Manual of Molecular and Clinical Laboratory Immunology E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: ASM Books
• Sprache: Englisch

Seitenzahl: 6059

Veröffentlichungsjahr: 2024

Beschreibung

THE authoritative guide for clinical laboratory immunology

For nearly 50 years, the Manual of Molecular and Clinical Laboratory Immunology has been the premier resource for laboratories, students, and professionals involved in the clinical and technical details of diagnostic immunology testing. The 9th Edition continues its tradition of providing comprehensive clinical and technical information on the latest technologies used in medical and diagnostic immunology.

Led by a world-renowned group of authors and editors, this new edition reflects substantial changes aimed at improving and updating the Manual’s utility while reflecting the significant transformations that have occurred since the last edition, including the revolution of gene editing and the widespread adoption of molecularly engineered cellular therapies.

Topical highlights include:

• Laboratory Management: three new chapters cover essential aspects of quality assurance, quality improvement, and quality management, aligning with the increasingly stringent and demanding regulatory environment.
• Inborn Errors of Immunity: the primary immunodeficiency section has been completely updated to align with the latest International Union of Immunological Societies’ classifications of inborn errors of immunity.
• Functional Cellular Assays: expanded content includes detailed discussions on various functional assays critical for modern immunologic testing.
• Autoimmune Diseases: expanded chapters on systemic and organ-specific autoimmune disorders, including new chapters on Sjögren’s syndrome and deficiency of ADA2, as well as significant updates on organ-specific autoimmune diseases.
• Transplantation Immunology: updated chapters detail the assessment of immune reconstitution and ABO testing, reflecting latest practices.

The 9th Edition of the Manual of Molecular and Clinical Laboratory Immunology serves as an invaluable resource for laboratory directors, clinicians, laboratory managers, technologists, and students. It provides critical insights into the selection, application, and interpretation of immunologic tests, offering practical guidance on troubleshooting, clinical application, and an understanding of test limitations. This comprehensive and up-to-date manual remains an essential tool for anyone involved in the diagnosis, evaluation, and management of immune-mediated and immune system-related disorders.

Leseprobe

Table of Contents

Cover

Table of Contents

Volume 1

Title Page

Copyright Page

Editorial Board

Contributors

Preface

Author and Editor Conflicts of Interest

section A: Molecular Methods

1 Introduction

REFERENCES

2 Molecular Methods for Genetic Diagnosis of Inborn Errors of Immunity

INTRODUCTION

SEQUENCING TECHNIQUE PROGRESSION

PRE‐ AND POSTSEQUENCING CONSIDERATIONS

ADDITIONAL TECHNIQUES

FUTURE CONSIDERATIONS

ACKNOWLEDGMENTS

REFERENCES

3 Immunoglobulin and T‐Cell Receptor Gene Assessment

INTRODUCTION

PROTEIN STRUCTURE OF IMMUNOGLOBULIN

PROTEIN STRUCTURE OF THE T‐CELL RECEPTOR (TCR)

T‐ AND B‐CELL DEVELOPMENT

GENETIC STRUCTURE OF IMMUNOGLOBULINS AND T‐CELL RECEPTOR

IMMUNOGLOBULIN AND T‐CELL RECEPTOR GENE REARRANGEMENT

MOLECULAR METHODS FOR TCR AND IG REARRANGEMENT TESTING

CONCLUSIONS

REFERENCES

section B: Immunoglobulin Methods

4 Introduction

REFERENCES

5 Clinical Indications and Applications of Serum and Urine Protein Electrophoresis

BACKGROUND ON PROTEIN STRUCTURE

PRINCIPLES OF PROTEIN ELECTROPHORESIS

QUALITY CONTROL AND QUALITY ASSURANCE

PROTEINS IDENTIFIED IN SERUM PROTEIN ELECTROPHORESIS

PATTERN INTERPRETATION IN SERUM

QUANTIFICATION OF SERUM M‐PROTEINS

PATTERN INTERPRETATION IN URINE

DETECTION OF M‐PROTEINS IN THE URINE

CLINICAL APPLICATIONS

REFERENCES

6 Immunochemical Characterization of Immunoglobulins in Serum, Urine, and Cerebrospinal Fluid

BACKGROUND

LABORATORY INVESTIGATION

PATTERN INTERPRETATIONS AND CLINICAL DISORDERS

QUALITY CONTROL

URINE IMMUNOFIXATION

CEREBROSPINAL FLUID

REFERENCES

7 Cryoglobulins and Cryofibrinogenemia

CRYOGLOBULINS

CRYOFIBRINOGENS

REFERENCES

8 Strategy for Detecting and Following Monoclonal Gammopathies

CLASSIFICATION OF MONOCLONAL GAMMOPATHIES

OVERVIEW OF LABORATORY TESTS FOR MONOCLONAL GAMMOPATHIES

DIAGNOSTIC TESTING STRATEGIES FOR M‐PROTEINS IN SYMPTOMATIC PATIENTS

MONITORING M‐PROTEINS

STRATIFICATION OF RISK

SUMMARY

REFERENCES

section C: Complement

9 Introduction

REFERENCES

10 Methods of Complement Analysis

INTRODUCTION

PREANALYTICAL CONSIDERATIONS

DIAGNOSTIC WORKUP

METHODS OF MODERN COMPLEMENT ANALYSIS

OUTLOOK

REFERENCES

11 Assessing Complement Dysregulation in the Thrombotic Microangiopathies and Ultrarare Complement‐Mediated Kidney Disease

ALTERNATIVE PATHWAY OF COMPLEMENT

COMPLEMENT‐MEDIATED RENAL DISEASE

ATYPICAL HEMOLYTIC UREMIC SYNDROME

C3 GLOMERULOPATHY

CONCLUSIONS

ACKNOWLEDGEMENTS

REFERENCES

12 Current and Future of Complement Therapeutics and their Impact on the Clinical Immunology Laboratory

C1‐INIHIBITOR CONCENTRATES

ANTI‐C5 ANTIBODIES

ANTI‐C5a ANTIBODY

ANTI‐MASP‐2 ANTIBODY

CYCLIC PEPTIDE C3 INHIBITOR

SMALL‐MOLECULE C5a RECEPTOR ANTAGONIST

ANTI‐C1 ANTIBODIES

ORAL SMALL‐MOLECULE INHIBITORS

PEGYLATED RNA APTAMERS

RNA INTERFERENCE

ADENO‐ASSOCIATED VIRUS (AAV) GENE THERAPY

REFERENCES

section D: Flow Cytometry

13 Introduction: Clinical Flow Cytometry Applications and Quality Control

REFERENCES

14 Polychromatic Flow Cytometry

TECHNOLOGY

SAMPLE PREPARATION

QUALITY ASSURANCE AND QUALITY CONTROL

DATA ANALYSIS AND INTERPRETATION

FUTURE DIRECTIONS

REFERENCES

15 High‐Sensitivity Detection of Paroxysmal Nocturnal Hemoglobinuria by Multiparameter Flow Cytometry

INTRODUCTION

CLINICAL FEATURES OF PNH

WHO SHOULD BE TESTED FOR PNH?

COMPLEMENT BLOCKADE THERAPY AND DISEASE MONITORING IN PNH

EARLY METHODS TO TEST FOR PNH

EVOLUTION OF FLOW CYTOMETRIC METHODS TO DETECT PNH

ISSUES WITH EARLY FLOW METHODS

ROUTINE VERSUS HIGH‐SENSITIVITY FLOW CYTOMETRY

HIGH‐SENSITIVITY ASSAYS FOR PNH RED AND WHITE BLOOD CELLS

HIGH‐SENSITIVITY 2‐C ASSAY FOR PNH IN MATURE RBCs

ASSAYS FOR PNH WITHIN IMMATURE RBCs

HIGH‐SENSITIVITY 4‐COLOR (4‐C) WBC ASSAYS

HIGH‐SENSITIVITY 5‐COLOR (5‐C) WBC ASSAYS

HIGH‐SENSITIVITY 6‐COLOR (6‐C) WBC ASSAYS

IS FLAER ESSENTIAL FOR HIGH‐SENSITIVITY TESTING OF PNH WBCs?

CROSS‐PLATFORM 5‐, 6‐, AND 7‐COLOR SINGLE TUBE ASSAYS FOR PNH WBCs

CONSIDERATIONS FOR VERIFICATION OF HIGH‐SENSITIVITY PNH ASSAYS

CONSIDERATIONS FOR VALIDATION OF HIGH‐SENSITIVITY PNH ASSAYS

ONGOING QC AND QC MONITORS

REPORTING

REFERENCES

16 Standardized Flow Cytometry Assays for Enumerating CD34

+

Hematopoietic Stem Cells

INTRODUCTION

HEMATOPOIETIC STEM/PROGENITOR CELLS EXPRESS CD34 ANTIGEN

TRANSPLANTATION OF HEMATOPOIETIC STEM CELLS

CLINICAL ISSUES IN ENUMERATING STEM CELLS BY FLOW CYTOMETRY

EARLY METHODS TO MEASURE CD34

+

CELLS BY FLOW CYTOMETRY

STATISTICAL ISSUES IN RARE EVENT DETECTION

APPROPRIATE CONTROLS FOR RARE EVENT DETECTION

TECHNICAL ISSUES IN CD34

+

CELL ENUMERATION BY MULTIPARAMETER FLOW CYTOMETRY

CD34

+

CELL ENUMERATION USING SEQUENTIAL BOOLEAN GATING

THE BASIC ISHAGE PROTOCOL AND GATING STRATEGY

SINGLE‐PLATFORM ABSOLUTE CD34

+

CELL COUNTING

ISHAGE SINGLE‐PLATFORM INCLUDING VIABILITY ASSESSMENT

ISHAGE‐BASED COMMERCIAL KITS FOR CD34

+

CELL ENUMERATION

BENEFITS OF SINGLE‐PLATFORM CD34

+

CELL ENUMERATION

NEGATIVE ANTIBODY CONTROLS

LYSING AGENTS

ISSUES IN THE ANALYSIS OF POSTTHAWED SAMPLES

QUALITY ASSURANCE OF CD34

+

CELL ENUMERATION

SIMULTANEOUS ENUMERATION OF CD34

+

AND CD3

+

CELLS IN THE ALLOGENEIC TRANSPLANT SETTING

IMMUNOLOGICAL CHARACTERIZATION OF CD34

+

STEM CELLS

DOES ENUMERATING CD34

+

SUBSETS HAVE CLINICAL UTILITY?

