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Karsten Conrad, Werner Schößler, Falk Hiepe,

Marvin J. Fritzler

Autoantibodies in Organ SpecificAutoimmune Diseases

PABST

The measurement of autoantibodies is an essential part of medicalinvestigation and diagnostics, and, in turn, the prognostics of organspecific autoimmune diseases. Since practically all organs and tis-sues can be affected by autoimmune processes, nearly all medicaldisciplines will be confronted with autoimmune diseases. The

remarkable spectrum of autoantibodies with confirmed or potential diagnosticand/or pathogenetic relevance to organ specific autoimmune diseases is everincreasing. Considerable progress has also been made in the development andoptimization of autoantibody detection methods. Therefore, more and moreautoantibodies are detectable in the normal routine laboratory. The diagnosticsand differential diagnostics of neurological diseases in particular have profitedfrom the knowledge gained and discoveries made in recent years. Through thisprogress however, the demands for serological tests as well as the interpretationof laboratory results has also increased. This reference book supplies useful infor-mation intended for all physicians active in the field of diagnostics, who are con-fronted with autoimmune diseases in their daily work. This volume covers notonly the autoantibodies occurring in organ specific autoimmune diseases, butalso the diseases themselves and their symptoms. In addition to those autoanti-bodies known to be diagnostic markers, the user will also be presented withautoantibodies of former but not current diagnostic relevance. Numerous newlydescribed autoantibodies with confirmed or potential clinical relevance, whichare currently not accessible for routine diagnostics, are also described so that thisvolume is also of interest to scientists active in the field of autoimmunology.

ISBN 978-3-89967-734-8www.pabst-publishers.com

A Diagnostic Reference

AUTOANTIGENS, AUTOANTIBODIES, AUTOIMMUNITYVolume 8 – 2011

umschlag_neutral.qxd 02.09.2011 11:56 Seite 1

Autoantibodies in Organ Specific Autoimmune DiseasesA Diagnostic Reference

Karsten Conrad, Werner Schößler, Falk Hiepe, Marvin J. Fritzler

Gesellschaft zur Förderung der Immundiagnostik e.V.Dresden

http://www.GFID-eV.de

AUTOANTIGENS, AUTOANTIBODIES, AUTOIMMUNITY

Edited by: K. Conrad (Dresden, Germany)U. Sack (Leipzig, Germany)Vol. 8 – 2011

Authors

PD Dr. Karsten ConradInstitute for ImmunologyMedical Faculty of the Technical University DresdenFetscherstraße 7401307 Dresden, GERMANY

Phone: +49 (0) 351-458-6540Fax: +49 (0) 351-458-6308E-mail: K Conrad@mail.zih.tu-dresden.de

Dr. Werner SchößlerRathenaustr. 1216341 Panketal, GERMANY

Fax: +49 (0) 30-983-119-94E-mail: Dr.Schoessler@arcor.de

Prof. Dr. Falk HiepeCharite University HospitalDepartment of Rheumatology & Clinical ImmunologySchumannstraße 20/2110117 Berlin, GERMANY

Phone: +49 (0) 30-450-513012Fax: +49 (0) 30-450-51392E-mail: Falk.Hiepe@charite.de

Prof. Marvin J. Fritzler, MD, PhDProfessor of MedicineArthritis Society ChairFaculty of MedicineUniversity of Calgary3330 Hospital Dr NWCalgary, Alberta, CANADA

T2N 4N1Phone: +01 403-220-3533Fax: +01 403-283-5666E-mail: Fritzler@ucalgary.ca

Karsten Conrad, Werner Schößler, Falk Hiepe, Marvin J. Fritzler

Autoantibodies in OrganSpecific AutoimmuneDiseases

A Diagnostic Reference

AUTOANTIGENS, AUTOANTIBODIES, AUTOIMMUNITY

Volume 8 – 2011

PABST SCIENCE PUBLISHERS

Lengerich, Berlin, Bremen, Miami,Riga, Viernheim, Wien, Zagreb

Bibliographic information published by Deutsche NationalbibliothekThe Deutsche Nationalbibliothek lists this publication in the Deutsche Na-tionalbibliografie; detailed bibliographic data is available in the Internet at<http://dnb.ddb.de>.

This work is subject to copyright. All rights are reserved, whether the whole or partof the material is concerned, specifically the rights of translation, reprinting, reuse ofillustrations, recitation, broadcasting, reproduction on microfilms or in other ways,and storage in data banks. The use of registered names, trademarks, etc. in this publi-cation does not imply, even in the absence of a specific statement, that such namesare exempt from the relevant protective laws and regulation and therefore free forgeneral use.

The authors and the publisher of this volume have taken care that the informa-tion and recommendations contained herein are accurate and compatible with thestandards generally accepted at the time of publication. Nevertheless, it is difficultto ensure that all the information given is entirely accurate for all circumstances. Thepublisher disclaims any liability, loss, or damage incurred as a consequence, directlyor indirectly, of the use and application of any of the contents of this volume.

© 2011 Pabst Science Publishers, 49525 Lengerich

http://www.pabst-publishers.de

Printing: MercedesDruck, BerlinTypesetting: Hilmar Schlegel, BerlinCover: Claudia Döring, Lengerich

ISBN 978-3-89967-734-8

Contents

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XV

Notes on the use of this book . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Autoantibodies Definitions and Characteristics . . . . . . . . . . . . . 2

Autoantibodies in the Diagnosis of Autoimmune Diseases . . . . . . . . 3

Part 1Autoantibodies in organ specific autoimmune diseases

17α-hydroxylase antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 621-hydroxylase antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 6AADC antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Acetylcholine receptor antibodies, general . . . . . . . . . . . . . . . . . 6Acetylcholine receptor antibodies, classical type . . . . . . . . . . . . . . 7Actin antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8ADAMTS13 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Adrenal cortex antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 10Adrenoceptor antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Alpha enolase antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Alveolar basement membrane antibodies . . . . . . . . . . . . . . . . . . 13AMA (anti-mitochondrial antibodies) . . . . . . . . . . . . . . . . . . . 14AMA-M2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16AMA-M4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19AMA-M8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20AMA-M9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21AMPA receptor antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 22Amphiphysin antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Angiotensin 1 receptor antibodies . . . . . . . . . . . . . . . . . . . . . . 24ANNA-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24ANNA-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24ANNA-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

