Multicenter systems analysis of human blood reveals immature neutrophils in males and during pregnancy

Journal of Immunology

Volumn 198, Issue 6, 2017, Pages 2479-2488

  Blazkova, Jana ^a   Gupta, Sarthak ^b   Liu, Yudong ^b   Gaudilliere, Brice ^c   Ganio, Edward A ^c   Bolen, Christopher R ^c   Saar Dover, Ron ^c   Fragiadakis, Gabriela K ^c   Angst, Martin S ^c   Hasni, Sarfaraz ^b   Aghaeepour, Nima ^c   Stevenson, David ^c   Baldwin, Nicole ^d   Anguiano, Esperanza ^e   Chaussabel, Damien ^a   Altman, Matthew C ^f   Kaplan, Mariana J ^b   Davis, Mark M ^c   Furman, David ^a,c  

^a SIDRA MEDICAL AND RESEARCH CENTER   (Qatar)

^b NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES   (United States)

^c STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d SCOTT AND WHITE MEMORIAL HOSPITAL   (United States)

^e JACKSON LABORATORY   (United States)

^f BENAROYA RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADULT; AGED; ARTICLE; AUTOIMMUNITY; BLOOD ANALYSIS; CELL MATURATION; COHORT ANALYSIS; CONTROLLED STUDY; CYTOMETRY; EXTRACELLULAR TRAP; FEMALE; GENE OVEREXPRESSION; HUMAN; HUMAN CELL; INFECTION SENSITIVITY; INNATE IMMUNITY; MALE; NEUTROPHIL; PREGNANCY; SEX DIFFERENCE; UPREGULATION; AGE; BLOOD CELL; CLINICAL TRIAL; COMPARATIVE STUDY; GRANULOCYTE PRECURSOR; MIDDLE AGED; MULTICENTER STUDY; PHYSIOLOGY; SEX; VERY ELDERLY; YOUNG ADULT;

TRANSCRIPTOME;

ADULT; AGE FACTORS; AGED; AGED, 80 AND OVER; BLOOD CELLS; FEMALE; GRANULOCYTE PRECURSOR CELLS; HUMANS; MALE; MIDDLE AGED; NEUTROPHILS; PREGNANCY; SEX; TRANSCRIPTOME; YOUNG ADULT;

EID: 85014696912     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1601855     Document Type: Article

References (88)