CD34

+

CELL SUBSETS IN BACKUP MARROW OF POOR MOBILIZERS

USE OF PLERIXAFOR IN PATIENTS WHO FAIL TO MOBILIZE WITH G‐CSF

REFERENCES

17 The Detection of Fetal Red Cells in Fetomaternal Hemorrhage by Flow Cytometry

INTRODUCTION

APPLICATION OF THE ASSAY

PROCEDURE

SAFETY

EQUIPMENT/INSTRUMENTATION

PROCEDURE

QUALITY CONTROL/ASSURANCE

INTERPRETATION

ACKNOWLEDGMENTS

REFERENCES

18 Functional Flow Cytometry‐Based Assays of Myeloid and Lymphoid Functions for the Diagnostic Screening of Inborn Errors of Immunity

FLOW CYTOMETRIC EVALUATION OF PHOSPHORYLATED KINASE SUBSTRATES TO EVALUATE ABNORMALITIES IN IMMUNE SIGNALING PATHWAYS

CELL SURFACE ADHESION MARKER UPREGULATION AS A SCREEN FOR LAD‐1

MEASUREMENT OF THE UPREGULATION OF CD40 LIGAND ON ACTIVATED T CELLS AS A SCREENING DIAGNOSTIC TEST FOR CD40 LIGAND DEFICIENCY (FORMALLY KNOWN AS X‐LINKED HYPER IGM SYNDROME [XHIM])

A FLOW CYTOMETRY‐BASED OXIDATIVE BURST ASSAY AS A SCREEN FOR THE DIAGNOSIS OF CGD

MEASUREMENT OF ABNORMAL T CELL AND NK CELL CYTOTOXICITY AS AN AID IN THE DIAGNOSIS OF PATIENTS SUSPECTED OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS SYNDROMES

MEASUREMENT OF CELL SURFACE CD278 EXPRESSION FOR THE DIAGNOSIS OF ICOS DEFICIENCY

SUMMARY

REFERENCES

19 Quality Assurance and Validation in Clinical Flow Cytometry

INTRODUCTION

REGULATION, ACCREDIDATION, AND QUALITY MANAGEMENT

STANDARDIZATION AND GUIDELINES

PROCEDURAL CODE STANDARDIZATION

REQUIREMENTS PRIOR TO ASSAY DEVELOPMENT AND VALIDATION

QUALITY ASSURANCE (QA)

CONCLUSION

REFERENCES

20 Future Cytometric Technologies and Applications

INTRODUCTION

PROS AND CONS OF THE TECHNOLOGIES

BEST APPLICATIONS FOR EACH TECHNOLOGY

IMAGING CYTOMETRY AS ANOTHER NEW FRONTIER

REFERENCES

section E: Functional Cellular Assays

21 Introduction

22 Cryopreservation of Blood Mononuclear Cells

TECHNICAL ASPECTS OF PBMC CRYOPRESERVATION, STORAGE, AND TRANSPORTATION

CELL QUALITY REQUIRED FOR IMMUNOLOGIC ASSAYS OF CRYOPRESERVED PBMCS

QUALITY CONTROL AND ADVANCES IN THE PROCESSING AND STORAGE OF CRYOPRESERVED PBMCs

REFERENCES

23 Functional Assays for B Cells and Antibodies

APPROACHES FOR ASSESSING B CELL FUNCTION

APPROACHES FOR ASSESSING ANTIBODY FUNCTION

ACKNOWLEDGMENTS

REFERENCES

24 Methods for Detection of Antigen‐Specific T Cells by Enzyme‐Linked Immunospot Assay

INTRODUCTION

ENZYME‐LINKED IMMUNOSPOT ASSAY (ELISPOT) PROTOCOL

METHODS OF ENHANCING ELISPOT SENSITIVITY

REFERENCES

25 Regulatory T Cell (Treg) Characterization

HUMAN CD4

+

REGULATORY T CELLS

CHARACTERISATION OF HUMAN CD4

+

TREG

TREG AND DISEASE

REFERENCES

26 Measurement of Natural Killer Cell Phenotype and Activity in Humans

INTRODUCTION

PROCEDURES

CONCLUSIONS

REFERENCES

27 Functional Assays for the Diagnosis of Chronic Granulomatous Disease

INTRODUCTION

ANALYSIS OF PMN H

2

O

2

PRODUCTION BY FLOW CYTOMETRY OF DIHYDRORHODAMINE 123 STAINING

ISOLATION AND CHARACTERIZATION OF PMN

HISTOCHEMICAL STAINING OF PMN WITH NITROBLUE TETRAZOLIUM

QUANTITATIVE ANALYSIS OF O

2

GENERATION USING SUPEROXIDE DISMUTASE‐INHIBITABLE FERRICYTOCHROME

c

REDUCTION

ANALYSIS OF PMN ROS GENERATION BY LUMINOL‐ENHANCED CHEMILUMINESCENCE

ANALYSIS OF gp91

phox

SURFACE EXPRESSION BY FLOW CYTOMETRY

FLOW CYTOMETRIC ANALYSIS OF PHOX PROTEIN EXPRESSION IN PERMEABILIZED CELLS

IMMUNOBLOT ANALYSIS OF PHOX SUBUNITS OF NOX2

CONCLUSION

ACKNOWLEDGEMENT

REFERENCES

28 Interferon Gamma Release Assays for Tuberculosis Diagnosis

QUANTIFERON ASSAY

TSPOT.TB

SUMMARY

REFERENCES

29 Methods for Evaluating Antigen‐Specific Cytotoxic T Lymphocyte Frequency and Activity

INTRODUCTION

FUNCTIONAL ASSAYS

QUANTITATIVE ASSAYS

REFERENCES

section F: Cytokines

30 Introduction

REFERENCES

31 Overview of the Cytokine Assay Multiverse

INTRODUCTION

CYTOKINE MEASUREMENTS AND MULTIPLEX PLATFORMS

OVERVIEW OF THE CYTOKINE MULTIVERSE: APPLICATIONS AND SYSTEM ASSAYS

CYTOKINE IL‐6 AND MULTIBIOMARKER DISEASE ACTIVITY

MULTIPLEX CYTOKINE ASSAYS AND COVID‐19

BEYOND MEASUREMENT: CYTOKINE SIGNALING CONVERSION AS AN IMMERSIVE IMMUNOTHERAPY TOOL

SUMMARY

ACKNOWLEDGEMENTS

REFERENCES

32 Monitoring Interferons in Autoimmune Diseases and Interferonopathies

INTRODUCTION

INTERFERONS IN THE ETIOLOGY OF AUTOIMMUNE DISEASES AND INTERFERONOPATHIES

IFNs IN DIAGNOSTICS

METHODS FOR IFN MEASUREMENT WITH POTENTIAL DIAGNOSTIC APPLICATION

REFERENCES

33 Detection of Anti‐Cytokine Autoantibodies and Clinical Applications

DETECTION STRATEGIES

FUNCTIONAL ASSAYS

ISOTYPE AND SUBCLASS ANALYSIS

TITER

MECHANISMS OF ACTION

OTHER DIAGNOSTIC CONSIDERATIONS

SUMMARY

ACKNOWLEDGMENTS

REFERENCES

section G: Laboratory Management

34 Licensure and Accreditation

INTRODUCTION

CLIA

35 Validation and Quality Control: General Principles and Application to the Clinical Immunology Laboratory

INTRODUCTION

GUIDELINES FOR ASSAY DEVELOPMENT AND VALIDATION

CLASSIFICATION OF ASSAYS

CLASSIFICATION ACCORDING TO PERFORMANCE CHARACTERISTICS

DEVELOPMENT AND VALIDATION

VALIDATION PARAMETERS

TOOLS TO MONITOR QUALITY

CONCLUDING REMARKS

REFERENCES

36 Quality Assurance and Quality Management of the Medical Laboratory

INTRODUCTION

QUALITY ASSURANCE PHASES OF CLINICAL TESTING: PREANALYTIC, ANALYTIC, POSTANALYTIC

INDIVIDUALIZED QC PLAN (IQCP)

ROLE OF PROFICIENCY TESTING (PT)/EQAS

DELTA CHECK, BIOLOGICAL VARIATION (BV) AND THE REFERENCE CHANGE VALUE (RCV)

NEW QM INITIATIVE IN THE MEDICAL LAB: ROLE OF THE DIAGNOSTIC MANAGEMENT TEAM (DMT)

THE CHOOSING WISELY CAMPAIGN

CONCLUDING DISCUSSION POINTS

REFERENCES

section H: Infectious Diseases Caused By Bacteria, Mycoplasmas, Chlamydiae, and Rickettsiae

37 Introduction

38 Diagnostic Methods for Group A Streptococcal Infections

INTRODUCTION

CLINICAL DESCRIPTION AND EPIDEMIOLOGY

DIAGNOSTIC METHODS

DETECTION OF ANTIBODIES TO EXTRACELLULAR ANTIGENS

RESEARCH‐USE‐ONLY TESTS

DETECTION OF ANTIBODIES TO CELLULAR ANTIGENS

CONCLUSIONS

REFERENCES

39 Laboratory Diagnosis of Syphilis

INTRODUCTION

CLINICAL FEATURES

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

METHODS

SEROLOGY

QUALITY CONTROL AND ASSURANCE

SYPHILIS TESTING ALGORITHMS

REFERENCES

40 Lyme Disease, Relapsing Fever, and Leptospirosis

INTRODUCTION

LYME BORRELIOSIS

RELAPSING FEVER

LEPTOSPIROSIS

REFERENCES

41 Immunological Tests in Tuberculosis

INTRODUCTION

CLINICAL DESCRIPTION

DIAGNOSIS

SCREENING TESTS FOR LATENT TB INFECTION

SEROLOGIC TESTS FOR ACTIVE TB INFECTION

REFERENCES

42

Mycoplasma

INTRODUCTION

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

REFERENCES

43 Chlamydia Infections

INTRODUCTION

CHLMAYDIA TRACHOMATIS

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

CHLAMYDIA PNEUMONIAE

CHLAMYDIA PSITTACI

REFERENCES

44 The

Rickettsiaceae

,

Anaplasmataceae

, and

Coxiellaceae

TAXONOMY

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

REFERENCES

45 The

Bartonellaceae

,

Brucellaceae

, and

Francisellaceae

INTRODUCTION

TAXONOMY

EPIDEMIOLOGY

CLINICAL MANIFESTATIONS

LABORATORYDIAGNOSIS

REFERENCES

section I: Mycotic and Parasitic Diseases

46 Introduction

47 Immunological and Molecular Approaches for the Diagnosis of Parasitic Infections

INTRODUCTION

BLOOD AND TISSUE PARASITES

GASTROINTESTINAL PARASITES

REFERENCES

48 Serological Diagnosis of Fungal Infections

INTRODUCTION

METHODS USED FOR THE DIAGNOSIS OF FUNGAL INFECTIONS

SERODIAGNOSIS OF FUNGAL INFECTIONS

SUPPLIERS

ACKNOWLEDGMENTS

REFERENCES

section J: Viral Diseases

49 Introduction

50 Herpes Simplex Virus and Varicella‐Zoster Virus

INTRODUCTION

HSV CLINICAL DESCRIPTION

HSV EPIDEMIOLOGY

HSV DIAGNOSIS

HSV LABORATORY TESTING

VZV CLINICAL DESCRIPTION

VZV EPIDEMIOLOGY

VZV DIAGNOSIS

VZV LABORATORY TESTING

REFERENCES

51 Epstein‐Barr Virus and Cytomegalovirus

EPSTEIN‐BARR VIRUS (EBV)

CYTOMEGALOVIRUS (CMV)

REFERENCES

52 Human Herpesviruses 6A, 6B, 7, and 8

HHV‐6A/B

HHV‐7

HHV‐8

ACKNOWLEDGEMENT

REFERENCES

53 Parvovirus B19

INTRODUCTION

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

REFERENCES

54 Severe Acute Respiratory Syndrome Coronavirus‐2

INTRODUCTION

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

REFERENCES

55 Enteroviruses

INTRODUCTION

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

REFERENCES

56 Measles, Mumps, and Rubella Viruses

INTRODUCTION

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

REFERENCES

57 Viral Hepatitis

INTRODUCTION

HEPATITIS A VIRUS

HEPATITIS B VIRUS

HEPATITIS C VIRUS

HEPATITIS DELTA VIRUS

HEPATITIS E VIRUS

REFERENCES

58 Arboviruses

INTRODUCTION

CLINICAL PRESENTATION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

REFERENCES

59 Hantavirus Infections

INTRODUCTION

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

REFERENCES

60 Rabies Virus

INTRODUCTION

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

CONSIDERATIONS FOR WORKING WITH RABV

LABORATORY TESTING

ACKNOWLEDGMENTS

REFERENCES

61 Human T‐Cell Lymphotropic Virus Types 1 and 2

INTRODUCTION

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

MOLECULAR DIAGNOSIS

REFERENCES

62 Human Immunodeficiency Virus

INTRODUCTION

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

REFERENCES

63 Bandavirus

INTRODUCTION

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

REFERENCES

Volume 2

Title Page

Copyright Page

Editorial Board

Contributors

Preface

Author and Editor Conflicts of Interest

section K: ERRORS OF IMMUNITY

64 Introduction to Inborn Errors of Immunity

REFERENCES

65 Newborn Screening for Severe Combined Immunodeficiency

OVERVIEW

METHODOLOGY

FOLLOW‐UP OF ABNORMAL TREC NBS

CONFIRMATORY TESTING

PHYSIOLOGIC T CELL LYMPHOPENIA DUE TO PREMATURITY

DIAGNOSTIC TESTING

SECONDARY CONDITIONS

TREATMENT

FUTURE DIRECTIONS

DETECTION OF 22Q11.2 COPY NUMBER IN 22Q11.2 DELETION SYNDROME

CONCLUSION

REFERENCES

66 Combined Immunodeficiencies

INTRODUCTION

DIAGNOSTIC METHODOLOGIES

CLINICAL EXAMPLES

TREATMENT

CONCLUSIONS

REFERENCES

67 Predominantly Antibody Deficiencies

DISORDERS CHARACTERIZED BY PREDOMINANTLY ANTIBODY DEFICIENCIES

WHO SHOULD BE INVESTIGATED FOR PREDOMINANTLY ANTIBODY DEFICIENCIES: CLINICAL MANIFESTATIONS OF PREDOMINANTLY ANTIBODY DEFICIENCIES

