Skip to main content
SpringerLink
Log in

Simultaneous detection of ferritin and HIV-1 in reactive microglia

  • Regular Papers
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Summary

Using ferritin as a marker of reactive microglia, we demonstrated a close association between proliferation of reactive microglia and expression of human immunodeficiency virus type 1 (HIV-1) in brain tissue from autopsied cases of acquired immunodeficiency syndrome (AIDS). An increased number of ferritin-positive reactive microglia was observed in formalin-fixed paraffin-embedded brain sections from all 13 AIDS cases examined. Similar findings were observed in brain tissue from other neurological diseases (subacute sclerosing penencephalitis, herpes simplex encephalitis and multiple sclerosis). Multinucleated giant cells were found in 7 of the AIDS cases which were also intensely labeled for ferritin. Dual-label immunohistochemistry using anti-ferritin and cell-specific markers showed that ferritin-positive cells were distinct from astrocytes, neurons and endothelia using anti-glial fibrillary acidic protein (anti-GFAP), anti-neurofilament protein and Ulex europaeus agglutinin 1, respectively. In 5 AIDS brains, only ferritin-positive cells were shown to contain HIV-1 gp41 antigen using dual-label immunohistochemistry. In addition, HIV-1 RNA was localized in territin-positive reactive microglia but not in GFAP-positive astrocytes using immunohistochemistry combined with in situ hybridization. Ferritin-positive reactive microglia and multinucleated giant cells were colabeled with the microglial marker, Ricinus communis agglutinin 1 (RCA-1). Howerver, RCA-1 also extensively stained resting microglia only a few of which were colabeled for ferritin. The density of ferritin-positive cells was correlated with the presence of HIV-1 RNA-positive cells in AIDS brain. Thus, ferritin immunoreactivity can be used as an activation marker of microglia in archival paraffin sections and reflects the extent of inflammation in HIV-1-infected brain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Andreesen R, Osterholz J, Bodemann H, Bross KJ, Costabel U, Löhr GW (1984) Expression of transferrin receptors and intracellular ferritin during terminal differentiation of human monocytes. Blut 49:195–202

    Google Scholar 

  2. Bignami A, Eng LF, Dahl D, Uyeda CT (1972) Localization of the glial fibrillary acidic protein in astrocytes by immunofluorescence. Brain Res 43:429–435

    Google Scholar 

  3. Botticelli AR, Criscuolo M, Gregorio C (1989) Multinucleated giant cells in AIDS encephalopathy: an immunohistochemical study. Ital J Neurol Sci 10:301–305

    Google Scholar 

  4. Budka H (1986) Multinucleated giant cells in brain: a hallmark of the acquired immune deficiency syndrome 9AIDS). Acta Neuropathol (Berl) 69:253–258

    Google Scholar 

  5. Budka H, Costanzi G, Cristina S, Lechi A, Parravicini C, Trabattoni R, Vago L (1987) Brain pathology induced by infection with the human immunodeficiency virus (HIV). A histological, immunocytochemical, and electron microscopical study of 100 autopsy cases. Acta Neuropathol (Berl) 75:185–198

    Google Scholar 

  6. Cayre Y, Raynal M-C, Darzynkiewicz Z, Dorner MH (1987) Model for intermediate steps in monocytic differentiation: c-myc, c-fms, and ferritin as markers. Proc Natl Acad Sci USA 84:7619–7623

    Google Scholar 

  7. Chou SM, Miles JM (1989) B-cell immunomarkers recognize rod cells in paraffin sections. J Neuropathol Exp Neurol 48:344

    Google Scholar 

  8. Clapham PR, Weiss RA, Dalgleish AG, Exley M, Whitby D, Hogg N (1987) Human immunodeficiency virus infection of monocytic and T-lymphocytic cells: receptor modulation and differentiation induced by phorbol ester. Virology 158:44–51

    Google Scholar 

  9. Cordell JL, Falini B, Erber WN, Ghosh AK, Abdulaziz Z, MacDonald S, Pulford KAF, Stein H, Mason DY (1984) Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem 32:219–229

    CAS  PubMed  Google Scholar 

  10. de la Monte SM, Ho DD, Schooley RT, Hirsch MS, Richardson EP (1987) Subacute encephalomyelitis of AIDS and its relation to HTLV-III infection. Neurology 37:562–569

