Clinical Immunodiagnostics

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC ImmunodiagnosticsNOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Laboratory Principles and Practices © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

Ian C. Clift, PhD MLS(ASCP)CM © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION IndianaNOT University FOR SALE OR DISTRIBUTION Program Director, Clinical Laboratory Science Indiana University South Bend South Bend, Indiana © Jones & BartlettScientific Learning, Consultant, BiomedicalLLC Associates © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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© Jones & BartlettCopyright Learning, © 2021 by Jones &LLC Bartlett Learning, LLC, an Ascend Learning© Jones Company & Bartlett Learning, LLC NOT FOR SALEAll ORrights reserved.DISTRIBUTION No part of the material protected by this copyrightNOT may be reproducedFOR SALE or utilized OR in any DISTRIBUTION form, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without written permission from the copyright owner. The content, statements, views, and opinions herein are the sole expression of the respective authors and not that of Jones & Bartlett Learning, LLC. Reference herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not constitute or imply its endorsement or recommendation by Jones & Bartlett Learning, LLC and such reference shall not be used for advertising or product endorsement purposes. All trademarks displayed are the trademarks of the parties noted herein. Clinical Immunodiagnostics: Laboratory© Jones Principles & Bartlettand Practices is Learning, an independent publication LLC and has not been authorized, sponsored,© Jones or otherwise & Bartlett Learning, LLC approved by the ownersNOT of the FORtrademarks SALE or service OR marks DISTRIBUTION referenced in this product. NOT FOR SALE OR DISTRIBUTION There may be images in this book that feature models; these models do not necessarily endorse, represent, or participate in the activities represented in the images. Any screenshots in this product are for educational and instructive purposes only. Any individuals and scenarios featured in the case studies throughout this product may be real or fictitious, but are used for instructional purposes only. Production Credits © VP,Jones Product Management:& Bartlett Amanda Learning, Martin LLC Cover Design: Theresa© JonesManley & Bartlett Learning, LLC Director of Product Management: Cathy L. Esperti Text Design: Kristin E. Parker NOTProduct FOR Assistant: SALE Melina LeonOR DISTRIBUTION Senior Media DevelopmentNOT Editor:FOR Troy SALE Liston OR DISTRIBUTION Product Specialist: Andrew LaBelle Rights Specialist: Rebecca Damon Project Specialist: Nora Menzi Rights Specialist: Liz Kincaid Digital Products Manager: Jessica deMartin Cover Image (Title Page, Part Opener, Chapter Opener): Marketing Manager: Suzy Balk © Science photo/Shutterstock VP, Manufacturing and Inventory Control: Therese Connell Printing and Binding: LSC Communications © Jones & BartlettComposition Learning, and Project Management: LLC Exela Technologies © Jones & Bartlett Learning, LLC NOT FOR SALELibrary OR of DISTRIBUTIONCongress Cataloging-in-Publication Data NOT FOR SALE OR DISTRIBUTION Names: Clift, Ian C., author. Title: Clinical immunodiagnostics : laboratory principles and practices / Ian C. Clift. Description: First edition. | Burlington, MA : Jones & Bartlett Learning, [2021] | Includes bibliographical references and index. | Summary: “The purpose of this project is to provide a contemporary guide to the diagnostic principles and practices of immunology and serology in the clinical laboratory. This book will focus on an entry level understanding of clinical immunology, serology, and immunodiagnostics for use in the diagnostic© Jones clinical lab, & itBartlett will also touch Learning, on conceptual overlaps LLC with blood banking (immunohematology),© Jones transfusion & Bartlett Learning, LLC medicine, infectiousNOT disease, FOR cellular SALEphenotyping, OR and DISTRIBUTIONoncology as they pertain to immunology-based clinical diagnostics.NOT FOR The book SALE OR DISTRIBUTION will be selective in its coverage; emphasizing entry-level knowledge and contemporary practical approaches. Content will also cover important historical and emerging concepts in the field”— Provided by publisher. Identifiers: LCCN 2019033935 | ISBN 9781284173017 (paperback) Subjects: MESH: Immunologic Tests Classification: LCC RB46.5 | NLM QY 250 | DDC 616.07/56—dc23 © JonesLC record &available Bartlett at https://lccn.loc.gov/2019033935 Learning, LLC © Jones & Bartlett Learning, LLC NOT6048 FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Printed in the United States of America 24 23 22 21 20 10 9 8 7 6 5 4 3 2 1