MAJOR CATEGORIES OF PREDOMINANTLY ANTIBODY DEFICIENCIES

APPROACH TO EVALUATION OF PATIENTS WITH SUSPECTED PREDOMINANTLY ANTIBODY DEFICIENCIES

THE LABORATORY INVESTIGATION OF PREDOMINANTLY ANTIBODY DEFICIENCY

TREATMENT

GENETIC ANALYSIS

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

68 Primary Immune Regulatory Disorders

INTRODUCTION

GENERAL METHODOLOGY: PIRD DIAGNOSIS AND TESTING

CLINICAL EXAMPLES: KEY MONOGENIC PIRDS

FUTURE DIRECTIONS

REFERENCES

69 Primary Innate Immune Defects (Including Phagocytic Disorders, TLR Defects, and NK Cell Deficiencies)

INTRODUCTION

ASSESSMENT OF TLR DEFECTS PREDISPOSING PREDOMINANTLY TO BACTERIAL INFECTIONS

DISORDERS OF NF‐κB ACTIVATION AND REGULATION

PHAGOCYTIC DISORDERS

SPECIFIC GRANULE DEFICIENCY (SGD)

DISORDERS OF NEUTROPHIL CHEMOTAXIS

DEFECTS IN RAC2

NK CELL DEFECTS

CONCLUSION

REFERENCES

70 Systemic Autoinflammatory Diseases

INTRODUCTION

EPIDEMIOLOGY

DIAGNOSIS

CLINICAL DESCRIPTIONS

REFERENCES

71 Complement Defects

INFECTIONS

SYSTEMIC LUPUS ERYTHEMATOSUS

HEREDITARY ANGIOEDEMA

CHAPLE SYNDROME

COLD AGGLUTININ DISEASE

SUMMARY

REFERENCES

72 Inherited Bone Marrow Failure Syndromes: Focus on Immunodeficiency and Diagnostic Evaluation

INTRODUCTION

CLINICAL FEATURES

DIAGNOSTIC TESTING

MANAGEMENT

CONCLUSION

REFERENCES

73 Phenocopies of Inborn Errors of Immunity

INTRODUCTION

SOMATIC GENE VARIANTS

ANTI‐CYTOKINE AUTOANTIBODIES (ACAAbs)

COMPLEMENT RELATED AUTOANTIBODIES

LABORATORY ANALYSIS OF ANTI‐CYTOKINE AUTOANTIBODIES

THERAPEUTIC APPROACHES FOR ACAAbs

CONCLUSION

REFERENCES

section L: Allergic Diseases

74 Introduction to Allergic Diseases

REFERENCES

75 Quantitation and Standardization of Allergens

OVERVIEW OF

IN VIVO

ASSESSMENTS OF ALLERGEN POTENCY

ID

50

EAL TEST(13, 21)

OVERVIEW OF

IN VITRO

ASSAYS OF ALLERGEN POTENCY

TESTS FOR INDIVIDUAL ALLERGENS

TESTS OF OVERALL POTENCY

OVERVIEW OF ELISA INHIBITION, OR COMPETITION ELISA

IDENTITY TESTING

MASS SPECTROMETRY: ABSOLUTE QUANTIFICATION OF ALLERGENS IN ALLERGEN EXTRACTS

QUALITY MANAGEMENT SYSTEM (QMS) OF CBER’S ALLERGENIC REFERENCE REAGENT LABORATORY

ACKNOWLEDGMENTS

REFERENCES

76 Immunological Methods in the Diagnostic Allergy Laboratory

ANALYTES RELEVANT TO THE EVALUATION OF PATIENTS FOR ALLERGIC DISEASE

TOTAL SERUM IgE

ALLERGEN‐SPECIFIC IgE ANTIBODY

ALLERGEN‐SPECIFIC SERUM IgG AND IgG4 ANTIBODIES

CONCLUDING THOUGHTS

APPENDIX A

REFERENCES

77

In Vitro

Assay Methods for Measurement of Mediators and Markers of Allergic Inflammation

HISTAMINE

LIPID MEDIATORS

CYTOKINE GENERATION BY BASOPHILS

BASOPHIL SURFACE ACTIVATION MARKERS: CLINICAL INDICATIONS

MAST CELL‐SPECIFIC MEDIATORS AND MARKERS

DENDRITIC CELLS: INNATE IMMUNE RESPONSES

QUALITY ASSURANCE OF

IN VITRO

ASSAYS

SUMMARY

APPENDIX

REFERENCES

section M: Systemic Autoimmune Diseases

78 Introduction

79 Standardization of Fluorescent Antinuclear Antibody Testing

BACKGROUND: ANTINUCLEAR ANTIBODY IDENTIFICATION BY INDIRECT IMMUNOFLUORESCENCE

THE AUTOANTIBODY STANDARDIZATION COMMITTEE: THE GENERATION OF REFERENCE MATERIALS FOR FLUORESCENT ANTINUCLEAR ANTIBODY TESTING

ICAP ACTIVITIES AND THE CLINICAL RELEVANCE OF ICAP MATERIALS FOR ANA PATTERNS

REFERENCES

80 Immunodiagnosis and Laboratory Assessment of Systemic Lupus Erythematosus

AUTOANTIBODIES TO UBIQUITOUS CELLULAR ANTIGENS

AUTOANTIBODIES TO ANTIGENS WITH A RESTRICTED DISTRUBUTION

EVALUATION OF COMPLEMENT IN SLE

MEASURING THE TYPE I INTERFERON GENE EXPRESSION SIGNATURE IN SLE

REFERENCES

81 Immunodiagnosis of Autoimmune Myopathies

IP ANALYSIS OF PROTEIN COMPONENTS

IP ANALYSIS OF SMALL RNAs

ELISA USING RECOMBINANT MYOSITIS AUTOANTIGENS

COMMERCIALLY AVAILABLE IMMUNOASSAYS

FUTURE DIRECTIONS OF MSA TESTING

REFERENCES

82 Immunodiagnosis of Scleroderma

INTRODUCTION

SSc‐RELATED AUTOANTIBODIES

ANTICENTROMERE ANTIBODY (ACA)

ANTI‐TOPOISOMERASE I/Scl‐70 (TOPO I/Scl‐70) ANTIBODY

ANTI‐RNA POLYMERASE (RNAP) III ANTIBODY

ANTI‐U3 RIBONUCLEOPROTEIN (RNP)/FIBRILLARIN ANTIBODY

ANTI‐Th/To ANTIBODY

ANTI‐U11/U12 RIBONUCLEOPROTEIN (RNP) ANTIBODY

ANTI‐EUKARYOTIC INITIATION FACTOR 2B (eIF2B) ANTIBODY

ANTI‐PM‐Scl ANTIBODY

ANTI‐Ku ANTIBODY

ANTI‐RuvBL1/2 ANTIBODY

ANTI‐U1 RIBONUCLEOPROTEIN (RNP) ANTIBODY

NEW SSc‐RELATED AUTOANTIBODIES

AUTOANTIBODIES FOUND IN SSc PATIENTS BUT NOT SPECIFIC TO SSc

PATHOGENIC ROLES OF SSc‐RELATED AUTOANTIBODIES

SCREENING OF SSc‐RELATED AUTOANTIBODIES

METHODS FOR DETECTION OF INDIVIDUAL SSc‐RELATED AUTOANTIBODIES

ASSAY PROCEDURES OF IMMUNOASSAYS

MULTIPLEX TECHNOLOGIES FOR DETECTION OF SSc‐RELATED AUTOANTIBODIES

DETECTION OF MINOR SSc‐RELATED AUTOANTIBODIES

REFERENCES

83 Immunodiagnosis of Rheumatoid Arthritis

INTRODUCTION

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

ACKNOWLEDGMENTS

REFERENCES

84 Antiphospholipid Antibody Syndrome

INTRODUCTION

USE OF THE ASSAY/USUAL CLINICAL APPLICATION

PROCEDURE

INTERPRETATION

REFERENCES

85 Immunodiagnosis of Systemic Vasculitis

ANCA‐ASSOCIATED VASCULITIS WITHIN THE SPECTRUM OF SYSTEMIC VASCULITIDES

HISTORIC PERSPECTIVE OF ANCA TESTING IN ANCA‐ASSOCIATED VASCULITIS

ANCA TESTING IN CLINICAL PRACTICE: THE REVISED 2017 INTERNATIONAL CONSENSUS

ANCA TESTING FOR FOLLOW‐UP OF PATIENTS WITH ANCA‐ASSOCIATED VASCULITIS

AUTOANTIBODIES IN IMMUNE COMPLEX SMALL‐VESSEL VASCULITIDES

FUTURE PERSPECTIVE FOR DIAGNOSTIC ANCA TESTING

REFERENCES

86 Immunodiagnosis of Sjögren’s Disease

INTRODUCTION

INFECTIOUS SEROLOGY

TISSUE‐SPECIFIC ANTIBODIES

NOT YET CLINICALLY AVAILABLE ANTIBODIES

COMPLEMENT COMPONENTS

CONCLUSION

ACKNOWLEDGEMENTS

REFERENCES

87 Diagnostic Testing for Deficiency of Adenosine Deaminase 2

INTRODUCTION

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

ACKNOWLEDGEMENT

REFERENCES

88 Future Direction of Laboratory Testing for Autoimmune Diseases

INTRODUCTION

IMMUNOASSAYS FOR AUTOANTIBODY TESTING

COMPLEMENT, ACUTE‐PHASE REACTANTS, CYTOKINES, AND OTHER SOLUBLE MOLECULES

GENETICS, EPIGENETICS, AND GENE EXPRESSION

PHARMACOGENETICS

PRECISION MEDICINE, MULTIANALYTE TESTING, AND THE FUTURE OF AUTOIMMUNITY LABORATORY TESTING

QUALITY ASSESSMENT AND STANDARDIZATION IN AUTOIMMUNE LABORATORY TESTING

REFERENCES

section N: Organ‐Localized Autoimmune Diseases

89 Introduction

90 Endocrinopathies: Hashimoto Thyroiditis, Graves Disease, Hypophysitis, Addison Disease, Premature Ovarian Failure, Male Infertility, and Diabetes

AUTOANTIBODIES IN HASHIMOTO THYROIDITIS

AUTOANTIBODIES IN GRAVES DISEASE

AUTOANTIBODIES IN AUTOIMMUNE HYPOPHYSITIS

AUTOANTIBODIES IN ADDISON DISEASE

AUTOANTIBODIES IN PREMATURE OVARIAN FAILURE

AUTOANTIBODIES IN MALE INFERTILITY

AUTOANTIBODIES IN DIABETES

REFERENCES

91 Myasthenia Gravis

DEFINITION

EPIDEMIOLOGY

CLASSIFICATION

IMMUNOPATHOGENESIS OF AUTOIMMUNE MG

DIAGNOSIS

REFERENCES

92 Autoantibodies to Brain and Spinal Cord

INTRODUCTION

SYNDROMES ASSOCIATED WITH NEURAL AUTOANTIBODIES

NEURAL AUTOANTIBODIES

ACKNOWLEDGEMENTS

REFERENCES

93 Autoantibodies to Glycolipids in Peripheral Neuropathy

INTRODUCTION

TECHNOLOGY/INSTRUMENTATION

QUALITY ASSURANCE AND CONTROL

COST ASSESSMENT

INTERPRETATION

REFERENCES

94 Detection of Antimitochondrial Autoantibodies in Primary Biliary Cholangitis and Liver Kidney Microsomal Antibodies in Autoimmune Hepatitis