    Google Scholar 

  11. Del Rio-Hortega P (1932) Microglia. In: Penfield W (ed) Cytology and cellular pathology of the nervous system, vol 2. Hoeber. New York, pp 483–534, in reprint edition (1965) Hafner, New York

    Google Scholar 

  12. Dickson DW (1986) Multinucleated giant cells in acquired immunodeficiency syndrome encephalopathy: origin from endogenous microglia? Arch Pathol Lab Med 110:967–968

    Google Scholar 

  13. Eilbott DJ, Peress N, Burger H, LaNeve D, Orenstein J, Gendelman HE, Seidman R, Weiser B (1989) Human immunodeficiency virus type 1 in spinal cords of acquired immunodeficiency syndrome patients with myelopathy: expression and replication in macrophages. Proc Natl Acad Sci USA 86:3337–3341

    Google Scholar 

  14. Epstein AL, Marder RJ, Winter JN, Fox RI (1984) Two new monoclonal antibodies (LN-1, LN-2) reactive in B5 formalinfixed, paraffin embedded tissues with follicular center and mantle zone human B lymphocytes and derived tumors. J Immunol 133:1028–1036

    Google Scholar 

  15. Folks TM, Justement J, Kinter A, Dinarello CA, Fauci AS (1987) Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science 238:800–802

    Google Scholar 

  16. Gartner S, Markovits P, Markovitz DM, Betts RF, Popovic M (1986) Virus isolation from and identification of HTLV-III/LAV-producing cells in brain tissue from a patient with AIDS. JAMA 256:2365–2371

    Google Scholar 

  17. Gendelman HE, Orenstein JM, Baca LM, Weiser B, Burger H, Kalter DC, Meltzer MS (1989) The macrophage in the persistence and pathogenesis of HIV infection. AIDS 3:475–495

    Google Scholar 

  18. Gerber MR, Connor JR (1989) Do Oligodendrocytes mediate iron regulation in the human brain? Ann Neurol 26:95–98

    Google Scholar 

  19. Gown AM, Tsukada T, Ross R (1987) Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol 25:191–207

    Google Scholar 

  20. Grundke-Iqbal I, Fleming J, Tung Y-C, Lassmann H, Iqbal K, Joshi JG (1990) Ferritin is a component of the neuritic (senile) plaque in Alzheimer dementia. Acta Neuropathol (Berl) 81:105–110

    Google Scholar 

  21. Kaneko Y, Kitamoto T, Teteishi J, Yamaguchi K (1989) Ferritin immunohistochemistry as a marker for microglia. Acta Neuropathol 79:129–136

    Google Scholar 

  22. Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA, Fauci AS (1986) Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233:1089–1093

    Google Scholar 

  23. Kure K, Lyman WD, Weidenheim KM, Dickson DW (1990) Cellular localization of an HIV-1 antigen in subacute AIDS encephalitis using an improved double-labeling immunohistochemical method. Am J Pathol 136:1085–1092

    Google Scholar 

  24. Kure K, Lyman WD, Weidenheim KM, Dickson DW (1990) Expression of HLA-DR and Fc receptor III in AIDS encephalitis. J Neuropathol Exp Neurol 49:326

    Google Scholar 

  25. Kurtin PJ, Pinkus GS (1985) Leukocyte common antigen: a diagnostic discriminant between hematopoietic and nonhematopoietic neoplasms in paraffin sections using monoclonal antibodies. Correlation with immunologic studies and ultrastructural localization. Hum Pathol 16:353–365

    Google Scholar 

  26. Mannoji H, Yeger H, Becker LE (1986) A specific histochemical marker (lectin Ricinus communis agglutinin-1) for normal human microglia, and application to routine histopathology. Acta Neuropathol (Berl) 71:341–343

    Google Scholar 

  27. Marder RJ, Variakojis D, Silver J, Epstein AL (1985) Immunohistochemical analysis of human lymphomas with monoclonal antibodies to B cell and Ia antigens reactive in paraffin sections. Lab Invest 52:497–504

    Google Scholar 

  28. Mason DY, Taylor CR (1975) The distribution of muramidase (lysozyme) in human tissues. J Clin Pathol 28:124–132

    Google Scholar 

  29. Mattiace LA, Davies P, Dickson DW (1990) Detection of HLA-DR on microglia in the human brain is a function of both clinical and technical factors. Am J Pathol 136:1101–1114

