Clinical Research Article | Published:

B-cell-specific accumulation of inclusion bodies loaded with HLA class II molecules in patients with mucolipidosis II (I-cell disease)

Pediatric Research (2018) | Download Citation

Subjects

Abstract

Background

I-cell disease is characterized by the presence of vacuole-like inclusions in lymphocytes. However, the nature and clinical significance of these inclusions have seldom been characterized. In this study, the authors tried to elucidate the distribution in different lymphocyte subpopulations, and the histological nature of the inclusions.

Methods

Blood samples from three unrelated patients were analyzed. Lymphocyte subpopulations were separated using monoclonal antibodies conjugated to immunomagnetic beads. Cytochemical studies were performed using FITC-conjugated lectins. The expressions of surface and cytoplasmic class II molecules were analyzed by flow cytometry.

Results

Virtually all B cells from the patients contained the inclusions. In contrast, CD4+ T cells, CD8+ T cells, natural killer cells, monocytes, or neutrophils did not contain the inclusions. Both fibroblasts and B cells from I-cell patients were stained intensely by multiple FITC-conjugated lectins with distinct binding profiles. The inclusions of B cells were stained intensely by fluorescence-conjugated antibodies against class II antigens.

Conclusions

Inclusions in I-cell disease reflect the accumulation of HLA class II molecules within B cells. These results suggest a potential role for N-acetylglucosamine-1-phosphotransferase in immune functions. Furthermore, the fact that only B cells contain the inclusions provides a novel diagnostic aid for the diagnosis of I-cell disease.

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References

  1. 1.

    Leroy, J. G. & DeMars, R. I. Mutant enzymatic and cytological phenotypes in cultured human fibroblats. Science 157, 804–806 (1967).

  2. 2.

    Leroy, J. G. et al. I-cell disease: a clinical picture. J. Pediatr. 79, 360–365 (1971).

  3. 3.

    Patriquin, H. B. et al. Neonatal mucolipidosis II (I-cell disease): clinical and radiologic features in three cases. Am. J. Roentogenol. 129, 37–43 (1977).

  4. 4.

    Okada, S. et al. I-cell disease: clinical studies of 21 Japanese cases. Clin. Genet. 28, 207–215 (1985).

  5. 5.

    Tiede, S. et al. Mucolipidosis II is caused by mutations in GNPTA encoding the α/β GlcNAc-1-phosphotransferase. Nat. Med. 11, 1109–1112 (2005).

  6. 6.

    Kudo, M., Brem, M. S. & Canfield, W. M. Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-Hurler polydystrophy) are caused by mutations in the GlcNAc- phosphotransferase α/β-subunits precursor gene. Am. J. Hum. Genet. 78, 451–463 (2006).

  7. 7.

    Tiede, S. et al. Missense mutation in the N-acetylglucosamine- 1-phosphotransferase gene (GNPTA) in a patient with mucolipidosis II induces changes in the size and cellular distribution of GNPTG. Hum. Mutat. 27, 830–831 (2006).

  8. 8.

    Braulke, T., Pohl, S. & Storch, S. Molecular analysis of the GlcNac-1-phosphotransferase. J. Inherit. Metab. Dis. 31, 253–257 (2008).

  9. 9.

    Reitman, A. L., Verki, A. & Kornfield, S. Fibroblasts from patients with I-cell disease and pseudo-Hurler polydystrophy are deficient in uridine 5-diphosphate-N-acetyl glucosamine: glycoprotein N-acetyl-gludosaminlyphosphotransferase activity. J. Clin. Invest. 67, 1574–1579 (1981).

  10. 10.

    Koga, M. et al. Histochemical and ultrastructural studies of inclusion bodies found in tissues from three siblings with I-cell disease. Pathol. Int. 44, 223–229 (1994).

  11. 11.

    Tang, X. et al. I-cell disease: report of an autopsy case. Tokai J. Exp. Clin. Med. 20, 109–120 (1995).

  12. 12.

    Carey, W. F. et al. Prenatal diagnosis of mucolipidosis II—electron microscopy and biochemical evaluation. Prenat. Diag 19, 252–256 (1999).

  13. 13.