INTRODUCTION

PRIMARY BILIARY CHOLANGITIS (PBC)

REFERENCES

95 Cardiovascular Diseases

INTRODUCTION

AUTOIMMUNE CARDIOMYOPATHIES

AUTOIMMUNE ARRHYTHMIAS

AUTOIMMUNE VASCULOPATHIES

IMMUNOTHERAPY

GAPS IN KNOWLEDGE AND FUTURE PERSPECTIVES

REFERENCES

96 Use of Laboratory Tests for Patients with Inflammatory Bowel Diseases

INTRODUCTION

IBD, HEREDITY, AND GENETICS

VERY‐EARLY‐ONSET IBD AND GENETICS

ROLE OF SEROLOGY IN DIAGNOSIS AND CLINICAL ASSESSMENT

LABORATORY MEASUREMENT OF DISEASE ACTIVITY

THERAPEUTIC DRUG MONITORING

INFECTION PREVENTION

MAINTENANCE OF NUTRITION

SUMMARY

ACKNOWLEDGMENT

REFERENCES

97 Celiac Disease

INTRODUCTION

CELIAC DISEASE

PATHOLOGY

CLINICAL MANIFESTATIONS

EPIDEMIOLOGY

HISTORICAL PERSPECTIVE

DIAGNOSIS

HLA TYPING

BIOPSY

OVERVIEW OF TESTING RECOMMENDATIONS IN NORTH AMERICA

MONITORING AND MANAGEMENT OF CELIAC DISEASE

FUTURE DIRECTIONS

REFERENCES

98 Primary Membranous Nephropathy

HISTOLOGY

PLA2R

PODOCYTES

PLA2R STRUCTURE

CLINICAL PLA2R ANTIBODY ASSAYS

SPONTANEOUS REMISSION

COMPLEMENT

EPIDEMIOLOGY OF PLA2R ANTIBODY pMN

PLA2R ANTIBODY‐NEGATIVE pMN

REFERENCES

99 Autoantibodies Directed against Erythrocytes in Autoimmune Hemolytic Anemia and Other Anemias

AUTOIMMUNE HEMOLYTIC ANEMIA

LABORATORY INVESTIGATION

DIFFERENTIAL DIAGNOSIS OF AUTOIMMUNE HEMOLYTIC ANEMIA

AUTOANTIBODIES THAT INTERFERE WITH ERYTHROPOIESIS

REFERENCES

100 Immune Thrombocytopenia

INTRODUCTION

DIAGNOSIS

CLINICAL DESCRIPTION

PATHOPHYSIOLOGY OF ITP

LABORATORY TESTING

ACKNOWLEDGEMENTS

REFERENCES

101 Monitoring Autoimmune Reactivity within the Retina

IMMUNE REACTIVITY IN THE EYE

CLASSIC EXAMPLES OF AUTOIMMUNE DISEASE IN THE RETINA

RETINOPATHIES ASSOCIATED WITH ANTIRETINAL ANTIBODIES

LABORATORY MONITORING OF ANTIRETINAL ANTIBODIES

LABORATORY MONITORING OF T‐CELL REACTIVITY

SUMMARY AND FUTURE DIRECTIONS

REFERENCES

102 Diagnosis of Autoimmune Blistering Diseases

INTRODUCTION

EPIDEMIOLOGY

DIAGNOSTIC TOOLS FOR AIBD

CLINICAL AND DIAGNOSTICALLY RELEVANT IMMUNOPATHOLOGICAL CHARACTERISTICS OF THE MOST COMMON AIBDs

ACKNOWLEDGMENTS

REFERENCES

section O: Cancer

103 Introduction

104 Immunoassay‐Based Tumor Marker Measurement

EVALUATION OF TUMOR MARKER ASSAYS

UTILIZATION OF TUMOR MARKERS

IMMUNOASSAY DESIGN METHODS

TYPES OF IMMUNOASSAYS

CLINICAL TEST DESIGN: IDENTIFICATION OF APPROPRIATE ANTIBODIES

IMMUNOASSAY INTERFERENCES

EXAMPLES OF TUMOR MARKERS

NEW DEVELOPMENTS IN PROTEIN‐BASED TUMOR MARKER DISCOVERY

THE FUTURE OF TUMOR MARKERS

REFERENCES

105 Immune Monitoring during Cancer Immunotherapy

INTRODUCTION

TUMOR‐BASED ASSAYS

BLOOD‐BASED ASSAYS

BLOOD CORRELATES OF RESPONSE

SINGLE‐CELL ASSAYS

FUNCTIONAL ASSAYS FOR IMMUNE MONITORING

PROTEOMICS

DATA QC AND ANALYSIS IN IMMUNE MONITORING CLINICAL TRIALS

CONCLUSIONS

REFERENCES

106 Immunophenotyping by Flow Cytometry of Acute Lymphoblastic Leukemia/Lymphoma

INTRODUCTION

DIAGNOSIS

LABORATORY TESTING

SUMMARY

REFERENCES

107 Acute Myeloid Leukemia: Diagnosis and Measurable Residual Disease Detection by Flow Cytometry

CURRENT DIAGNOSTIC AND CLASSIFICATION SCHEME OF AML

FLOW CYTOMETRY IN THE DIAGNOSIS OF AML

POSTTHERAPY MONITORING OF MEASURABLE RESIDUAL DISEASE (MRD)

SUMMARY

REFERENCES

108 Chronic Lymphocytic Leukemia

INTRODUCTION

CLINICAL DESCRIPTION

EPIDEMIOLOGY

DIAGNOSIS

LABORATORY TESTING

MINIMAL/MEASURABLE RESIDUAL DISEASE (MRD) ASSESSMENT

REFERENCES

109 Evaluation of Plasma Cell Neoplasms

OVERVIEW OF ANTIBODY‐SECRETING CELL ORIGIN

LYMPHOMAS WITH PLASMABLASTIC PHENOTYPE

OTHER B CELL NEOPLASMS PRESENTING WITH PLASMA CELL EXPANSIONS

PRIMARY PLASMA CELL NEOPLASM CLASSIFICATION

A BRIEF INTRODUCTION TO CLINICAL INVESTIGATION OF THE PRIMARY PLASMA CELL NEOPLASMS

MORPHOLOGIC FINDINGS

SEROLOGIC AND URINE ANALYSIS

ROLE OF FLOW CYTOMETRY IN THE DIAGNOSIS OF PLASMA CELL NEOPLASMS

FLOW CYTOMETRY FOR PROGNOSTICATION OF PCN DISEASE COURSE AT DIAGNOSIS

REQUIREMENTS FOR BONE MARROW SAMPLE COLLECTION AND STORAGE

A BRIEF OVERVIEW OF THE QUANTITATIVE ASPECTS OF MRD DETERMINATION

ANTIBODY PANEL SELECTION AND ANALYSIS IN MYELOMA FC

MOLECULAR GENETIC MRD EVALUATION

SEROLOGIC TESTS FOR MRD

REMAINING CHALLENGES IN MRD DETECTION

REFERENCES

section P: Transplantation Immunology

110 Introduction: Immunogenetics, Histocompatibility Testing, and Transplantation

111 Human Leukocyte Antigen Biology and Genetics

INTRODUCTION

GENOMIC STRUCTURE AND GENE CONTENTS OF THE MHC REGION

HLA GENETIC CHARACTERISTICS

HLA NOMENCLATURE

HLA PROTEIN STRUCTURE

HLA EXPRESSION

HLA PROTEIN FUNCTION

REFERENCES

112 Human Leukocyte Antigen Genotyping for Allogeneic Transplantations

INTRODUCTION AND BACKGROUND

HLA TYPING FOR ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATIONS (HSCT)

HLA TYPING FOR SOLID ORGAN TRANSPLANTATION

OVERVIEW OF MOLECULAR HLA TYPING METHODS AND AMBIGUITY

HLA TYPING BY SNP‐BASED METHODS

HLA TYPING BY SANGER SEQUENCING

HLA TYPING BY NEXT‐GENERATION SEQUENCING

CONCLUDING REMARKS

ACKNOWLEDGMENT

REFERENCES

113 Human Leukocyte Antigen Antibodies

INTRODUCTION

HLA ANTIBODY TESTING FOR DIAGNOSIS AND PATIENT MANAGEMENT OF VARIOUS CLINICAL CONDITIONS

CLINICAL HLA ANTIBODY TESTING METHODS

CONCLUSION

REFERENCES

114 Non‐HLA Antibodies

INTRODUCTION

NON‐HLA ANTIBODIES IMPLICATED IN ALLOGRAFT REJECTION AND GRAFT LOSS

MECHANISMS OF NON‐HLA ANTIBODY FORMATION

MECHANISMS OF NON‐HLA ANTIBODY‐MEDIATED ALLOGRAFT INJURY

CLINICAL APPLICATION

PROCEDURE AND INTERPRETATION

QUALITY CONTROL (QC)/ASSURANCE (QA)

REFERENCES

115 ABO Blood Groups and Transplantation

INTRODUCTION

CLINICAL DESCRIPTION

LABORATORY TESTING

REFERENCES

116 Cellular Immune Responses in Transplantation

INTRODUCTION

CLINCIAL IMPLICATIONS

LABORATORY TESTING

REFERENCES

117 Molecular Characterization of Injury and Rejection in Solid Organ Transplant

CELL‐FREE DNA

CLINICAL APPLICATION OF DDCFDNA

GENE EXPRESSION PROFILING TECHNIQUES

CLINICAL APPLICATIONS OF TRANSCRIPTOMIC‐BASED METHODS

CONCLUDING REMARKS

REFERENCES

118 Killer Cell Immunoglobulin‐Like Receptors (KIR) in Clinical Transplantation

OVERVIEW OF NK CELLS AND KIR RECEPTORS

KIR IN HEMATOPOIETIC STEM CELL TRANSPLANTATION

KIR IN SOLID ORGAN TRANSPLANTATION

KIR GENOTYPING

CONCLUSION

REFERENCES

119 Chimerism Monitoring

INTRODUCTION

CLINICAL APPLICATION

PROCEDURE

INTERPRETATION OF MOLECULAR METHODS

QUALITY ASSURANCE

SUMMARY

REFERENCES

Index

End User License Agreement

List of Tables

Chapter 2

TABLE 1 Comparison of sequencing platforms

a

TABLE 2 Top 20 filtered genes with highest CADD scores

a

,

b

TABLE 3 Databases for variant frequency, genome browsers, and genomic varia...

Chapter 3

TABLE 1 Approximate number of human V(D)J gene segments used in TCR/Ig gene...

Chapter 5

TABLE 1 Location of radiocontrast and antibiotic spikes on capillary electr...

TABLE 2 Comparison of serum protein intervals by agarose and capillary zone...

TABLE 3 Reflex testing for suspicious bands

a

Chapter 6

TABLE 1 Reported migration characteristics of selected therapeutic monoclon...

TABLE 2 Protocol for urine concentration used at Beaumont Laboratory

Chapter 7

TABLE 1 Classification of cryoglobulins: frequency and concentration

TABLE 2 Classification of cryoglobulins: clinical and laboratory associatio...

TABLE 3 Laboratory abnormalities in cryoglobulinemia

Chapter 8

TABLE 1 Categorization of monoclonal gammopathies (Mayo Clinic 50‐year expe...

