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. 1994 Aug;94(2):761–770. doi: 10.1172/JCI117395

Antimyenteric neuronal antibodies in scleroderma.

S Howe 1, E Y Eaker 1, J E Sallustio 1, C Peebles 1, E M Tan 1, R C Williams Jr 1
PMCID: PMC296156  PMID: 8040331

Abstract

The pathogenesis of gastrointestinal (GI) dysmotility in scleroderma is incompletely understood, although previous studies have proposed a neuropathic mechanism. We studied patients with scleroderma as compared with other connective tissue disease patients and normal controls for the presence of circulating antibodies to myenteric neurons. Serial dilutions of sera were overlaid on rat intestine, double-labeled with antineurofilament antibody as a myenteric plexus marker, and imaged using indirect immunofluorescence techniques. High titer sera (> or = 1:50) from 19 out of 41 scleroderma patients stained myenteric neurons, whereas none of 22 normals or 5 patients with idiopathic GI dysmotility were positive. Although 6 out of 20 SLE and 6 out of 10 mixed connective tissue disease patients' sera stained myenteric plexus neurons, when positive sera were absorbed with calf thymus extract to remove antinuclear antibody, 15 scleroderma sera, 0 SLE, and 2 mixed connective tissue disease patients retained positive staining of myenteric neurons. Western blotting using actin and neuronal intermediate filament preparations failed to show immunoreactivity with scleroderma sera containing antimyenteric neuronal antibodies. Paraneoplastic sera associated with GI dysmotility stained myenteric neurons in a different pattern than seen with scleroderma sera. A positive correlation between the presence of Raynaud's phenomenon and antimyenteric neuronal antibodies was observed in scleroderma patients. Our results indicate that IgG antibodies reacting with myenteric neurons are present in many patients with scleroderma. Although the neuronal antigen has not yet been identified, the presence of myenteric neuronal antibodies in patients with GI dysmotility and scleroderma suggests a neuropathic process.

