This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nau, G. J. Articles by Young, R. A. Search for Related Content PubMed PubMed Citation Articles by Nau, G. J. Articles by Young, R. A.

(American Journal of Pathology. 2000;157:37-42.)
© 2000 American Society for Investigative Pathology

Short Communications

Osteopontin Expression Correlates with Clinical Outcome in Patients with Mycobacterial Infection

Gerard J. Nau^*, Geoffrey L. Chupp, Jean-François Emile^§, Emmanuelle Jouanguy^¶, Jeffrey S. Berman^||, Jean-Laurent Casanova^¶ and Richard A. Young^*

From the Whitehead Institute for Biomedical Research and Department of Biology,^*
the Massachusetts Institute of Technology, Cambridge, Massachusetts; the Infectious Disease Unit,
Massachusetts General Hospital, Boston, Massachusetts; the Pulmonary Center,
Boston University School of Medicine, Boston, Massachusetts; the Service d’Anatomie Pathologiques,^§
Hôpital Paul Brousse, Universite Paris Sud, Villejuif, France; the Laboratory of Human Genetics of Infectious Diseases,^¶
Necker-Enfants Malades Medical School, Paris, France; and the Boston Veterans Administration Medical Center,^||
Boston, Massachusetts

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Osteopontin (OPN) is a protein that is expressed in chronic inflammatory diseases including tuberculosis, and its deficiency predisposes to more severe mycobacterial infections in mice. However, no reports have identified altered OPN expression in, or correlated these alterations to, infections in humans. The data presented herein identify alterations in the tissue expression of OPN protein and describe an inverse correlation between these levels and disease progression after inoculation of Mycobacterium bovis bacillus Calmette-Guérin vaccine in humans. Patients with regional adenitis and good clinical outcomes had abundant OPN in infected lymph nodes. This pattern of OPN accumulation was also observed in patients infected by M. avium-intracellulare. In contrast, patients with disseminated infection and histologically ill-defined granulomas had no significant osteopontin accumulation in infected lymph nodes; these patients had either deficiencies in the interferon- receptor 1 or idiopathic immune defects. The level of OPN protein expression was inversely correlated with disseminated infection and, of particular interest, with death of the patient. We conclude that osteopontin expression correlates with an effective immune and inflammatory response when humans are challenged by a mycobacterial infection and that osteopontin contributes to human resistance against mycobacteria.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

We have studied the interaction between macrophages and mycobacteria to gain insight into host defense mechanisms and, ultimately, to identify possible diagnostic and therapeutic targets. Using a system of cDNA library screening of macrophages infected with BCG, we discovered an association between osteopontin (OPN) and infections with mycobacteria.¹³ OPN is a secreted protein that is expressed in chronic inflammatory diseases, particularly tuberculosis.^13,14 It is produced by macrophages, T cells, and natural killer cells on activation.¹⁵ The protein is known to activate adhesion and migration of several cell types,^15,16 including macrophages.¹⁷ OPN also affects T-cell migration, adhesion, and proliferation in vitro.¹⁸

Experiments using OPN null mice support the idea that this protein enhances host resistance to infection. Mice that lack OPN are more susceptible to mycobacterial infection with a delayed clearance of the mycobacteria.¹⁹ These animals are also more susceptible to tumor progression and have impaired wound remodeling, likely because of reduced macrophage migration and activity.^20,21 Thus, OPN seems to modulate macrophage function and its absence impairs host responses in mice.

OPN has also been detected in several pathological conditions.^13,14,22-25 The amount of tissue OPN expression in glioblastomas has been directly correlated with the tumor’s histological grade.²⁶ Serum levels of OPN are directly correlated with the burden of metastatic breast cancer and are inversely correlated with survival.²⁷ However, there have been no reports of altered levels of OPN expression as an indicator of the host response during infection. The objective of the current study was to determine whether OPN expression varied according to the severity of mycobacterial infections. We tested for OPN expression in tissue from patients suffering from infection after inoculation with BCG vaccine, both from patients with localized infection and from patients with disseminated infection. The results demonstrate that OPN expression varied between patients with infection and that the level of expression correlated with the clinical outcome for the patient.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Patient Specimens

The clinical features and genetic defects of the patients with severe BCG or nontuberculous mycobacterial infection have been reported elsewhere. These patients have been found to have recessive complete IFNR1 defects (C2), recessive partial IFNR1 defects (P1), and dominant negative IFNR1 defects (DN1, DN2).^8,9,11 One patient (C1) with disseminated disease is included in another manuscript.³⁸ Two other patients with severe infection have uncharacterized immune defects (ID1, ID2).^3,28 Several patients with localized, benign infection by BCG or nontuberculous mycobacteria and no identifiable underlying immunodeficiency are included in this report: L1 is a female who presented at 3 months, L2 is a female who presented at 6 months, L3 is a female who presented at 2.6 years, and L4 is a male who presented at 2.1 years.