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© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE ORStep-by-Step DISTRIBUTION Procedures NOT FOR SALE OR DISTRIBUTIONxiii Preface xv A Visual Walk-Through of Key Box Features xvii © Jones & Bartlett Learning, LLCContributors © Jones & Bartlett Learning, LLC xix NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Chapter 1 The Serological Specimen...... 1 Chapter 2 Fundamentals of the Immune System...... 15 Chapter© 3 Jones Lymphocytes & Bartlett in Learning, Adaptive Immunity LLC ...... © . .Jones . . . & Bartlett37 Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Chapter 4 Safety and Standards ...... 69 Chapter 5 Classic Principles in Immunodiagnostics ...... 93 © JonesChapter & Bartlett 6 Learning,Immunoassay LLC Design...... ©. . Jones . . . . .& . Bartlett . . . . . Learning,111 LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Chapter 7 Serological and Immunodiagnostic Instrumentation and Automation ...... 133 Chapter 8 Immunophenotyping...... 155 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE ORChapter DISTRIBUTION 9 Viral Serology...... NOT . . . FOR. . . . SALE . . . . .OR . . DISTRIBUTION. . . . . 175 Chapter 10 Bacterial Serology and Immunodiagnostics...... 199 Chapter 11 Fungal and Parasitic Serology © Jonesand & Immunodiagnostics Bartlett Learning,. . . .LLC ...... © . Jones & Bartlett237 Learning, LLC ChapterNOT 12 FORBlood SALE Bank SerologyOR DISTRIBUTION and Immunotyping for TransfusionNOT FOR SALE OR DISTRIBUTION and Transplant Medicine ...... 267 Chapter 13 Autoimmunity: Diseases and Testing ...... 295 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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Chapter 14 Tumor Immunology...... 333 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Chapter 15 NOTManagement, FOR SALE Regulation, OR DISTRIBUTION and Clinical Translation NOT FOR SALE OR DISTRIBUTION in Immunodiagnostic Testing ...... 351 Appendix 361 Glossary 389 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALEIndex OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION401

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© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FORStep-by-Step SALE Procedures OR DISTRIBUTION...... xiii Pattern RecognitionNOT FOR Receptors SALE. . .OR . . . . .DISTRIBUTION . . . 27 Preface...... xv Mechanism of Internalization of Pathogens: A Visual Walk-Through of Key Box Features...... xvii Endocytosis...... 28 Major Histocompatibility Complex...... 29 Contributors ...... xix © Jones & Bartlett Learning, LLC © Jones &The Bartlett Adaptive ImmuneLearning, Response LLC...... 32 Case Study...... 32 NOT FOR SALE ORChapter DISTRIBUTION 1 The Serological Specimen . . NOT. . .1 FOR SALE OR DISTRIBUTION References ...... 35 The Roots of Immunodiagnostics...... 1 Fundamentals...... 2 Chapter 3 Lymphocytes in Adaptive Blood© and Jones Other Body & Bartlett Fluids . . . . .Learning, ...... 3 LLC Immunity. . ©. .Jones . . . . &. . Bartlett .37 Learning, LLC Proteins and Subcellular Products...... 8 TechnicalNOT Underpinnings FOR SALE of Serodiagnosis OR DISTRIBUTION. . . . .12 Lymphocytes...... NOT ...... FOR SALE . 38 OR DISTRIBUTION References ...... 14 B Cells...... 38 B-Cell Development...... 40 Chapter 2 Fundamentals of the Generation of the BCR...... 41 © Jones & BartlettImmune System Learning, .LLC ...... 15 Recombination© Jones Activation & Bartlett Genes (RAGs)Learning,...... 43 LLC NOT FOR SALE OR DISTRIBUTION AntibodiesNOT and FOR Their SALE Effector FunctionsOR DISTRIBUTION...... 46 Introduction...... 16 Immunoglobulins and Their Associations...... 46 History...... 16 Class Switching...... 49 Antimicrobial Small Molecules as Affinity Maturation ...... 51 the First Barrier of Protection ...... 17 B Cells Response to Pathogens ...... 51 © Jones & Bartlett Learning,Organs of the LLCImmune System: Sites of © Jones &B-Cell Bartlett Activation Learning,...... LLC . . . . 52 NOT FOR SALE OR DISTRIBUTIONImmune Cell Development and Activity. . .NOT . . 18 FOR FormationSALE OR of Memory DISTRIBUTION...... 53 Hematopoiesis...... 20 Laboratory Roles for Antibodies...... 53 Primary Lymphoid Organs: Bone Marrow...... 21 Antibodies in the Clinic...... 55 Primary Lymphoid Organs: Thymus...... 22 T Cells...... 55 Secondary Lymphoid Organs: Lymph Nodes. . . . 22 T-Cell Development...... 56 Secondary© Jones Lymphoid & Organs:Bartlett Spleen Learning,...... 24 LLC Naïve, Effector, and Memory© JonesT Cells. . . .& . .Bartlett . . .56 Learning, LLC SecondaryNOT Lymphoid FOR SALE Organs: OR DISTRIBUTIONT-Cell Response to PathogensNOT. . .FOR . . . . . SALE. . .57 OR DISTRIBUTION Mucosa-Associated Lymphoid Organs. . . . . 24 T-Cell Selection: Positive and Innate and Adaptive Cells...... 24 Negative Selection...... 58 Myeloid Cells: Granulocytes: Neutrophils, T-Cell Maturation...... 59 Basophils, Eosinophils, and Mast Cells...... 24 © Jones & Bartlett Learning, LLC Other© T-Cell Jones Lineages & Bartlett Learning, LLC Mononuclear Phagocytes: Monocytes, That Arise in the Thymus...... 59 NOT FOR SALEMacrophages, OR DISTRIBUTION and DCs...... 25 CD4+NOT vs CD8+ FOR T Cells SALE...... OR. . . . . DISTRIBUTION. 59 Complement Cascade...... 25 T Helper Subsets ...... 60