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Selected References

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

  1. Akesson A., Ekman R. Gastrointestinal regulatory peptides in systemic sclerosis. Arthritis Rheum. 1993 May;36(5):698–703. doi: 10.1002/art.1780360519. [DOI] [PubMed] [Google Scholar]
  2. Altermatt H. J., Rodriguez M., Scheithauer B. W., Lennon V. A. Paraneoplastic anti-Purkinje and type I anti-neuronal nuclear autoantibodies bind selectively to central, peripheral, and autonomic nervous system cells. Lab Invest. 1991 Oct;65(4):412–420. [PubMed] [Google Scholar]
  3. Altermatt H. J., Williams C. L., Lennon V. A. Paraneoplastic cerebellar autoantibodies associated with gynecological cancer bind to myenteric plexus neurons. Ann Neurol. 1991 Jun;29(6):687–688. doi: 10.1002/ana.410290621. [DOI] [PubMed] [Google Scholar]
  4. Belch J. J., Land D., Park R. H., McKillop J. H., MacKenzie J. F. Decreased oesophageal blood flow in patients with Raynaud's phenomenon. Br J Rheumatol. 1988 Dec;27(6):426–430. doi: 10.1093/rheumatology/27.6.426. [DOI] [PubMed] [Google Scholar]
  5. Bernstein R. M., Steigerwald J. C., Tan E. M. Association of antinuclear and antinucleolar antibodies in progressive systemic sclerosis. Clin Exp Immunol. 1982 Apr;48(1):43–51. [PMC free article] [PubMed] [Google Scholar]
  6. Catoggio L. J., Bernstein R. M., Black C. M., Hughes G. R., Maddison P. J. Serological markers in progressive systemic sclerosis: clinical correlations. Ann Rheum Dis. 1983 Feb;42(1):23–27. doi: 10.1136/ard.42.1.23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cohen S., Fisher R., Lipshutz W., Turner R., Myers A., Schumacher R. The pathogenesis of esophageal dysfunction in scleroderma and Raynaud's disease. J Clin Invest. 1972 Oct;51(10):2663–2668. doi: 10.1172/JCI107084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. De Villiers W. J., Jordaan H. F., Bates W. Systemic sclerosis sine scleroderma presenting with vitiligo-like depigmentation and interstitial pulmonary fibrosis. Clin Exp Dermatol. 1992 Mar;17(2):127–131. doi: 10.1111/j.1365-2230.1992.tb00180.x. [DOI] [PubMed] [Google Scholar]
  9. DiMarino A. J., Carlson G., Myers A., Schumacher H. R., Cohen S. Duodenal myoelectric activity in scleroderma. Abnormal responses to mechanical and hormonal stimuli. N Engl J Med. 1973 Dec 6;289(23):1220–1223. doi: 10.1056/NEJM197312062892304. [DOI] [PubMed] [Google Scholar]
  10. Eaker E. Y., Shaw G., Sninsky C. A. Neurofilament immunoreactivity in myenteric neurons differs from that found in the central nervous system. Gastroenterology. 1990 Nov;99(5):1364–1371. doi: 10.1016/0016-5085(90)91163-z. [DOI] [PubMed] [Google Scholar]
  11. Ferri C., Bernini L., Cecchetti R., Latorraca A., Marotta G., Pasero G., Neri R., Bombardieri S. Cutaneous and serologic subsets of systemic sclerosis. J Rheumatol. 1991 Dec;18(12):1826–1832. [PubMed] [Google Scholar]
  12. Fulp S. R., Castell D. O. Scleroderma esophagus. Dysphagia. 1990;5(4):204–210. doi: 10.1007/BF02412688. [DOI] [PubMed] [Google Scholar]
  13. Greydanus M. P., Camilleri M. Abnormal postcibal antral and small bowel motility due to neuropathy or myopathy in systemic sclerosis. Gastroenterology. 1989 Jan;96(1):110–115. doi: 10.1016/0016-5085(89)90770-1. [DOI] [PubMed] [Google Scholar]
  14. Harris J., Ayyub C., Shaw G. A molecular dissection of the carboxyterminal tails of the major neurofilament subunits NF-M and NF-H. J Neurosci Res. 1991 Sep;30(1):47–62. doi: 10.1002/jnr.490300107. [DOI] [PubMed] [Google Scholar]
  15. Lennon V. A., Sas D. F., Busk M. F., Scheithauer B., Malagelada J. R., Camilleri M., Miller L. J. Enteric neuronal autoantibodies in pseudoobstruction with small-cell lung carcinoma. Gastroenterology. 1991 Jan;100(1):137–142. doi: 10.1016/0016-5085(91)90593-a. [DOI] [PubMed] [Google Scholar]
  16. RODNAN G. P., FENNELL R. H., Jr Progressive systemic sclerosis sine scleroderma. JAMA. 1962 May 26;180:665–670. doi: 10.1001/jama.1962.03050210027006. [DOI] [PubMed] [Google Scholar]
  17. STEVENS M. B., HOOKMAN P., SIEGEL C. I., ESTERLY J. R., SHULMAN L. E., HENDRIX T. R. APERISTALSIS OF THE ESOPHAGUS IN PATIENTS WITH CONNECTIVE-TISSUE DISORDERS AND RAYNAUD'S PHENOMENON. N Engl J Med. 1964 Jun 4;270:1218–1222. doi: 10.1056/NEJM196406042702303. [DOI] [PubMed] [Google Scholar]
  18. Schuffler M. D., Beegle R. G. Progressive systemic sclerosis of the gastrointestinal tract and hereditary hollow visceral myopathy: two distinguishable disorders of intestinal smooth muscle. Gastroenterology. 1979 Oct;77(4 Pt 1):664–671. [PubMed] [Google Scholar]
  19. Senécal J. L., Ichiki S., Girard D., Raymond Y. Autoantibodies to nuclear lamins and to intermediate filament proteins: natural, pathologic or pathogenic? J Rheumatol. 1993 Feb;20(2):211–219. [PubMed] [Google Scholar]
  20. Senécal J. L., Oliver J. M., Rothfield N. Anticytoskeletal autoantibodies in the connective tissue diseases. Arthritis Rheum. 1985 Aug;28(8):889–898. doi: 10.1002/art.1780280808. [DOI] [PubMed] [Google Scholar]
  21. Shaw G., Hou Z. C. Bundling and cross-linking of intermediate filaments of the nervous system. J Neurosci Res. 1990 Apr;25(4):561–568. doi: 10.1002/jnr.490250414. [DOI] [PubMed] [Google Scholar]
  22. Shelanski M. L., Albert S., DeVries G. H., Norton W. T. Isolation of filaments from brain. Science. 1971 Dec 17;174(4015):1242–1245. doi: 10.1126/science.174.4015.1242. [DOI] [PubMed] [Google Scholar]
  23. Soudah H. C., Hasler W. L., Owyang C. Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma. N Engl J Med. 1991 Nov 21;325(21):1461–1467. doi: 10.1056/NEJM199111213252102. [DOI] [PubMed] [Google Scholar]
  24. Spudich J. A., Watt S. The regulation of rabbit skeletal muscle contraction. I. Biochemical studies of the interaction of the tropomyosin-troponin complex with actin and the proteolytic fragments of myosin. J Biol Chem. 1971 Aug 10;246(15):4866–4871. [PubMed] [Google Scholar]
  25. Stefansson K., Marton L. S., Dieperink M. E., Molnar G. K., Schlaepfer W. W., Helgason C. M. Circulating autoantibodies to the 200,000-dalton protein of neurofilaments in the serum of healthy individuals. Science. 1985 May 31;228(4703):1117–1119. doi: 10.1126/science.4039466. [DOI] [PubMed] [Google Scholar]
  26. TREACY W. L., BAGGENSTOSS A. H., SLOCUMB C. H., CODE C. F. SCLERODERMA OF THE ESOPHAGUS. A CORRELATION OF HISTOLOGIC AND PHYSIOLOGIC FINDINGS. Ann Intern Med. 1963 Sep;59:351–356. doi: 10.7326/0003-4819-59-3-351. [DOI] [PubMed] [Google Scholar]
  27. Tan E. M. Autoantibodies to nuclear antigens (ANA): their immunobiology and medicine. Adv Immunol. 1982;33:167–240. doi: 10.1016/s0065-2776(08)60836-6. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. 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]
  30. Weiner E. S., Earnshaw W. C., Senécal J. L., Bordwell B., Johnson P., Rothfield N. F. Clinical associations of anticentromere antibodies and antibodies to topoisomerase I. A study of 355 patients. Arthritis Rheum. 1988 Mar;31(3):378–385. doi: 10.1002/art.1780310309. [DOI] [PubMed] [Google Scholar]

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