Immunohistochemistry

Specimens were processed with standard histological techniques. Paraffin-embedded sections were dewaxed with HistoClear (National Diagnostics, Atlanta, GA) and rehydrated with graded alcohol. The sections were treated with pronase for 6 minutes (DAKO Corporation, Carpinteria, CA) followed by 0.01% azide/0.3% hydrogen peroxide in water for 20 minutes to inactivate endogenous peroxidases. After blocking with 20% goat serum in phosphate-buffered saline (PBS), primary antibodies (1% in 10% goat serum/PBS) were incubated for 2 hours at room temperature. Antibodies MPIIIB10, specific for osteopontin, and QH-1, an isotype control specific for quail endothelium, were obtained from the Developmental Studies Hybridoma Bank (University of Iowa, Iowa City, IA). Antibody KP-1, specific for human CD68 on macrophages, was obtained from DAKO. The secondary goat anti-mouse immunoglobulin G (5 µg/ml), the avidin-biotin tertiary reagents, and the color substrates were from Vector Laboratories (Burlingame, CA). After counterstaining with hematoxylin (DAKO) or methyl green (Vector), samples were dehydrated in graded ethanol and ClearRite 3 (Richard-Allan Scientific, Kalamazoo, MI) before mounting with Permount (Fisher, Fair Lawn, NJ).

OPN Scoring and Statistical Analysis

A simple histological score was devised to estimate the amount of OPN present in tissue sections. Macrophages and giant cells, identified by morphology and by CD68 staining, and lymphocytes, identified by morphology, were individually scored for OPN with the following scale: >50% of cells positive = 2, <50% of cells positive = 1, no cells positive = 0.

Statistical analyses were performed using Statview software (SAS Institute, Inc., Cary, NC). Two-tailed Student’s t-test was used to compare mean ± SD of OPN scores. Contingency tables and chi-square analysis of OPN score versus dissemination or clinical outcome were set up with an OPN score cutoff of 2. P values <0.05 were considered statistically significant.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Osteopontin Expression in Patients with Localized Infection

OPN is closely associated with granulomatous inflammation in humans infected by MTB.^13,14 Before analyzing patients with disseminated BCG infection, it was important to determine whether OPN is normally expressed in humans infected by mycobacteria other than MTB. To investigate this question, pathological lymph nodes obtained from patients with localized infection after inoculation with BCG vaccine or with localized M. avium-intracellulare infection were stained for OPN protein. The tissues of these patients showed histological features characteristic of a mycobacterial infection: well-formed granulomas of histiocytes surrounded by lymphocytes and the formation of giant cells. As shown in Figure 1A , localized adenitis after BCG inoculation resulted in extensive OPN accumulation identified by the MPIIIB10 monoclonal antibody (Figure 1A) . Although M. avium-intracellulare is not a member of the MTB complex, this organism also elicited OPN accumulation in lymph node granulomas of a host with localized disease (Figure 1B) . The presence of macrophages was confirmed on adjacent sections that were stained for CD68 (Figure 1, C and D) . Thus, OPN expression in BCG or M. avium-intracellulare infection co-localized with macrophages and giant cells, similar to what was observed with pulmonary MTB infection.¹³ In addition, similar widespread staining of lymphoid cells has been observed in pulmonary tuberculosis infections.¹³ An isotype control antibody for MPIIIB10 failed to show significant staining (Figure 1, E and F) .

View larger version (165K): [in this window] [in a new window]   Figure 1. OPN expression in normal patients with localized adenitis. OPN protein detected in tissue sections by immunohistochemistry with monoclonal antibody MPIIB10 and diaminobenzidine substrate. A and B: Widespread expression of OPN was identified with the brown color of the diaminobenzidine in numerous cell types including histiocytes and lymphoid cells with darkly staining nuclei identified by hematoxylin. C and D: The presence of macrophage and giant cells was confirmed with staining for CD68, red color from Vector red substrate and methyl green counterstain. Isotype control antibody for MPIIIB10 showed no (E) or little (F) background staining (diaminobenzidine substrate, hematoxylin counterstain). Original magnification, x100.