VI C

Anti-mitochondrial antibodies . . . . . . . . . . . . . . . . . . . . . . . . 26Anti-neuronal nuclear antibodies (ANNA) . . . . . . . . . . . . . . . . . 26Anti-neutrophil cytoplasmic antibodies (ANCA) . . . . . . . . . . . . . 26Anti-nuclear antibodies (ANA) . . . . . . . . . . . . . . . . . . . . . . . 27Anti-Saccharomyces cerevisiae antibodies (ASCA) . . . . . . . . . . . . . 28Aquaporin 4 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30Aromatic L-amino acid decarboxylase antibodies . . . . . . . . . . . . . 31ASGPR antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Atypical ANCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34Beta 1 adrenergic receptor antibodies . . . . . . . . . . . . . . . . . . . . 34Bithermal hemolysins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35BP180 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35BP230 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35C1 inhibitor antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36C1q antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37C3 nephritic factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38C4 nephritic factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40Calcium channel antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 40Calcium sensitive receptor antibodies . . . . . . . . . . . . . . . . . . . . 42CAR antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Carboanhydrase II antibodies . . . . . . . . . . . . . . . . . . . . . . . . 44Caspr2 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Coagulation factor antibodies . . . . . . . . . . . . . . . . . . . . . . . . 45Cold antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Complement antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Collagen VII antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Colonic epithelial antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 47CV2/CRMP5 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 47CYP antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49Cytochrome P450 antibodies . . . . . . . . . . . . . . . . . . . . . . . . 49Cytochrome P450 side chain cleavage enzyme (P450scc) antibodies . . 49Desmoglein 1 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 50Desmoglein 3 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 50Dihydropyridine receptor antibodies . . . . . . . . . . . . . . . . . . . . 50Donath-Landsteiner antibodies . . . . . . . . . . . . . . . . . . . . . . . 51Endomysium antibodies (EmA) . . . . . . . . . . . . . . . . . . . . . . . 51Enterocyte antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53Erythrocyte antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54Factor VIII antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56Factor B antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59Factor H antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59FcεRI antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

C VII

Fc receptor antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60Folate receptor antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 60GABAB receptor antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 61GAD antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61Ganglionic nAChR antibodies . . . . . . . . . . . . . . . . . . . . . . . . 63Ganglioside antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65Gephyrin antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69Gliadin antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70Glomerular basement membrane antibodies . . . . . . . . . . . . . . . . 72GluR3 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74Glutamate receptor antibodies . . . . . . . . . . . . . . . . . . . . . . . . 75Goblet cell antibodies (GAB) . . . . . . . . . . . . . . . . . . . . . . . . 75GOR antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78gp210 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79GWB antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81Heart muscle antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 82Heat shock protein antibodies . . . . . . . . . . . . . . . . . . . . . . . . 83H+/K+ ATPase antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 84Hormone antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84Hu antibodies (ANNA-1) . . . . . . . . . . . . . . . . . . . . . . . . . . . 85IA2 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87Insulin antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89Insulin receptor antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 90Intrinsic factor antibodies (IFA) . . . . . . . . . . . . . . . . . . . . . . . 91Islet cell antibodies (ICA) . . . . . . . . . . . . . . . . . . . . . . . . . . 93LAD-1 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95Lamin antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95Lamin B receptor antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 96LAMP-2 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98LC1 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99Leydig cell antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101Lgi1-antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102LKM1-antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102LKM2 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105LKM3 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105LM antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106LP/SLA antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107Ma1 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107Ma2 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108MAG antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110Moesin antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111MuSK antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

VIII C

NALP5 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112Neutrophil antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112Neutrophil specific antibodies . . . . . . . . . . . . . . . . . . . . . . . . 113NMDA receptor antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 114Nuclear body antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 116Nuclear envelope antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 117Nucleoporin antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117ONA antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118Ovarian antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121p62 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121p95C antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121pANCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121Pancreas acinar antibodies (PAb) . . . . . . . . . . . . . . . . . . . . . . 123Pancreas antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124Paraneoplastic antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 124Parietal cell antibodies (PCA) . . . . . . . . . . . . . . . . . . . . . . . . 124PBCNA antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126Pemphigus antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126Pemphigoid antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128Phospholipase A2 receptor antibodies . . . . . . . . . . . . . . . . . . . 131Phospholipid antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 131PKCγ antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133PML antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133Potassium channel antibodies . . . . . . . . . . . . . . . . . . . . . . . . 134Purkinje cell antibodies type 2 (PCA-2) . . . . . . . . . . . . . . . . . . 136Receptor antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137Recoverin antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138Reticulin antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138Retina antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138Ri antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140Ryanodine receptor antibodies . . . . . . . . . . . . . . . . . . . . . . . 141SLA/LP antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142SMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144SOX1 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146SOX13 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147Sp100 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147Spermatozoa antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 149Steroid producing cell antibodies . . . . . . . . . . . . . . . . . . . . . . 151SUMO antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153Thrombocyte antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 153Thyroglobulin antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . 155Thyroperoxidase antibodies . . . . . . . . . . . . . . . . . . . . . . . . . 157

C IX

Tissue transglutaminase antibodies (TTG) . . . . . . . . . . . . . . . . . 159Titin antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162Tr antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163Trib2 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164Tropomyosin 5 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 164Tryptophan hydroxylase (TPH) antibodies . . . . . . . . . . . . . . . . 165TSH receptor antibodies (TRAb) . . . . . . . . . . . . . . . . . . . . . . 165Tyrosinase antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167Tyrosine hydroxylase (TH) antibodies . . . . . . . . . . . . . . . . . . . 168Vasopressin producing cell antibodies . . . . . . . . . . . . . . . . . . . 168VGCC antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169VGPC antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169Warm antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169von Willebrand factor antibodies . . . . . . . . . . . . . . . . . . . . . . 169xANCA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170Yo antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170Zic antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172ZnT8 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

