Autoimmunity Reviews 2 (2003) 204–210 1568-9972/03/$ - see front matter  2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1568-9972(03)00009-0 Proinsulin—a pathogenic autoantigen in type 1 diabetes Parth Narendran, Stuart I. Mannering, Leonard C. Harrison* The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Australia Accepted 2 January 2003 Abstract Type 1 diabetes (T1D) is an autoimmune disease characterised by immunity to pancreatic b-cell autoantigens, associated with b-cell destruction leading to insulin deficiency and hyperglycaemia. The rigorous definition of an autoimmune disease requires evidence that an autoantigen elicits pathological immune responses. Using criteria for the pathogenicity of an autoantigen, we examine the evidence for proinsulin as an autoantigen in T1D. We conclude that proinsulin satisfies these criteria. As a corollary, proinsulin is a potential immunotherapeutic tool for the prevention of T1D.  2003 Elsevier Science B.V. All rights reserved. Keywords: Type 1 diabetes; Immunity; Autoantigen; Proinsulin; Insulin 1. Introduction Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by cell-mediated destruction of pancreatic, insulin-producing b cells w1x. The major autoantigens in T1D, identified by circulating autoantibodies, are glutamic acid decar- boxylase (GAD), tyrosine phosphatase-like insu- linoma antigen and (pro)insulin. It is not clear, however, which if any drive pathogenic T cells. This knowledge may improve current approaches to the management of T1D. In 1882, Robert Koch proposed criteria for identifying pathogenic microorganisms w2x. Anal- ogous postulates can be used to identify ‘patho- genic’ autoantigens. *Corresponding author. Tel.: q61-3-93452460; fax: q61- 3-93470852. E-mail address: harrison@wehi.edu.au (L.C. Harrison). We suggest that for an autoantigen to be patho- genic it must be 1. expressed in the affected tissue 2. disease-specific and the target of immune responses that predate and predict clinical disease 3. the target of antibodies or T cells that transfer disease to healthy recipients 4. able to prevent disease when presented in a ‘tolerogenic’ form Here, we apply these postulates to proinsulin. 2. Postulate 1: Proinsulin is expressed in b cells With the possible exception of rare self-antigen- expressing cells in lymphoid tissue w3x, proinsulin is the only known autoantigen in T1D expressed uniquely in b cells. Proinsulin is synthesised in b