Having established the pattern of OPN expression in patients with localized adenitis, we tested samples from patients with disseminated BCG infection.

Recessive Complete IFNRI Deficiency

Patients with a complete deficiency of IFNRI showed no significant OPN accumulation in infected lymph nodes (Figure 2, A and C) despite numerous macrophages identified by staining for CD68 (Figure 2, B and D) . These patients succumbed to their infections despite antimicrobial therapy.

View larger version (101K): [in this window] [in a new window]   Figure 2. OPN expression in patients with immune defects. Sections were stained for OPN (brown, diaminobenzidine substrate) and CD68 (Vector red substrate). Patients with complete deficiency of IFNRI showed no significant OPN accumulation (A and C) in macrophages within the section (B and D). A patient with partial deficiency of IFNRI demonstrated OPN (E) present in macrophages (F). A patient with a dominant negative IFNRI had no OPN detectable (G) although macrophages were present (H). Two patients with idiopathic immune defects had no (I) or little (K) detectable OPN although macrophages were identified (J and L). In some specimens there were occasional OPN-positive cells with small, dark nuclei interpreted as lymphoid cells (C and K). There was no significant staining with control antibody in these specimens. Original magnification, x100.

Recessive Partial IFNRI Deficiency

Tissue from one patient with a recessive, partial defect in IFNRI expression demonstrated less intense OPN staining (Figure 2E) compared to those with localized disease (Figure 1, A and B) , but more than that seen in patients with a complete deficiency (Figure 2, A and C) . The OPN expression co-localized with macrophages seen on an adjacent section (Figure 2F) . This same patient had a milder clinical course and survived the disseminated BCG infection after antibiotic therapy.

Dominant Negative IFNRI

In contrast to the patient with the recessive partial receptor defect, two patients with dominant negative mutations in IFNRI demonstrated patterns of OPN expression more like those patients with complete receptor deficiencies. Tissue from one of these patients is shown in Figure 2G . The specimen showed no OPN in the infected lymph node although macrophages were present (Figure 2H) .

Idiopathic Immune Defect

Finally, tissue from two patients with idiopathic immune defects were tested (Figure 2, I–L) . These patients also had no or little OPN demonstrated in infected lymph nodes (Figure 2, I and K) despite macrophage infiltration (Figure 2, J and L) . In some instances, patients with immune defects demonstrated low levels of staining in cells with a lymphocyte morphology; see Figure 2, C and K . This pattern of staining appeared distinct from the macrophage staining seen in other samples and may represent direct cellular activation, such as by a T-cell antigen receptor which can induce OPN production.²⁹

A summary of the patient samples analyzed in this study is listed in Table 1 . Patients with local disease tended to have high levels of OPN expression. Conversely, patients with immune defects tended to have absent or low levels of OPN expression. Statistical analyses verified correlations between OPN expression and either dissemination or clinical outcome. The mean OPN scores (mean ± SD) were statistically different by Student’s t-test in both analyses for dissemination: localized (3.75 ± 0.5) versus disseminated (0.71 ± 0.76), P = 0.0065; and for outcome: alive (3.00 ± 1.26) versus dead (0.40 ± 0.55), P = 0.0086. On contingency tables, an OPN score of <2 was associated with dissemination whereas a score of 2 was associated with localized disease (chi-square = 7.54, P = 0.0060). Similarly, an OPN score of <2 was associated with death whereas a score of 2 was associated with survival after infection (chi-square = 7.64, P = 0.0057).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

The current findings further substantiate the beneficial effects of OPN accumulation during infection. Several reports indicated that allelic variation of the Ric locus, now known to be OPN,³⁰ affected host susceptibility to infection.^31-33 BCG infection of OPN null mice demonstrated the absence of OPN led to more severe infections.¹⁹ This indicated the protein has a salutary effect on the host’s efforts to eradicate the BCG. Recent data have shown that OPN can activate interleukin-12 production from macrophages and can enhance Th1-type cell-mediated immunity.³⁴ The data from human tissues infected with mycobacteria show a correlation between OPN expression and clinical outcome: patients did better when there was OPN in abundance after infection. Taken together, these observations support the idea that OPN enhances host resistance to mycobacterial infections in both mice and humans. Based on mouse studies, the effects of OPN are likely to involve the activation of macrophages and the initiation of a Th1-type response.

