Microbicidal/cytotoxic proteins of neutrophils are deficient in two disorders: Chediak-Higashi syndrome and "specific" granule deficiency (original) (raw)

Abstract

Although several genetic defects are known to impair oxidative microbicidal/cytotoxic mechanisms in human PMN, no deficiencies of PMN granule components that mediate oxygen-independent microbicidal activity have yet been reported. We analyzed PMN from patients with various granulocyte disorders for their content of two azurophil granule constituents, defensins and cathepsin G, that exert microbicidal/cytotoxic activity in vitro, and one component, elastase, that has ancillary microbicidal/cytotoxic activity. PMN from two (of two) patients with specific granule deficiency (SGD) displayed an almost complete deficiency of defensins, which in normal cells constitute greater than 30% of the protein content of azurophil granules. The SGD PMN contained normal or mildly decreased amounts of cathepsin G and elastase. Conversely, the PMN of three (of three) patients with Chediak-Higashi syndrome (CHS) substantially lacked cathepsin G and elastase, but their defensin content was normal or mildly decreased. Both CHS and SGD patients suffer from frequent and severe bacterial infections, and CHS patients frequently develop an atypical lymphoproliferative syndrome. The profound deficiency of PMN components with microbicidal/cytotoxic activity in SGD and CHS may contribute to the clinical manifestations of these disorders.