    Google Scholar 

  30. McGeer PL, Itagaki S, McGeer EG (1988) Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol 76:550–557

    Google Scholar 

  31. Michaels J, Price RW, Rosenblum MK (1988) Microglia in the giant cell encephalitis of acquired immune deficiency syndrome: proliferation, infection and fusion. Acta Neuropathol 76:373–379

    Google Scholar 

  32. Nagano I, Nakamura S, Yoshioka M, Kogure K (1991) Immunocytochemical analysis of the cellular infiltrate in brain lesions in subacute sclerosing panencephalitis. Neurology 41:1639–1642

    Google Scholar 

  33. Nakajima T, Kameya T, Watanabe S, Hirota T, Sato Y, Shimosato Y (1982) An immunoperoxidase study of S-100 protein distribution in normal and neoplastic tissues. Am J Surg Pathol 6:715–727

    Google Scholar 

  34. Navia BA, Cho E-S, Petito CK, Price RW (1986) The AIDS dementia complex: II. Neuropathology. Ann Neurol 19:525–535

    Google Scholar 

  35. Nielsen SL, Petito CK, Urmacher CD, Posner JB (1984) Subacute encephalitis in acquired immune deficiency syndrome: a postmortem study. Am J Clin Pathol 82:678–682

    Google Scholar 

  36. Ordóñez NG, Batsakis JG (1984) Comparison of Ulex europaeus I lectin and factor VIII-related antigen in vascular lesions. Arch Pathol Lab Med 108:129–132

    Google Scholar 

  37. Papadimitriou CS, Stein H, Papacharalampous NX (1980) Presence of alphal-antichymotrypsin and alphal-antitrypsin in haematopoietic and lymphoid tissue cells as revealed by the immunoperoxidase method. Pathol Res Pract 169:287–297

    Google Scholar 

  38. Penfield W (1925) Microglia and the process of phagocytosis in gliomas. Am J Pathol 1:77–89

    Google Scholar 

  39. Petit AJ, Terpstra FG, Miedema F (1987) Human immunodeficiency virus infection downregulates HLA class II expression and induces differentiation in promonocytic U937 cells. J Clin Invest 79:1883–1889

    Google Scholar 

  40. Price RW, Brew B, Sidtis J, Rosenblum M, Scheck AC, Cleary P (1988) The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science 239:586–592

    Google Scholar 

  41. Pumarola-Sune T, Navia BA, Cordon-Cardo C, Cho E-S, Price RW (1987) HIV antigen in the brains of patients with the AIDS dementia complex. Ann Neurol 21:490–496

    Google Scholar 

  42. Shapshak P, Sun NCJ, Resnick L, Hsu MYK, Tourtellotte WW, schmid P, Conrad A, Fiala M, Imagawa DT (1990) The detection of HIV by in sity hybridization. Mod Pathol 3:146–153

    Google Scholar 

  43. Shapshak P, Sun NCJ, Resnick L, Thornthwaite JT, Schiller P, Yoshioka M, Svenningsson A, Tourtellotte WW, Imagawa DT (1991) HIV-1 propagates in human neuroblastoma cells. J Acquir Immune Defic Syndr 4:228–237

    Google Scholar 

  44. Shaw GM, Harper ME, Hahn BH, Epstein LG, Gajdusek DC, Price RW, Navia BA, Petito CK, O'Hara CJ, Groopman JE, Cho E-S, Oleske JM, Wong-Staal F, Gallo RC (1985) HTLV-III infection in brains of children and adults with AIDS encephalopathy. Science 227:177–182

    Google Scholar 

  45. Shivers BD, Harlan RE, Pfaff DW, Schachter BS (1986) Combination of immunocytochemistry and in situ hybridization in the same tissue section of rat pituitary. J Histochem Cytochem 34:39–43

    Google Scholar 

  46. Snider WD, Simpson DM, Nielsen S, Gold JWM, Metroka CE, Posner JB (1983) Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol 14:403–418

