Rare phenotypes in the understanding of autoimmunity.

Yvonne Zeissig, Britt-Sabina Petersen, Andre Franke, Richard S Blumberg, Sebastian Zeissig
Year of publication:
Journal title abbreviated:
Immunol. Cell Biol.
Journal title long:
Immunology and cell biology
Impact factor:
The study of rare phenotypes has a long history in the description of autoimmune disorders. First Mendelian syndromes of idiopathic tissue destruction were defined more than one hundred years ago and were later revealed to result from immune-mediated reactivity against self. In the past two decades, continuous advances in sequencing technology and particularly the advent of next generation sequencing have allowed to define the genetic basis of an ever-growing number of Mendelian forms of autoimmunity. This has provided unique insight into the molecular pathways that govern immunological homeostasis and that are indispensable for the prevention of self-reactive immune-mediated tissue damage and "horror autotoxicus". Here, we will discuss selected examples of past and recent investigations into rare phenotypes of autoimmunity that have delineated pathways critical for central and peripheral control of the adaptive immune system. We will outline the implications of these findings for rare and common forms of autoimmunity and will discuss the benefits and potential pitfalls of the integration of next generation sequencing into algorithms for clinical diagnostics. Due to the concise nature of this review, we will focus on syndromes caused by defects in the control of adaptive immunity. We refer the reader to the article by Rothstein and Fitzgerald in this issue for recent insight into innate immune-mediated autoinflammatory disorders and to other excellent recent reviews for a more detailed and comprehensive discussion of Mendelian and polygenic forms of autoimmunity. (1-4)Immunology and Cell Biology accepted article preview online, 26 August 2016. doi:10.1038/icb.2016.76.