TABLE 2 Clinical features of MM at time of diagnosis

a

TABLE 3 IMWG criteria for MM

a

,

b

TABLE 4 Comparison of outcomes: IgM MGUS vs non‐IgM MGUS

a

TABLE 5 Total diagnostic interval for the ratio of free kappa/free lambda v...

TABLE 6 Diagnostic sensitivity of monoclonal gammopathy screening panels wi...

TABLE 7 International Myeloma Working Group criteria for response to therap...

Chapter 10

TABLE 1 Methods of clinical complement laboratory diagnostics

a,

b

TABLE 2 Assay formats, combined analytes, and sample types for research‐bas...

Chapter 11

TABLE 1 Interpretation of complement protein levels in complement‐mediated ...

TABLE 2 Autoantibody assays for C3G

a

Chapter 12

TABLE 1 Complement therapeutics

Chapter 14

TABLE 1 The most abundant families of antigens and the number of members wi...

TABLE 2 Summary of types of dyes used in flow cytometry

a

,

b

Chapter 15

TABLE 1 Recommended reagent conjugates for cross‐platform high‐sensitivity ...

TABLE 2 Recommended reagent conjugates for high‐sensitivity detection of PN...

TABLE 3 Recommended reagent conjugates for high‐sensitivity detection of PN...

TABLE 4 Recommended reagent conjugates for cross‐platform, 6‐, and 7‐C high...

Chapter 16

TABLE 1 Logical gate setup for Stem‐Kit on BD FACSCalibur (Fig. 1A and B)

TABLE 2 Commercial kits for CD34

+

cell enumeration

Chapter 17

TABLE 1 RhIG dose calculator

a

Chapter 18

TABLE 1 Functional flow cytometry‐based assays which have been used as aids...

Chapter 19

TABLE 1 Flow cytometry CPT codes

TABLE 2 Reagent stability

a

TABLE 3 External quality assessment (EQA)/proficiency testing (PT) programs

TABLE 4 Correlation of DPMO

a

Chapter 20

TABLE 1 Applications and preferred platforms

Chapter 23

TABLE 1 B cell markers used in flow cytometry

TABLE 2 Associations with humoral or B lymphocyte deficiencies

TABLE 3 Assays for measurement of B cells and antibodies

TABLE 4

In vitro

activators of B cell proliferation and immunoglobulin prod...

TABLE 5 Pneumococcal target strains for the MOPA

a

Chapter 24

TABLE 1 Methods of enhancing ELISPOT sensitivity

TABLE 2 Parameters influencing ELISPOT assay variability

TABLE 3 Methods of analyzing ELISPOT data

Chapter 25

TABLE 1 Essential phenotypic and functional characteristics of human FOXP3

+

Chapter 26

TABLE 1 Suggested antibody panels for protocol 1: adaptive NK cells and diff...

TABLE 2 Suggested antibody panels for protocol 2: granule constituents

TABLE 3 Suggested antibody panels for protocol 3: functional assay

TABLE 4 Genes associated with strong defects in NK cell development or func...

Chapter 27

TABLE 1 Tube setup for quantitative analysis of generation using superoxi...

TABLE 2 Volumes of specific anti‐phox antibody or nonspecific IgG

1

isotype ...

TABLE 3 Summary of assay characteristics

Chapter 28

TABLE 1 Positivity thresholds for the QuantiFERON‐TB Gold Plus (QFT‐Plus)

TABLE 2 Positivity thresholds for the T‐SPOT.TB test

Chapter 29

TABLE 1 Comparison of functional assays

TABLE 2 Comparison of quantitative assays

Chapter 32

TABLE 1 Characteristics of available IFN measurement methods

Chapter 33

TABLE 1 Anti‐cytokine autoantibody‐associated syndromes

a

Chapter 34

TABLE 1 CLIA‐approved accrediting organizations

TABLE 2 CLIA‐specified personnel positions

TABLE 3 CMS‐approved laboratory director qualifying board examinations

Chapter 35

TABLE 1 Assay validation or verification requirements per CLIA standard 493...

TABLE 2 Considerations prior to development or validation studies

TABLE 3 Example of acquisition requirements for rare event analysis

a

Chapter 36

TABLE 1 Basics of quality assurance (QA) measures

TABLE 2 Key focus areas of laboratory quality management (QM)

TABLE 3 Examples of medical laboratory regulatory agencies

TABLE 4 Selected clinical examples where clinical lab personnel can aid hea...

Chapter 38

TABLE 1 M serotypes associated with nonsuppurative sequelae

a

TABLE 2 Clinical manifestations of group A streptococcal infection and ARF...

TABLE 3 Host immune response to group A streptococcal infection

Chapter 39

TABLE 1 Nontreponemal serologic tests for syphilis

TABLE 2 Common treponemal antibody tests

a

Chapter 40

TABLE 1 Comparative sensitivity of different immunologic methods to detect ...

TABLE 2

Leptospira

species of the pathogenic and intermediate pathogenic gr...

Chapter 41

TABLE 1 Definition of a positive tuberculin test

TABLE 2 Methodological characteristics of T‐SPOT and QFT‐Gold Plus assays

TABLE 3 Pooled sensitivities and specificities of T‐SPOT, QFT‐GIT, and QFT‐...

Chapter 42

TABLE 1 Major commercial serologic test formats for

M. pneumoniae

Chapter 44

TABLE 1 Summary of representative human pathogens

Chapter 47

TABLE 1 Summary of FDA‐cleared serologic assays for

T. cruzi

a

TABLE 2 Sensitivity and specificity of diagnostic tests for

Entamoeba histo

...

TABLE 3 Commercially available molecular amplification panels with stool pa...

Chapter 48

TABLE 1 Commercially available antibody detection tests for fungal diseases...

TABLE 2 Commercially available antigen detection tests for fungal diseases...

Chapter 51

TABLE 1 Recommended laboratory tests for diagnosis and management of EBV in...

TABLE 2 EBV infection category according to patterns of EBV‐specific antibo...

TABLE 3 Laboratory tests for diagnosis and management of CMV infections

Chapter 52

TABLE 1 Biological characteristics of HHV‐6A, HHV‐6B, HHV‐7, and HHV‐8

TABLE 2 Epidemiologic and clinical characteristics of HHV‐6A, HHV‐6B, HHV‐7...

TABLE 3 Diagnostic methods for HHV‐6A/B, HHV‐7, and HHV‐8

Chapter 53

TABLE 1 Common clinical presentations of parvovirus B19 infection

Chapter 54

TABLE 1 Representative SARS‐CoV‐2 serology and adaptive immune response ass...

TABLE 2 Representative antigen assays

TABLE 3 Representative NAATs

a

TABLE 4 Representative point of care (POC) and over‐the‐counter (OTC) NAAT ...

Chapter 55

TABLE 1 Clinical specimens recommended for diagnostic testing

a

Chapter 57

TABLE 1 Characteristics of the five primary hepatitis viruses

TABLE 2 Clinical forms of hepatitis

TABLE 3 Algorithm and interpretation of serological and molecular tests for...

TABLE 4 Algorithm and interpretation of serological and molecular tests for...

TABLE 5 Algorithm and interpretation of serological and molecular tests for...

TABLE 6 Algorithm and interpretation of serological and molecular tests for...

TABLE 7 Algorithm and interpretation of serological and molecular tests for...

Chapter 58

TABLE 1 Medically important arboviruses that infect humans

a

TABLE 2 Clinical manifestations for select clinically relevant arboviruses ...

TABLE 3 Methodologies available for laboratory diagnosis of select acute ar...

Chapter 59

TABLE 1 Laboratory methods used for hantavirus diagnosis

a

Chapter 60

TABLE 1 Selected laboratory (fixed) strains of rabies virus

a

Chapter 61

TABLE 1 Interpretation of the recommended screening and confirmatory test r...

Chapter 62

TABLE 1 Major HIV proteins of diagnostic significance

TABLE 2 FDA‐approved laboratory HIV immunoassays

TABLE 3 FDA‐approved rapid and point‐of‐care HIV screening tests

TABLE 4 FDA‐approved nucleic acid assays and specimen requirements

a

TABLE 5 Viral RNA HIV‐1 resistance and tropism assays

Chapter 63

TABLE 1 Viruses in the genus

Bandavirus

Chapter 65

TABLE 1

S

econdary conditions with congenital T‐cell lymphopenia

TABLE 2 Urgent interventions for neonates with probable SCID or severe TCL ...

TABLE 3 Recommended medical treatment for infection prophylaxis

a

Chapter 66

TABLE 1 CIDs, their immunophenotypes, and select diagnostic tests

a

,

b

Chapter 67

TABLE 1 The main phenotypes of primary antibody deficiencies

a

TABLE 2 Inheritance of antibody deficiencies

a

TABLE 3 Markers defining B cell subsets

TABLE 4 Markers defining T cell subsets

Chapter 68

TABLE 1 Common diagnostic abnormalities in PIRDs

a

Chapter 69

TABLE 1 Summary of common innate immune defects, clinical manifestations, a...

TABLE 2 TLR targets and their ligands used in TLR functional testing to dia...

Chapter 70

TABLE 1 Systemic autoinflammatory disease (SAID) gene‐disease relationships...

Chapter 71

TABLE 1 Complement deficiencies

a

,

b

TABLE 2 Complement testing indicated for investigation of complement defect...

TABLE 3 Genes identified to cause monogenic lupus or lupus‐like disease

a

,

b

...

Chapter 72

TABLE 1 List of genes associated with inherited bone marrow failure syndrom...

Chapter 73

TABLE 1 Somatic pathogenic gene variants that result in an IEI phenocopy

a

TABLE 2 Anti‐cytokine and anti‐complement AAbs resulting in an IEI phenocop...

TABLE 3 Laboratory methods for analysis of anticytokine autoantibodies

a

Chapter 75

TABLE 1 Allergenic extracts currently standardized in the United States

a

Chapter 76

TABLE 1 Clinical conditions in which serological determination of IgE and I...

Chapter 79

TABLE 1 Summary of the clinical relevance of Hep‐2 IFA nuclear patterns

a,

b

...

TABLE 2 Summary of the clinical relevance of Hep‐2 IFA cytoplasmic patterns

TABLE 3 Summary of the clinical relevance of Hep‐2 IFA mitotic patterns

a

,

b

...

Chapter 80

TABLE 1 Some non‐DNA/chromatin autoantibodies useful in the diagnosis of sy...

TABLE 2 Prevalence of some non‐DNA/chromatin autoantibodies by disease

Chapter 81

TABLE 1 Clinical features associated with autoantibodies in autoimmune infl...

TABLE 2 Identification of myositis autoantibodies by IP analysis 

a

,

b

TABLE 3 Summary of validation studies of LIA, ELISA, and PMAT in autoimmune...

Chapter 82

TABLE 1 Structure and function of molecules targeted by SSc‐related autoant...

TABLE 2 Methods for detection and clinical associations with SSc‐related au...

TABLE 3 Commercially available kits for detection of anti‐topo I/Scl‐70, AC...

TABLE 4 American College of Rheumatology/European League Against Rheumatism...

Chapter 83

TABLE 1 Occurrence of IgM RF and anti‐CCP2 among 2,825 patients in the Swed...

Chapter 84

TABLE 1 2023 ACR/EULAR APS clinical classification criteria

TABLE 2 2023 ACR/EULAR APS laboratory classification criteria

a

TABLE 3 APS

non

‐classification laboratory criteria

TABLE 4 Clinical conditions in which the search for aPL is required or sugg...

TABLE 5 Most common variables that may affect LA testing

Chapter 85

TABLE 1 Positioning of ANCA results in the 2022 ACR/EULAR classification cr...

TABLE 2 Comparison of ANCA assays by alignment of cutoff levels

a

,

b

TABLE 3 Harmonization of ANCA assays by likelihood ratios and alignment of ...

Chapter 86

TABLE 1 Immunological testing in Sjögren’s disease

a

Chapter 88

TABLE 1 Phenotypic associations of autoantibodies

a

TABLE 2 Autoantibodies that precede the clinical onset of autoimmune diseas...