In the patient samples studied, the expression of OPN by macrophages was closely linked to functional interferon- (IFN-) receptors, suggesting that IFN- signaling is important for accumulation of OPN in vivo. Consistent with this inference is the fact that the promoter region of the OPN gene has an IRF-1 binding sequence.³⁵ IFN- and its receptor are key components of the host response against MTB.^36,37 It is not known if the two patients with idiopathic immunodeficiency and disseminated BCG infection had defects with the pathway of IFN- signaling. However, it is possible that there is a primary defect in OPN production by macrophages or another defect that secondarily reduces OPN production in some patients with immune deficiency. Based on animal studies, one would predict that a primary defect in OPN production would lead to greater bacterial burden and delayed resolution of infection, leading to death in some instances.^19,32 In any case, increases of OPN expression may represent a common endpoint of several pathways of macrophage activation.

Because tissue expression of OPN was associated with a successful outcome after infection, it may be possible to use OPN as a tool to measure the competency of host defenses. OPN may be of diagnostic value to identify patients with severe underlying immunodeficiencies such as the IFN- signaling defects or the idiopathic immune defects tested here. In addition, measuring OPN responses in vitro before administering a vaccine, such as BCG, may be useful to test vaccine safety in a particular host. Prospective studies will be required to determine whether OPN expression is useful to predict the integrity of host responses against infection.

	Acknowledgements

 
We thank Drs. N. Brousse, F. Gaillard, B. Gosselin, and O. Verola for providing slides for some of the patients and Dr. A. Schlesinger for critical reading of this manuscript. The MPIIIB10 hybridoma supernatant was obtained from the Developmental Studies Hybridoma Bank maintained by the Department of Pharmacology and Molecular Sciences, the John Hopkins University School of Medicine, Baltimore, MD, and the Department of Biological Sciences, University of Iowa, Iowa City, IA, under contract N01-HD-6–2915 from the National Institute of Child Health and Human Development.

	Footnotes

 
Address reprint requests to Richard Young, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142. E-mail: young{at}wi.mit.edu

Supported by Public Health Service grants AI37869 (to R. A. Y.) and AI01305 (to G. J. N.).

