Autoantibodies

Yehuda Shoenfeld, Pier Luigi Meroni, M. Eric Gershwin

• Publisher: Elsevier
• Year: 2013
• Edition: 3
• eBook ISBN:
  9780444593771
• Topic: Medicine
• Subtopic: Immunology

Autoimmune diseases are characterized by the occurrence of antibodies reacting with self-constituents of the body. The fully updated third edition of Autoantibodies is an in-depth review of the main autoantibodies identified up to now, with particular emphasis on those that display a diagnostic or prognostic clinical value. The new edition covers recent scientific advances, diagnostic techniques, and therapeutic technologies. Each chapter is focused on a single family of autoantibodies. This important reference contains historical notes, definitions, origins and sources of antigens recognized genetic associations, mediated pathogenic mechanisms, methods of detection, as well as clinical utility (disease prevalence and association, diagnostic value, sensitivity and specificity, prognostic value). This is an ideal reference for anyone involved in the field of autoimmune diseases. - Presents all known, important autoantibodies in a single source, focusing on the antibodies needed for autoimmune disorder diagnosis - Includes clinical applications for each autoantibody along with general information - Organized by disease and disorder type, by autoantibody family, and completely cross-referenced

Part 1

Introduction: Autoantibodies-Unique Characteristics

Outline

Chapter 2 What Is an Autoantibody?

Chapter 3 Natural Autoantibodies—Homeostasis, Autoimmunity, and Therapeutic Potential

Chapter 4 Molecular Mimicry

Chapter 5 Affinity and Avidity of Autoantibodies

Chapter 6 Pathogenic Mechanisms and Clinical Relevance of Autoantibodies

Chapter 7 Predictive Autoantibodies

Chapter 8 Antibodies Against Acute Phase Proteins

Chapter 9 Idiotypes and Anti-Idiotypes

Chapter 10 Introductory Remarks for the Diagnostic and Therapeutic Applications of Monoclonal Antibodies and Various Formats

Chapter 2

What Is an Autoantibody?

Ana Lleo^1,2, ¹Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano (MI), Italy, ²Department of Translational Medicine, Università degli Studi di Milano, Milan, Italy

Abstract

The critical function of the immune system is to discriminate self from nonself. Tolerance against self-antigens is a highly regulated process and, in order to maintain it, the immune system must be able to distinguish self-reactive lymphocytes as they develop. The presence of autoantibodies is the consequence of breakdown of tolerance and, although they are an important serologic feature of autoimmune diseases, their presence is not exclusive of these conditions. Antibodies against self-antigens are also found in cancer, during massive tissue damage and even in healthy subjects. Natural autoantibodies provide immediate protection against infection and also prevent inflammation by facilitating the clearance of oxidized lipids, oxidized proteins, and apoptotic cells; their role in development of autoimmunity is still unclear. Detection of serum autoantibodies in clinical practice has become more available to clinicians worldwide while providing a powerful diagnostic tool. The recognition that self-reactivity may not be synonymous of disease is an important concept and a challenge in the everyday life of the clinical immunologist.

Keywords

antigens; autoimmune disease; B cell; epitopes; immunoglobulins; tolerance

Introduction

A large number of serum antibodies directed against functional structures of the cell (nucleic acid, nuclear molecules, receptors, or other functional cell components) can be detected in human autoimmune diseases (AD); its presence plays a central role in the diagnosis and classification of this type of disorders. Moreover, several longitudinal cohort studies have shown that patients may carry autoantibodies many years before they manifest clinical symptoms and detecting these antibodies in serum has been shown to have strong predictive value. Despite the growing knowledge of immunology during the past decades, more than one challenge regarding autoantibodies remains open, such as determining the mechanism involved in the breakdown of tolerance as well as identifying the nature of the autoimmune damage mediated by many of them.