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T-Cell Receptor Signaling...... 62 Enzyme Assays...... 121 T-Cell Activation© Jones and Clonal Expansion & Bartlett. . . .Learning,. . 63 LLCFluorescence Assays...... ©. . .Jones . . &124 Bartlett Learning, LLC Methods to NOTDetect ImmuneFOR SALE OR DISTRIBUTIONChemiluminescence Assays . . . .NOT . . . . . FOR. . 126 SALE OR DISTRIBUTION Cells’ Development, Activation...... 63 Rapid Immunoassays...... 126 Conclusion...... 66 Multimodal Assays...... 127 References ...... 66 Assay Validation...... 129 Case Study...... 129 © ChapterJones 4& SafetyBartlett and Learning, Standards. . LLC . . . .69 References . . . .© . .Jones ...... & . .Bartlett . . . . Learning, .130 LLC NOTFundamentals FOR SALE. . . . . OR. . . . DISTRIBUTION ...... 69 NOT FOR SALE OR DISTRIBUTION Biosafety Oversight...... 70 Chapter 7 Serological and Developing a Safe Laboratory Environment. . . . .74 Immunodiagnostic Quality Assurance...... 80 Instrumentation and © Jones & BartlettSpecimen Learning, Collection LLC and Processing...... 88 © Jones & AutomationBartlett Learning,...... LLC . . .133 NOT FOR SALECase OR Study DISTRIBUTION...... 90 NOT FOR SALE OR DISTRIBUTION Instrumentation in Serology and References ...... 91 Immunodiagnostics...... 134 Chapter 5 Classic Principles in Biosensors...... 135 Immunodiagnostics...... 93 Microfluidics...... 136 © Jones & Bartlett Learning, LLCMultiplexed Immunoassays...... © . . .Jones . . &136 Bartlett Learning, LLC Fundamental PrinciplesNOT FOR...... SALE ...... OR DISTRIBUTION . 94 Principles of Automation...... NOT . . . . . FOR. 137 SALE OR DISTRIBUTION Antigens and Antibodies...... 94 Instrument Automation ...... 138 Precipitation...... 98 Continuous Flow...... 138 Light Scatter...... 99 Discrete Analysis...... 139 Passive Immunodiffusion...... 100 Centrifugal Analysis...... 139 © JonesActive & Immunodiffusion Bartlett Learning,...... LLC . 101 Liquid Handling© Jones Systems and Robotics& Bartlett. . . . Learning, . 139 LLC NOTAgglutination FOR SALE...... OR...... DISTRIBUTION. . . . 104 Total LaboratoryNOT Automation FOR SALE...... OR . . . DISTRIBUTION140 Sensitization...... 105 Laboratory Information Systems...... 141 Lattice Formation and Enhancement...... 105 Serology Analyzers ...... 141 Methods of Agglutination...... 105 Principles...... 142 © Jones & BartlettAutomation Learning,. . . . .LLC ...... 109 © JonesDevice & Design Bartlett...... Learning, ...... LLC 142 NOT FOR SALEReferences OR DISTRIBUTION...... 109 NOT FOROperations SALE. . . . . OR. . . . .DISTRIBUTION ...... 143 Analysis...... 143 Chapter 6 Immunoassay Design...... 111 Immunoassay Analyzers...... 143 Fundamentals...... 112 Principles...... 144 Antibody/Antiserum...... 112 Device Design...... 144 Unlabeled Assays© Jones...... & . . Bartlett. . . . . Learning,113 LLCOperations...... © . .Jones . &145 Bartlett Learning, LLC The First LabeledNOT Immunoassays FOR SALE...... OR . . DISTRIBUTION113 Analysis...... NOT . . . FOR146 SALE OR DISTRIBUTION Standards and Calibrators...... 115 Hematology Analyzers...... 146 Labeled Tracers...... 115 Principles...... 146 Label Conjugation...... 117 Operations...... 148 © JonesSeparation & Bartlett Techniques Learning, ...... LLC...... 117 Analysis. . . ©. . .Jones ...... & . . Bartlett...... Learning,148 LLC NOTCommon FOR Assays SALE. . . . .OR . . . . .DISTRIBUTION ...... 119 Flow CytometryNOT. . . . .FOR . . . . .SALE ...... OR DISTRIBUTION .148 Radiological Assays...... 119 Principles...... 148