Accepted for publication April 3, 2000.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Pablos-Mendez A, Raviglione MC, Laszlo A, Binkin N, Rieder HL, Bustreo F, Cohn DL, Lambregts-van Weezenbeek CS, Kim SJ, Chaulet P, Nunn P: Global surveillance for antituberculosis-drug resistance, 1994–1997, World Health Organization–International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. N Engl J Med 1998, 338:1641–1649
2. Valway SE, Sanchez MPC, Shinnick TF, Orme I, Agerton T, Hoy D, Jones JS, Westmoreland H, Onorato IM: An outbreak involving extensive transmission of a virulent strain of Mycobacterium tuberculosis. N Engl J Med 1998, 338:633-639[Abstract/Free Full Text]
3. Casanova JL, Jouanguy E, Lamhamedi S, Blanche S, Fischer A: Immunological conditions of children with BCG disseminated infection. Lancet 1995, 346:581[Medline]
4. Casanova JL, Blanche S, Emile JF, Jouanguy E, Lamhamedi S, Altare F, Stephan JL, Bernaudin F, Bordigoni P, Turck D, Lachaux A, Albertini M, Bourrillon A, Dommergues JP, Pocidalo MA, Le Deist F, Gaillard JL, Griscelli C, Fischer A: Idiopathic disseminated bacillus Calmette-Guerin infection: a French national retrospective study. Pediatrics 1996, 98:774-778[Abstract/Free Full Text]
5. Altare F, Lammas D, Revy P, Jouanguy E, Doffinger R, Lamhamedi S, Drysdale P, Scheel-Toellner D, Girdlestone J, Darbyshire P, Wadhwa M, Dockrell H, Salmon M, Fischer A, Durandy A, Casanova JL, Kumararatne DS: Inherited interleukin 12 deficiency in a child with bacille Calmette-Guerin and Salmonella enteritidis disseminated infection. J Clin Invest 1998, 102:2035-2040[Medline]
6. Altare F, Durandy A, Lammas D, Emile JF, Lamhamedi S, Le Deist F, Drysdale P, Jouanguy E, Doffinger R, Bernaudin F, Jeppsson O, Gollob JA, Meinl E, Segal AW, Fischer A, Kumararatne D, Casanova JL: Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 1998, 280:1432-1435[Abstract/Free Full Text]
7. de Jong R, Altare F, Haagen IA, Elferink DG, Boer T, van Breda Vriesman PJ, Kabel PJ, Draaisma JM, van Dissel JT, Kroon FP, Casanova JL, Ottenhoff TH: Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science 1998, 280:1435–1438
8. Jouanguy E, Altare F, Lamhamedi S, Revy P, Emile JF, Newport M, Levin M, Blanche S, Seboun E, Fischer A, Casanova JL: Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection. N Engl J Med 1996, 335:1956-1961[Free Full Text]
9. Jouanguy E, Lamhamedi-Cherradi S, Lammas D, Dorman SE, Fondaneche MC, Dupuis S, Doffinger R, Altare F, Girdlestone J, Emile JF, Ducoulombier H, Edgar D, Clarke J, Oxelius VA, Brai M, Novelli V, Heyne K, Fischer A, Holland SM, Kumararatne DS, Schreiber RD, Casanova JL: A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nat Genet 1999, 21:370-378[Medline]
10. Newport MJ, Huxley CM, Huston S, Hawrylowicz CM, Oostra BA, Williamson R, Levin M: A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med 1996, 335:1941-1949[Abstract/Free Full Text]
11. Jouanguy E, Lamhamedi-Cherradi S, Altare F, Fondaneche MC, Tuerlinckx D, Blanche S, Emile JF, Gaillard JL, Schreiber R, Levin M, Fischer A, Hivroz C, Casanova JL: Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guerin infection and a sibling with clinical tuberculosis. J Clin Invest 1997, 100:2658-2664[Medline]
12. Dorman SE, Holland SM: Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection. J Clin Invest 1998, 101:2364-2369[Medline]
13. Nau GJ, Guilfoile P, Chupp GL, Berman JS, Kim SJ, Kornfeld H, Young RA: A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis. Proc Natl Acad Sci USA 1997, 94:6414-6419[Abstract/Free Full Text]
14. Carlson I, Tognazzi K, Manseau EJ, Dvorak HF, Brown LF: Osteopontin is strongly expressed by histiocytes in granulomas of diverse etiology. Lab Invest 1997, 77:103-108[Medline]
15. Uede T, Katagiri Y, Iizuka J, Murakami M: Osteopontin, a coordinator of host defense system: a cytokine or an extracellular adhesive protein? Microbiol Immunol 1997, 41:641-648[Medline]
16. Denhardt DT, Guo X: Osteopontin: a protein with diverse functions. FASEB J 1993, 7:1475-1482[Abstract]
17. Singh RP, Patarca R, Schwartz J, Singh P, Cantor H: Definition of a specific interaction between the early T lymphocyte activation 1 (Eta-1) protein and murine macrophages in vitro and its effect upon macrophages in vivo. J Exp Med 1990, 171:1931-1942[Abstract/Free Full Text]
18. O’Regan AW, Chupp GL, Lowry JA, Goetschkes M, Mulligan N, Berman JS: Osteopontin is associated with T cells in sarcoid granulomas and has T cell adhesive and cytokine-like properties in vitro. J Immunol 1999, 162:1024-1031[Abstract/Free Full Text]
