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Introduction to the Immune System

Chapter 360 | Harrison's 22e

KEY CLINICAL POINTS

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[PAGE 2755] Immune-Mediated, Inflammatory, and Rheumatologic Disorders PART 11 regions, and signal the B cell to terminally differentiate to make Section 1 The Immune System in Health antigen-specific antibody. and Disease - B lymphocytes—bone marrow–derived lymphocytes that express surface immunoglobulin (the BCR for antigen) and secrete specific antibody after interaction with antigen. - B regulatory cells—a population of suppressive B cells that aid in the 360 Introduction to the inhibition of inflammation through the release of cytokines such as Immune System interleukin-(IL) 10. - CD classification of human lymphocyte differentiation antigens—the development of monoclonal antibody technology led to the discov- Barton F. Haynes, Kelly A. Cuttle, ery of a large number of new leukocyte surface molecules. From Anthony S. Fauci a series of International Workshop on Leukocyte Differentiation Antigens has come the cluster of differentiation (CD) classification of leukocyte antigens. DEFINITIONS - CD4 T cell—T lymphocyte subset that participates in adaptive immunity and helps B cells make antibody. - Adaptive immune system—recently evolved system of immune - CD8 T cell—cytotoxic T lymphocyte subset that kills tumor cells and responses mediated by T and B lymphocytes. Immune responses by cells infected with pathogens. these cells are based on specific antigen recognition by clonotypic - Chemokines—soluble molecules that direct and determine immune receptors that are products of genes that rearrange during devel- cell movement and circulation pathways. opment and throughout the life of the organism. Additional cells - Complement—cascading series of plasma enzymes and effector of the adaptive immune system include various types of antigen- proteins that function to lyse pathogens and/or target them to be presenting cells (APCs). phagocytized by neutrophils and monocyte/macrophage lineage - Antibody—B cell–produced molecules encoded by genes that rear- cells of the reticuloendothelial system. range during B-cell development consisting of immunoglobulin - Co-stimulatory molecules—molecules of APCs (such as B7-1, B7-2, heavy and light chains that together form the central component or CD40) that lead to T-cell activation when bound by ligands on of the B-cell receptor (BCR) for antigen. Antibody can exist as B cell– activated T cells (such as CD28 or CD40 ligand). surface antigen-recognition molecules or as secreted molecules in - Crystallopathies—nanoparticle- or microparticle-sized deposits of plasma and other body fluids. crystals, misfolded proteins, or airborne particulate matter that can - Antigens—foreign or self-molecules that are recognized by the adap- stimulate the inflammasome and initiate inflammation and tissue tive and innate immune systems resulting in immune cell triggering, damage. T-cell activation, and/or B-cell antibody production. - Cytokines—soluble proteins that interact with specific cellular recep- - Antigen-presenting cells (APCs)—a group of immune cells that tors that are involved in the regulation of the growth and activation process antigens to mediate both adaptive immune responses and of immune cells and mediate normal or pathologic inflammatory the maintenance of peripheral tolerance. Classical APCs include and immune responses. dendritic cells, macrophages, and B cells. - Dendritic cells—myeloid and/or lymphoid lineage APCs of the - Apoptosis—the process of programmed cell death whereby signal- adaptive immune system. Immature dendritic cells (DCs), or DC ing through “death receptors” on the surface of cells (e.g., tumor precursors, are key components of the innate immune system by necrosis factor [TNF] receptors, CD95) leads to signaling cascades responding to infections with production of high levels of cytokines. that involve activation of the caspase family of molecules and leads DCs are key initiators of innate immune responses via cytokine pro- to DNA cleavage and cell death. Apoptosis, which does not lead to duction and mediators of adaptive immune responses via presenta- induction of inordinate inflammation, is to be contrasted with cell tion of antigen to T lymphocytes. necrosis, which does lead to induction of inflammatory responses. - Ig fragment crystallizable (Fc) receptors (Rs)—receptors found on - Autoimmune diseases—diseases such as systemic lupus erythemato- the surface of certain cells including B cells, natural killer (NK) sus and rheumatoid arthritis in which cells of the adaptive immune cells, macrophages, neutrophils, and mast cells. Fc receptors bind system such as autoreactive T and B cells become overreactive and to the Fc domains of antibodies that have attached to invading produce pathogenic T-cell and antibody responses. pathogen-infected cells. FcRs stimulate cytotoxic cells to destroy - Autoinflammatory diseases—hereditary disorders such as heredi- microbe-infected cells through antibody-dependent cell-mediated tary periodic fevers (HPFs) characterized by recurrent episodes of cytotoxicity (ADCC). Examples of important FcRs include CD16 severe inflammation and fever due to mutations in controls of the (Fc γ RIIIa), CD23 (Fc ε R), CD32 (Fc γ RII), CD64 (Fc γ RI), and CD89 innate inflammatory response, i.e., the inflammasome (see below (Fc α R). and Table 360-5). Patients with HPFs also have rashes and serosal - Inflammasome—large cytoplasmic complexes of intracellular pro- and joint inflammation, and some can have neurologic symptoms. teins that link the sensing of microbial products and cellular stress Autoinflammatory diseases are different from autoimmune diseases to the proteolytic activation of IL-1 β and IL-18 inflammatory in that evidence for activation of adaptive immune cells such as cytokines. Activation of molecules in the inflammasome is a key autoreactive B cells is not present. step in the response of the innate immune system for intracellular - Autophagy—lysosomal degradation pathway mechanism of cells to recognition of microbial and other danger signals in both health and dispose of intracellular debris and damaged organelles. Autophagy pathologic states. by cells of the innate immune system is used to control intracel- - Innate immune system—ancient immune recognition system of lular infectious agents such as mycobacteria, in part by initiation host cells bearing germline-encoded pattern recognition receptors of phagosome maturation and enhancing major histocompatibility (PRRs) that recognize pathogens and trigger a variety of mecha- complex (MHC) class II antigen presentation to CD4 T cells. nisms of pathogen elimination. Cells of the innate immune system - B-cell receptor (BCR) for antigen—complex of surface molecules that include NK cell lymphocytes, monocytes/macrophages, DCs, neu- rearrange during postnatal B-cell development, made up of surface trophils, basophils, eosinophils, tissue mast cells, and epithelial cells. immunoglobulin (Ig) and associated Ig αβ chain molecules that - Innate lymphoid cells (ILCs)—lymphocytes that do not express the recognize nominal antigen via Ig heavy- and light-chain variable type of diversified antigen receptors on T cell and B cells. ILC1s, [PAGE 2756] 2756 PART Immune-Mediated, Inflammatory, and Rheumatologic Disorders ILC2s, and ILC3s are tissue resident cells and functionally may be - Trained immunity—the epigenetic, transcriptional, and functional analogous to CD4 T 1, T 2, and T 17 cells, respectively. reprogramming of innate immune cells to adapt to previous encoun- H H H - Natural killer (NK) cells—a type of ILC that kills target cells express- ters with pathogens and respond to a second challenge in an altered ing few or no human leukocyte antigen (HLA) class I molecules, manner. such as malignantly transformed cells and virally infected cells. NK cells express receptors that inhibit killer cell function when I INTRODUCTION self-MHC class I is present. Innate NK cells mirror the cytolytic The human immune system has evolved over millio