AD include more than 70 different disorders affecting approximately 5% of the population of the Western countries. They manifest a wide variability in terms of targeted tissues, age of onset, and response to immunosuppressive treatments. A shared feature of AD is the contribution of both humoral and cellular immune response to tissue injury; it is generally accepted that AD are the result of a complex interaction between genetic and environmental factors, most of which have not been identified [1–5].

Since the discovery of anti-deoxyribonucleic acid (DNA) antibodies in systemic lupus erythematosus (SLE) sera, over 50 years ago [6], specific autoantibodies have been widely studied and defined and a large number of autoepitopes have been mapped, often despite the incomplete understanding of their pathogenic role. Among the identified autoantigens, DNA molecules and the bound histones are among the most common nuclear autoantigens, being recognized by up to 65% of sera from patients with SLE, while antihistone antibodies directed against H2A and H2B more specifically characterize drug-induced lupus. Other autoantibodies are directed against nuclear proteins expressed or activated during specific phases of the cell cycle (i.e., anticentromere antibodies (ACA)). The nucleus presents other autoepitopes, such as groups of antigens called extractable nuclear antigens (ENA): anti-Scl70 antibodies directed against topoisomerase I, anti-Sm, small nuclear ribonucleic particles (snRNPs), SSB (or La) and SSA (or Ro) antibodies found in Sjögren syndrome, and Jo1.

Functional sites are also found in mitochondrial proteins, as well as membrane receptors and active molecules; that is, thyroid peroxidase (TPO) and thyrotropin receptor (TSHR) are recognized by autoantibodies in autoimmune thyroid disease and localized on the cell membrane. Furthermore, lupus anticoagulant, or antiphospholipid antibodies, is an example of extracellular protein interference resulting in a systemic clinical syndrome.

Although for a long time in the story of immunology, the presence of autoantibodies was considered synonymous to AD, we know now that is not always the case and that other clinical conditions (cancer, acute tissue damage) are associated with their presence. It is hence essential to know their role and the real meaning of their presence in each condition: is it a real breakdown of self-tolerance or just an epiphenomenon [7]?

Historical notes

The nucleus was the first intracellular structure to be identified by Franz Bauer in 1802 and in 1943, over a century later, serum reactivity against nuclear structures, that is, antinuclear antibodies (ANA), was observed in a positive LE cell test [8]. However, it was not until 1964 that the reality of autoimmunity as an important cause of human disease received public acknowledgment and consensus on during an International Conference on Autoimmunity, assembled by the New York Academy of Sciences.

During that 20-year window, some of the most important discoveries regarding autoantibodies were made [9]: the Coombs test was developed and applied in the 1940s; in 1940, E. Waaler, confirmed independently in 1948 by H. Rose, described for the first time the presence of a serum factor that agglutinated globulin-coated sheep erythrocytes. The serum agent, currently known as rheumatoid factor, was later ascertained to be an immunoglobulin (Ig)M autoantibody that reacted with the Fc fragment of the IgG molecule. In 1951, Harrington et al. transfused the serum of patients with idiopathic thrombocytopenic purpura into volunteers, himself included. This resulted in an immediate decrease in levels of circulating blood platelets, indicative of passive transfer of a serum agent, presumably an autoantibody, capable of reacting with platelets and causing their destruction. In addition, 1955 and 1956 were the years of autoimmune thyroiditis: antibodies to thyroglobulin and against the receptor on thyroid cells for natural thyroid-stimulating hormone were reported; it became the prototype for a novel group of autoantibodies that reacted with cell surface receptors with adverse functional effects. Moreover, the presence of autoantibodies in the serum of patients with primary biliary cirrhosis (PBC) was first suggested by Ian Mackay and colleagues in 1958 [10]. These authors found high titers of circulating complement-fixing autoantibodies directed against the liver, kidneys, and other human tissue antigens. In the following years, PBC sera were found to manifest a characteristic pattern when tested against animal tissues by indirect immunofluorescence (IIF) and the cytoplasmic target identified as the mitochondria.