Part 2Organ specific autoimmune diseases –symptoms, entities, syndromes

Achalasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174Acquired angioedema type II . . . . . . . . . . . . . . . . . . . . . . . . 174Acute disseminated encephalomyelitis (ADEM) . . . . . . . . . . . . . . 174Acute inflammatory demyelinating polyneuropathy (AIDP) . . . . . . 175Acute motor axonal neuropathy (AMAN) . . . . . . . . . . . . . . . . . 175Acute motor sensory axonal neuropathy (AMSAN) . . . . . . . . . . . . 175Acute pandysautonomia . . . . . . . . . . . . . . . . . . . . . . . . . . . 175Addison’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176Adenohypophysitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176Adrenocortical insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . 177AIH-PBC-overlap syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 177AIH-PSC overlap syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 178Alkaline phosphatase increase . . . . . . . . . . . . . . . . . . . . . . . . 178Aminotransferase increase . . . . . . . . . . . . . . . . . . . . . . . . . . 179Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179Angioedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180Anti-GBM nephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181Anti-NMDA receptor encephalitis . . . . . . . . . . . . . . . . . . . . . . 181Aplastic anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

X C

Arthrogryposis multiplex congenital (AMC) . . . . . . . . . . . . . . . . 182Ataxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183Autoimmune adrenalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 183Autoimmune autonomic gangliopathy (AAG) . . . . . . . . . . . . . . . 183Autoimmune blistering diseases . . . . . . . . . . . . . . . . . . . . . . . 185Autoimmune cholangitis (AIC) . . . . . . . . . . . . . . . . . . . . . . . 185Autoimmune cytopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186Autoimmune enteropathy (AIE) . . . . . . . . . . . . . . . . . . . . . . . 186Autoimmune gastritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187Autoimmune gastrointestinal dysmotility (AIGD) . . . . . . . . . . . . . 189Autoimmune hemolytic anemia (AIHA) . . . . . . . . . . . . . . . . . . 189Autoimmune hemophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . 190Autoimmune hepatitis (AIH) . . . . . . . . . . . . . . . . . . . . . . . . 191Autoimmune hepatitis (AIH) type 1 . . . . . . . . . . . . . . . . . . . . . 194Autoimmune hepatitis (AIH) type 2 . . . . . . . . . . . . . . . . . . . . 195Autoimmune hepatitis (AIH) type 3 . . . . . . . . . . . . . . . . . . . . 195Autoimmune hyperparathyroidism . . . . . . . . . . . . . . . . . . . . . 196Autoimmune hypoparathyroidism . . . . . . . . . . . . . . . . . . . . . 196Autoimmune hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . 197Autoimmune hypophysitis . . . . . . . . . . . . . . . . . . . . . . . . . . 198Autoimmune liver disease . . . . . . . . . . . . . . . . . . . . . . . . . . 200Autoimmune lymphoproliferative syndrome (ALPS) . . . . . . . . . . . 200Autoimmune neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . 201Autoimmune neutropenia . . . . . . . . . . . . . . . . . . . . . . . . . . 201Autoimmune pancreatitis (AIP) . . . . . . . . . . . . . . . . . . . . . . . 202Autoimmune pancreatocholangitis (AIPC) . . . . . . . . . . . . . . . . . 204Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy

syndrome (APECED) . . . . . . . . . . . . . . . . . . . . . . . . . 204Autoimmune polyglandular syndrome (APS) . . . . . . . . . . . . . . . 205Autoimmune polyglandular syndrome type 1 (APS-1) . . . . . . . . . . 205Autoimmune polyglandular syndrome type 2 (APS-2) . . . . . . . . . . 207Autoimmune sclerosing cholangitis (ASC) . . . . . . . . . . . . . . . . . 208Autoimmune thrombocytopenia (AITP) . . . . . . . . . . . . . . . . . . 208Autoimmune thyroiditis (AIT) . . . . . . . . . . . . . . . . . . . . . . . . 209Autoimmune thyropathies (AITP) . . . . . . . . . . . . . . . . . . . . . 210Autoimmune urticaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210Bickerstaff ’s encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 211Blistering dermatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212Brainstem encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212Bullous pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213CANOMAD syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214CAR syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

C XI

CEC syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215Celiac disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215Cerebellar ataxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219Cerebral folate deficiency syndrome . . . . . . . . . . . . . . . . . . . . 220Chagas cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . 220Cholangiopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221Chronic atrophic gastritis . . . . . . . . . . . . . . . . . . . . . . . . . . 221Chronic gastrointestinal pseudo-obstruction . . . . . . . . . . . . . . . 221Chronic hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222Chronic inflammatory demyelinating polyneuropathy (CIDP) . . . . . 222Chronic non-purulent destructive cholangitis . . . . . . . . . . . . . . . 223Chronic sensory ataxic neuropathy with anti-disialosyl antibodies . . . 223Cogan syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224Collagenous celiac disease . . . . . . . . . . . . . . . . . . . . . . . . . . 224Collagenous colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225Crohn’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225Cryptogenic hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226Cryptogenic liver cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . 226Dermatitis herpetiformis (DH) . . . . . . . . . . . . . . . . . . . . . . . 226Diabetes insipidus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227Diabetes mellitus type 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . 228Diabetes mellitus type 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . 230Dilated cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . 230Down syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231Drug induced (autoimmune) hepatitis . . . . . . . . . . . . . . . . . . . 231Encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231Encephalomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232Endemic pemphigus foliaceus . . . . . . . . . . . . . . . . . . . . . . . . 232Endocrine orbitopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233Epidermolysis bullosa acquisita . . . . . . . . . . . . . . . . . . . . . . . 234Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235Evans syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235Funicular myelosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235Gamma glutamyltransferase (γGT) elevation . . . . . . . . . . . . . . . 236Glomerulonephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236Gluten ataxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238Gluten sensitive enteropathy . . . . . . . . . . . . . . . . . . . . . . . . . 238Goiter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238Goodpasture syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239Graves’ disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239Guillain-Barre syndrome (GBS) . . . . . . . . . . . . . . . . . . . . . . . 239Hashimoto’s encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

