Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Mar 15;99(6):1238–1250. doi: 10.1172/JCI119281

Comparative analysis of antibody and cell-mediated autoimmunity to transaldolase and myelin basic protein in patients with multiple sclerosis.

E Colombo 1, K Banki 1, A H Tatum 1, J Daucher 1, P Ferrante 1, R S Murray 1, P E Phillips 1, A Perl 1
PMCID: PMC507938  PMID: 9077532

Abstract

Antibody and T cell-mediated immune responses to oligodendroglial autoantigens transaldolase (TAL) and myelin basic protein (MBP) were examined in patients with multiple sclerosis (MS). Immunohistochemical studies of postmortem brain sections revealed decreased staining by MBP- and TAL-specific antibodies in MS plaques, indicating a concurrent loss of these antigens from demyelination sites. By Western blot high titer antibodies to human recombinant TAL were found in 29/94 sera and 16/23 cerebrospinal fluid samples from MS patients. Antibodies to MBP were undetectable in sera or cerebrospinal fluid of these MS patients. Proliferative responses to human recombinant TAL (stimulation index [SI] = 2.47+/-0.3) were significantly increased in comparison to MBP in 25 patients with MS (SI = 1.37+/-0.1; P < 0.01). After a 7-d stimulation of PBL, utilization of any of 24 different T cell receptor Vbeta gene segments in response to MBP was increased less than twofold in the two control donors and six MS patients investigated. In response to TAL-H, while skewing of individual Vbeta genes was also less than twofold in healthy controls, usage of specific Vbeta gene segments was differentially increased ranging from 2.5 to 65.9-fold in patients with MS. The results suggest that TAL may be a more potent immunogen than MBP in MS.