552

Images in this article

Selected References

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

  1. Ambruso D. R., Sasada M., Nishiyama H., Kubo A., Komiyama A., Allen R. H. Defective bactericidal activity and absence of specific granules in neutrophils from a patient with recurrent bacterial infections. J Clin Immunol. 1984 Jan;4(1):23–30. doi: 10.1007/BF00915283. [DOI] [PubMed] [Google Scholar]
  2. Blume R. S., Wolff S. M. The Chediak-Higashi syndrome: studies in four patients and a review of the literature. Medicine (Baltimore) 1972 Jul;51(4):247–280. [PubMed] [Google Scholar]
  3. Borregaard N., Boxer L. A., Smolen J. E., Tauber A. I. Anomalous neutrophil granule distribution in a patient with lactoferrin deficiency: pertinence to the respiratory burst. Am J Hematol. 1985 Mar;18(3):255–260. doi: 10.1002/ajh.2830180306. [DOI] [PubMed] [Google Scholar]
  4. Boxer L. A., Coates T. D., Haak R. A., Wolach J. B., Hoffstein S., Baehner R. L. Lactoferrin deficiency associated with altered granulocyte function. N Engl J Med. 1982 Aug 12;307(7):404–410. doi: 10.1056/NEJM198208123070704. [DOI] [PubMed] [Google Scholar]
  5. Bretz U., Baggiolini M. Biochemical and morphological characterization of azurophil and specific granules of human neutrophilic polymorphonuclear leukocytes. J Cell Biol. 1974 Oct;63(1):251–269. doi: 10.1083/jcb.63.1.251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Clark R. A., Olsson I., Klebanoff S. J. Cytotoxicity for tumor cells of cationic proteins from human neutrophil granules. J Cell Biol. 1976 Sep;70(3):719–723. doi: 10.1083/jcb.70.3.719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clawson C. C., Repine J. E., White J. G. The Chediak-Higashi syndrome: quantitation of a deficiency in maximal bactericidal capacity. Am J Pathol. 1979 Mar;94(3):539–547. [PMC free article] [PubMed] [Google Scholar]
  8. Gallin J. I., Fletcher M. P., Seligmann B. E., Hoffstein S., Cehrs K., Mounessa N. Human neutrophil-specific granule deficiency: a model to assess the role of neutrophil-specific granules in the evolution of the inflammatory response. Blood. 1982 Jun;59(6):1317–1329. [PubMed] [Google Scholar]
  9. Gallin J. I. Neutrophil specific granule deficiency. Annu Rev Med. 1985;36:263–274. doi: 10.1146/annurev.me.36.020185.001403. [DOI] [PubMed] [Google Scholar]
  10. Ganz T. Extracellular release of antimicrobial defensins by human polymorphonuclear leukocytes. Infect Immun. 1987 Mar;55(3):568–571. doi: 10.1128/iai.55.3.568-571.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ganz T., Selsted M. E., Lehrer R. I. Antimicrobial activity of phagocyte granule proteins. Semin Respir Infect. 1986 Jun;1(2):107–117. [PubMed] [Google Scholar]
  12. Ganz T., Selsted M. E., Szklarek D., Harwig S. S., Daher K., Bainton D. F., Lehrer R. I. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest. 1985 Oct;76(4):1427–1435. doi: 10.1172/JCI112120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kimball H. R., Ford G. H., Wolff S. M. Lysosomal enzymes in normal and Chediak-Higashi blood leukocytes. J Lab Clin Med. 1975 Oct;86(4):616–630. [PubMed] [Google Scholar]
  14. Lichtenstein A., Ganz T., Selsted M. E., Lehrer R. I. In vitro tumor cell cytolysis mediated by peptide defensins of human and rabbit granulocytes. Blood. 1986 Dec;68(6):1407–1410. [PubMed] [Google Scholar]
  15. Nakajima K., Powers J. C., Ashe B. M., Zimmerman M. Mapping the extended substrate binding site of cathepsin G and human leukocyte elastase. Studies with peptide substrates related to the alpha 1-protease inhibitor reactive site. J Biol Chem. 1979 May 25;254(10):4027–4032. [PubMed] [Google Scholar]
  16. Parmley R. T., Tzeng D. Y., Baehner R. L., Boxer L. A. Abnormal distribution of complex carbohydrates in neutrophils of a patient with lactoferrin deficiency. Blood. 1983 Sep;62(3):538–548. [PubMed] [Google Scholar]
  17. Parry M. F., Root R. K., Metcalf J. A., Delaney K. K., Kaplow L. S., Richar W. J. Myeloperoxidase deficiency: prevalence and clinical significance. Ann Intern Med. 1981 Sep;95(3):293–301. doi: 10.7326/0003-4819-95-3-293. [DOI] [PubMed] [Google Scholar]
  18. REISFELD R. A., LEWIS U. J., WILLIAMS D. E. Disk electrophoresis of basic proteins and peptides on polyacrylamide gels. Nature. 1962 Jul 21;195:281–283. doi: 10.1038/195281a0. [DOI] [PubMed] [Google Scholar]
  19. Rest R. F., Cooney M. H., Spitznagel J. K. Bactericidal activity of specific and azurophil granules from human neutrophils: studies with outer-membrane mutants of Salmonella typhimurium LT-2. Infect Immun. 1978 Jan;19(1):131–137. doi: 10.1128/iai.19.1.131-137.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rice W. G., Ganz T., Kinkade J. M., Jr, Selsted M. E., Lehrer R. I., Parmley R. T. Defensin-rich dense granules of human neutrophils. Blood. 1987 Sep;70(3):757–765. [PubMed] [Google Scholar]
  21. Root R. K., Rosenthal A. S., Balestra D. J. Abnormal bactericidal, metabolic, and lysosomal functions of Chediak-Higashi Syndrome leukocytes. J Clin Invest. 1972 Mar;51(3):649–665. doi: 10.1172/JCI106854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Smedly L. A., Tonnesen M. G., Sandhaus R. A., Haslett C., Guthrie L. A., Johnston R. B., Jr, Henson P. M., Worthen G. S. Neutrophil-mediated injury to endothelial cells. Enhancement by endotoxin and essential role of neutrophil elastase. J Clin Invest. 1986 Apr;77(4):1233–1243. doi: 10.1172/JCI112426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Smith P. K., Krohn R. I., Hermanson G. T., Mallia A. K., Gartner F. H., Provenzano M. D., Fujimoto E. K., Goeke N. M., Olson B. J., Klenk D. C. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985 Oct;150(1):76–85. doi: 10.1016/0003-2697(85)90442-7. [DOI] [PubMed] [Google Scholar]
  24. Spitznagel J. K. Nonoxidative antimicrobial reactions of leukocytes. Contemp Top Immunobiol. 1984;14:283–343. doi: 10.1007/978-1-4757-4862-8_10. [DOI] [PubMed] [Google Scholar]
  25. Stossel T. P., Root R. K., Vaughan M. Phagocytosis in chronic granulomatous disease and the Chediak-Higashi syndrome. N Engl J Med. 1972 Jan 20;286(3):120–123. doi: 10.1056/NEJM197201202860302. [DOI] [PubMed] [Google Scholar]
  26. Strauss R. G., Bove K. E., Jones J. F., Mauer A. M., Fulginiti V. A. An anomaly of neutrophil morphology with impaired function. N Engl J Med. 1974 Feb 28;290(9):478–484. doi: 10.1056/NEJM197402282900903. [DOI] [PubMed] [Google Scholar]
  27. Takeuchi K., Wood H., Swank R. T. Lysosomal elastase and cathepsin G in beige mice. Neutrophils of beige (Chediak-Higashi) mice selectively lack lysosomal elastase and cathepsin G. J Exp Med. 1986 Mar 1;163(3):665–677. doi: 10.1084/jem.163.3.665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Vassalli J. D., Granelli-Piperno A., Griscelli C., Reich E. Specific protease deficiency in polymorphonuclear leukocytes of Chédiak-Higashi syndrome and beige mice. J Exp Med. 1978 Apr 1;147(4):1285–1290. doi: 10.1084/jem.147.4.1285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. West B. C. Chédiak-Higashi syndrome neutrophils are characterized by the absence of both normal azurophilic granules. Am J Pathol. 1986 Jan;122(1):177–189. [PMC free article] [PubMed] [Google Scholar]
  30. White C. J., Gallin J. I. Phagocyte defects. Clin Immunol Immunopathol. 1986 Jul;40(1):50–61. doi: 10.1016/0090-1229(86)90068-1. [DOI] [PubMed] [Google Scholar]
  31. ZUCKER-FRANKLIN D., HIRSCH J. G. ELECTRON MICROSCOPE STUDIES ON THE DEGRANULATION OF RABBIT PERITONEAL LEUKOCYTES DURING PHAGOCYTOSIS. J Exp Med. 1964 Oct 1;120:569–576. doi: 10.1084/jem.120.4.569. [DOI] [PMC free article] [PubMed] [Google Scholar]