XII C

Hashimoto’s thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242Heparin induced thrombocytopenia (HIT) . . . . . . . . . . . . . . . . 242Hemolytic uremic syndrome (HUS) . . . . . . . . . . . . . . . . . . . . 242Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243Hypocomplementemic urticaria-vasculitis syndrome (HUVS) . . . . . 243Hypogonadism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244Hypopituitarism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246Idiopathic lymphadenopathy . . . . . . . . . . . . . . . . . . . . . . . . . 247IgA nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247Immune cholangiopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . 248Immunoglobulin G4 associated cholangitis (IAC) . . . . . . . . . . . . . 248Immunoglobulin G4 associated sclerosing disease . . . . . . . . . . . . 248Indeterminate colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249Inflammatory bowel disease (IBD) . . . . . . . . . . . . . . . . . . . . . 250Infundibuloneurohypophysitis . . . . . . . . . . . . . . . . . . . . . . . . 250Insulin autoimmune syndrome (IAS) . . . . . . . . . . . . . . . . . . . . 251Insulin resistance type B . . . . . . . . . . . . . . . . . . . . . . . . . . . 251Interstitial pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252IPEX syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252Küttner tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253LADA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253Lambert-Eaton myasthenic syndrome (LEMS) . . . . . . . . . . . . . . 253Lichen ruber pemphigoides . . . . . . . . . . . . . . . . . . . . . . . . . 254Limbic encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255Linear IgA dermatosis (LAD) . . . . . . . . . . . . . . . . . . . . . . . . 256Liver cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257Longtitudinally extensive transverse myelitis (LETM) . . . . . . . . . . 257Lymphocytic colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257Lymphocytic gastritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258Membranoproliferative glomerulonephritis (MPGN) . . . . . . . . . . . 258Membranous glomerulonephritis . . . . . . . . . . . . . . . . . . . . . . 259Microscopic colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260Mikulicz syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260Miller Fisher syndrome (MFS) . . . . . . . . . . . . . . . . . . . . . . . 261Minimal change glomerulonephritis . . . . . . . . . . . . . . . . . . . . 261Monogenic autoimmune diseases . . . . . . . . . . . . . . . . . . . . . . 261Morvan’s syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262Motor neuropathy with monoclonal IgM gammopathy . . . . . . . . . . 262Mucous membrane pemphigoid . . . . . . . . . . . . . . . . . . . . . . . 263Multifocal acquired demyelinating sensorimotor neuropathy (MADSAM) 264Multifocal motor neuropathy (MMN) . . . . . . . . . . . . . . . . . . . 264

C XIII

Multiple sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265Myasthenia gravis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266Narcolepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267Neuromyelitis optica (NMO) . . . . . . . . . . . . . . . . . . . . . . . . 268Neuromyotonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270Neuropathies with anti-sulfatide antibodies . . . . . . . . . . . . . . . . 271Opsoclonus myoclonus syndrome (OMS) . . . . . . . . . . . . . . . . . 271Optic neuritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272Ord’s thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272Ormond’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273Ovarian insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273Overlap syndromes of autoimmune liver diseases . . . . . . . . . . . . . 274PANDAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274Paraneoplastic autonomic neuropathies . . . . . . . . . . . . . . . . . . 275Paraneoplastic cerebellar degeneration (PCD) . . . . . . . . . . . . . . . 276Paraneoplastic diseases (syndromes) . . . . . . . . . . . . . . . . . . . . 276Paraneoplastic encephalomyelitis (PEM) . . . . . . . . . . . . . . . . . . 277Paraneoplastic neurological diseases . . . . . . . . . . . . . . . . . . . . 277Paraneoplastic pemphigus . . . . . . . . . . . . . . . . . . . . . . . . . . 279Paraneoplastic retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . 280Paraproteinemic demyelinating neuropathies . . . . . . . . . . . . . . . 280Partial lipodystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281Pemphigoid gestationis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281Pemphigus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282Pemphigus foliaceus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283Pemphigus herpetiformis . . . . . . . . . . . . . . . . . . . . . . . . . . . 283Pemphigus vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284Pernicious anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285Polyneuropathy (PNP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285Portal hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286Postinfectious (autoimmune) hepatitis . . . . . . . . . . . . . . . . . . . 287Postpartum hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287Postpartum thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288Posttransplant nephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . 288Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289Premature ovarian insufficiency . . . . . . . . . . . . . . . . . . . . . . . 289Primary biliary cirrhosis (PBC) . . . . . . . . . . . . . . . . . . . . . . . 290Primary myxedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292Primary sclerosing cholangitis (PSC) . . . . . . . . . . . . . . . . . . . . 292Pruritus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

XIV C

Pulmorenal syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295Rapid-progressive glomerulonephritis (RPGN) . . . . . . . . . . . . . . 295Rasmussen’s encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 295Retroperitoneal fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296Riedel’s thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296Sclerosing cholangitis (SC) . . . . . . . . . . . . . . . . . . . . . . . . . . 296Sclerosing sialadenitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297Sensorineural hearing loss . . . . . . . . . . . . . . . . . . . . . . . . . . 297Sicca symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297Stiff person syndrome (SPS) . . . . . . . . . . . . . . . . . . . . . . . . . 297Subacute cerebellar degeneration . . . . . . . . . . . . . . . . . . . . . . 298Subacute sensory neuropathy (SSN) . . . . . . . . . . . . . . . . . . . . 298Sudeck’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299Sydenham chorea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299Sympathetic ophthalmia . . . . . . . . . . . . . . . . . . . . . . . . . . . 300Thrombotic microangiopathy . . . . . . . . . . . . . . . . . . . . . . . . 300Thrombotic thrombocytopenic purpura (TTP) . . . . . . . . . . . . . . 301Transverse myelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301Tubulointerstitial nephritis . . . . . . . . . . . . . . . . . . . . . . . . . . 302Ulcerative colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303

Foreword

Autoimmune diseases, after heart and circulatory disorders and cancer, are themost common diseases in industrialized nations. Their prevalence, which is inaddition increasing, is around 5 %. This means that in Germany alone more thanfour million people suffer from an autoimmune disease. Therefore, due to the highcosts of treatment, hospital stays and early retirement, autoimmune diseases haveboth medical and economic importance.

Autoimmune processes can affect practically all organs and systems, meaning theyconcern almost all medical disciplines. In the last years it has been clearly demon-strated in some autoimmune diseases that early and targeted treatment improvesdisease management and avoids late effects. As a result, long-term healthcare costscan be reduced and, not least, patient’s quality and length of life can be increased.

With the reference book‘Autoantibodies in Systemic Autoimmune Disease

a Diagnostic Guide’; the authors had initially faced the field of autoantibody di-agnostics in systemic autoimmune disease. Due to the positive response to thisbook, within a few years the third German, second English and the first Spanishedition were published. Thanks to the suggestions of many readers and colleagues,it is now the time to present the sequel covering autoantibodies in organ specificautoimmune disease.

As the boundaries between systemic and organ specific autoimmune diseases arenot always clearly defined, the guide to systemic autoimmune disease is referencedin respective places.

