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Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice

Abstract

The influence of maternally transmitted immunoglobulins on the development of autoimmune diabetes mellitus in genetically susceptible human progeny remains unknown. Given the presence of islet β cell–reactive autoantibodies in prediabetic nonobese diabetic (NOD) mice1,2, we abrogated the maternal transmission of such antibodies in order to assess their influence on the susceptibility of progeny to diabetes. First, we used B cell–deficient NOD mothers to eliminate the transmission of maternal immunoglobulins. In a complementary approach, we used immunoglobulin transgenic NOD mothers to exclude autoreactive specificities from the maternal B-cell repertoire. Finally, we implanted NOD embryos in pseudopregnant mothers of a non-autoimmune strain. The NOD progeny in all three groups were protected from spontaneous diabetes. These findings demonstrate that the maternal transmission of antibodies is a critical environmental parameter influencing the ontogeny of T cell-mediated destruction of islet β cells in NOD mice3. It will be important to definitively determine whether the transmission of maternal autoantibodies in humans4,5,6,7,8 affects diabetes progression in susceptible offspring.

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Figure 1: Serum immunoglobulin and IAA in B cell–deficient (μMT−/−) pups of B cell–sufficient (μMT+/−) mothers.
Figure 2: Reduced diabetes incidence in NOD progeny of B cell–deficient mothers.
Figure 3: NOD progeny of non-autoimmune strain surrogate mothers are protected from spontaneous diabetes.

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References

  1. Yu, L. et al. Early expression of antiinsulin autoantibodies of humans and the NOD mouse: Evidence for early determination of subsequent diabetes. Proc. Natl. Acad. Sci. USA 97, 1701–1706 (2000).

  2. Abiru, N. et al. Transient insulin autoantibody expression independent of development of diabetes: comparison of nod and nor strains. J. Autoimmun. 17, 1–6 (2001).

    Article  CAS  Google Scholar 

  3. Bach, J.-F. & Chatenoud, L. Tolerance to islet autoantigens in type 1 diabetes. Annu. Rev. Immunol. 19, 131–161 (2001).

    Article  CAS  Google Scholar 

  4. Ziegler, A.G. et al. On the appearance of islet associated autoimmunity in offspring of diabetic mothers: a prospective study from birth. Diabetologia 36, 402–408 (1993).

    Article  CAS  Google Scholar 

  5. Naserke, H.E., Bonifacio, E. & Ziegler, A.G. Immunoglobulin G insulin autoantibodies in BABYDIAB offspring appear postnatally: sensitive early detection using a protein A/G-based radiobinding assay. J. Clin. Endocrinol. Metab. 84, 1239–1243 (1999).

    CAS  PubMed  Google Scholar 

  6. Ziegler, A.G., Hummel, M., Schenker, M. & Bonifacio, E. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Diabetes 48, 460–468 (1999).

    Article  CAS  Google Scholar 

  7. Hamalainen, A.M., Ronkainen, M.S., Akerblom, H.K. & Knip, M. Postnatal elimination of transplacentally acquired disease-associated antibodies in infants born to families with type 1 diabetes. The Finnish TRIGR Study Group. Trial to Reduce IDDM in the Genetically at Risk. J. Clin. Endocrinol. Metab. 85, 4249–4253 (2000).

    CAS  PubMed  Google Scholar 

  8. Naserke, H.E., Bonifacio, E. & Ziegler, A.-G. Prevalence, characteristics and diabetes risk associated with transient maternally acquired islet antibodies and persistent islet antibodies in offspring of parents with Type 1 diabetes. J. Clin. Endocrinol. Metab. 86, 4826–4833 (2001).

    Article  CAS  Google Scholar 

  9. Oldstone, M.B. Prevention of type I diabetes in nonobese diabetic mice by virus infection. Science 239, 500–502 (1988).

    Article  CAS  Google Scholar 

  10. Hermitte, L. et al. Paradoxical lessening of autoimmune processes in non-obese diabetic mice after infection with the diabetogenic variant of encephalomyocarditis virus. Eur. J. Immunol. 20, 1297–1303 (1990).

    Article  CAS  Google Scholar 

  11. Takei, I. et al. Suppression of development of diabetes in NOD mice by lactate dehydrogenase virus infection. J. Autoimmunity 5, 665–673 (1992).

    Article  CAS  Google Scholar 

  12. Bras, A. & Aguas, A.P. Diabetes-prone NOD mice are resistant to Mycobacterium avium and the infection prevents autoimmune disease. Immunol. 89, 20–25 (1996).

    Article  CAS  Google Scholar 

  13. Cooke, A. et al. Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice. Parasite Immunol. 21, 169–176 (1999).

    Article  CAS  Google Scholar 

  14. Serreze, D.V. et al. B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new “speed congenic” stock of NOD.Ig mu null mice. J. Exp. Med. 184, 2049–2053 (1996).

    Article  CAS  Google Scholar 

  15. Serreze, D.V. et al. B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice. J. Immunol. 161, 3912–3918 (1998).

    CAS  PubMed  Google Scholar 

  16. Falcone, M., Lee, J., Patstone, G., Yeung, B. & Sarvetnick, N. B lymphocytes are crucial antigen-presenting cells in the pathogenic autoimmune response to GAD65 antigen in nonobese diabetic mice. J. Immunol. 161, 1163–1168 (1998).

    CAS  PubMed  Google Scholar 

  17. Noorchashm, H. et al. I-Ag7-mediated antigen presentation by B lymphocytes is critical in overcoming a checkpoint in T cell tolerance to islet beta cells of nonobese diabetic mice. J. Immunol. 163, 743–750 (1999).

    CAS  PubMed  Google Scholar 

  18. Noorchashm, H. et al. Impaired CD4 T cell activation due to reliance upon B cell-mediated costimulation in nonobese diabetic (NOD) mice. J. Immunol. 165, 4685–4696 (2000).

    Article  CAS  Google Scholar 

  19. Greeley, S.A. et al. Impaired activation of islet-reactive cd4 T cells in pancreatic lymph nodes of B cell-deficient nonobese diabetic mice. J. Immunol. 167, 4351–4357 (2001).

    Article  CAS  Google Scholar 

  20. Hulbert, C., Riseili, B., Rojas, M. & Thomas, J.W. Cutting edge: B cell specificity contributes to the outcome of diabetes in nonobese diabetic mice. J. Immunol. 167, 5535–5538 (2001).

    Article  CAS  Google Scholar 

  21. Goodnow, C.C. et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334, 676–682 (1988).

    Article  CAS  Google Scholar 

  22. Reilly, M.P. et al. Preparation of recombinant hemoglobin in transgenic mice. in Methods in Enzymology, Vol. 231 (eds. Everse, J., Vandergriff, K.D. & Winslow, R.M.) 403–434 (Academic, New York, 1994).

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Acknowledgements

We thank H.K. Song, T.H. Lin, L.E. Noto and A. Schlachterman for their helpful discussion and assistance; and J. Ahn, K.W. Greeley and A.J. Reed for critical reading of the manuscript. This work was supported by grants HD37754 and DK54215 from the National Institutes of Health.

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Correspondence to Ali Naji.

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Greeley, S., Katsumata, M., Yu, L. et al. Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice. Nat Med 8, 399–402 (2002). https://doi.org/10.1038/nm0402-399

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