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Device Design...... 148 Chikungunya Virus...... 178 Operations© Jones...... & . . Bartlett...... Learning,. . 150 LLC West Nile Virus...... ©. . .Jones. . . & Bartlett178 Learning, LLC AnalysisNOT. . . .FOR . . . . . SALE...... OR. . . . . DISTRIBUTION151 Zika Virus...... NOT ...... FOR. SALE179 OR DISTRIBUTION Case Study...... 152 Encephalitis Viruses...... 179 References ...... 152 Case Study...... 180 Hepatitis Viruses...... 181 Chapter 8 Immunophenotyping...... 155 Hepatitis A Virus (HAV)...... 181 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Fundamentals of Immunophenotyping...... 155 Hepatitis B Virus (HBV)...... 182 NOT FOR SALE OR DISTRIBUTION HepatitisNOT C Virus FOR (HCV) SALE...... OR . . . . . DISTRIBUTION183 Clusters of Differentiation (CD) Markers: An Overview...... 156 Hepatitis D Virus (HDV)...... 185 Blood and Bone Marrow Smears...... 156 Hepatitis E Virus (HEV)...... 186 Immunohistochemistry and Herpes Family Viruses...... 186 © Jones & Bartlett Learning,Immunocytochemistry LLC ...... ©160 Jones &Cytomegalovirus Bartlett Learning, (CMV) ...... LLC ...... 186 NOT FOR SALE OR DISTRIBUTIONFluorescence Microscopy...... NOT160 FOR Epstein-BarrSALE OR Virus DISTRIBUTION (EBV)...... 187 Flow Cytometry...... 161 Herpes Simplex Virus (HSV), Types 1 and 2. . . . 189 Karyotyping...... 163 Varicella Zoster Virus (VZV)...... 190 Western Blotting ...... 164 Human Immunodeficiency Viruses and Erythroid Markers...... 165 Other Retroviruses ...... 190 Lymphoid© Markers Jones. . . .& . . .Bartlett ...... Learning, . 165 LLC Human Immunodeficiency© Virus,Jones & Bartlett Learning, LLC Type 1 (HIV-1)...... 191 B-CellNOT Phenotyping FOR. .SALE ...... OR. . . . . DISTRIBUTION166 NOT FOR SALE OR DISTRIBUTION Human Immunodeficiency Virus T-Cell Phenotyping...... 166 Type 2 (HIV-2)...... 193 NK Cell Phenotyping ...... 167 Human T-Cell Lymphotropic Virus, Myeloid/Granulocyte Markers...... 167 Type 1 (HTLV-1)...... 193 © Jones &Neutrophils Bartlett. . ..Learning, ...... LLC 167 Human© JonesT-Cell Lymphotropic & Bartlett Virus, Learning, LLC NOT FOR BasophilsSALE . .OR . . . . DISTRIBUTION...... 168 TypeNOT 2 (HTLV-2) FOR. . SALE...... OR. . . . DISTRIBUTION. . . 194 Eosinophils...... 168 Measles, Mumps, and Rubella Viruses...... 194 Monocytes...... 168 Measles Virus...... 194 Blast Markers and Markers of Development. . . .168 Mumps Virus...... 195 Lymphoblast Markers...... 169 Rubella Virus...... 195 © Jones & Bartlett Learning,Myeloblast LLC Markers...... ©169 JonesRespiratory & Bartlett and Enteric Viruses Learning,. . LLC...... 195 NOT FOR SALE ORMajor DISTRIBUTION Clinical Utility and Disease Correlations. .NOT . .169 FOR RespiratorySALE OR Viruses DISTRIBUTION...... 195 Chronic Lymphocytic Leukemia ...... 170 Adenovirus...... 196 Acute Myeloid Leukemia ...... 170 Coronaviruses...... 196 Acute Lymphoblastic Leukemia...... 170 Influenza A and B...... 196 Nonmalignant© Jones Disorders & Bartlett...... Learning, . 170 LLC Parainfluenza 1, 2, 3, and ©4 (Para) Jones...... & . . Bartlett196 Learning, LLC Respiratory Syncytial Virus (RSV)...... 197 Case StudyNOT. . . . FOR . . . . . SALE...... OR. . . . DISTRIBUTION .171 NOT FOR SALE OR DISTRIBUTION References ...... 172 Rhinovirus...... 197 Enteric Viruses...... 197 Chapter 9 Viral Serology ...... 175 “Enteroviruses” (Coxsackievirus, Poliovirus, Echovirus, and Others) and Parechoviruses. . . 197 © JonesIntroduction & Bartlett to Viral Learning, Serology. . .LLC ...... 176 Norovirus© Jones...... & . . .Bartlett ...... Learning,198 LLC NOT FORArboviruses SALE. . OR...... DISTRIBUTION...... 177 RotavirusNOT. . .FOR . . . . . SALE...... OR. . . . . DISTRIBUTION198 Dengue Virus...... 178 References ...... 198