TABLE 3 Monogenic defects leading to autoimmune phenotypes

a

Chapter 90

TABLE 1 Summary of techniques used to detect pituitary antibodies in human ...

TABLE 2 Summary of 42 cohort studies using indirect immunofluorescence and ...

Chapter 92

TABLE 1 Neurological syndromes associated with neural autoantibodies

a

TABLE 2 Autoantibody‐mediated encephalitis

TABLE 3 Neuronal and glial autoantibodies against intracellular antigens

a

TABLE 4 Neural autoantibodies against surface antigens

a

Chapter 93

TABLE 1 Clinical syndromes associated with specific antiglycolipid autoanti...

Chapter 94

TABLE 1 Summary of the 2‐oxo‐acid dehydrogenase mitochondrial antigens in P...

TABLE 2 Clinical characteristics of primary biliary cholangitis

TABLE 3 Diagnostic criteria of autoimmune hepatitis

a

TABLE 4 Heterogeneity of microsomal antigens

a

Chapter 95

TABLE 1 Summary of autoantibodies associated with cardiovascular diseases an...

Chapter 96

TABLE 1 Serologic markers available for patients with IBD

a

Chapter 97

TABLE 1 Diagnostic performance of available autoantibodies in celiac diseas...

Chapter 99

TABLE 1 Typical serologic characteristics in autoimmune hemolytic anemia (A...

TABLE 2 Interpretation of serologic findings in suspected cases of autoimmu...

TABLE 3 Immunofluorescence interpretation for GPCA testing

Chapter 100

TABLE 1 International ITP Working Group consensus recommendations for the d...

TABLE 2 Therapies for ITP

Chapter 101

TABLE 1 Antibody responses directed against retinal antigens in sera from p...

Chapter 102

TABLE 1 Target antigens, clinical signs, and diagnostic characteristics of ...

Chapter 104

TABLE 1 FDA‐approved protein tumor markers

TABLE 2 Assay interferences that cause falsely elevated or decreased tumor ...

Chapter 106

TABLE 1 WHO classification of lymphoblastic leukemia/lymphoma

a

TABLE 2 Phenotype‐genotype correlations in ALL

TABLE 3 Sample MRD flow cytometry panels in B‐ALL

a

Chapter 107

TABLE 1 Antibody panels for the evaluation of acute myeloid leukemia

a

Chapter 108

TABLE 1 Typical immunophenotype and differential diagnosis of CLL by flow c...

TABLE 2 Typical immunophenotype and differential diagnosis of CLL by immunoh...

TABLE 3 CLL IPI score sheet

TABLE 4 CLL IPI score predicting risk category

TABLE 5 Comparison between flow cytometry, PCR, and NGS for CLL MRD detectio...

Chapter 111

TABLE 1 Selected HLA associations with autoimmune diseases

a

TABLE 2 Selected HLA antigens/alleles associations with drug hypersensitivi...

Chapter 112

TABLE 1 Evolving NMDP requirements on confirmatory HLA typing performed at ...

Chapter 113

TABLE 1 Therapeutic drugs interfering in crossmatch assays

Chapter 114

TABLE 1 Non‐HLA antibodies implicated in allograft rejection and graft loss...

Chapter 115

TABLE 1 Compatible and incompatible combinations of blood groups for potent...

TABLE 2 Parallels between HLA and ABO antibody detection; common challenges...

Chapter 117

TABLE 1 Selected studies in the development of ddcfDNA as a marker for reje...

TABLE 2 Advantages and disadvantages of expression‐based technologies

Chapter 119

TABLE 1 List of CODIS STR loci

List of Illustrations

Chapter 2

FIGURE 1 Example of short‐ and long‐read sequencing. (A) Short‐read sequenci...

FIGURE 2 Alignment of NGS reads against a reference and variant identificati...

FIGURE 3 Heterozygous short structural variations. (Top) Short‐read sequenci...

FIGURE 4 RNA‐Seq data visualization. (Top) Transcript alignment across a gen...

FIGURE 5 Constraint scores from gnomAD for three genes. (A)

TLR5

demonstrate...

FIGURE 6 Filtering of variants from whole‐exome sequencing. Starting with al...

FIGURE 7 Use of protein domains and conservation to predict damaging variant...

FIGURE 8 Splicing motifs which may be mutated leading to disease. (Top) Line...

Chapter 3

FIGURE 1 Immunoglobulin structure. Immunoglobulins (Igs), the primary compon...

FIGURE 2 Structure of the αβ and γδ T‐cell receptor....

FIGURE 3 B‐cell receptor loci. The BCR comprises two identical κ...

FIGURE 4 αβ T‐cell receptor loci. The variable region of the...

FIGURE 5 Somatic V(D)J rearrangement of the B‐cell receptor (Ig). Somatic re...

FIGURE 6 Somatic V(D)J rearrangement of the T‐cell receptor α. ...

FIGURE 7 Representative clonal versus polyclonal patterns generated by PCR a...

FIGURE 8 Workflow of NGS‐based gene rearrangement testing for Ig and/or TCR....

FIGURE 9 Representative output data of NGS‐based TCR rearrangement testing. ...

Chapter 5

FIGURE 1 General structure of an amino acid. The R group determines the spec...

FIGURE 2 The peptide bond formation between two amino acids creates a dipept...

FIGURE 3 Serum has sharp separation of major protein bands on the electrophe...

FIGURE 4 (A) The capillary zone electropherogram pattern has two alpha‐1 ant...

FIGURE 5 The top panel shows a capillary zone electropherogram from a patien...

FIGURE 6 (A) This Levey‐Jennings chart monitors the daily variation of album...

FIGURE 7 Capillary zone electropherogram demonstrating a characteristic spli...

FIGURE 8 The left shows a capillary zone electropherogram pattern with a fla...

FIGURE 9 Evaluation of fluid for possible cerebral spinal fluid (CSF) origin...

FIGURE 10 A capillary zone electropherogram from a patient with nephrotic sy...

FIGURE 11 (A) Agarose gel electrophoresis with four samples. The bottom samp...

FIGURE 12 Representative normal capillary zone electropherogram with typical...

FIGURE 13 Capillary zone electropherogram with a prominent M‐protein spike (...

FIGURE 14 On the left, a capillary zone electropherogram demonstrates serum ...

FIGURE 15 On the left, a capillary zone electropherogram is shown from serum...

FIGURE 16 Capillary zone electropherogram demonstrating a broad increase in ...

FIGURE 17 This capillary zone electropherogram demonstrates a cirrhosis patt...

FIGURE 18 This capillary zone electropherogram demonstrates a nephrotic patt...

FIGURE 19 This agarose gel electrophoresis demonstrates 30 serum patterns. S...

FIGURE 20 This capillary zone electropherogram shows a prominent beta region...

FIGURE 21 This capillary zone electropherogram shows an increase in the C3 b...

FIGURE 22 Two capillary zone electropherogram patterns. On the left, the C3 ...

FIGURE 23 Measurement of M‐proteins, especially with underlying polyclonal b...

FIGURE 24 Several urine protein electrophoretic patterns are shown on concen...

FIGURE 25 A densitometric scan of an agarose gel is shown from a urine sampl...

FIGURE 26 A capillary zone electropherogram demonstrates the radiocontrast d...

Chapter 6

FIGURE 1 (A) Normal serum electropherogram; (B) normal serum immunofixation ...

FIGURE 2 (A) Electropherogram with monoclonal protein in gamma region; (B) i...

FIGURE 3 (A) Serum immunofixation gel with no staining in the lambda lane, d...

FIGURE 4 (A) Antigen excess present in IgM lane; (B) antigen excess present ...

FIGURE 5 (A) Normal serum immunosubtraction pattern; (B) immunosubtraction s...

FIGURE 6 (A) Electropherogram with polyclonal increase in gamma globulins; (...

FIGURE 7 (A) Rounded peak in beta‐gamma region representing increased polycl...

FIGURE 8 Serum immunofixation gel with both IgM lambda and IgG kappa monoclo...

FIGURE 9 Serum immunofixation gel with a free lambda monoclonal protein demo...

FIGURE 10 IgG heavy chain disease. (A) Immunosubtraction showing removal of ...

FIGURE 11 Sequential studies in a single patient. (A) Original PEP pattern. ...

FIGURE 12 Prominent oligoclonal banding. (A) Immunosubtraction; (B) immunofi...

FIGURE 13 Contrast medium artifact. (A) Electropherogram from capillary elec...

FIGURE 14 Shadow artifact on immunofixation gel caused by incomplete washing...

FIGURE 15 (A) A densitometric scan from concentrated urine showing a monoclo...

FIGURE 16 IFE on concentrated urine demonstrating a dominant free kappa and ...

FIGURE 17 (A) IFE on concentrated urine demonstrating a free kappa and free ...

FIGURE 18 Eight paired CSF (lanes 1 to 4 and 6 to 9) and sera (lanes 1′ to 4...

Chapter 7

FIGURE 1 Cryoglobulinemic vasculitis occurs when immunoglobulins are deposit...

FIGURE 2 Cryoglobulinemia was initially missed in a patient with cutaneous v...

FIGURE 3 Kinetics of cryoprecipitation, assessed by turbidimetric analysis, ...

FIGURE 4 Isolated washed cryofibrinogen (arrows) visualized by agarose gel e...

Chapter 8

FIGURE 1 (A) Densitometric scan from agarose gel electrophoresis of normal s...

FIGURE 2 (A) IEF on normal serum shows typical locations and broad distribut...

FIGURE 3 ISUB from a patient with IgGL M‐protein. The M‐protein spike is rem...

FIGURE 4 (A) Serum with decreased albumin, a prominent broad restriction in ...

FIGURE 5 (A) SPEP from a patient with AL amyloidosis with a normal electroph...

FIGURE 6 CAP guidelines (modified from Keren et al. 2022 [1]). *Additional t...

FIGURE 7 Measurements of 3 different pairs of serum samples by tangent skimm...

FIGURE 8 (A) SPEP revealing an increased total beta region with a beta‐2 (C3...

FIGURE 9 Average progress from SMM to MM for 417 patients based on the Mayo ...

Chapter 10

FIGURE 1 Spectrum of diseases either initiated or triggered by complement de...

FIGURE 2 Algorithm of complement analysis.

Chapter 11

FIGURE 1 The complement system, an important branch of innate immunity, prov...

FIGURE 2 (Top) Complement activity on host surfaces is prevented by both flu...

FIGURE 3 Environmental triggers of HUS include bacterial infections, viruses...

FIGURE 4 DDD and C3GN are driven by dysregulation of the C3 and C5 convertas...

Chapter 14

FIGURE 1 Schematics of the main components of a flow cytometer. A single‐cel...

FIGURE 2 Schematics of the voltage pulse and time delay. Area, height, and w...

FIGURE 3 Example of QC plots. On a daily basis, eight peak beads are run on ...

FIGURE 4 Illustration of Ficoll‐Hypaque and whole blood as samples to stain....

FIGURE 5 Summary tables of the most common fluorochromes used in flow cytome...

FIGURE 6 Illustration of the stain index. (A) Theoretical stain index (SI) r...

FIGURE 7 Illustration of titration of monoclonal antibody. An FCS format rep...

FIGURE 8 Tubes (staining) of CLIP panel organized by lineage. Black, markers...

FIGURE 9 Spectral cytometer 23‐color panel design. (A) Similarity index and ...

Chapter 15

FIGURE 1 (A) Instrument setup for a high‐sensitivity RBC assay on a BD FACSC...

FIGURE 2 Example of a 3‐C iRBC/mRBC assay; PNH sample stained with CD235a FI...

FIGURE 3 Example of 4‐C high‐sensitivity neutrophil assay. A sample from a l...

FIGURE 4 Example of PNH case stained with 4‐C high‐sensitivity monocyte assa...

FIGURE 5 (A) Example of normal sample stained with a 4‐C high‐sensitivity ne...

FIGURE 6 Example of a 5‐C single‐tube CD157‐based assay for PNH neutrophils ...