Much has changed since 1964, when autoimmunity was officially accepted; basic immunological concepts (B lymphocytes, T-lymphocyte subsets, regulatory T cells, a major histocompatibility complex, antigen presentation, and cytokines) were unknown at the time; techniques and animal models that today we consider essential did not exist [11].

Tolerance and autoimmunity

The immune system has an extraordinary capacity for preventing self-antigens to stimulate an inflammatory reaction; the presence of autoantibodies is, therefore, the consequence of a breakdown or failure of B-cell tolerance toward the corresponding autoantigens.

B-cell development takes place in the bone marrow from hematopoietic stem cells; the first step of their maturation (central tolerance) involves the rearrangement of the Ig heavy chain. This phase, independent of antigens, requires a close interaction with the bone marrow stromal cells, which generates an in-frame sequence that leads to the generation of a cell surface protein: the pre-B-cell receptor (BCR). This complex regulates further development of the B cell and determines its reactivity. Indeed, BCR cross-linking by high-avidity self-antigens drives B cells to receptor editing, a process that, through the rearrangement of light-chain Ig genes, allows the substitution of self-reactive receptors with nonself-reactive receptors. Those B cells that still display autoreactive Igs after receptor editing will die by apoptosis, whereas B cells surviving the development in the central lymphoid organs immigrate to the periphery where they will complete their maturation to immunocompetent naive B cells [12,13].

The homing of lymphocytes in peripheral lymphoid tissue is controlled by chemokines but the mechanisms involved are still in part unknown. B cells constitutively express the chemokine receptor CXCR5 and are attracted to the follicles by the ligand of this receptor, CXCL13, also called B-lymphocyte chemokine (BLC), most likely secreted by the follicular dendritic cell. The production of CXCL13 drives the organization of B cells into discrete B cell areas around the follicular dendritic cells and contributes to the further recruitment of B cells from the circulation into the lymph node. In contrast, those B cells that fail to enter the lymphoid follicles will die within 3 days.

At this point a large amount of autoreactive lymphocytes have been purged from the population of new lymphocytes in the central organs; however, this selection regards only the antigens expressed in the central lymphoid organs and not all the potential self-antigens are accessible there. It is hence necessary that newly emigrated autoreactive B cells that encounter self-antigens in the periphery must be depleted (peripheral tolerance). Those B lymphocytes that encounter self-antigens for the first time in the periphery can follow three different pathways: deletion, anergy, or survival (or ignorance). Mature B cells that encounter strongly cross-reactive antigens in the periphery will undergo clonal depletion, whereas both mature and immature B cells will become anergized following the binding with soluble antigens. B-cell activating factor (BAFF) is a B-cell survival factor that inhibits B-cell apoptosis and favors B-cell proliferation and maturation, antibody production, and IgG class switching. Functional BAFF receptors on B cells appear at the transitional stage, thus affecting only the survival of mature B cells and making BAFF ineffective on the B-cell precursors that express CD20 and not BAFF receptors. The inhibition of BAFF has proven to be successful in large phase III clinical trials that led to the approval of an anti-BAFF monoclonal antibody (belimumab) for the treatment of SLE [14].

The failure of both central and peripheral tolerance maturation leads to an increased number of circulating self-reactive B cells, favoring the development of autoimmunity [15]. Nevertheless, unless a B cell engaged with a self-antigen interacts with a T-helper cell, it will be led to apoptosis, which demonstrates that autoreactive T-helper cells are deeply involved in the breakdown of B-cell self-tolerance leading to the production of autoantibodies [13,16]. Hence the potential for B-cell growth in response to self-antigen is limited by dependence on two cooperating cells, a B-cell and a T cell, both of which must bypass multiple checkpoint mechanisms [12]. However, in spite of a powerful regulation against autoantibody production, autoimmunity affects 5% of the population in Western countries. There are a small number ...