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Chapter 10 Bacterial Serology and Epidemiology and Pathogenesis...... 246 Immunodiagnostics© Jones & Bartlett. . . .Learning, . .199 LLCConventional Methods...... © . . .Jones . . . &247 Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTIONImmunodiagnostic Methods . . .NOT ...... FOR . 247 SALE OR DISTRIBUTION History of Immunodiagnostics for Microbial Molecular Diagnostic Methods...... 247 Identification...... 200 Dimorphic Fungi ...... 247 Immunodiagnostic Methods for Blastomycosis...... 248 Identification...... 201 Etiology...... 248 © JonesTest Complexity & Bartlett. . . . .Learning, ...... LLC 201 © Jones & Bartlett Learning, LLC Epidemiology and Pathogenesis...... 248 NOT AgglutinationFOR SALE. . . .OR . . . .DISTRIBUTION ...... 201 NOT FOR SALE OR DISTRIBUTION Conventional Methods...... 248 Flocculation...... 201 Immunodiagnostic Methods ...... 249 Enzyme Immunoassays...... 201 Molecular Diagnostic Methods...... 249 Immunofluorescent Assays...... 204 Histoplasmosis...... 250 Bacterial Infections ...... 205 © Jones & Bartlett Learning, LLC © JonesEtiology &. .Bartlett ...... Learning,...... LLC 250 Host Response to Bacterial Infections...... 205 NOT FOR SALE OR DISTRIBUTION NOT FOREpidemiology SALE and OR Pathogenesis DISTRIBUTION...... 250 Streptococcus Pyogenes (Group A Streptococcus) ...... 207 Conventional Methods...... 250 Mycobacterium Tuberculosis...... 209 Immunodiagnostic Methods ...... 250 Syphilis...... 214 Molecular Diagnostic Methods...... 251 Lyme Disease©. . .Jones ...... & . . .Bartlett . Learning,220 Coccidioidomycosis LLC ...... © . . Jones. . .251& Bartlett Learning, LLC Rickettsial InfectionsNOT FOR...... SALE ...... OR DISTRIBUTION224 Etiology...... NOT . . . FOR251 SALE OR DISTRIBUTION Helicobacter Pylori ...... 227 Epidemiology and Pathogenesis...... 251 Neisseria Gonorrhoeae and Chlamydia Conventional Methods...... 252 Trachomatis...... 229 Immunodiagnostic Methods ...... 252 Case Study...... 233 Molecular Diagnostic Methods...... 253 © ReferencesJones &. .Bartlett ...... Learning, ...... LLC .234 Parasitic Infections© Jones...... & . . .Bartlett . . . Learning, . 253 LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Ova and Parasite Examination...... 254 Chapter 11 Fungal and Parasitic Cryptosporidium...... 255 Serology and Giardia ...... 258 Immunodiagnostics...... 237 Etiology...... 258 © Jones & BartlettFungal Learning, Infections. . . LLC...... 238 © JonesEpidemiology & Bartlett and Pathogenesis Learning,...... LLC . . . 259 NOT FOR SALE ORImmunoassay DISTRIBUTION Methods...... 238 NOT FORConventional SALE Methods OR . DISTRIBUTION...... 259 Immunodiffusion...... 239 Immunodiagnostic Methods ...... 260 Complement Fixation ...... 239 Molecular Methods...... 261 Candidiasis...... 240 Toxoplasmosis...... 262 Etiology. . . .© . .Jones ...... & . .Bartlett . . . . . Learning,240 LLCEtiology...... © . .Jones . &262 Bartlett Learning, LLC EpidemiologyNOT and Pathogenesis FOR SALE...... OR. . . DISTRIBUTION241 Epidemiology and Pathogenesis.NOT ...... FOR . 262 SALE OR DISTRIBUTION Conventional Methods...... 245 Conventional Methods...... 263 Immunodiagnostic Methods ...... 245 Immunodiagnostic Methods ...... 263 Molecular Diagnostic Methods...... 246 Molecular Methods...... 264 Case Study...... 264 © CryptococcosisJones & Bartlett...... Learning, ...... LLC .246 © Jones & Bartlett Learning, LLC Etiology...... 246 References ...... 264 NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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Chapter 12 Blood Bank Serology and Chapter 13 Autoimmunity: Diseases © JonesImmunotyping & Bartlett for Learning, LLC and Testing©. .Jones . . . . .& . Bartlett .295 Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Transfusion and Fundamentals...... 296 Transplant Medicine...... 267 Tolerance and Autoimmunity...... 296 Fundamentals of Blood-Bank Immunology. . . 268 Causes of Autoimmunity...... 297 Role of Antibody Testing in the General Transfusion Medicine Laboratory © Jones & Bartlett Learning, LLC Broader© Jones Clinical Context& Bartlett...... Learning,. . 298 LLC Operations...... 269 Antibodies: Pertinence to Autoimmune NOT FOR TransfusionSALE OR Services DISTRIBUTION Operating Procedures. . . 269 NOT FOR SALE OR DISTRIBUTION Diseases...... 298 Regulators...... 269 Sensitivity, Specificity, and Predictive Values. . . 299 Blood Group Genetics...... 270 Testing Algorithms: Single Tests, Profiles, Pretransfusion Testing...... 273 Reflexes...... 299 © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC International Society of Blood Transfusion Testing Modalities with Examples...... 300 NOT FOR SALE OR DISTRIBUTIONNumeric Terminology...... NOT .275 FOR Immunofluorescence,SALE OR DISTRIBUTION Direct and ABO Blood Grouping...... 276 Indirect: Cell-Based and Tissue-Based ...... 300 Procedure...... 277 Live Cell-Based Flow Cytometry...... 302 Clinical Utility...... 278 Tissue-Based Assays...... 303 Rh D Typing© Jones...... & . . Bartlett...... Learning,. .279 LLC Immunoprecipitation Assay© . Jones ...... &. . . . Bartlett . . . . 304 Learning, LLC ProcedureNOT. . .FOR . . . . . SALE ...... OR . . . . .DISTRIBUTION279 ELISA...... NOT...... FOR SALE304 OR DISTRIBUTION Clinical Utility...... 279 Double-Stranded DNA (dsDNA) Antibody Testing...... 305 Coombs Antiglobulin Tests...... 280 Chemiluminescent Immunoassays...... 306 Clinical Utility...... 281 Multiplex Bead Assay: Connective Tissue © JonesAntibody & Bartlett Screening Learning,...... LLC ...... 283 Cascade© Jones...... & . . Bartlett ...... Learning, . . 307 LLC NOT FOR Procedure:SALE OR Tube DISTRIBUTIONMethod ...... 283 MicrofluidicsNOT FOR...... SALE...... OR DISTRIBUTION307 Clinical Utility...... 283 Antibody Detection by Agglutination-PCR Antibody Identification and Other Red Cell (ADAP)...... 307 Antigens...... 284 Functional Assays...... 307 Antiglobulin Crossmatch...... 285 CSF Testing...... 308 © Jones & Bartlett Learning,Other Immunodiagnostic LLC Testing in © JonesAutoimmune & Bartlett Diseases Learning, and Pertinent LLC NOT FOR SALE OR DISTRIBUTIONImmunohematology...... NOT .286 FORAntibody SALE Markers OR DISTRIBUTION...... 308 Transfusion vs Transplant: Similarities and Non-Organ-Specific Connective Differences...... 286 Tissue Diseases ...... 308 Organ-Specific Connective Tissue Diseases . . . . 313 Common Transfusion Reactions...... 286 Organ-Specific Endocrine Disorders...... 314 Transplant Serology ...... 288 © Jones & Bartlett Learning, LLC Hematologic Autoimmune© DiseasesJones. . .& . . .Bartlett . 316 Learning, LLC Transplant-specific Testing...... 289 NOT FOR SALE OR DISTRIBUTIONOrgan-Specific Renal NOT FOR SALE OR DISTRIBUTION The CDC Test...... 290 Autoimmune Diseases...... 318 HLA ELISA...... 291 Organ-Specific Gastrointestinal Disorders. . . . 319 HLA Crossmatch...... 291 Autoimmune Cardiac Disorders...... 320 Case Study...... 291 © Jones & Bartlett Learning, LLC Blistering© Jones Autoimmune & Bartlett Dermatoses Learning,...... 320 LLC References ...... 292 Organ-Specific Neurological Disorders...... 321 NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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Other Inflammatory Neurological Disorders Where Case Study...... 348 Igg Measures© Jones (without Antigen& Bartlett Specificity) Learning, References LLC ...... ©. . . Jones .&349 Bartlett Learning, LLC Are Biomarkers...... 328 NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Case Study...... 329 Chapter 15 Management, Regulation, References ...... 330 and Clinical Translation in Immunodiagnostic Chapter 14 Tumor Immunology ...... 333 © Jones & Bartlett Learning, LLC Testing© Jones. . . .& . Bartlett . . . . . Learning, .351 LLC NOTIntroduction FOR SALE to Tumor OR Development DISTRIBUTION and NOT FOR SALE OR DISTRIBUTION Immunology...... 334 History of Regulation of Serology and Immunodiagnostics in the Tumors and the Immune System...... 334 United States...... 352 Immunosurveillance System for Tumor Recognition...... 336 Current Regulatory and Management © Jones & BartlettTumor-Associated Learning, Antigens LLC and © JonesParadigms & . .Bartlett ...... Learning, . . . . . LLC . 353 Tumor Markers...... 338 Laboratory Oversight NOT FOR SALE OR DISTRIBUTION NOT FORand Management SALE OR. . . . .DISTRIBUTION ...... 353 Carcinoembryonic Antigen (CEA)...... 338 Oversight of Laboratory Developed Tests. . . . 354 Alpha-1 Antitrypsin (α1-AT)...... 339 Regulation and Management of Point-of- Prostate-Specific Antigen (PSA)...... 339 Care Testing...... 355 Beta-2 Microglobulin...... 339 Future Directions in Clinical Translation of Immunoassays Used© Jones in Clinical & BartlettDiagnosis Learning, LLC © Jones & Bartlett Learning, LLC Immunodiagnostic Tests ...... 356 of CirculatingNOT and Other Tumors FOR SALE. . . . .OR . . DISTRIBUTION . 340 NOT FOR SALE OR DISTRIBUTION Extending Regulatory Oversight Immunohistochemistry (IHC)...... 340 by the FDA...... 356 Enzyme-Linked Immunosorbent Assay Rapid Translation of LDTs and IVDs During (ELISA)...... 341 Emergency Situations...... 357 Flow Cytometry...... 341 © Jones & Bartlett Learning, LLC Case Study. . . .© . .Jones ...... &. . .Bartlett . . . . Learning, .358 LLC Radioimmunoassay (RIA)...... 341 References ...... 359 NOTTumor FOR Immunotherapy SALE OR. . . .DISTRIBUTION ...... 341 NOT FOR SALE OR DISTRIBUTION Vaccines...... 342 Appendix...... 361 Chimeric Antigen Receptor T Cells...... 343 Immunomodulating Antibody Therapies . . . . 344 Glossary...... 389 © Jones & BartlettSummary Learning,...... LLC...... 344 © IndexJones...... & . .Bartlett ...... Learning, . . . . . LLC 401 NOT FOR SALEFlow OR Cytometry DISTRIBUTION in the Workup for Cancer. . . . 344 NOT FOR SALE OR DISTRIBUTION