Full Text

The Full Text of this article is available as a PDF (562.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antel J. P., Cashman N. R. Human retrovirus and multiple sclerosis. Mayo Clin Proc. 1991 Jul;66(7):752–755. doi: 10.1016/S0025-6196(12)62089-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Banki K., Colombo E., Sia F., Halladay D., Mattson D. H., Tatum A. H., Massa P. T., Phillips P. E., Perl A. Oligodendrocyte-specific expression and autoantigenicity of transaldolase in multiple sclerosis. J Exp Med. 1994 Nov 1;180(5):1649–1663. doi: 10.1084/jem.180.5.1649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Banki K., Halladay D., Perl A. Cloning and expression of the human gene for transaldolase. A novel highly repetitive element constitutes an integral part of the coding sequence. J Biol Chem. 1994 Jan 28;269(4):2847–2851. [PubMed] [Google Scholar]
  4. Banki K., Perl A. Inhibition of the catalytic activity of human transaldolase by antibodies and site-directed mutagenesis. FEBS Lett. 1996 Jan 8;378(2):161–165. doi: 10.1016/0014-5793(95)01446-2. [DOI] [PubMed] [Google Scholar]
  5. Baquer N. Z., Hothersall J. S., McLean P., Greenbaum A. L. Aspects of carbohydrate metabolism in developing brain. Dev Med Child Neurol. 1977 Feb;19(1):81–104. doi: 10.1111/j.1469-8749.1977.tb08027.x. [DOI] [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Deibler G. E., Martenson R. E., Kies M. W. Large scale preparation of myelin basic protein from central nervous tissue of several mammalian species. Prep Biochem. 1972;2(2):139–165. doi: 10.1080/00327487208061467. [DOI] [PubMed] [Google Scholar]
  8. Fujinami R. S., Oldstone M. B. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science. 1985 Nov 29;230(4729):1043–1045. doi: 10.1126/science.2414848. [DOI] [PubMed] [Google Scholar]
  9. Genevée C., Diu A., Nierat J., Caignard A., Dietrich P. Y., Ferradini L., Roman-Roman S., Triebel F., Hercend T. An experimentally validated panel of subfamily-specific oligonucleotide primers (V alpha 1-w29/V beta 1-w24) for the study of human T cell receptor variable V gene segment usage by polymerase chain reaction. Eur J Immunol. 1992 May;22(5):1261–1269. doi: 10.1002/eji.1830220522. [DOI] [PubMed] [Google Scholar]
  10. Gulwani-Akolkar B., Akolkar P. N., Minassian A., Pergolizzi R., McKinley M., Mullin G., Fisher S., Silver J. Selective expansion of specific T cell receptors in the inflamed colon of Crohn's disease. J Clin Invest. 1996 Sep 15;98(6):1344–1354. doi: 10.1172/JCI118921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. HOTTA S. S. Glucose metabolism in brain tissue: the hexosemonophosphate shunt and its role in glutathione reduction. J Neurochem. 1962 Jan-Feb;9:43–51. doi: 10.1111/j.1471-4159.1962.tb07491.x. [DOI] [PubMed] [Google Scholar]
  12. Hauser S. L., Bhan A. K., Gilles F., Kemp M., Kerr C., Weiner H. L. Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann Neurol. 1986 Jun;19(6):578–587. doi: 10.1002/ana.410190610. [DOI] [PubMed] [Google Scholar]
  13. JACOBSON S. SEQUENCE OF MYELINIZATION IN THE BRAIN OF THE ALBINO RAT. A. CEREBRAL CORTEX, THALAMUS AND RELATED STRUCTURES. J Comp Neurol. 1963 Aug;121:5–29. doi: 10.1002/cne.901210103. [DOI] [PubMed] [Google Scholar]
  14. James J. A., Gross T., Scofield R. H., Harley J. B. Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B'-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity. J Exp Med. 1995 Feb 1;181(2):453–461. doi: 10.1084/jem.181.2.453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kotzin B. L., Karuturi S., Chou Y. K., Lafferty J., Forrester J. M., Better M., Nedwin G. E., Offner H., Vandenbark A. A. Preferential T-cell receptor beta-chain variable gene use in myelin basic protein-reactive T-cell clones from patients with multiple sclerosis. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9161–9165. doi: 10.1073/pnas.88.20.9161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Linington C., Waksman B. The T-cell receptor in multiple sclerosis. Ann N Y Acad Sci. 1995 Jul 7;756:294–304. doi: 10.1111/j.1749-6632.1995.tb44526.x. [DOI] [PubMed] [Google Scholar]
  17. Martin R., McFarland H. F., McFarlin D. E. Immunological aspects of demyelinating diseases. Annu Rev Immunol. 1992;10:153–187. doi: 10.1146/annurev.iy.10.040192.001101. [DOI] [PubMed] [Google Scholar]
  18. Martin R., Utz U., Coligan J. E., Richert J. R., Flerlage M., Robinson E., Stone R., Biddison W. E., McFarlin D. E., McFarland H. F. Diversity in fine specificity and T cell receptor usage of the human CD4+ cytotoxic T cell response specific for the immunodominant myelin basic protein peptide 87-106. J Immunol. 1992 Mar 1;148(5):1359–1366. [PubMed] [Google Scholar]
  19. McCarron R. M., Fallis R. J., McFarlin D. E. Alterations in T cell antigen specificity and class II restriction during the course of chronic relapsing experimental allergic encephalomyelitis. J Neuroimmunol. 1990 Sep-Oct;29(1-3):73–79. doi: 10.1016/0165-5728(90)90149-h. [DOI] [PubMed] [Google Scholar]
  20. Murphy P. M. Molecular mimicry and the generation of host defense protein diversity. Cell. 1993 Mar 26;72(6):823–826. doi: 10.1016/0092-8674(93)90571-7. [DOI] [PubMed] [Google Scholar]
  21. Oksenberg J. R., Panzara M. A., Begovich A. B., Mitchell D., Erlich H. A., Murray R. S., Shimonkevitz R., Sherritt M., Rothbard J., Bernard C. C. Selection for T-cell receptor V beta-D beta-J beta gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis. Nature. 1993 Mar 4;362(6415):68–70. doi: 10.1038/362068a0. [DOI] [PubMed] [Google Scholar]