The following work, as the previous diagnostic guide, is addressed to all physi-cians and scientists who are confronted with autoimmune disease in their dailywork. It is dedicated to both the autoantibodies occurring in autoimmune disease,as well as the diseases themselves and their symptoms. In addition to autoanti-bodies currently more or less well known as diagnostic markers, some which areno longer diagnostically relevant are included on historical grounds. Numerousnewly described autoantibodies with proven or potential diagnostic and/or patho-genic relevance, which are so far not available for routine diagnostic use, are also

XVI F

included so that this work is also of interest to scientists working in the field ofautoimmunity.

For the critical proofreading of this document and the many useful tips and ad-ditions, the authors sincerely thank: Samantha Goddard, Reinhild Klein (Eduard-Karls University Tübingen, Germany), Michael Kirschfink (Ruprecht-Karls Uni-versity Heidelberg, Germany), Matthias Schott (University Düsseldorf, Germany),Klaus-Peter Wandinger (Euroimmun AG Medical Laboratory Diagnostics,Lübeck,Germany), Silke Zwjatkow (GFID e.V., Dresden, Germany) and Klaus Zöphel(Technical University Dresden, Germany).

Karsten ConradMarvin J. FritzlerFalk HiepeWerner Schößler

Notes on the use of this book

This guide to the serological diagnosis of organ specific autoimmune diseasesconsists of two alphabetically organized sections. The first deals with autoanti-bodies, the second with autoimmune or potential autoimmune diseases as well assymptoms related to particular organ specific autoimmune diseases. Appropriatecross-references (marked with �) allow quick and easy navigation (from symp-tom to disease, from disease to relevant autoantibodies). The dark arrow (

�

�) refersyou to the relevant chapter in the book

‘Autoantibodies in Systemic Autoimmune

Disease a Diagnostic Guide’.

Due to the diversity of the subject matter, the authors decided against includingcomprehensive literature references. Only in some cases the first author of impor-tant historical or current publications is mentioned. Original and review articles,as well as results and experiences used as sources for this guide, can be requestedfrom the authors.

To allow for better orientation, the‘anti-’ prefix in the alphabetical listing of auto-

antibodies is omitted. When relevant, alternative names and synonyms are alsogiven. In cases where these are still in use, the description favored by the authorsis given in the alphabetical listing and cross-reference.

Introduction

Autoantibodies –Definitions and Characteristics

Autoantibodies, in terms of their specificity, induction, effectiveness and clinicalrelevance, are a very heterogenic group of immunoglobulins:

• Autoantibodies are directed against self antigens (autoantigens). Autoantibodytargets can be proteins (e. g. intracellular enzymes, receptors, structural pro-teins), glycoproteins (e. g. β2 glycoprotein I), nucleic acids (e. g. dsDNA, tRNA),nucleic acid protein complexes (e. g. nucleosomes), phospholipids (e. g. cardi-olipin) or glycolipids (glycosphingolipids, e. g. gangliosides).

• Autoantibodies are detectable in serum, and in some cases in other body fluids(e. g. synovial or cerebrospinal fluid) too. Depending on the recognized targetstructure, they can also be bound in tissue (e. g. autoantibodies in autoimmuneblistering diseases).

• Autoantibodies can be induced through specific antigen contact (non-naturalor pathogenic autoantibodies), or be present in the natural repertoire withoutsuch induction (natural autoantibodies). Whereas the natural antibodies ratherhave a physiological role (e. g. a first defense against infection, immune regula-tion), non-natural autoantibodies can have a pathological effect (e. g. blockingor stimulating of receptors).

• Regardless of whether a pathogenic effect occurs or not, a large number ofnon-natural autoantibodies have great diagnostic relevance. They may displaysignificantly higher prevalence and titers in disease groups when compared tolocal age and sex matched control groups.The titer of pathogenic autoantibodiesoften correlates with disease activity.

In organ-specific autoimmune diseases, diagnostically relevant autoantibodies arepredominantly directed against autoantigens of the organ addressed (e. g. TSH-re-ceptor autoantibodies in Graves’ disease). Clinically significant autoantibodies in

A D A D 3

organ-specific autoimmune diseases are almost always of IgG type, and rarely IgA(e. g. in autoimmune intestinal disease) or IgM (e. g. in autoimmune hemolyticanemia).

Autoantibodies in the Diagnosis of Autoimmune Diseases

About 5 % of the population of industrialized nations suffer from autoimmune dis-eases. The most commonly occurring organ specific autoimmune diseases are thegroup of autoimmune thyroid diseases, followed by gluten-sensitive enteropathy(celiac disease) and autoimmune liver diseases.The prevalence of most other organspecific autoimmune diseases is comparatively lower. As autoimmune processescan involve practically all organs, the presence of organ specific autoimmune dis-eases should be considered in all cases of idiopathic inflammation or dysfunction,of any type and location. The measurement of autoantibodies often points the wayahead in the diagnosis of such diseases.

In the majority of the up to now described autoimmune entities, autoantibodieswith high disease-specificity are detectable. This is true even for those diseases thatare predominantly cellular (autoreactive T-lymphocytes) mediated (e. g. diabetesmellitus type 1). The number of newly described autoantibodies with proven orpotential diagnostic and/or pathogenic relevance in organ specific autoimmunedisease is ever increasing. Considerable progress has also been made in the devel-opment and optimization of autoantibody detection methods. Therefore, autoanti-body measurement is increasingly in demand in the routine diagnostic laboratory.In particular, the detection and differential diagnosis of neurological diseases hasprofited significantly from the insights and developments in this area of recentyears. For example, neuromyelitis optica can be distinguished as a separate entityfrom multiple sclerosis due to the discovery of aquaporin 4 antibodies. Also, moreand more diseases previously considered to be idiopathic can now be classified ashaving autoimmune etiology, following the discovery of new disease specific auto-antibodies. In turn, it is not uncommon that particular diseases are found to have amuch wider clinical spectrum (e. g. celiac disease, ganglioside and GAD associateddiseases) or to occur much more frequently (e. g. autoimmune encephalopathies)than previously thought.

Part 1

Autoantibodies in organ specificautoimmune diseases

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17α-hydroxylase antibodies

17α-hydroxylase is the main target antigen of antibodies directed againststeroid-producing cells (� steroid producing cell antibodies).

21-hydroxylase antibodies

21-hydroxylase is the target antigen of � adrenal cortex antibodies.

AADC antibodies

See � aromatic L-amino acid decarboxylase antibodies.