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HRP Antibody: Enzyme Conjugation with Succinimidyl Ester © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION Ouchterlony Double Diffusion AssayNOT FOR SALE OR DISTRIBUTION

Peripheral Blood Processing

Preparing© Jones a Blood& Bartlett Control Learning, for Flow LLCCytometry Assays © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Rapid Plasma Reagin (RPR) Test for Syphilis

Sensitization of Sheep RBCs for use in Complement Fixation © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Tube Typing for D NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALEhe diagnostic OR DISTRIBUTION clinical laboratory and the of focusingNOT only onFOR studies SALE in the historicalOR DISTRIBUTION demarca- field of medical laboratory science, often tions provided by laboratory unit structuring. called clinical laboratory science or med- While only 5 to 10% of the coverage in the Tical technology, was a 20th-century invention American Society for Clinical Pathology’s (ASCP) that arose as an outgrowth of the massive clini- Board of Certification (BOC) generalist Medical © Jones & Bartlett Learning,cal and scientific LLC discoveries of that and previous© Jones Laboratory & Bartlett Scientist Learning, exam is specifically LLC focused NOT FOR SALE OReras. DISTRIBUTION The field, in effect, was the applicationNOT arm FORon immunology,SALE OR DISTRIBUTIONimmunodiagnostic tests are for biological and chemical investigations aimed performed in every laboratory unit including the at diagnosing disease in medical facilities. The major areas of microbiology, blood bank, hema- practitioners of these skills were fundamentally tology, and chemistry; this suggests that a funda- biological scientists specifically experienced in mental understanding of immune principles and the techniques© Jones and skills& Bartlett most suited Learning, to patho- LLCtheory is one of a few competency© Jones areas & thatBartlett are Learning, LLC genic identification.NOT FOR Their SALE role ORin the DISTRIBUTION healthcare essential for future work inNOT the profession. FOR SALE OR DISTRIBUTION team, although often unsung, is still pivotally im- In the 21st century, the models used to define portant in increasing the overall efficacy of med- competency will require significant remodeling if ical diagnosis and treatment. This text focuses laboratory professionals are to compete well for not on the entire medical laboratorian profession healthcare jobs, which may go hand in hand with © Jonesbut & on Bartlett several key Learning, technologies LLC of continuing the remodeling© Jones of the & labBartlett itself around Learning, the key LLC NOT FORimportance SALE in OR the field,DISTRIBUTION namely serology and im- diagnosticNOT techniques FOR SALEgaining ORtraction—namely DISTRIBUTION munology as they pertain to clinical diagnostics. clinical immunodiagnostics, already taking up a The text is intended for both undergraduates significant market share of testing—and molecular and graduate students engaged in a condensed diagnostics, with its rapidly growing utility. The 8-week course or traditional 16-week course in laboratorian of the 21st century will also find an © Jones & Bartlett Learning,clinical immunology, LLC clinical serology, immu© Jones- ever-increasing & Bartlett requirement Learning, to LLC understand the NOT FOR SALE ORnodiagnostics, DISTRIBUTION or an advanced methods courseNOT FORmechanical SALE and OR computer DISTRIBUTION components of com- taught within the medical laboratory science plex laboratory instrumentation. Therefore, a curriculum or within other programs focused on streamlined course curriculum would focus on clinical diagnostics. the most important methodological principles underlying these evolved diagnostic tests. © Jones & Bartlett Learning, LLC Additionally, this text© provides Jones what & Bartlett I feel Learning, LLC ▸▸ ApproachNOT FOR SALE OR DISTRIBUTIONis a deeper analysis of theNOT theoretical FOR principles SALE OR DISTRIBUTION surrounding the development of the innate and This text departs from other texts in the field by adaptive immune system pertaining to the study attempting to establish a restructuring of the clini- of immunodiagnostics and may seem to expand cal laboratory science scholastic curriculum for use on subjects traditionally found in other texts © Jonesin the& Bartlett21st century. Learning, It does so byLLC focusing on the in the larger© Jones clinical & laboratory Bartlett field. Learning, For exam -LLC NOT FORtheoretical SALE principles OR DISTRIBUTION that underlie a diversity of ple, oneNOT will see FOR within SALE these ORpages DISTRIBUTION a reference diagnostic tests performed in the clinical lab instead to microbiological testing by immunodiagnostic

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approaches, a subject often contained only in texts immunodiagnostics as they are described by the for microbiology;© oneJones will also & Bartlettsee blood banking Learning, ASCP LLC and through the American© Society Jones of Clin & -Bartlett Learning, LLC serology as it pertainsNOT toFOR antigen SALE and antibody OR DISTRIBUTION in- ical Laboratory Sciences (ASCLS)NOT entry-level FOR cur SALE- OR DISTRIBUTION teractions, as well as discussions of transfusion, riculum (ELC) documents. Subsequent chapters cancer, virology, and autoimmune diseases as they discuss specific pathogenic testing through serol- pertain to immunodiagnostics. However, a fuller ogy and immunodiagnostics, such as bacterial, analysis of these other subject areas is outside the viral, and fungal assays as well as immunohema- © scopeJones of the & contentBartlett and Learning, should not be LLC neglected tology (blood banking)© Jones and transfusion& Bartlett medicine. Learning, LLC NOTin generalized FOR SALE study. OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

▸▸ Organization ▸▸ Instructor Resources This text holds true to many of the immunodiag- The instructor who adopts this text can also re- © Jones & Bartlett Learning, LLC © questJones access & toBartlett a robust set Learning, of ancillaries, LLC including nostic areas that are traditionally covered in en- NOT FOR SALEtry-level OR DISTRIBUTION texts on serology and clinical immunolo- NOTthe following:FOR SALE OR DISTRIBUTION gy; early chapters begin by defining the specimens ■■ Test Bank for each chapter found in the serological lab, generalized immu- ■■ Slides in PowerPoint format for each nodiagnostic testing methods and the fundamen- chapter ■ tal knowledge ©in Jonesimmunology, & Bartlett and the Learning, most ■ LLCInstructor Manual © Jones & Bartlett Learning, LLC common safety and operational practices. The ■■ Answers to case study questions text then proceedsNOT with FOR an examination SALE OR of DISTRIBUTIONboth NOT FOR SALE OR DISTRIBUTION the classical and contemporary methods used in Ian Clift, 2019

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© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC A VisualNOT FOR SALE ORWalk-Through DISTRIBUTION NOT FOR SALE OR DISTRIBUTION © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FORof Key SALE OR DISTRIBUTION Box FeaturesNOT FOR SALE OR DISTRIBUTION