Table of contents

• Cover
• Front Matter
• Table of Contents
• Copyright
• Dedication
• Cover image credits
• Preface
• List of Contributors
• List of Illustrations
• List of Tables
• Chapter 1 : The Concept of Immunodiagnosis
• Chapter 2 : What Is an Autoantibody?
• Chapter 3 : Natural Autoantibodies—Homeostasis, Autoimmunity, and Therapeutic Potential
• Chapter 4 : Molecular Mimicry
• Chapter 5 : Affinity and Avidity of Autoantibodies
• Chapter 6 : Pathogenic Mechanisms and Clinical Relevance of Autoantibodies
• Chapter 7 : Predictive Autoantibodies
• Chapter 8 : Antibodies Against Acute Phase Proteins
• Chapter 9 : Idiotypes and Anti-Idiotypes
• Chapter 10 : Introductory Remarks for the Diagnostic and Therapeutic Applications of Monoclonal Antibodies and Various Formats
• Chapter 11 : Human Autoantibodies in Urticaria, Angioedema, and Other Atopic Diseases
• Chapter 12 : Antineutrophil Cytoplasmic Autoantibodies with Specificity for Myeloperoxidase
• Chapter 13 : Antineutrophil Cytoplasmic Antibodies with Specificity for Proteinase 3
• Chapter 14 : Neutrophil-Specific Antinuclear and Anticytoplasmic Autoantibodies in Chronic Inflammatory Diseases
• Chapter 15 : Antinuclear Antibodies: General Introduction
• Chapter 16 : Autoantibodies to Survival of Motor Neuron (SMN) Complex
• Chapter 17 : Antinucleolar Antibodies as Diagnostic Markers in Systemic Autoimmune Diseases
• Chapter 18 : Anti-U1RNP and -Sm Antibodies
• Chapter 19 : Antibodies to Rods and Rings
• Chapter 20 : Antinucleosome Autoantibodies
• Chapter 21 : Centromere Autoantibodies
• Chapter 22 : dsDNA Autoantibodies
• Chapter 23 : Histone Autoantibodies
• Chapter 24 : Ku and Ki Autoantibodies
• Chapter 25 : Neuronal Nuclear Autoantibodies, Type 1 (Hu)
• Chapter 26 : Nuclear Envelope Protein Autoantibodies/Antilamin Autoantibodies
• Chapter 27 : Antiribosomal P Antibodies
• Chapter 28 : Ro/SSA Autoantibodies
• Chapter 29 : Topoisomerase I (SCL 70) Autoantibodies
• Chapter 30 : SS-B (La) Autoantibodies
• Chapter 31 : Autoantibodies to GW/P Bodies and Components of the MicroRNA Pathway
• Chapter 32 : Golgi Complex and Endosome Antibodies
• Chapter 33 : Tumor-Associated Autoantibodies
• Chapter 34 : p53 Autoantibodies
• Chapter 35 : Naturally Occurring Anti-HLA-E Autoantibodies: Evidences of HLA-Ia Reactivity of Anti-HLA-E Antibodies
• Chapter 36 : Autoantibodies in Therapeutic Preparations of Human Intravenous Immunoglobulin (IVIg)
• Chapter 37 : Cytoskeletal Autoantibodies/Antiactin Antibodies
• Chapter 38 : Fibrillarin Autoantibodies
• Chapter 39 : Fibronectin Autoantibodies
• Chapter 40 : IFI16 Autoantibodies
• Chapter 41 : Heat Shock Protein Autoantibodies
• Chapter 42 : Antimyocardial Autoantibodies (AMCA)
• Chapter 43 : Gastric Autoantibodies
• Chapter 44 : Thyroid Autoantibodies: Thyroid Peroxidase and Thyroglobulin Antibodies
• Chapter 45 : Thyrotropin Receptor Antibodies
• Chapter 46 : Glutamic Acid Decarboxylase Antibody
• Chapter 47 : Antibodies to Gonadal and Adrenal Tissue