FIGURE 7 (A and B) Two samples containing type II neutrophils and monocytes....

FIGURE 8 Example of a CD157‐negative case. This represents a rare case in wh...

FIGURE 9 Example of a 6‐C single‐tube Navios assay for PNH neutrophils and m...

FIGURE 10 Example of a cross‐platform 7‐C assay on a Canto II cytometer; ana...

FIGURE 11 Generic reporting template for mRBCs, iRBCs, neutrophils, and mono...

Chapter 16

FIGURE 1 (A) Enumeration of viable CD34

+

cells with the single‐platform ISHA...

FIGURE 2 Enumeration of viable CD34

+

cells with Stem‐Kit on a Beckman Navios...

FIGURE 3 Enumeration of viable CD34

+

cells with Stem‐Kit on a Navios cytomet...

FIGURE 4 Absolute viable CD34

+

cell counting with the ISHAGE single‐platform...

FIGURE 5 Absolute viable CD34

+

cell counting with the ISHAGE single‐platform...

FIGURE 6 Absolute viable CD34

+

cell counting with the ISHAGE single‐platform...

FIGURE 7 Comparison of recovery of viable CD34

+

cells in a postthawed cord b...

FIGURE 8 Enumeration of CD34

+

cells in a stabilized peripheral blood sample ...

FIGURE 9 Simultaneous detection of absolute viable CD34

+

and CD3

+

cells usin...

FIGURE 10 Simultaneous enumeration of viable CD34

+

cells and viable CD3

+

cel...

FIGURE 11 Simultaneous enumeration of viable CD34

+

and viable CD3

+

cells in ...

FIGURE 12 Identifying CD34

+

cell subsets using the

CPC

support protocol (42,...

FIGURE 13 Identifying CD34

+

cell subsets in the marrow of poor mobilizer. CD...

Chapter 17

FIGURE 1 (A) log FSC‐A/log FSC‐H dot plot used for excluding doublets and ag...

FIGURE 2 (A and B) Normal control (A) results versus patient specimen result...

FIGURE 3 FSC/SSC dot plot. (A) RBCs with a primary gate (R1) drawn around th...

FIGURE 4 Histograms, assay values, and expected ranges for all FETALtrol 3‐l...

FIGURE 5 Histogram of a normal/negative control sample. There are few if any...

FIGURE 6 Patient test sample with FRBCs present within the R2‐statistical ga...

FIGURE 7 Summary of results of an FRBC flow panel showing the gate (R1) arou...

Chapter 18

FIGURE 1 Flow cytometry‐based LAD screening assay on a nondiseased healthy d...

FIGURE 2 Gating algorithm and histogram display of CD40‐ligand upregulation ...

FIGURE 3 The flow cytometry oxidative burst CGD screening assay performed on...

FIGURE 4 Example of the flow cytometry oxidative burst assay results for a C...

Chapter 19

FIGURE 1 The quality management system model for laboratory services: path o...

FIGURE 2 Factorial design for precision.

FIGURE 3 Level‐Jennings plots of flow cytometry instrument quality control d...

FIGURE 4 Linearity and the background signal of an unstained bead population...

FIGURE 5 Example QI metrics for percent late due to laboratory.

Chapter 21

FIGURE 1 Laboratory‐based assays related to functional cellular assays and t...

Chapter 22

FIGURE 1 Proliferation assays on cryopreserved PBMCs. (A) The effect of cryo...

FIGURE 2 Effect of viability on ELISPOT results using cryopreserved PBMCs. D...

FIGURE 3 Immunophenotypic assays using cryopreserved PBMCs. (A and B) The ef...

FIGURE 4 Effect of cryopreserved PBMC viability on functional responses meas...

FIGURE 5 Viability and recovery data for long‐term repository samples. Nine ...

FIGURE 6 CEF and CMV response for long‐term repository samples as measured b...

FIGURE 7 Effect of cell concentration in cryopreserved PBMCs on cell recover...

FIGURE 8 Effects of leukopak processing on ELISPOT functional response. Afte...

Chapter 25

FIGURE 1 Regulatory T cell (Treg) classification. Tr1 type 1 regulatory T ce...

FIGURE 2 Most common assays to interrogate the phenotype and function of Tre...

Chapter 26

FIGURE 1 (A) Gating strategy for flow cytometric analysis of CD56

dim

CD16

+

NK...

FIGURE 2 (A) Gating strategy for flow cytometric analysis of NK cells. The s...

FIGURE 3 Functional responses by CD3

–

CD56

dim

NK cells from patients an...

Chapter 27

FIGURE 1 Analysis of H

2

O

2

production by dihydrorhodamine 123 staining. PMN p...

FIGURE 2 Histochemical staining of PMN with NBT. (A) PMN from a healthy volu...

FIGURE 3 Analysis of PMN ROS generation by luminol‐enhanced chemiluminescenc...

FIGURE 4 Analysis of phox protein expression in permeabilized PMN by flow cy...

FIGURE 5 Immunoblot analysis of phox subunits of NOX2. DFP‐treated...

Chapter 33

FIGURE 1 Summary of anticytokine autoantibody detection assays. LIPS, lucife...

Chapter 35

FIGURE 1 Stages in assay development and validation.

FIGURE 2 Intra‐ and interassay precision for soluble CD25 measurement by ELI...

FIGURE 3 Calculation of LoB, LoD, and LoQ. LoD, LoB, and LoQ were calculated...

FIGURE 4 Example of a Levey‐Jennings chart. The sample mean is indicated by ...

FIGURE 5 Assay results were trended over the course of 12 months. The shaded...

Chapter 36

FIGURE 1 Preanalytical factors.

FIGURE 2 Analytical factors.

FIGURE 3 Postanalytical factors.

FIGURE 4 IQCP process.

Chapter 38

FIGURE 1 Schematic diagram of cellular and extracellular antigens of group A...

Chapter 39

FIGURE 1 Traditional algorithm. The traditional algorithm begins with a nont...

FIGURE 2 Reverse testing algorithm. Sera are first tested with a treponemal ...

Chapter 40

FIGURE 1 (A) Examples of positive Lyme IgM (lane 1) and IgG (lane 2) Western...

Chapter 41

FIGURE 1 (A) Tuberculin skin test. Intradermal injection of PPD (0.1 ml) on ...

FIGURE 2 Reading of the T‐SPOT TB test. The positive‐control mitogen should ...

Chapter 43

FIGURE 1 Example of culture positive for

Chlamydia trachomatis

, as confirmed...

FIGURE 2 Example of a positive microimmunofluorescence (MIF) serologic react...

Chapter 44

FIGURE 1 Taxonomy of representative human pathogens in the order

Rickettsial

...

Chapter 45

FIGURE 1 Taxonomy of the major human pathogens in the families

Bartonellacea

...

Chapter 48

FIGURE 1 Examples of ID results observed when a seven‐well agar gel pattern ...

FIGURE 2 Organization of the microtiter plates and results for the CF assay....

Chapter 51

FIGURE 1 Correlations between time of primary infection, disease expression,...

Chapter 53

FIGURE 1 Electron micrograph of serum from a patient with sickle cell diseas...

FIGURE 2 Virologic, immunologic, and clinical courses after parvovirus B19 i...

Chapter 54

FIGURE 1 SARS‐CoV‐2 disease course and diagnostics.

Chapter 55

FIGURE 1 Picornavirus phylogeny. The

Picornaviridae

family can be divided in...

FIGURE 2 Confirmed cases of acute flaccid myelitis (AFM) in the United State...

Chapter 57

FIGURE 1 Typical course of the virological and immunological manifestations ...

FIGURE 2 Virological profiles observed in patients infected with HBV. (Top) ...

FIGURE 3 Virological profiles observed in patients infected with HCV: the co...

FIGURE 4 Virological profiles observed in patients infected with HDV. There ...

Chapter 59

FIGURE 1 The time course of the clinical manifestations, laboratory findings...

Chapter 60

FIGURE 1 RABV genomic and virion structure. N designates the nucleoprotein, ...

FIGURE 2 Schematic representation of the RFFIT method to quantify serum VNA ...

Chapter 61

FIGURE 1 Representative examples of HTLV‐1‐positive and HTLV‐2‐positive WB p...

Chapter 62

FIGURE 1 Structure of the HIV virion. The HIV genome consists of three major...

FIGURE 2 Diagnostic HIV testing algorithm showing the sequence of follow‐up ...

FIGURE 3 Approximate time course (median, 25th,75th, and 99th percentiles) f...

Chapter 63

FIGURE 1 Genetic relatedness of the genus

Bandavirus

. The L protein amino ac...

FIGURE 2 Geographic distribution of virus strains in the genus

Bandavirus

. C...

Chapter 65

FIGURE 1 Schematic representation of the

TCRAD

locus and the formation of TR...

FIGURE 2 Example of an algorithm for managing an abnormal TREC NBS, assuming...

Chapter 66

FIGURE 1 Flow cytometry immunophenotyping results from a healthy control (to...

FIGURE 2 (A) The relative proportion of 24 different TCR Vβ...

FIGURE 3 (A) Flow cytometry analysis showing phosphorylated ATM (pATM) at 1 ...

Chapter 67

FIGURE 1 Extended B‐cell immunophenotyping. The fluorescence‐activated cell ...

FIGURE 2 Representative flow cytometry histograms of BTK protein expression ...

FIGURE 3 CD40L expression. Lymphocytes are defined by CD45 versus SSC. Prior...

FIGURE 4 XIAP and SAP by flow cytometry. Lymphocytes are defined based on FS...

Chapter 68

FIGURE 1 Clinical categorization of PIRDs, including relevant genes.

FIGURE 2 Autoinflammatory and hyperinflammatory PIRD gene defects.

FIGURE 3 Common autoimmune and lymphoproliferation clinical profile of PIRDs...

FIGURE 4 Representative immunohistological abnormalities noted in PIRDs. (A ...

FIGURE 5 (A to E) Illustrative flow cytometric T cell profile in PIRD, demon...

FIGURE 6 (A to D) Illustrative flow cytometric B cell profile in PIRD, inclu...

FIGURE 7 Flow cytometry plots of heathy control (HC) and hypomorphic

FOXP3

m...

FIGURE 8 JPM50.6 transfection test for novel CARD11 variants based on TCR‐in...

Chapter 69

FIGURE 1 IκBα degradation across TNF‐α concentrations measured...

FIGURE 2 Characteristic flow plots showing unstimulated granulocytes (blue) ...

FIGURE 3 Overview of the workflow for natural killer (NK) cell laboratory te...

Chapter 70

FIGURE 1

(

A) Pathogenesis of inflammasome‐mediated disorders. Gain of functi...

Chapter 71

FIGURE 1 Testing for complement defects may have three tiers. Suggested test...

FIGURE 2 Challenges associated with homologous gene regions using next‐gener...

FIGURE 3 Classification criteria for systemic lupus erythematosus updated by...

Chapter 72

FIGURE 1 An algorithmic approach to screen and diagnose patients with inheri...

Chapter 73

FIGURE 1 Anti‐cytokine autoantibodies, corresponding IEIs, and the spectrum ...

FIGURE 2 Laboratory analyses for anticytokine autoantibodies. Functional ana...

FIGURE 3 Flow cytometry analysis for neutralizing anti‐IFN‐γ...

Chapter 75

FIGURE 1 Sample calculation of D

50

. Serial 3‐fold dilutions of test material...

FIGURE 2 Hypothetical parallel line bioassay curves. In panel A, the bioassa...

FIGURE 3 Diameters are measured from the inner margins of the penned outline...

Chapter 77

FIGURE 1 Diagrammatic representation of preparation of peripheral blood baso...

Chapter 79

FIGURE 1 Nomenclature and classification tree of ANA patterns based on IFA o...

FIGURE 2 Example of Hep‐2 IFA test report according to the ICAP initiative g...

Chapter 80

FIGURE 1 Immunoprecipitation analysis of lupus autoantibodies. (A) Proteins...

