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The Genetics of Autoimmunity

Immunological diseases result from the combined effects of environmental triggers and inherited susceptibility genes. Studies of human autoimmune diseases show that patients with organ-specific autoimmunity have activated, autoreactive T cells specific for the target tissue. However, conventional immunological studies have not identified the next level of pathogenesis of spontaneous autoimmune diseases. There has consequently been great interest in identifying genes conferring susceptibility to autoimmune diseases.  This book focuses on genes that may be associated with autoimmunity, how they can be identified, and how the functions of the gene products can be elucidated.

Progress in the Human Genome Project has reached the point where the tools required for whole genome screens are likely to be developed soon.  International efforts to catalogue human genetic variation have provided a huge genetic marker source. The genome-wide map of single nucleotide polymorphisms (SNPs) has grown from just 4000 in 1999 to more than 3.5 million in early 2005.  This provides a map of genetic variants at an average density of one every 1.5 kb in the human genome.  Detailed analysis of the way in which variants are inherited is concentrated on certain ‘ hotspots’   between which SNP alleles on the same chromosome (so-called haplotypes) tend to remain together and be inherited as a unit.  In some populations arising from small founding groups, there are usually only a few haplotypes seen within each of the DNA blocks defined by recombinational hotspots (typically 30-60 kb in size). This reduced haplotype diversity means that only a small proportion of the SNPsin each block need to be tested for association. 

A large amount of data on disease-associated chromosomal loci has been accumulated from inbred mice.  One of the interesting messages to emerge is that some susceptibility loci are common to many diseases, whereas others are relatively disease-specific. Moving from chromosomal loci to defined genes is proving to be a major challenge. Finally, many individual genes that influence the choice between tolerance and activation, and whose expression is altered in tolerant cells, have now been identified, and more continue to be discovered. These may provide the foundation for more guided or ‘ rational’ searches for disease-associated genes in various diseases.

This book describes the key problems and challenges facing those working on the genetics of autoimmunity and features unique in-depth discussion by experts from around the world.  It will prove fascinating reading to anyone involved in the study of autoimmune diseases.

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Table of Contents

Symposiumon Genomics of autoimmunity, held at the Novartis Foundation, London, 22-24 June, 2004. Editors: Gregory Bock (Organizer) and Jamie Goode. This symposium is based on a proposal by Abul Abbas, David Hafler and John Rioux. Abbul Abbas: Chair's introduction. Mark Daly: Patterns of genetic variation in humans and mice. Discussion. David B. Goldstein: Haplotype tagging in pharmacogenetics. Discussion. Simon J. Foote, Justin P. Rubio, Melanie Bahlo, Trevor J. Kilpatrick, Terence P. Speed, Jim Stankovich, Rachel Burfoot, Helmut Butzkueven, Laura Johnson, Chris Wilkinson, Bruce Taylor, Michele Sale, Ingrid A. F. van derMei, Joanne L. Dickinson and Patricia Groom: Multiple sclerosis: a haplotype association study. Discussion. Juha Kere: Mapping genes for asthma and psoriasis. Discussion. Linda S. Wicker, Carolyn L. Moule, Heather Fraser, Carlos Penha-Goncalves, Dan Rainbow, Valerie E. S. Garner, Giselle Chamberlain, Kara Hunter, Sarah Howlett, Jan Clark, Andrea Gonzalez-Munoz, Anne Marie Cumiskey, Paul Ti!en, Joanna Howson, Barry Healy, Luc J. Smink, Amanda Kingsnorth, Paul A. Lyons, Simon Gregory, Jane Rogers, John A.Todd and Laurence B. Peterson: Natural genetic variants influencing type 1 diabetes in humans and in the NOD mouse. Discussion. Srividya Subramanian and Edward K. Wakeland: The importance of epistatic interactions in the development of autoimmunity. Discussion. Timothy J. Vyse, Angela Richardson, EmilyWalsh, Lisa Farwell, MarkJ. Daly, Cox Terhorst and John D. Rioux: Mapping autoimmune disease genes in humans: lessons from IBD and SLE. Discussion. Cisca Wijmenga and Martin C. Wapenaar: A combined genetics and genomics approach to unravelling molecular pathways in coeliac disease. Discussion. Timothy W. Behrens, Robert R. Graham, Chieko Kyogoku, Emily C. Baechler, Paula S. Ramos, Clarence Gillett, Jason Bauer, Ward A. Ortmann, Keli L. Hippen, Erik Peterson, Carl D. Langefeld, Kathy L.Moser, Patrick M. Ga!neyand Peter K. Gregersen: Progress towards understanding the genetic pathogenesis of systemic lupus erythematosus. Discussion. Vigo Heissmeyer, Fernando Macia n, Rajat Varma, Sin-Hyeog Im, Francisco Garcia-Cozar, Heidi F.Horton, Michael C. Byrne, Stefan Feske, K. Venuprasad, Hua Gu, Yun-Cai Liu, Michael L. Dustin and Anjana Rao: A molecular dissection of lymphocyte unresponsiveness induced by sustained calcium signaling. Discussion. Adrian Liston and Christopher C. Goodnow: Genetic lesions in thymicTcell clonal deletion and thresholds for autoimmunity. Discussion. Lalitha Vijayakrishnan, Jacqueline M. Slavik, Zsolt Illes, Dan Rainbow, Laurence B. Peterson, Arlene S. Sharpe, Linda S. Wickerand, Vijay K. Kuchroo: An autoimmune disease-associated CTLA4 splice variant lacking the B7 binding domain signals negatively in Tcells. Discussion. Adrian Ting, Stefan Lichtenthaler, Ramnik Xavier, Soon-Young Na, Shahrooz Rabizadeh,TaraHolmes and Brian Seed: Large-scale screens for cDNAs with in vivo activity. Discussion. Jenny Ting: Genomic mining of new genes and pathways in innate and adaptive Immunity. Discussion. Index of contributors. Subject index.

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