Acetylcholine receptor antibodies,general

Acetylcholine receptors (AChR) are transmembrane receptors, which bind the neu-rotransmitter acetylcholine (Ach). Two forms exist, the nicotinergic or nicotinic(nAChR, nicotine receptors) and the muscarinergic or muscarinic AChR (mAChR,muscarine receptors). Clinically relevant, or potentially relevant, antibodies can bedirected against various nAChR or mAChR:

• The‘classic’ � AChR antibodies (α1-nAChR antibodies) in � myasthenia

gravis are directed against α1 and other nAChR subunits in the neuromuscularjunction.

• The � ganglionic AChR antibodies (α3-nAChR antibodies) in autoimmune� autonomic gangliopathy bind the α3 nAChR subunit in the sympatheticand parasympathetic postganglionic fibers.

• In one form of autoimmune encephalopathy (Baker 2009), and also in � Ras-mussen’s encephalitis (Watson 2005), autoantibodies directed against the α4and/or α7 nAChR subunit in the central nervous system (cortex and hippocam-pus) have been described (α4-nAChR antibodies, α7-nAChR antibodies).

• Autoantibodies against the muscarinic type 3 AChR (M3mAChR antibodies)are detectable in patients with

�

� Sjögren’s syndrome,

�

� systemic sclerosis andgastrointestinal dysmotility (Singh 2009).

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• Autoantibodies against the muscarinic type 2 AChR (M2mAChR antibodies)have been described in� Chagas disease, in idiopathic� dilated cardiomyopa-thy (in 40 % of cases) and in idiopathic atrial fibrillation (23 %) (Baba 2004; Fu2002).

Acetylcholine receptor antibodies,classical type

Synonym: AChR antibodies.

Autoantigen

The nicotinic acetylcholine receptor (nAChR) of the neuromuscular junction is aglycoprotein with a molecular weight of 300 kDa and is comprised of five subunits:α1, β, δ, γ/ε. Autoantibodies are predominantly directed against the α1 subunit.

Pathologic relevance

AChR antibodies influence nicotinic acetylcholine receptors in three ways: (1) In-fluencing the neuromuscular function of these receptors through binding andcross-linking, accelerating their internalization and degradation. (2) To a smallextent blocking acetylcholine binding sites. (3) Activating complement locally,leading to destruction of the postsynaptic membrane, with the consequence thatneuromuscular stimulus transmission is wholly or partially inhibited.

Detection methods

Radioimmunoprecipitation with 125I-α-bungarotoxin labeled native acetylcholinereceptor.

Note: Other methods, such as enzyme immunoassays or indirect immunofluorescence, arenot currently popular due to their low sensitivity and specificity. An immunofluorescencetest utilizing transfected AChR cells is under development.

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Clinical relevance

• Acetylcholine receptor antibodies are pathognomonic for � myasthenia gravis(MG) and are detectable in 80–90 % of patients with generalized MG. AChRantibodies are found in only ~50 % of ocular MG cases. A positive AChR an-tibody test is seen as proof of MG due to the high specificity (almost 100 %),however a negative result does not exclude MG (‘seronegative’ MG).

• In healthy individuals and patients with an inherited form of MG, as well as� Lambert-Eaton myasthenic syndrome (LEMS) which has a very similar clin-ical picture, AChR antibodies are not detectable.

• Low titers of AChR antibodies can be found, for example in

�

� rheumatoidarthritis patients taking penicillamine therapy,� primary biliary cirrhosis andthymoma. These patients have an elevated risk of suffering from MG.

• AChR antibody titers do not correlate with the severity of myasthenic symp-toms. However, the follow-up of AChR antibody levels can allow conclusionsto be made on the prognosis of individual patients. A 50 % reduction in anti-body titer is often (but not always!) associated with a marked improvement incondition.

Indications

1. Suspicion of myasthenia gravis.2. Monitoring of myasthenia gravis patients.

Actin antibodies

Autoantigen

Actin is a component of smooth muscle microfilaments, and one of the targetstructures of autoantibodies against smooth muscle cells (� SMA). PolymericF-actin, with a molecular weight of 41 kDa, has been identified as the relevantantigen in the diagnosis of autoimmune hepatitis.

Detection methods

• Indirect immunofluorescence on cryostat sections of rat stomach, liver andkidney. The typical immunofluorescence picture shows staining of the smooth

ADAMTS13 9

muscle layer of the stomach and blood vessels, as well as the septa of stomachinterparietal cells. Depending on the recognized autoantigen target structures,numerous other structures may also be stained.

• Indirect immunofluorescence with HEp-2 cells or fibroblasts. The typical im-munofluorescence picture shows fibrous cytoskeletal staining.

Note: The detection of actin antibodies on rodent tissue sections is more sensitive thandetection with HEp-2 cells.

• Enzyme immunoassay with F-actin.• Line/dot immunoassay with F-actin.

Note: According to the consensus report of the International Autoimmune HepatitisGroup, indirect immunofluorescence on multi-organ rodent sections (kidney, stomach,liver) is the method of choice for the detection of AIH relevant autoantibodies (Vergani2004). Larger studies are needed to evaluate the diagnostic value of F-actin antibodies asthe basis of enzyme or line/dot immunoassays. So far, commercially available immunoas-says (E, line/dot immunoassays) for the detection of actin antibodies have mostlydisplayed specificities too low to serve as a diagnostic of AIH.

Clinical relevance

• High concentrations (titers) of actin antibodies are largely specific for � auto-immune hepatitis (AIH) type 1. The sensitivity ranges from 52–85 %, although(usually low titers of) actin antibodies have also been observed in healthy in-dividuals (3–18 %), primary biliary cirrhosis (PBC) (22 %), hepatitis C (7 %),connective tissue diseases and celiac disease (IgA antibodies).

• In about 19 % of � SMA positive patients, no actin antibodies are detectable.• Patients with actin antibodies have an earlier disease onset and a more severe

prognosis than actin antibody negative patients with� anti-nuclear antibodies(ANA).

Indications

1. Suspicion of autoimmune hepatitis type 1.2. Differential diagnosis of autoimmune hepatitis.

ADAMTS13 antibodies

ADAMTS13 (“a disintegrin and metalloprotease with thrombospondin-1 like do-mains 13”) is a von Willebrand factor (vWF) cleaving protease, which strongly

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regulates the size of the high molecular weight vWF, and thereby its biological ac-tivity. In patients with acquired� thrombotic thrombocytopenic purpura (TTP),autoantibodies against ADAMTS13 are detectable in most cases. These antibod-ies can inhibit the protease function of ADAMTS13 (Furlan 1998; Tsai 1998), orinduce the elimination of ADAMTS13 from the circulation (Scheiflinger 2003;Rieger 2005). Therefore, the high molecular weight vWF complexes remain un-cleaved, leading to formation of microvascular thrombi. Patients with ADAMTS13antibodies have a more severe disease progression and higher mortality rates thanTTP patients without these antibodies.