    Van der Meer, W. et al. Peripheral blood lymphocyte appearance in a case of I cell disease. J. Clin. Pathol. 54, 724–726 (2001).

  14. 14.

    Kawashima, I. et al. Cytochemical analysis of storage materials in cultured skin fibroblastas from patients with I-cell disease. Clin. Chim. Acta 378, 142–146 (2007).

  15. 15.

    Toga, A. et al. Clinical significance of cloned expansion and CD5 down-regulation in Epstein-Barr virus (EBV)-infected CD8+ T lymphocytes in EBV-associated hemophagocytic lymphohistiocytosis. J. Infect. Dis. 201, 1923–1932 (2010).

  16. 16.

    Lynch, D. T. & Czuchlewski, D. R. Peripheral blood findings in GM1 gangliosidosis. Blood 127, 2161 (2016).

  17. 17.

    Smith, H. & Collins, R. J. A population of lymphocytes in human blood distinctive in morphology and other characteristics. J. Clin. Pathol. 30, 243–249 (1977).

  18. 18.

    Hagemans, M. L. C. et al. PAS-positive lymphocyte vacuoles can be used as diagnostic screening test for Pompe disease. J. Inherit. Metab. Dis. 33, 133–139 (2010).

  19. 19.

    Anderson, G. et al. Blood film examination for vacuolated lymphocytes in the diagnosis of metabolic disorders; retrospective experience of more than 2500 cases from a single centre. J. Clin. Pathol. 58, 1305–1310 (2005).

  20. 20.

    Davidson, R. J. & McPhie, J. L. Cytoplasmic vacuolation of peripheral blood cells in acute alcoholism. J. Clin. Pathol. 33, 1193–1196 (1980).

  21. 21.

    Dittmer, F. et al. Alternative mechanisms for trafficking of lysosomal enzymes in mannose 6-phospahte receptor-deficient mice are cell type-specific. J. Cell Sci. 112, 1591–1597 (1999).

  22. 22.

    Griffiths, G. M. & Isaaz, S. Granzymes A and B are targeted to the lytic granules of lymphocytes by the mannose-6-phosphate receptor. J. Cell Biol. 120, 885–896 (1993).

  23. 23.

    Kato, E., Yokoi, T. & Taniguchi, N. Lysosomal acid hydrolases in lymphocytes of I-cell disease. Clin. Chim. Acta 95, 285–290 (1979).

  24. 24.

    Tsuji, A., Omura, K. & Suzuki, Y. I-cell disease: evidence for a mannose 6-phosphate independent pathway for translocation of lysosomal enzymes in lymphoblastoid cells. Clin. Chim. Acta 176, 115–121 (1988).

  25. 25.

    Glickman, J. N. & Kornfeld, S. Mannose 6-phosphate-independent targeting of lysosomal enzymes in I-cell disease B lymphoblasts. J. Cell Biol. 123, 99–108 (1993).

  26. 26.

    Glickman, J. N. et al. The biogenesis of the MHC class II compartment in human I-cell disease B lymphoblasts. J. Cell Biol. 132, 769–785 (1996).

  27. 27.

    Otomo, T. et al. Mannose 6 phosphorylation of lysosomal enzymes controls B cell functions. J. Cell Biol. 208, 171–180 (2015).

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Acknowledgements

We would like to thank Ms. Harumi Matsukawa for her excellent technical assistance. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and a grant from the Ministry of Health, Labour, and Welfare of Japan, Tokyo.

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Affiliations

  1. Department of Pediatrics, School of Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan

    • Ayano Yokoi
    • , Mondo Kuroda
    • , Yoko Imi-Hashida
    • , Tomoko Toma
    •  & Akihiro Yachie
  2. Division of Clinical Genetics, Multidisciplinary Medical Center, Kanazawa Medical University Hospital, Uchinada, Japan

    • Yo Niida

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Contributions

A.Y. and Y.I.-H.: Provided substantial contributions to the conception and design of the study, the acquisition of data, and the analysis and interpretation of the data. T.T.: Provided critical advice for the technical aspects of the study. M.K.: Drafted the article and revised it critically for important intellectual content. Y.N. and A.Y.: Provided final approval of the version to be published.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Akihiro Yachie.

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DOI

https://doi.org/10.1038/s41390-018-0234-2