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION A Deeper Look boxes expand upon specific chapter concepts and define important key terms. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FORStep-by-Step SALE OR DISTRIBUTIONProcedures are provided in all chapters that contain a discussion of a specific procedure. These box features provide clear and easy to follow steps to help with student learning and retention. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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Case Studies provide students with challeng- © ingJones real-world & Bartlett scenarios Learning,to test their knowlLLC- © Jones & Bartlett Learning, LLC NOTedge FORand critical SALE thinking OR skills.DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION Appendix A: Advanced Concepts is a back- ground guide on topics that aren’t fully explored in the main chapters and also expands on several topics that are already included. This addition © Jones & Bartlett Learning, LLC © isJones a great &way Bartlett to expand Learning, on knowledge LLC in these areas, which include properties of other chemical NOT FOR SALE OR DISTRIBUTION NOTdiluents FOR and SALE buffers OR used DISTRIBUTION in serological testing, diagnostic polyclonal and monoclonal antibody development, expanded isolation considerations for blood products, and more. © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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© Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FORBarsha SALE Dash, PhD OR (Chapter DISTRIBUTION 2, 3) Andrew McKeon,NOT MD FOR D(ABMLI) SALE (Chapter OR 13) DISTRIBUTION Department of Immunology Neurologist Graduate School of Biomedical Sciences Departments of Laboratory Medicine and Mayo Clinic Pathology and Neurology Rochester, Minnesota Mayo Clinic © Jones & Bartlett Learning, LLC © JonesRochester, & Bartlett Minnesota Learning, LLC NOT FOR SALE ORBrittney DISTRIBUTION Dinkel, PhD (Chapter 2, 3) NOT FOR SALE OR DISTRIBUTION Assistant Professor Barbara Spinda, MS, MLS(ASCP)CM (Chapter 10, 11) Biology Program Professor School of Science Division of Clinical Laboratory Science Buena Vista University School of Applied Health Sciences Storm Lake,© Jones Iowa & Bartlett Learning, LLCVera Z. Dwyer College of Health© Jones Sciences & Bartlett Learning, LLC Indiana University South Bend AlexandraNOT Greenberg-Worisek, FOR SALE PhD, MPHOR (Chapter DISTRIBUTION 15) NOT FOR SALE OR DISTRIBUTION South Bend, Indiana Center for Regenerative Medicine Mayo Clinic Rosalie Sterner, MD, PhD (Chapter 14) Rochester, Minnesota Graduate School of Biomedical Sciences Mayo Clinic © JonesShaheen & Bartlett Kurani, ScM Learning, (Chapter 15) LLC © Jones & Bartlett Learning, LLC Rochester, Minnesota NOT FORGraduate SALE School OR of DISTRIBUTION Biomedical Sciences NOT FOR SALE OR DISTRIBUTION Mayo Clinic Elitza S . Theel, PhD (Chapter 15) Rochester, Minnesota Consultant, Division of Clinical Microbiology and Annika Lee Associate Professor School of Medicine Department of Laboratory Medicine and Pathology © Jones & Bartlett Learning,Emory University LLC © Jones & Bartlett Learning, LLC Mayo Clinic NOT FOR SALE ORAtlanta, DISTRIBUTION Georgia NOT FOR SALE OR DISTRIBUTION Rochester, Minnesota Diane Leland, PhD (Chapter 9) Professor Emeritus Department of Laboratory Medicine and Pathology ▸▸ Reviewers and © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Program NOTDirector, FOR Clinical SALE Laboratory OR DISTRIBUTION Science Pamela B . Primrose, PhD, MLS(ASCP)NOT FOR SALE OR DISTRIBUTION Bachelor of Science Degree Faculty School of Medicine Department of Medical Laboratory Technology Indiana University–Purdue University School of Health Sciences Indianapolis Ivy Tech Community College–South Bend © JonesIndianapolis, & Bartlett Indiana Learning, LLC South Bend,© Jones Indiana & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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Dick Y . Teshima, MPH, MT(ASCP) ▸▸ Associate Professor© Jones and Chair & Bartlett Learning, LLCStudent Reviewers© Jones & Bartlett Learning, LLC Department of MedicalNOT FOR Technology SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION John A. Burns School of Medicine Esther Boateng, BS University of Hawai‘i at Mānoa Indiana University South Bend CLS Graduate Honolulu, Hawaii James Dishman, BS Patricia Tille, PhD, MLS(ASCP), FACSc Indiana University South Bend CLS Graduate © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC Instructor RJ Dudash, BS NOTDepartment FOR SALE of Medical OR Laboratory DISTRIBUTION Science Indiana UniversityNOT South FOR Bend SALE CLS Graduate OR DISTRIBUTION College of Pharmacy and Allied Health Professions South Dakota State University Molly Feller, BS, MLS(ASCP) Brookings, South Dakota Indiana University South Bend CLS Graduate © Jones & BartlettReannon Learning, Wilkerson, BS, LLCMS, MLS(ASCP) © BrandieJones Morgan, & Bartlett BS, MLS(ASCP) Learning, LLC NOT FOR SALEInstructor OR DISTRIBUTION NOTIndiana FOR University SALE South OR BendDISTRIBUTION CLS Graduate Medical Laboratory Assistant Program Chantel Shores, BS, MLS(ASCP) Department of Health Sciences Indiana University South Bend CLS Graduate Calhoun Community College–Huntsville Campus Huntsville, Alabama © Jones & Bartlett Learning, LLC © Jones & Bartlett Learning, LLC NOT FOR SALE OR DISTRIBUTION NOT FOR SALE OR DISTRIBUTION

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