Adrenal cortex antibodies

Synonyms: ACA, 21-hydroxylase antibodies.

Autoantigen

21-hydroxylase (21-OH), an enzyme with a molecular weight of 55 kDa involvedin the synthesis of steroid hormones (cortisol), has been identified as the maintarget antigen. The conformation-dependent epitope is localized in the C terminalregion of hemoproteins.

Detection methods

• Indirect immunofluorescence using cryostat sections of human adrenal cor-tex (preferably from patients with Cushing syndrome). The immunofluores-cence picture shows cytoplasmic staining of the hormone producing cells ofthe adrenal cortex (Fig. 1).

• Radioimmunoassay with recombinant 125I labeled 21-hydroxylase.• Radioimmunoprecipitation with 35S labeled 21-hydroxylase.• Western blot with native or recombinant 21-hydroxylase.

Note: The concurrence between immunofluorescence and immunoassays is relatively good,although discrepant results can be obtained in some cases. Immunoassays have a somewhathigher sensitivity.

Clinical relevance

• ACA are markers of autoimmune � adrenalitis (idiopathic Addison’s disease).Autoimmune adrenalitis can manifest as a solitary disease or as part of an

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Adrenal medulla

Zona reticularis

Adrenal cortex

Figure 1. Indirect immunofluorescence using cryostat sections of human adrenal cortex.Adrenal cortex antibodies show a strong cytoplasmic staining pattern in the hormone pro-ducing cells of the adrenal cortex. The cells of the adrenal medulla are negative.

� autoimmune polyglandular syndrome. In solitary diseases, ACA are de-tectable in 65–81% of cases with a specificity of 98–100 %. With autoimmunepolyglandular syndrome these autoantibodies are found in 86–92 % (type 1)and 89–100 % (type 2), respectively.

• The prevalence of these antibodies may decline as disease progresses.• ACA/21-hydroxylase antibodies have a predictive role, as they can precede dis-

turbed adrenocortical function and disease manifestation. Children in partic-ular with autoantibodies against the adrenal cortex have an increased risk ofbeing diagnosed with Addison’s disease (on average after 2.7 years). It is recom-mended that children with an organ specific autoimmune disease (especiallyidiopathic hypoparathyroidism and� diabetes mellitus type 1) are tested annu-ally for adrenal cortex antibodies.

Indications

1. Suspicion of Addison’s disease.2. Differentiation between Addison’s disease from tuberculous adrenal insuffi-

ciency or necrosis of the adrenal glands (Waterhouse-Friderichsen syndrome).3. Suspicion of autoimmune polyglandular syndrome (APS type 1 or type 2).

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4. Evaluation of the risk of developing Addison’s disease, particularly in childrenwith organ specific autoimmune diseases.

Adrenoceptor antibodies

Adrenoceptors are adrenergic receptors, that are responsible for adrenalin and no-radrenalin mediated effects. Autoantibodies can exert an agonistic or antagonisticinfluence on the corresponding adrenoceptor, and therefore have a pathogenic ef-fect. Pathologically relevant or potentially relevant autoantibodies can be directedagainst various adrenoceptors:

• Stimulating� beta-1 adrenergic receptor antibodies are a pathologically signifi-cant marker of idiopathic� dilative cardiomyopathy, as well as the cardiopathyof Chagas disease.

• Autoantibodies against beta-2 adrenergic receptors were found in patients withasthma, myasthenia gravis and Chagas disease (Eng 1992; Wallukat 1991).

• Beta-3 adrenoceptor antibodies were found in patients with heart failure (Li2005).

• Agonistic alpha-1 adrenoceptor antibodies have been described as potentialpathogenic factors in refractory hypertension (Wenzel 2008).

Alpha enolase antibodies

Autoantigen

The ubiquitously occurring glycolytic enzyme α-enolase. It has 82 % homologywith the two other isoforms β- and γ-enolase, as well as homology with the solublelens protein tau (a crystalline).

Detection methods

Enzyme immunoassay or immunoblot with purified α-enolase.

Part 2

Organ specific autoimmune diseases –symptoms, entities, syndromes

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Achalasia

Achalasia is a motility disorder of the oesophagus characterized by aperistalsiswith inadequate lower sphincter relaxation. Etiologically, achalasia can be classi-fied as primary (idiopathic) or secondary to another disease. In primary achalasiainhibitory nitrergic myenteric plexus neurons are lost. The cause of these neu-ronal degeneration is not known, but mononuclear and lymphocyte infiltrationin the myenteric plexus, the association with class histocompatibility complex hap-lotypes, and the presence of autoantibodies support autoimmune mechanisms foridiopathic achalasia. In some studies, autoantibodies binding the myenteric plexuswere found by indirect immunofluorescence on rat digestive tissue sections (Ruizde Leon 2002). However, it has been discussed that at least a part of this bind-ing is attributable to non-organ specific autoantibodies. In a recently publishedstudy,�GAD antibodies were detected in 21% of patients with primary achalasia(Kraichely 2010). Therefore, primary achalasia may be added to the growing listof GAD antibody positive neurological disorders.

Acquired angioedema type II

A form of � angioedema caused by � C1 inhibitor antibodies.

Acute disseminated encephalomyelitis(ADEM)

Synonyms: Perivenous encephalomyelitis, Hurst’s encephalitis.

ADEM is a rare, monophasic inflammatory demyelinating disease of the CNS. Theneurological symptoms, as with other forms of� encephalitis, are variable depend-ing on the location of the lesions. The manifestation spectrum ranges from min-imal disturbances to fulminant, progressive symptoms with seizures and coma.A characteristic symptom is� optic neuritis. Very severe (fulminant) courses canbe fatal. It is postulated that ADEM is a post-infective autoimmune disease, usu-ally triggered by a viral infection in which autoreactive T-lymphocytes are directedagainst proteins of the white matter. So far, specific autoantibodies have not beenfound.