  22. Oksenberg J. R., Sherritt M., Begovich A. B., Erlich H. A., Bernard C. C., Cavalli-Sforza L. L., Steinman L. T-cell receptor V alpha and C alpha alleles associated with multiple and myasthenia gravis. Proc Natl Acad Sci U S A. 1989 Feb;86(3):988–992. doi: 10.1073/pnas.86.3.988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. PONTREMOLI S., PRANDINI B. D., BONSIGNORE A., HORECKER B. L. The preparation of crystalline transaldolase from Candida utilis. Proc Natl Acad Sci U S A. 1961 Dec 15;47:1942–1949. doi: 10.1073/pnas.47.12.1942. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Perl A., Banki K. Human endogenous retroviral elements and autoimmunity: data and concepts. Trends Microbiol. 1993 Jul;1(4):153–156. doi: 10.1016/0966-842x(93)90131-a. [DOI] [PubMed] [Google Scholar]
  25. Perl A., Gonzalez-Cabello R., Láng I., Gergely P. Effector activity of OKT4+ and OKT8+ T-cell subsets in lectin-dependent cell-mediated cytotoxicity against adherent HEp-2 cells. Cell Immunol. 1984 Mar;84(1):185–193. doi: 10.1016/0008-8749(84)90089-3. [DOI] [PubMed] [Google Scholar]
  26. Perl A., González-Cabello R., Onody K., Bodó I., Gergely P. Independence of depressed lectin-dependent cell-mediated cytotoxicity from interleukin 2 production in patients with systemic lupus erythematosus. Clin Exp Immunol. 1986 Aug;65(2):286–292. [PMC free article] [PubMed] [Google Scholar]
  27. Poser C. M., Paty D. W., Scheinberg L., McDonald W. I., Davis F. A., Ebers G. C., Johnson K. P., Sibley W. A., Silberberg D. H., Tourtellotte W. W. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983 Mar;13(3):227–231. doi: 10.1002/ana.410130302. [DOI] [PubMed] [Google Scholar]
  28. Query C. C., Keene J. D. A human autoimmune protein associated with U1 RNA contains a region of homology that is cross-reactive with retroviral p30gag antigen. Cell. 1987 Oct 23;51(2):211–220. doi: 10.1016/0092-8674(87)90148-6. [DOI] [PubMed] [Google Scholar]
  29. Richert J. R., Robinson E. D., Johnson A. H., Bergman C. A., Dragovic L. J., Reinsmoen N. L., Hurley C. K. Heterogeneity of the T-cell receptor beta gene rearrangements generated in myelin basic protein-specific T-cell clones isolated from a patient with multiple sclerosis. Ann Neurol. 1991 Mar;29(3):299–306. doi: 10.1002/ana.410290312. [DOI] [PubMed] [Google Scholar]
  30. Seboun E., Robinson M. A., Doolittle T. H., Ciulla T. A., Kindt T. J., Hauser S. L. A susceptibility locus for multiple sclerosis is linked to the T cell receptor beta chain complex. Cell. 1989 Jun 30;57(7):1095–1100. doi: 10.1016/0092-8674(89)90046-9. [DOI] [PubMed] [Google Scholar]
  31. Shaw S. Y., Laursen R. A., Lees M. B. Analogous amino acid sequences in myelin proteolipid and viral proteins. FEBS Lett. 1986 Oct 27;207(2):266–270. doi: 10.1016/0014-5793(86)81502-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Shimonkevitz R., Murray R., Kotzin B. Characterization of T-cell receptor V beta usage in the brain of a subject with multiple sclerosis. Ann N Y Acad Sci. 1995 Jul 7;756:305–306. doi: 10.1111/j.1749-6632.1995.tb44527.x. [DOI] [PubMed] [Google Scholar]
  33. Smith D. B., Johnson K. S. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene. 1988 Jul 15;67(1):31–40. doi: 10.1016/0378-1119(88)90005-4. [DOI] [PubMed] [Google Scholar]
  34. Steinman L. Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell. 1996 May 3;85(3):299–302. doi: 10.1016/s0092-8674(00)81107-1. [DOI] [PubMed] [Google Scholar]
  35. Tan E. M., Cohen A. S., Fries J. F., Masi A. T., McShane D. J., Rothfield N. F., Schaller J. G., Talal N., Winchester R. J. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov;25(11):1271–1277. doi: 10.1002/art.1780251101. [DOI] [PubMed] [Google Scholar]
  36. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Traugott U., Reinherz E. L., Raine C. S. Multiple sclerosis: distribution of T cell subsets within active chronic lesions. Science. 1983 Jan 21;219(4582):308–310. doi: 10.1126/science.6217550. [DOI] [PubMed] [Google Scholar]
  38. Traugott U., Scheinberg L. C., Raine C. S. On the presence of Ia-positive endothelial cells and astrocytes in multiple sclerosis lesions and its relevance to antigen presentation. J Neuroimmunol. 1985 Apr;8(1):1–14. doi: 10.1016/s0165-5728(85)80043-6. [DOI] [PubMed] [Google Scholar]
  39. Utz U., Biddison W. E., McFarland H. F., McFarlin D. E., Flerlage M., Martin R. Skewed T-cell receptor repertoire in genetically identical twins correlates with multiple sclerosis. Nature. 1993 Jul 15;364(6434):243–247. doi: 10.1038/364243a0. [DOI] [PubMed] [Google Scholar]
  40. Utz U., Martin R., Brooks J. A., Biddison W. E., McFarland H. F. T-cell receptor use in multiple sclerosis. Ann N Y Acad Sci. 1995 Jul 7;756:259–264. doi: 10.1111/j.1749-6632.1995.tb44523.x. [DOI] [PubMed] [Google Scholar]
  41. Vandenbark A. A., Hashim G., Offner H. TCR peptide therapy in autoimmune diseases. Int Rev Immunol. 1993;9(4):251–276. doi: 10.3109/08830189309051210. [DOI] [PubMed] [Google Scholar]
  42. Whitham R. H., Jones R. E., Hashim G. A., Hoy C. M., Wang R. Y., Vandenbark A. A., Offner H. Location of a new encephalitogenic epitope (residues 43 to 64) in proteolipid protein that induces relapsing experimental autoimmune encephalomyelitis in PL/J and (SJL x PL)F1 mice. J Immunol. 1991 Dec 1;147(11):3803–3808. [PubMed] [Google Scholar]
  43. Wucherpfennig K. W., Newcombe J., Li H., Keddy C., Cuzner M. L., Hafler D. A. T cell receptor V alpha-V beta repertoire and cytokine gene expression in active multiple sclerosis lesions. J Exp Med. 1992 Apr 1;175(4):993–1002. doi: 10.1084/jem.175.4.993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Zhang J., Markovic-Plese S., Lacet B., Raus J., Weiner H. L., Hafler D. A. Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med. 1994 Mar 1;179(3):973–984. doi: 10.1084/jem.179.3.973. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES