-α IL-6 Neutrophil Complement Plasma cell Antibodies Abbreviations: IL, interleukin; TNF, tumor necrosis factor. References: 1. Murphy K, ed. Janeway’s Immunobiology. 2012. 2. Chaplin DD. J Allergy Clin Immunol. 2010;125(2 suppl 2):S3-S23. What is the Function of Innate Immunity? 1. Limit the extent of the initial microbial infection a) Phagocytosis, macrophage activation b) Neutrophil activation, degranulation c) Release of antimicrobial peptides d) Cytokine, chemokine production 2. Prime the adaptive immune system a) Antigen presentation b) Expression of costimulatory molecules c) Cytokine, chemokine production 3. Wound repair and tissue remodeling a) DAMPs = Danger-associated Molecular Patterns Immune Response - Innate • All of these defenses are without MEMORY • Early response ( minutes to 3-5 days) consisting of CELLULAR and SOLUBLE elements • Expressed by GERMLINE encoded receptors • Does not recognize every antigen but rather highly conserved structures DAMP The Roles of Innate Cell Types: Neutrophils, Monocytes, Macrophages, and Dendritic Cells1,2 INNATE Dendritic cell Inflammatory Antimicrobial functions: . stimulus Neutrophils - Phagocytose and kill extracellular pathogens IL-15 - Release proinflammatory IL-12 factors and antibacterial proteins NET generation . Neutrophil Macrophages - Secrete proinflammatory cytokines, antimicrobial TNF-α peptides, and degradative enzymes IL-6 IL-1β Granule - Phagocytose pathogens release - Present antigen Macrophage . Dendritic cells Complement - Phagocytose pathogens - Present antigen - Secrete cytokines such as IL- Phagocytosis 12, IL-15, IL-23 Abbreviation: NET, neutrophil extracellular trap. References: 1. Murphy K, ed. Janeway’s Immunobiology. 2012. 2. Kolaczkoska E, Kubes P. Nat Rev Immunol. 2013:13(3):159-175. Pattern Recognition Molecule (PRMs) • Toll-like Receptors (TLRs) TOLL 1996 • NOD-like Receptors (NLRs) inflammation, apoptosis • RIG-I-like Receptors (RLRs) • Pentraxins opsonization, complement cascade • Collectins • Ficollins • C-type lectins phagocytosis • Scavenger receptors History of TLRs • Christiane Nusslein-Vollhard 1985/1995* • Janeway linked TLR to NFkB 1997 • Jules Hoffman immune defense connection 95/2011 • Bruce Beutler Role of the LPS receptor 2011 Capsule Cytoplasm Cell Wall Ribosomes Few species have an DNA Mesosome adaptiive immune system (nucleoid) Plasma Membrane Adaptive Immunity innate immunity Key properties of the adaptive immune Diverse repertoire of clonally distributed antigen receptors Assembled by combinatorial assembly from an immense number of germline genes Antigens can induce clonal selection to address a specific threat Memory of a past exposure is banked away for more rapid responses Memory at a cellular level is not passed to the next generation Bad self-reactive memory can drive an autoimmune disease Basic B cell biology Somatic recombination generates functional Ig heavy and light chain genes Antigen receptor genes move during B- and T-cell differentiation Acquired tolerance necessitates alternative fates driven by the same antigen receptor Two signal hypothesis (Bretscher and Cohn) Science 1970 169(3950):1042-9. 1 Signal 1 only = death/inactivation 1 Signal 1+ Signal 2 = activation 2 Courtesy of M. Cancro, U Penn Acquired tolerance necessitates alternative fates driven by the same antigen receptor Two signal hypothesis (Bretscher and Cohn) Science 1970 169(3950):1042-9. 1 Signal 1 only = death/inactivation 1 Signal 1+ Signal 2 = activation 2 Signal 3 – molds the immune bias of the lymphocyte Courtesy of M. Cancro, U Penn B-cell development: Three types of Mature B cells B1 lineage Central and Natural antibodies peripheral (defense from infection, tolerance Inflammation and autoimmunity) Short-lived HSC plasma cell Self Short-lived Bone marrow renewal or foetal liver Mature plasma cell B1 cell Extrafollicular Antigen response Peripheral Central tolerance GC reaction GC tolerance (after T-cell reaction) B cell Mature T cell Activated B cell HSC B2 cell Bone Immature T1 T2 Memory marrow B cell B cell B cell B cell Short-lived MZ B cell plasma cell Plasma Long-lived cell plasma cell HSC = haemopoietic stem cell; GC = germinal centre MZ = marginal zone Adapted from Dörner T, et al. Nature Rev Rheumatol 2009;5:433–41 Antigen-specific clonal selection Humans have ~ 1011 B cells and 1011 T cells distributed into ~ 106 B-cell and T-cell clones Optimal T-dependent responses require coordination (physical interactions) of complementary B and T cell clones For optimal kinetics of responses, this cannot come from random encounters Spatiotemporal organization of B-T cell interactions Frequencies of antigen-specific B cells and complementary and antigen-specific T cells are generally low How do the B and T cells find each other in the body? Each should provide what the other needs. INNATE Germinal centers: Arenas for -cell clonal selection Properties of T Follicular Helper (TFH) cells IL-21- pleotropic cytokine activates most lymphocytes induces proliferation of CD40L activated B cells induces Activation Induced Deaminase (AID) for somatic hypermutation With downregulation of T cell zone homing CC receptor 7 (CCR7) and IL-7 receptor-a (IL-7Ra) TFH differentiation also affected by CD40L, CD26, STAT3, SLAM associated protein that all induce Bcl6. Induce B cell differentiation at B-T border into extrafollicular plasmablasts From Tangye et al. Nat Rev Immunol 2013 Germinal center reactions provide benefits for the mammalian adaptive immune system • 1. Specialized anatomic site for coordinated spatiotemporal interactions of antigen-specific B cells and T cells. • 2. Antigen-specific T cells (TFH) are required for second signals (soluble and membrane) inducing: - hypermutation machinery (e.g., AID) - survival (e.g., BAFF/BLyS) - differentiation (to plasma cell) - class-switch recombination (CSR). • 3. Follicular dendritic cells help to provide a well furnished arena for competition between clonal daughters based on stregth of BDR signal and availability of second signals Ag specific B cells and cognate peptide-antigen specific T cells: The perfect couple! As each may represent < 1:10,0000 Lymphocyte clones, How do they find each other? Don’t forget ICOS/ICOS-L and modulating inhibitory paired R-L systems BLyS/BAFF play fundamental roles in ensuring the survival of B cells • Potentially expressed by multiple immune cells1,2 –Neutrophils –Monocytes –Dendritic Cells –activated T cells –Plasma cells –B cells • BLyS (TNFSF13B) exists membrane-bound and soluble forms1 • Related to A Proiferation Inducing Ligand (APRIL,TNFSF13) • Three molecules bind together to form the trimeric soluble protein1,3 • BLyS is important in ensuring that new B cells mature, survive and differentiate1,3 1. Cancro MP, et al. J Clin Invest 2009;119:1066–73 2. Chu T, et al. Arthritis Rheum 2009;60:2083–93 3. Miller JP, et al. J Immunol 2006;176:6405–10 Mechanisms of B-cell tolerance for self-antigens in health – many steps that can be dysregulated causing autoimmune responses Peripheral lymphoid organs GC Short-lived T Extrafollicular Fas-mediated response T PC T B lymphoblast apoptosis T B T Absence of T Memory T T T-cell help Follicular T naïve Autoantigen-mediated T T apoptosis Anergy Somatic Absence of hypermutation Long-lived PC T-cell help • Increase avidity for foreign antigen • Eliminate autoreactivity Competitive disadvantage • Create autoreactivity de novo for survival factors (BAFF) Courtesy of Jen Anolik U of Rochester Human Autoimmune Diseases associated with aberrant TFH cells From Tangye et al. Nat Rev Immunol 2013 Ectopic Lymphoid Structures: Powerhouse of Autoimmunity Corsiero Pitzalis 2016 Front Immunol. 2016 7:430. Long lived plasma cells provide persistent high level Ab defenses Current Opin Immunol 20(2) 2008, Pages 162–169 Plasma cells are antibody producing factories Lots of endoplasmic reticulum (ER) ! Autoimmune Disease: Seropositive Rheumatoid Arthritis is an archetype Autoimmunity and Pathogenetic B-cell mechanisms Mature Bone Marrow Activation Blast Immature T1 T2 Plasma cell Pro B Pre B Spleen FO MZ Plasmablast Memory GC B B T DC B IL- TNF-α LT FDC 6 DC
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