• Chapter 48 : Humoral Immunity in Type 1 Diabetes Mellitus
• Chapter 49 : Autoantibody Profile in Inflammatory Bowel Disease
• Chapter 50 : Anti-Intestinal Goblet Cell Antibodies
• Chapter 51 : Antipancreatic Autoantibodies
• Chapter 52 : Cryoglobulins and Cryoglobulins Secondary to Hepatitis C Virus Infection
• Chapter 53 : Autoantibodies in Autoimmune Hepatitis
• Chapter 54 : Antitissue Transglutaminase and Antiendomysial Antibodies
• Chapter 55 : Antigliadin and Antideamidated Gliadin Peptide Antibodies
• Chapter 56 : Liver Cytosol Antigen Type 1 Autoantibodies (LC-1), Liver Kidney Microsomal Autoantibodies (LKM), and Liver Microsomal Autoantibodies (LM)
• Chapter 57 : Antimitochondrial Antibodies
• Chapter 58 : Smooth Muscle Autoantibodies
• Chapter 59 : Coagulation Factor Autoantibodies
• Chapter 60 : Autoantibodies in Heparin-Induced Thrombocytopenia
• Chapter 61 : Platelet Autoantibodies
• Chapter 62 : Red Cell Autoantibodies
• Chapter 63 : Lymphocytotoxic Autoantibodies
• Chapter 64 : Anti-Phospholipase A2 Receptor Autoantibodies
• Chapter 65 : Glomerular Basement Membrane Autoantibodies
• Chapter 66 : Nephritic Factor Autoantibodies
• Chapter 67 : IgA Nephropathies
• Chapter 68 : Acetylcholine Receptor and Muscle-Specific Kinase Autoantibodies
• Chapter 69 : Human Anti-Glycosphingolipids Antibodies in Guillain-Barré Syndrome
• Chapter 70 : Central Nervous System Neuronal Surface Antibodies
• Chapter 71 : Antibodies to AQP4
• Chapter 72 : Myositis Autoantibodies
• Chapter 73 : Myelin Oligodendrocyte Glycoprotein (MOG): An Archetypal Target for Demyelinating Autoantibodies in the Central Nervous System
• Chapter 74 : Autoantibodies in the Lambert-Eaton Myasthenic Syndrome (LEMS) and Amyotrophic Lateral Sclerosis (ALS)
• Chapter 75 : Antimyelin-Associated Glycoprotein, Antimyelin Basic Protein, and Antiproteolipid Autoantibodies in Neurologic Diseases
• Chapter 76 : Paraneoplastic Neurologic Antibodies
• Chapter 77 : Retinal Autoantibodies
• Chapter 78 : Antifodrin Antibodies
• Chapter 79 : Antibodies to Laminin
• Chapter 80 : Autoantibodies Against Muscarinic Acetylcholine Receptor in Patients with Sjögren Syndrome
• Chapter 81 : β2-Glycoprotein I Autoantibodies
• Chapter 82 : C1 Inhibitor Autoantibodies
• Chapter 83 : Autoantibodies to C1q
• Chapter 84 : Anticollagen Antibodies
• Chapter 85 : Antiendothelial Cell Antibodies
• Chapter 86 : Lupus Anticoagulant Testing
• Chapter 87 : Anticardiolipin Antibodies
• Chapter 88 : Phospholipid Autoantibodies (Nonanticardiolipin)-Antiprothrombin Antibodies
• Chapter 89 : Rheumatoid Factors
• Chapter 90 : Antibodies to Specific Citrullinated Proteins in Rheumatoid Arthritis
• Chapter 91 : Autoantibodies to Mucocutaneous Antigens
• Chapter 92 : Autoimmunity and the Newer Biopharmaceuticals
• Chapter 93 : Antibodies Against “Human” Biopharmaceuticals: Individualized Therapy with TNF-alpha Inhibitors Guided by Immunopharmacologic Assessments
• Chapter 94 : Autoantibodies and Pregnancy Loss
• Chapter 95 : Autoantibodies – Future Trends
• Index
• A