19. Nau GJ, Liaw L, Chupp GL, Berman JS, Hogan BLM, Young RA: Attenuated host resistance against Mycobacterium bovis BCG infection in mice lacking osteopontin. Infect Immun 1999, 67:4223-4230[Abstract/Free Full Text]
20. Liaw L, Birk DE, Ballas CB, Whitsitt JS, Davidson JM, Hogan BLM: Altered wound healing in mice lacking a functional osteopontin gene (supp1). J Clin Invest 1998, 101:1468-1478[Medline]
21. Crawford HC, Matrisian LM, Liaw L: Distinct roles of osteopontin in host defense activity and tumor survival during squamous cell carcinoma progression in vivo. Cancer Res 1998, 58:5206-5215[Abstract/Free Full Text]
22. Giachelli CM, Bae N, Almeida M, Denhardt DT, Alpers CE, Schwartz SM: Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques. J Clin Invest 1993, 92:1686-1696
23. Hirota S, Imakita M, Kohri K, Ito A, Morii E, Adachi S, Kim HM, Kitamura Y, Yutani C, Nomura S: Expression of osteopontin messenger RNA by macrophages in atherosclerotic plaques: a possible association with calcification. Am J Pathol 1993, 143:1003-1008[Abstract]
24. Murry CE, Giachelli CM, Schwartz SM, Vracko R: Macrophages express osteopontin during repair of myocardial necrosis. Am J Pathol 1994, 145:1450-1462[Abstract]
25. Brown LF, Papadopoulos-Sergiou A, Berse B, Manseau EJ, Tognazzi K, Perruzzi CA, Dvorak HF, Senger DR: Osteopontin expression and distribution in human carcinomas. Am J Pathol 1994, 145:610-623[Abstract]
26. Saitoh Y, Kuratsu J, Takeshima H, Yamamoto S, Ushio Y: Expression of osteopontin in human glioma: its correlation with the malignancy. Lab Invest 1995, 72:55-63[Medline]
27. Singhal H, Bautista DS, Tonkin KS, O’Malley FP, Tuck AB, Chambers AF, Harris JF: Elevated plasma osteopontin in metastatic breast cancer associated with increased tumor burden and decreased survival. Clin Cancer Res 1997, 3:605-611[Abstract]
28. Emile JF, Patey N, Altare F, Lamhamedi S, Jouanguy E, Boman F, Quillard J, Lecomte-Houcke M, Verola O, Mousnier JF, Dijoud F, Blanche S, Fischer A, Brousse N, Casanova JL: Correlation of granuloma structure with clinical outcome defines two types of idiopathic disseminated BCG infection. J Pathol 1997, 181:25-30[Medline]
29. Patarca R, Freeman GJ, Singh RP, Wei FY, Durfee T, Blattner F, Regnier DC, Kozak CA, Mock BA, Morse HC 3rd, Jerrells TR, Cantor H: Structural and functional studies of the early T lymphocyte activation 1 (Eta-1) gene. Definition of a novel T cell-dependent response associated with genetic resistance to bacterial infection. J Exp Med 1989, 170:145–161
30. Fet V, Dickinson ME, Hogan BL: Localization of the mouse gene for secreted phosphoprotein 1 (Spp-1) (2ar, osteopontin, bone sialoprotein 1, 44-kDa bone phosphoprotein, tumor-secreted phosphoprotein) to chromosome 5, closely linked to Ric (Rickettsia resistance). Genomics 1989, 5:375-377[Medline]
31. Goodman GT, Koprowski H: Macrophages as cellular expression of inherited natural resistance. Proc Natl Acad Sci USA 1962, 48:160-165[Free Full Text]
32. Groves MG, Rosenstreich DL, Taylor BA, Osterman JV: Host defenses in experimental scrub typhus: mapping the gene that controls natural resistance in mice. J Immunol 1980, 125:1395-1399[Abstract]
33. Patarca R, Saavedra RA, Cantor H: Molecular and cellular basis of genetic resistance to bacterial infection: the role of the early T-lymphocyte activation-1/osteopontin gene. Crit Rev Immunol 1993, 13:225-246[Medline]
34. Ashkar S, Weber GF, Panoutsakopoulou V, Sanchirico ME, Jansson M, Zawaideh S, Rittling SR, Denhardt DT, Glimcher MJ, Cantor H: Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 2000, 287:860-864[Abstract/Free Full Text]
35. Hijiya N, Setoguchi M, Matsuura K, Higuchi Y, Akizuki S, Yamamoto S: Cloning and characterization of the human osteopontin gene and its promoter. Biochem J 1994, 303:255-262
36. Cooper AM, Dalton DK, Stewart TA, Griffin JP, Russell DG, Orme IM: Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med 1993, 178:2243-2247[Abstract/Free Full Text]
37. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR: An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med 1993, 178:2249-2254[Abstract/Free Full Text]
38. Jouauguy E, Dupuis S, Pallier A, Döffinger R, Fondanèche M, Fieschi C, Lamhanedi-Cherradi S, Altare F, Emile J-F, Lutz P, Bordigoui P, Cokugras Y, Casanova J-L: In a novel form of IFN- receptor 1 deficiency, cell surface receptors fail to bind IFN-. J Clin Invest 2000, 105:1429-1436[Medline]