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Acute inflammatory demyelinatingpolyneuropathy (AIDP)

AIDP is the classic and most common form of acute � Guillain-Barre syndrome.In AIDP � ganglioside antibodies against GM1 of mainly IgG, and rarely IgMclass, are detectable. In addition to GM1 antibodies, IgG autoantibodies againstGD1a, GD1b and GT1b are found.

Acute motor axonal neuropathy (AMAN)

AMAN is a rare variant of acute � Guillain-Barre syndrome (primary axonalGBS), characterized by the acute onset of paralysis with particularly rapid pro-gression, but without sensory disturbance. Some patients show a rapid remission.The disease is associated with IgG autoantibodies against the gangliosides GM1,GM1b, GD1a and GalNAc-GD1a. IgG autoantibodies against GD1b and/or GT1bare rarely detectable (see also � ganglioside antibodies).

Acute motor sensory axonal neuropathy(AMSAN)

AMSAN is a rare variant of acute � Guillain-Barre syndrome (primary axonalGBS with sensory involvement) characterized by severe paralysis, sensory distur-bances, rapid progress and incomplete recovery. The disease is associated with IgGautoantibodies against the gangliosides GM1, GM1b and GD1a. Rarely, IgG auto-antibodies against GD1b and/or GT1b are also present (see also � gangliosideantibodies).

Acute pandysautonomia

Acute pandysautonomia was originally considered to be a special form of � Guil-lain-Barre syndrome with manifestations exclusive of the vegetative nervous sys-tem. With the discovery of � ganglionic nAChR antibodies, pandysautonomy isnow regarded as a separate entity (� autoimmune autonomic gangliopathy).

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Addison’s disease

Synonym: Primary adrenocortical insufficiency.

Addison’s diseases (named after the physician Thomas Addison from London)is the result of progressive destruction of the adrenal cortex. Whereas previouslytuberculosis was responsible for most Addison’s disease cases, currently autoim-mune reactions against the tissue of the adrenal cortex (� autoimmune adrenalitis)are the most common cause of � adrenocortical insufficiency. Disease symptomsfirst occur when ~90 % of the adrenal cortex (AC) tissue is destroyed, causing apathological deficiency of hormones produced by AC (predominantly cortisol andaldosterone). The diverse symptoms (weight loss, abdominal discomfort, nausea,vomiting, diarrhea, anemia, collapse after physical exertion, muscle weakness, hy-perpigmentation (‘bronzing’) of the skin and mucous membranes, loss of libido,appetite for salt, low pulse rate and low blood pressure) essentially result from thedeficiency of cortisol and aldosterone. Addison’s disease can occur in isolation oras part of an � autoimmune polyglandular syndrome (APS).

Autoantibodies

� Adrenal cortex antibodies directed against 21-hydroxylase are markers of theautoimmune form of Addison’s disease. These antibodies are predictive becausethey are detectable even in the preclinical stage. With increasing disease durationthe prevalence of adrenal cortex antibodies can decrease. As Addison’s diseaseis often (mostly as part of an APS) associated with other autoimmune diseases,the autoantibodies typical of these conditions (e. g. � autoimmune thyropathy,� diabetes mellitus type 1, � celiac disease) should be measured.

Adenohypophysitis

Lymphocytic adenohypophysitis (LAH) is the classic and most prevalent form of� autoimmune hypophysitis.

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Adrenocortical insufficiency

Adrenocortical insufficiency (AC insufficiency) refers to all forms of adrenal cor-tex hypofunction. Primary (� Addison’s disease) and secondary forms can bedifferentiated. Whereas the somewhat more common primary AC insufficiencyresults from the absence or deficiency of all AC hormones as a result of adrenalcell destruction (e. g. in autoimmune adrenalitis, sepsis, tuberculosis, adrenal cor-tex metastases), in the secondary form the basis is a disturbance in the areaof the pituitary gland (e. g. � autoimmune hypophysitis) or the hypothalamuswith consecutive deficiency of adrenocorticotropic hormone (ACTH, which con-trols hormone production in the adrenal cortex) and/or corticotropin releasinghormone (CRH, stimulates the distribution of ACTH). AC insufficiency is asso-ciated with a deficit in glucocorticoids, adrenal androgens and in primary ACinsufficiency mineralocorticoids in addition. The most common cause of ACinsufficiency is an autoimmune related inflammation of the AC (� autoimmuneadrenalitis), either as a solitary disease or as part of an � autoimmune polyglan-dular syndrome.

Autoantibodies

For the diagnosis of autoimmune related primary AC insufficiency, � adrenalcortex antibodies (� 21-hydroxylase antibodies) should be measured.

AIH-PBC-overlap syndrome

Overlap syndrome with the characteristics of � autoimmune hepatitis (AIH) and� primary biliary cirrhosis (PBC); see also� overlap syndromes of autoimmuneliver diseases.According to Chazouilleres (1998), an AIH-PBC overlap can be diag-nosed when at least two of the following AIH and at least two of the PBC criteriaare fulfilled:

AIH Criteria PBC criteria

(1) Alanine aminotransferase (ALT)elevation (5 times the normallimit).

(1) Alkaline phosphatase (2 timesthe normal limit) or gammaglutamyltransferase (5 times thenormal limit) elevation.

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AIH Criteria PBC criteria

(2) Serum IgG elevation (2 timesthe normal limit) or � SMApositive.

(2) � Anti-mitochondrial antibodypositive.

(3) Histology: Moderate to severeportal or periportal lymphocyticpiecemeal necrosis.

(3) Histology: florid bile duct lesions.

Autoantibodies

�Anti-mitochondrial antibodies,� anti-nuclear antibodies,� SMA (should dis-play an anti-actin specificity),� SLA/LP antibodies.

AIH-PSC overlap syndrome

Overlap syndrome with characteristics of � autoimmune hepatitis (AIH) and� primary sclerosing cholangitis (PSC) usually appears in children, adolescentsand young adults. In contrast to AIH, AIH-PSC overlap primarily affects males.Similar to PSC, a link can be made to � chronic inflammatory bowel disease.AIH-PSC overlap-syndrome usually reacts well to immunosuppressive therapy.See also � autoimmune sclerosing cholangitis (ASC).

Autoantibodies

Atypical � anti-neutrophil cytoplasmic antibodies, � anti-nuclear antibodies,� SMA. See also � autoimmune sclerosing cholangitis (ASC).

Alkaline phosphatase increase

The increase of alkaline phosphatase of hepatic origin is a sign of cholestatic liverdisease, and is, among others, characteristic of � primary biliary cirrhosis (PBC)and � primary sclerosing cholangitis (PSC).