Congenital rubella, diabetes and HLA

Abstract

Keywords Congenitalrubella.HLA.Type1diabetes.VirusAbbreviationCRS Congenital rubella syndromeTo the Editor: In a recent Editorial, Edwin Gale reviewedthe congenital rubella syndrome (CRS) and the postulatedrole of viruses in type 1 diabetes, pulling together most ofthe literature that links congenital rubella and diabetes [1].He concluded that the case appears sound for type 2diabetes, but is at most only suggestive for type 1 diabetes.However, he did not reveal the whole story, in particular,the evidence for HLA associations with diabetes in CRS.Gale quotes Menser et al. [2] on the incidence ofdiabetes following CRS, but fails to mention that theseinvestigators also reported that the HLA A1-B8 haplotypewas present in 44% (eight out of 18) of their CRSparticipants with diabetes. HLA A1-B8 was first docu-mented as being increased in frequency in insulin-depen-dent diabetes just 2 months earlier in the same journalin 1974 [3]. In the CRS participants, this haplotype waspresent in 75% (three out of four) who were insulin-dependent, with ages at onset of 1.5, 12, 12 and 24 years,and in 36% (five out of 14) who were on oral agents or dietalone, with ages of onset of 28–34 years. The frequency ofHLA A1-B8 in the background white population is 10%.Gale states that these studies were carried out ‘by authorswith no special interest in diabetes’, but in fact co-authorJ.A. Burgess was, and still is, a diabetologist.HLA A1-B8 (-DR3-DQ2) is the classic autoimmunehaplotype—associated not only with susceptibility to type 1diabetes in the non-CRS population but also with otherautoimmune diseases such as myasthenia gravis, systemiclupus erythematosus, chronic active hepatitis and coeliacdisease—and has been associated with the epidemiology ofrubella [4, 5]. The CRS–diabetes–HLA association wasconfirmed in the New York cohort of 274 patients [6]. Inthis case, Gale acknowledges the high rate of insulin-requiring diabetes following the rubella epidemic of 1964–1966 in New York, but judges that ‘given the interest of theinvestigators, the sample may have included a dispropor-tionate number of children with diabetes’, and, ‘ascertain-ment bias may have contributed to this very high rate, whichis otherwise unexplained’. In the context of a critical eval-uation of the literature, these statements appear distinctlysubjective. The New York data strengthened the associationof CRS with type 1 diabetes, because not only was thefrequency of HLA DR3 higher in the CRS patients, but alsothe frequency of HLA DR2, known to be protective againsttype 1 diabetes in non-CRS populations [7], was decreased.Further evidence for an autoimmune mechanism in CRS-associated diabetes comes from other studies not includedin the review. These demonstrated that T cell clones fromboth CRS and non-CRS type 1 diabetic individuals, raisedin response to epitopes in the islet autoantigen glutamicacid decarboxylase, reacted to peptides from rubella virus[8]. There are several cogent reasons why CRS could haveset the stage for type 2 diabetes. Babies with CRS were‘small for dates’ and had a reduced beta cell mass, and may