    Google Scholar 

  47. Sternberger LA, Hardy PH Jr, Cuculis JJ, Meyer HG (1970) The unlabeled antibody enzyme method of immunohistochemistry. Preparation and properties of soluble antigen-antibody complex (horseradish peroxidase-antihorseradish peroxidase) and its use in identification of spirochetes. J Histochem Cytochem 18:315–333

    Google Scholar 

  48. Sternberger LA, Hardwell LW, Sternberger NH (1982) Neurotypy: regional individuality in rat brain detected by immunocytochemistry with monoclonal antibodies. Proc Natl Acad Sci USA 79:1326–1330

    Google Scholar 

  49. Stoler MH, Eskin TA, Benn S, Angerer RC, Angerer LM (1986) Human T-cell lymphotropic virus type III infection of the central nervous system: a preliminary in situ analysis. JAMA 256:2360–2364

    Google Scholar 

  50. Sun NJC, Lubran MM (1982) Immunoperoxidase tests. In: Sunderman FW (ed) Manual of procedures for the Seminar of Laboratory Diagnosis and Monitoring of Cancer. Association of Clinical Scientists, Philadelphia, pp 155–164

    Google Scholar 

  51. Theil EC (1987) Ferritin: structure, gene regulation, and cellular function in animals, plants, and microorganisms. Annu Rev Biochem 56:289–315

    Google Scholar 

  52. Tourtellotte WW, Verity AN, Schmid P, Martinez S, Shapshak P (1987) Covalent binding of formalin-fixed paraffin-embedded brain tissue sections to glass slides suitable for in situ hybridization. J Virol Methods 15:87–99

    Google Scholar 

  53. Vazeux R, Brousse N, Jarry A, Henin D, Marche C, Vedrenne C, Mikol J, Wolff M, Michon C, Rozenbaum W, Bureau J-F, Montagnier L, Brahic M (1987) AIDS subacute encephalitis: identification of HIV-infected cells. Am J Pathol 126:403–410

    Google Scholar 

  54. Wiley CA, Schrier RD, Nelson JA, Lampert PW, Oldstone MBA (1986) Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci USA 83:7089–7093

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, Sieron Building (D-28), 3rd floor, 33136, Miami, FL, USA

    M. Yoshioka & P. Shapshak

  2. Department of Pathology, University of Miami School of Medicine, 1425 N. W. 10th Avenue, 33136, Miami, FL, USA

    P. Shapshak, S. J. Nelson, L. G. Tate & V. Pardo

  3. Department of Neurology, University of Miami School of Medicine, 1425 N. W. 10th Avenue, 33136, Miami, FL, USA

    P. Shapshak

  4. Department of Microbiology/Immunology, University of Miami School of Medicine, 1425 N. W. 10th Avenue, 33136, Miami, FL, USA

    P. Shapshak

  5. Department of Neurology, Tohoku University School of Medicine, 980, Sendai, Japan

    M. Yoshioka

  6. Department of Pathology, Harbor-UCLA Medical Center, 90509, Torrance, CA, USA

    N. C. J. Sun

  7. Jonsson Cancer Center, UCLA School of Medicine, 90024, Los Angeles, CA, USA

    N. C. J. Sun

  8. Department of Clinical Chemistry, Sahlgrenska Hospital, University of Göteborg School of Medicine, Göteborg, Sweden

    A. Svenningsson

  9. Electron Microscopy Laboratory, Veterans Affairs Medical Center, 33125, Miami, FL, USA

    V. Pardo

  10. Department of Research, Mount Sinai Medical Center, 33140, Miami Beach, FL, USA

    L. Resnick

Authors
  1. M. Yoshioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Shapshak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. C. J. Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. J. Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Svenningsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. G. Tate
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V. Pardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. Resnick
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported in part by NIH Grants RO1 DA04787, RO1 HD26621, PO1 NS25569, the Biopsychosocial Center for the Study of AIDS (NIMH P50 MH 43455), the Department of Veterans Affairs, the Mary Jane Crowe Foundation, the Swedish Society of Medicine (Stockholm, Sweden), and the Multiple Sclerosis Society of Göteborg (Göteborg, Sweden)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoshioka, M., Shapshak, P., Sun, N.C.J. et al. Simultaneous detection of ferritin and HIV-1 in reactive microglia. Acta Neuropathol 84, 297–306 (1992). https://doi.org/10.1007/BF00227823

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00227823

Key words

Search

Navigation