Chapter 81

FIGURE 1 IP analysis of protein components of autoantigens recognized by aut...

FIGURE 2 IP analysis of RNA components of autoantigens recognized by autoant...

Chapter 82

FIGURE 1 Diagram showing SSc subsets stratified by autoantibodies. Areas of ...

FIGURE 2 Typical indirect immunofluorescence patterns on Hep‐2 cell slides. ...

FIGURE 3 Outline flowchart for identification of SSc‐related autoantibodies,...

Chapter 83

FIGURE 1 (A to C) Correlation between RF values obtained with non‐isotype‐sp...

FIGURE 2 (A and B) Distribution of levels of (A) IgM RF and (B) anti‐CCP in ...

Chapter 84

FIGURE 1 Main pathogenic mechanisms mediated by β2GPI‐dependent...

FIGURE 2 aPL as a risk factor for APS manifestation.

FIGURE 3 Anti‐CL and anti‐β2GPI ELISA principles....

Chapter 85

FIGURE 1 International consensus on ANCA testing in ANCA‐associated vasculit...

FIGURE 2 Autoantibody testing in small‐vessel vasculitis. Small‐vessel vascu...

Chapter 87

FIGURE 1 Illustration of adenosine metabolism and methods to detect ADA acti...

FIGURE 2 Sample data from spectrophotometric measurement of plasma ADA2 acti...

FIGURE 3 Plasma ADA2 measurement from healthy controls, carriers with monoal...

Chapter 88

FIGURE 1 Schematic representation of the structure of an immunoglobulin G wi...

FIGURE 2 Schematic representation of Western blot and immunoprecipitation us...

FIGURE 3 Schematic representation of multiplex immunoassays: planar arrays a...

FIGURE 4 Schematic representation of precision medicine steps highlighting h...

Chapter 90

FIGURE 1 Evolution of the TSHR antibody assay.

FIGURE 2 Detection of serum pituitary antibodies by indirect immunofluoresce...

FIGURE 3 Progression to diabetes in children positive for islet autoantibodi...

FIGURE 4 ICA and biochemically defined islet autoantibodies.

FIGURE 5 General outline of fluid‐phase 96‐well plate radiobinding assays fo...

FIGURE 6 Format of the electrochemiluminescence (ECL) assay. In the illustra...

FIGURE 7 Illustration of a multiplex ECL assay. The autoantibodies in serum ...

FIGURE 8 3‐Screen ICA ELISA assay principle. The figure has been reproduced ...

FIGURE 9 Workflow of ADAP. The serum is incubated with islet antigen conjuga...

Chapter 91

FIGURE 1 The fetal and adult AChR.

FIGURE 2 Mechanisms of antibody‐mediated MG (see text).

FIGURE 3 A recommended testing algorithm for MG diagnosis (see text).

Chapter 92

FIGURE 1 Neural and glial intracellular autoantibodies. The pictures show di...

FIGURE 2 Antibodies against neuronal surface antigens.

FIGURE 3 Immunohistochemical patterns of neuronal surface autoantibodies. Th...

FIGURE 4 Antigen‐specific tests for autoantibody detection. (A) Autoantibodi...

Chapter 93

FIGURE 1 Examples of clinically relevant ganglioside structures.

FIGURE 2 Standard antiganglioside ELISA pattern of ganglioside coating. Pair...

FIGURE 3 Screening plate layout with 4 patient samples per plate at a single...

FIGURE 4 Titration plate with 2 patient samples per plate, at 2 concentratio...

Chapter 94

FIGURE 1 Detection of AMAs by indirect immunofluorescence on HEp‐2 cells. No...

FIGURE 2 Reactivity of PBC sera with bovine heart mitochondria. Bovine heart...

FIGURE 3 Detection of liver kidney microsomal (LKM) and antimitochondrial an...

Chapter 95

FIGURE 1 Cardiac excitation‐contraction coupling. βAR,...

FIGURE 2 Autoantibodies and cardiomyopathies. ACM, arrhythmogenic cardiomyop...

FIGURE 3 Autoantibodies and cardiac arrhythmias. AF, atrial fibrillation; AT...

FIGURE 4 Autoantibodies and vasculopathies. αAR,

Chapter 96

FIGURE 1 IBD genes and their associated pathways in mucosal homeostasis.

FIGURE 2 TDM may not offer an advantage to patient management compared to cl...

FIGURE 3 Distribution of leukopenia frequency among patient groups with diff...

Chapter 97

FIGURE 1 Histologic grades of intestinal mucosa damage in patients with CD. ...

Chapter 98

FIGURE 1 Scanning electron micrograph of podocytes (P) wrapping around a glo...

FIGURE 2 The structure of PLA2R. CysR, cysteine rich domain; FnII, fibronect...

FIGURE 3 Cell‐based indirect immunofluorescence assay (CBA IFA) for positive...

FIGURE 4 Time course of PLA2R antibody in serum and kidney and clinical dise...

FIGURE 5 Thrombospondin type‐1 domain containing 7A (THSD7A) structure.

Chapter 100

FIGURE 1 Pathophysiology of ITP (adapted from reference 36). Multiple cells ...

FIGURE 2 Outline of the MAIPA (adapted from references 69–71). Platelets whi...

Chapter 101

FIGURE 1 Immunofluorescence staining for antiretinal antibodies. Frozen sect...

Chapter 102

FIGURE 1 Differential diagnosis of autoimmune blistering diseases based on d...

FIGURE 2 n‐Serrated pattern (left) and u‐serrated pattern (right) detected u...

FIGURE 3 Differential diagnosis of autoimmune blistering diseases based on t...

FIGURE 4 BIOCHIP mosaic for multivariate diagnostic testing of the most comm...

FIGURE 5 Clinical presentation of selected autoimmune bullous diseases. (A) ...

Chapter 104

FIGURE 1 (Left) Schematic diagram of a competitive binding (labeled‐antigen)...

FIGURE 2 Schematic diagram of a noncompetitive binding two‐site sandwich imm...

FIGURE 3 In immunometric assays, a Hook effect can occur when the capture an...

FIGURE 4 Schematic diagram showing result deviation from linearity that may ...

Chapter 105

FIGURE 1 Representative illustration of the various immune monitoring techno...

FIGURE 2 Illustration of the experimental assay setup geared at evaluating T...

Chapter 106

FIGURE 1 Normal B‐cell maturation in the bone marrow. Bone marrow aspirate s...

FIGURE 2 Normal T‐cell maturation in the thymus. Flow‐cytometric analysis of...

FIGURE 3 Lineage assignment of lymphoid progenitor populations. Peripheral b...

FIGURE 4 Comprehensive panel for diagnosis and MRD monitoring of B‐ALL. Bone...

FIGURE 5 Comprehensive panel for diagnosis and MRD monitoring of T‐ALL. Bone...

FIGURE 6 Example of B‐ALL MRD. Bone marrow aspirate sample. Compared to norm...

FIGURE 7 Example of T‐ALL MRD. Bone marrow aspirate sample. Compared to norm...

Chapter 107

FIGURE 1 Population identification and normal differentiation from stem cell...

FIGURE 2 Acute promyelocytic leukemia with

PML

::

RARA

fusion. The upper‐left ...

FIGURE 3 Acute myeloid leukemia with FLT3 ITD and NPM1 mutation. The upper‐l...

FIGURE 4 Detection of MRD for acute myeloid leukemia with a RAM‐phenotype by...

Chapter 108

FIGURE 1 Peripheral blood involvement by chronic lymphocytic leukemia/small ...

FIGURE 2 Three patterns of bone marrow involvement by chronic lymphocytic le...

FIGURE 3 Lymph node involvement by chronic lymphocytic leukemia/small lympho...

FIGURE 4 Diagnosing chronic lymphocytic leukemia (CLL) by flow cytometry. CL...

FIGURE 5 Minimal/measurable residual disease (MRD) detection by flow cytomet...

Chapter 109

FIGURE 1 Diagnostic algorithm and potential outcomes of evaluation for a sus...

FIGURE 2 Typical phenotypic findings in a primary plasma cell neoplasm (A) a...

FIGURE 3 Plasma cell neoplasm (magenta) lacking both informative CD38 and CD...

FIGURE 4 Phenotypic heterogeneity of normal plasma cells. Note the CD56

+

, CD...

FIGURE 5 Evaluation of sample hemodilution in an MM MRD sample. Note maturin...

Chapter 111

FIGURE 1 Gene map of the HLA region. White, gray, striped, and black boxes s...

FIGURE 2 HLA‐DR haplotype groups.

FIGURE 3 Nomenclature of HLA alleles.

FIGURE 4 Scheme and 3D structure of MHC class I (left) and class II (right) ...

Chapter 112

FIGURE 1 Commonly used HLA typing methods in contemporary histocompatibility...

FIGURE 2 HLA typing ambiguity in the context of typing methods and allele fr...

FIGURE 3 Various approaches to targeted NGS HLA typing (A) and bioinformatic...

Chapter 113

FIGURE 1 Mechanisms of antibody production and antibody‐mediated cell and ti...

FIGURE 2 CDC assay principle. (A) Assay set up. (B) Interpretation of PRA re...

FIGURE 3 Various formats for SPI assays and test setup.

FIGURE 4 HLA antibody detection and immunologic risk assessment for TRALI.

FIGURE 5 HLA antibody detection and immunologic risk assessment for PR.

FIGURE 6 HLA antibody detection and immunologic risk assessment for HCT.

FIGURE 7 HLA antibody detection and immunologic risk assessment for SOT. *Th...

FIGURE 8 Assay platform comparison. The same serum was tested by different a...

Chapter 114

FIGURE 1 Mechanisms of non‐HLA antibody generation and allograft injury. (A)...

FIGURE 2 Clinical assays to detect non‐HLA antibodies include both solid‐pha...

Chapter 115

FIGURE 1 ABH antigen subtypes and tissue distribution (46, 48, 85).

FIGURE 2 A‐subtype antigen expression in an A1 human heart (13).

FIGURE 3 A‐subtype antigen expression in an A1 human kidney (49).

FIGURE 4 Red blood cell suspension is added to serial doubling dilutions of ...

FIGURE 5 Numerous modifications exist to the ABO titer assay, including but ...

FIGURE 6 A comprehensive understanding of the ABO genotype, ABO phenotype an...

Chapter 116

FIGURE 1 Comparison of direct versus indirect allorecognition. Alloreactivit...

Chapter 117

FIGURE 1 Preparation of labeled complementary RNA (cRNA) proceeds through th...

Chapter 118

FIGURE 1 Natural killer (NK) cell recognition. NK cells are fast‐acting effe...

FIGURE 2 Killer cell immunoglobulin‐like receptors (KIRs). Fourteen distinct...

FIGURE 3 KIR haplotypes have variable gene content. Map of KIR haplotypes as...

FIGURE 4 The NK cells acquire functional maturation by interacting with thei...

Chapter 119

FIGURE 1 Donor and recipient loci examples of noninformative (both recipient...

Guide

Cover Page

Title Page

Copyright Page

Editorial Board

Contributors

Preface

Author and Editor Conflicts of Interest

Title Page

Copyright Page

Editorial Board

Contributors

Preface

Author and Editor Conflicts of Interest

Table of Contents

Begin Reading

Index

WILEY END USER LICENSE AGREEMENT

Pages

iii

iv

xi

xiii

xiv

xv

xvi

xvii

xviii

xix

xx

xxi

xxii

xxiii

xxiv

xxv

xxvi

1

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

107

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

333

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

363

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

622

617

618

619

620

621

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644

645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665

666

667

668

669

670

671

672

673

674

675

676

677

iii

iv

xi

xiii

xiv

xv

xvi

xvii

xviii

xix

xx

xxi

xxii

xxiii

xxiv

xxv

xxvi

679

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743

744

745

746

747

748

749

750

751

752

753

754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780

781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

845

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866

867

868

869

870

871

872

873

874

875

876

877

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936

937

938

939

940

941

942

943

944

945

946

947

948

949

950