This article has been cited by other articles:

				E. L. Karcher, D. O. Bayles, J. P. Bannantine, D. C. Beitz, and J. R. Stabel Osteopontin: A Novel Cytokine Involved in the Regulation of Mycobacterium avium subspecies paratuberculosis Infection in Periparturient Dairy Cattle J Dairy Sci, August 1, 2008; 91(8): 3079 - 3091. [Abstract] [Full Text] [PDF]

				M. Scatena, L. Liaw, and C. M. Giachelli Osteopontin: A Multifunctional Molecule Regulating Chronic Inflammation and Vascular Disease Arterioscler. Thromb. Vasc. Biol., November 1, 2007; 27(11): 2302 - 2309. [Abstract] [Full Text] [PDF]

				M. Hashimoto, D. Sun, S. R. Rittling, D. T. Denhardt, and W. Young Osteopontin-Deficient Mice Exhibit Less Inflammation, Greater Tissue Damage, and Impaired Locomotor Recovery from Spinal Cord Injury Compared with Wild-Type Controls J. Neurosci., March 28, 2007; 27(13): 3603 - 3611. [Abstract] [Full Text] [PDF]

				M. L. Shinohara, M. Jansson, E. S. Hwang, M. B. F. Werneck, L. H. Glimcher, and H. Cantor T-bet-dependent expression of osteopontin contributes to T cell polarization PNAS, November 22, 2005; 102(47): 17101 - 17106. [Abstract] [Full Text] [PDF]

				I. Sato, N. Yamamoto, H. Yamazaki, S. Hashimoto, M. Hino, F. Sakai, and A. Fujie Prevention of the Cryptic Epitope SLAYGLR within Osteopontin Does Not Influence Susceptibility to Candida albicans Infection Antimicrob. Agents Chemother., July 1, 2005; 49(7): 3053 - 3055. [Abstract] [Full Text] [PDF]

				K. Kawamura, K. Iyonaga, H. Ichiyasu, J. Nagano, M. Suga, and Y. Sasaki Differentiation, Maturation, and Survival of Dendritic Cells by Osteopontin Regulation Clin. Vaccine Immunol., January 1, 2005; 12(1): 206 - 212. [Abstract] [Full Text] [PDF]

				J. Morimoto, M. Inobe, C. Kimura, S. Kon, H. Diao, M. Aoki, T. Miyazaki, D. T. Denhardt, S. Rittling, and T. Uede Osteopontin affects the persistence of {beta}-glucan-induced hepatic granuloma formation and tissue injury through two distinct mechanisms Int. Immunol., March 1, 2004; 16(3): 477 - 488. [Abstract] [Full Text] [PDF]

				Y. Koguchi, K. Kawakami, K. Uezu, K. Fukushima, S. Kon, M. Maeda, A. Nakamoto, I. Owan, M. Kuba, N. Kudeken, et al. High Plasma Osteopontin Level and Its Relationship with Interleukin-12-mediated Type 1 T Helper Cell Response in Tuberculosis Am. J. Respir. Crit. Care Med., May 15, 2003; 167(10): 1355 - 1359. [Abstract] [Full Text] [PDF]

				Y. Koguchi, K. Kawakami, S. Kon, T. Segawa, M. Maeda, T. Uede, and A. Saito Penicillium marneffei Causes Osteopontin-Mediated Production of Interleukin-12 by Peripheral Blood Mononuclear Cells Infect. Immun., March 1, 2002; 70(3): 1042 - 1048. [Abstract] [Full Text] [PDF]

				M. Mazzali, T. Kipari, V. Ophascharoensuk, J.A. Wesson, R. Johnson, and J. Hughes Osteopontin--a molecule for all seasons QJM, January 1, 2002; 95(1): 3 - 13. [Full Text] [PDF]

				A. W. O'REGAN, J. M. HAYDEN, S. BODY, L. LIAW, N. MULLIGAN, M. GOETSCHKES, and J. S. BERMAN Abnormal Pulmonary Granuloma Formation in Osteopontin-deficient Mice Am. J. Respir. Crit. Care Med., December 15, 2001; 164(12): 2243 - 2247. [Abstract] [Full Text] [PDF]

				K. J. Bayless and G. E. Davis Identification of Dual alpha 4beta 1 Integrin Binding Sites within a 38 Amino Acid Domain in the N-terminal Thrombin Fragment of Human Osteopontin J. Biol. Chem., April 13, 2001; 276(16): 13483 - 13489. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nau, G. J. Articles by Young, R. A. Search for Related Content PubMed PubMed Citation Articles by Nau, G. J. Articles by Young, R. A.