Commentary | Published:

The clinical significance of an autoimmune response against glutamic acid decarboxylase

Nature Medicinevolume 2pages148153 (1996) | Download Citation


Glutamic acid decarboxylase is attracting much interest because of its putative involvement in two clinical disorders: stiff-man syndrome and insulin-dependent diabetes. Here we discuss the clinical significance of an autoimmune response against CAD and consider how such information may help identify the disease mechanisms of these disorders.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Erlander, M.G. & Tobin, A.J. The structural and functional heterogeneity of glutamic acid decarboxylase: A review. Neurochem. Res. 16, 215–226 (1991).

  2. 2

    Erdo, S. & Wolff, J. Gamma-aminobutyric acid outside the mammalian brain. J. Neurochem. 54, 363–372 (1990).

  3. 3

    Kaufman, D.L., Houset, C.R. & Tobin, A.J. Two forms of the GABA synthetic enzyme glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions. J. Neurochem. 56, 720–723 (1991).

  4. 4

    Moersch, P.P. & Woltman, H.W. Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome): Report of a case and some observations in 13 other cases. Mayo Clin. Proc. 31, 421–427 (1957).

  5. 5

    Layzer, R.B. Stiff-man syndrome—an autoimmune disease? N. Engl. J. Med. 318, 1060–1062 (1988).

  6. 6

    Solimena, M. et al. Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy and type-1 diabetes. N. Engl. J. Med. 318, 1012–1020 (1988).

  7. 7

    Solimena, M., Folli, F., Aparisi, R., Pozza, G. & De Camilli, P. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N. Engl. J. Med. 322, 1555–1560 (1990).

  8. 8

    Baekkeskov, S. et al. The 64kD autoantigen in insulin-dependent diabetes is the GABA synthesizing enzyme glutamic acid decarboxylase. Nature 347, 151–156 (1990).

  9. 9

    Aanstoot, H. et al. Stiff-man syndrome and insulin dependent diabetes mellitus similarities in autoimmune reactions. in Motor Unit Hyperactivity States (ed.Layzer,R.B.) 53–67 (Raven, New York, 1993).

  10. 10

    Atkinson, M.A. & Maclaren, N.K. The pathogenesis of insulin dependent diabetes. N. Engl. J. Med. 331, 1428–1436 (1994).

  11. 11

    Baekkeskov, S. et al. Autoantibodies in newly diagnosed diabetic children with immunoprecipitate human pancreatic islet cell proteins. Nature 298, 167–169 (1982).

  12. 12

    Atkinson, M.A., Maclaren, N.K., Scharp, D.W., Lacy, P.E. & Riley, W.J. 64,000 Mr autoantibodies are predictive of insulin dependent diabetes. Lancet 335, 1357–1360 (1990).

  13. 13

    Richter, W., Shi Y. & Baekkeskov, S. Autoreactive epitopes defined by diabetes-associated human monoclonal antibodies are localized in the middle and C-terminal domains of the smaller form of glutamate decarboxylase. Proc. Natl. Acad. Sci. USA 90, 2832–2836 (1993).

  14. 14

    Gianani, R.A. et al. Prognostically significant heterogeneity of cytoplasmic islet cell antibodies of patients with type 1 diabetes. Diabetes 41, 347–353 (1992).

  15. 15

    Atkinson, M.A., Kaufman, D.L., Newman, D., Tobin, A.J. & Maclaren, N.K. Islet cell cytoplasmic autoantibody reactivity to glutamate decarboxylase in insulin-dependent diabetes. J. Clin. Invest. 91, 350–356 (1993).

  16. 16

    Tuomilehto, J. et al. Antibodies to glutamic acid decarboxylaseaspredictorsofinsulin-dependent diabetes mellitus before clinical onset of disease. Lancet 343, 1383–1385 (1994).

  17. 17

    Atkinson, M.A. et al. Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes. Lancet 339, 458–459 (1992).

  18. 18

    Harrison, L.C. et al. Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependentdiabetes. Lancet 341, 1365–1369 (1993).

  19. 19

    Lohmann, T. et al. Immunodominant epitopes of glutamic acid decarboxylase 65and 67 in insulin-dependent diabetes mellitus. Lancet 343, 1606–1608 (1994).

  20. 20

    Atkinson, M.A. et al. Cellular immunity to a determinant common to glutamate decarboxylase and Coxsackie virus in insulin-dependent diabetes. J. Clin. Invest. 94, 2125–2129 (1994).

  21. 21

    Kaufman, D.L. et al. Spontaneous loss of T cell self tolerance to glutamate decarboxylase is a key event in the pathogenesis of murine insulin-dependent diabetes. Nature 366, 69–71 (1993).

  22. 22

    Jones, D.B. & Armstrong, N.W. Coxsackie virus and diabetes revisited. Nature Med. 1, 284 (1995).

  23. 23

    Tian, J., Lehmann, P.V. & Kaufman, D.L. T cell cross-reactivity between coxsackievirus and glutamate decarboxylase is associated with a murine diabetes susceptibility allele. J Exp. Med. 180, 1979–1984 (1994).

  24. 24

    Kaufman, D. et al. Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent mellitus. J. Clin. Invest. 89, 283–292 (1992).

  25. 25

    Solimena, M. & DeCamilli, P. Autoimmunity to glutamate decarboxylase (GAD) in stiff man syndrome and insulin-dependent diabetes mellitus. Trends Neurosci. 14, 452–457 (1991).

  26. 26

    Kim, J. et al. Higher autoantibody levels and recognition of a linear NH-2 terminal epitope in the autoantigen GAD65, distinguish stiff-man syndrome from insulin dependentdiabetes mellitus. J. Exp. Med. 180, 595–606 (1994).

  27. 27

    Butler, M.H., Solimena, M., Dirkx, R., Mayday, A. & DeCamilli, P. Identification of a dominant epitope of glutamic acid decarboxylase (GAD-65) recognized by autoantibodies is stiff-man syndrome. J. Exp. Med. 178, 2097–2106 (1993).

  28. 28

    Ujihara, N. et al. Identification of glutamic acid decarboxylase autoantibody heterogeneity and epitope regions in type 1 diabetes. Diabetes 43, 968–975 (1994).

  29. 29

    Seder, R.A. & Paul, W.E. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu. Rev. Immunol. 12, 635–673 (1994).

  30. 30

    Tish, R. et al. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 366, 72–75 (1993).

Download references

Author information


  1. Department of Pathology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, 32610, USA

    • T.M. Ellis
    •  & M.A. Atkinson


  1. Search for T.M. Ellis in:

  2. Search for M.A. Atkinson in:

About this article

Publication history

Issue Date


Further reading