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QTL influencing autoimmune diabetes and encephalomyelitis map to a 0.15-cM region containing Il2

Nature Genetics volume 21, pages 158–160 (1999)Cite this article

Insulin-dependent diabetes in NOD mice and mouse experimental autoimmune encephalomyelitis (EAE) are the major disease models for human type I diabetes and multiple sclerosis, respectively. In recent genetic analyses, a number of quantitative trait loci (QTL) controlling susceptibility to these autoimmune diseases have been identified1,2,3,4. Some QTL overlap between the two diseases, raising the possibility that there may be disease genes common to diabetes and EAE (ref. 5). Given the large number of QTL identified and the large QTL support interval sizes attained in the genetic segregation analyses used, we investigated whether this overlap was due to a shared 'autoimmunity gene' or merely to the coincidental grouping of two unrelated genes. Among the diabetes QTL mapped so far in NOD mice, two overlap with QTL that we identified in EAE (ref. 1). One of these QTL, in the medial region of chromosome 3, has been further analysed through the generation of congenic mice and was found to be composed of QTL Idd3, Idd17, Idd10 and Idd18 (refs 6,7). We were able to more precisely examine the effect of the diabetes QTL on EAE using these NOD congenic lines, which carry diabetes-resistance alleles at one or more of these QTL (refs 6,7).

Previously, the location of Idd3 was narrowed to an interval of 0.35 cM and Ccna2, Il2 and Fgf2 were shown to map in this interval7. Using Idd3 congenic strains with increasingly smaller congenic intervals, the smallest of which defines the proximal end of Idd3 to the 0.07-cM genetic interval between Il2 and Ccna2 (L.S.W., unpublished data), we have now demonstrated that an EAE-resistance gene is colocalized with the Idd3 diabetes resistance gene in a genetic interval of less than 0.15 cM. This interval contains Il2, known to differ allelically between NOD and B6 mice4,7,9, and Fgf2 ; thus Il2 and Fgf2 are implicated as possible genes within Idd3 involved in EAE susceptibility. Aod2, a QTL associated with autoimmune ovarian dysgenesis, has also been mapped to this general region10. Due to its role in T-cell growth and differentiation, Il2 is a candidate for involvement in EAE and diabetes susceptibility7. To determine whether the pair of strains (SJL/J and B10.S) we used to identify the EAE-susceptibility locus on chromosome 3 differ similarly in their Il2 alleles, exon 1 of Il2, which is known to contain a number of sequence polymorphisms in the mouse4,7,9,11, was sequenced in SJL/J and B10.S mice. It has been reported9 that SJL/J and NOD mice share an allele of Il2, whereas C57BL/10 and B6 mice share another allele of Il2. We sequenced exon 1 of Il2 and confirmed that SJL/J mice have an Il2 sequence identical to that of NOD mice; similarly, B10.S mice were found to have a sequence identical to that of B6 (Table 1). As in the NOD allele, the SJL/J allele differs from the B6 allele by a single base change (T to C) that results in a serine-to-proline substitution in the sixth amino acid residue of the mature protein. The SJL/J allele also has a duplication of a 12-bp segment of DNA that results in a 4-aa insertion, and a compensatory 12-bp deletion that results in a deletion of 4 glutamines from a stretch of 12 consecutive glutamines.

Table 1 Comparison between strains of the portion of the Il–2 protein sequence encoded by exon 1 of Il2
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Figure 1: EAE susceptibility of NOD congenic mice.

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Acknowledgements

We thank A. Abbas and L. Nicholson for review of the manuscript. These studies were carried out with the support of grants from the National Institutes of Health (RO1 NS 30843, RO1 NS 35685 and PO1 AI 39671) and National Multiple Sclerosis Society (RG 2571 and 2320) to V.K.K.

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Author notes

  1. C.E.S. and J.G.S. are supported by Howard Hughes Medical Institute.

Authors and Affiliations

  1. Department of Medicine, Center for Neurologic Diseases, Brigham & Women's Hospital, Boston, 02115, Massachusetts , USA

    Jeffrey A. Encinas, Akiko Mukasa, Howard L. Weiner & Vijay K. Kuchroo

  2. Department of Autoimmune Diseases Research, Merck Research Laboratories, Rahway, 07065, New Jersey, USA

    Linda S. Wicker

  3. Department of Cellular and Molecular Pharmacology, Merck Research Laboratories, Rahway, 07065, New Jersey, USA

    Laurence B. Peterson

  4. Department of Veterinary Pathobiology, The University of Illinois at Urbana–Champaign, Urbana, 61802, Illinois , USA

    Cory Teuscher

  5. Department of Pathology, Stanford University School of Medicine and Laboratory Service, Veterans Affairs Medical Center, Palo Alto, 94304, California, USA

    Raymond Sobel

  6. Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Christine E. Seidman & J.G. Seidman

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  1. Jeffrey A. Encinas
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Correspondence to Vijay K. Kuchroo.

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Encinas, J., Wicker, L., Peterson, L. et al. QTL influencing autoimmune diabetes and encephalomyelitis map to a 0.15-cM region containing Il2. Nat Genet 21, 158–160 (1999). https://doi.org/10.1038/5941

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