1. Furman, D. 2015. Sexual dimorphism in immunity: improving our understanding of vaccine immune responses in men. Expert Rev. Vaccines 14: 461-471.
2. Klein, S. L. 2012. Immune cells have sex and so should journal articles. Endocrinology 153: 2544-2550.
3. Klein, S. L., and K. L. Flanagan. 2016. Sex differences in immune responses. Nat. Rev. Immunol. 16: 626-638.
4. Engler, R. J. M., M. R. Nelson, M. M. Klote, M. J. VanRaden, C.-Y. Huang, N. J. Cox, A. Klimov, W. A. Keitel, K. L. Nichol, W. W. Carr, and J. J. Treanor, Walter Reed Health Care System Influenza Vaccine Consortium. 2008. Half-vs full-dose trivalent inactivated influenza vaccine (2004-2005): age, dose, and sex effects on immune responses. Arch. Intern. Med. 168: 2405-2414.
5. Klein, S. L., A. Jedlicka, and A. Pekosz. 2010. The Xs and Y of immune responses to viral vaccines. Lancet Infect. Dis. 10: 338-349.
6. Cook, I. F., I. Barr, G. Hartel, D. Pond, and A. W. Hampson. 2006. Reactogenicity and immunogenicity of an inactivated influenza vaccine administered by intramuscular or subcutaneous injection in elderly adults. Vaccine 24: 2395-2402.
7. Libert, C., L. Dejager, and I. Pinheiro. 2010. The X chromosome in immune functions: when a chromosome makes the difference. Nat. Rev. Immunol. 10: 594-604.
8. Trigunaite, A., J. Dimo, and T. N. Jørgensen. 2015. Suppressive effects of androgens on the immune system. Cell. Immunol. 294: 87-94.
9. Straub, R. H. 2007. The complex role of estrogens in inflammation. Endocr. Rev. 28: 521-574.
10. Kovats, S. 2015. Estrogen receptors regulate innate immune cells and signaling pathways. Cell. Immunol. 294: 63-69.
11. Robertson, S. A., G. Mayrhofer, and R. F. Seamark. 1996. Ovarian steroid hormones regulate granulocyte-macrophage colony-stimulating factor synthesis by uterine epithelial cells in the mouse. Biol. Reprod. 54: 183-196.
12. Furman, D., B. P. Hejblum, N. Simon, V. Jojic, C. L. Dekker, R. Thiébaut, R. J. Tibshirani, and M. M. Davis. 2014. Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proc. Natl. Acad. Sci. USA 111: 869-874.
13. Davidson, W. M., and D. R. Smith. 1954. A morphological sex difference in the polymorphonuclear neutrophil leucocytes. Br. Med. J. 2: 6-7.
14. Clayton, J. A., and F. S. Collins. 2014. Policy: NIH to balance sex in cell and animal studies. Nature 509: 282-283.
15. Mor, G., and I. Cardenas. 2010. The immune system in pregnancy: A unique complexity. Am. J. Reprod. Immunol. 63: 425-433.
16. Furman, D., V. Jojic, B. Kidd, S. Shen-Orr, J. Price, J. Jarrell, T. Tse, H. Huang, P. Lund, H. T. Maecker, et al. 2013. Apoptosis and other immune biomarkers predict influenza vaccine responsiveness. [Published erratum appears in 2014 Mol. Syst. Biol. 10: 750; 2013 Mol. Syst. Biol. 9: 680.] Mol. Syst. Biol. 9: 659.
17. Wang, C., Y. Liu, L. T. Xu, K. J. Jackson, K. M. Roskin, T. D. Pham, J. Laserson, E. L. Marshall, K. Seo, J. Y. Lee, et al. 2014. Effects of aging, cytomegalovirus infection, and EBVinfection on human B cell repertoires. J. Immunol. 192: 603-611.
18. Jojic, V., T. Shay, K. Sylvia, O. Zuk, X. Sun, J. Kang, A. Regev, D. Koller, A. J. Best, J. Knell, et al; Immunological Genome Project Consortium. 2013. Identification of transcriptional regulators in the mouse immune system. Nat. Immunol. 14: 633-643.
19. Segal, E., M. Shapira, A. Regev, D. Pe'er, D. Botstein, D. Koller, and N. Friedman. 2003. Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data. Nat. Genet. 34: 166-176.
20. Akaike, H. 1974. A new look at the statistical model identification. IEEE Trans. Automat. Contr. 19: 716-723.
21. Subramanian, A., P. Tamayo, V. K. Mootha, S. Mukherjee, B. L. Ebert, M. A. Gillette, A. Paulovich, S. L. Pomeroy, T. R. Golub, E. S. Lander, and J. P. Mesirov. 2005. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102: 15545-15550.
22. Yaari, G., C. R. Bolen, J. Thakar, and S. H. Kleinstein. 2013. Quantitative set analysis for gene expression: A method to quantify gene set differential expression including gene-gene correlations. Nucleic Acids Res. 41: e170.
23. Nakaya, H. I., J. Wrammert, E. K. Lee, L. Racioppi, S. Marie-Kunze, W. N. Haining, A. R. Means, S. P. Kasturi, N. Khan, G. M. Li, et al. 2011. Systems biology of vaccination for seasonal influenza in humans. Nat. Immunol. 12: 786-795.
24. Behbehani, G. K., C. Thom, E. R. Zunder, R. Finck, B. Gaudilliere, G. K. Fragiadakis, W. J. Fantl, and G. P. Nolan. 2014. Transient partial permeabilization with saponin enables cellular barcoding prior to surface marker staining. Cytometry A 85: 1011-1019.
25. Zunder, E. R., R. Finck, G. K. Behbehani, A. D. Amir, S. Krishnaswamy, V. D. Gonzalez, C. G. Lorang, Z. Bjornson, M. H. Spitzer, B. Bodenmiller, et al. 2015. Palladium-based mass tag cell barcoding with a doublet-filtering scheme and single-cell deconvolution algorithm. Nat. Protoc. 10: 316-333.
26. Finck, R., E. F. Simonds, A. Jager, S. Krishnaswamy, K. Sachs, W. Fantl, D. Pe'er, G. P. Nolan, and S. C. Bendall. 2013. Normalization of mass cytometry data with bead standards. Cytometry A 83: 483-494.
27. Amir, E.-a. D., K. L. Davis, M. D. Tadmor, E. F. Simonds, J. H. Levine, S. C. Bendall, D. K. Shenfeld, S. Krishnaswamy, G. P. Nolan, and D. Pe'er. 2013. viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nat. Biotechnol. 31: 545-552.
28. Lood, C., and G. C. Hughes. 2016. Neutrophil extracellular traps as a potential source of autoantigen in cocaine-associated autoimmunity. Rheumatology (Oxford) DOI: 10.1093/rheumatology/kew256.
29. Hochberg, M. C. 1997. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40: 1725.
30. Tan, E. M., A. S. Cohen, J. F. Fries, A. T. Masi, D. J. McShane, N. F. Rothfield, J. G. Schaller, N. Talal, and R. J. Winchester. 1982. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25: 1271-1277.
31. Dai, H., J. S. Leeder, and Y. Cui. 2014. A modified generalized Fisher method for combining probabilities from dependent tests. Front. Genet. 5: 32.
32. Tusher, V. G., R. Tibshirani, and G. Chu. 2001. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl. Acad. Sci. USA 98: 5116-5121.
33. Chen, H., and P. C. Boutros. 2011. VennDiagram: A package for the generation of highly-customizable Venn and Euler diagrams in R. BMC Bioinformatics 12: 35.
34. Furman, D., V. Jojic, S. Sharma, S. S. Shen-Orr, C. J. Angel, S. Onengut-Gumuscu, B. A. Kidd, H. T. Maecker, P. Concannon, C. L. Dekker, et al. 2015. Cytomegalovirus infection enhances the immune response to influenza. Sci. Transl. Med. 7: 281ra43.
35. Brodin, P., V. Jojic, T. Gao, S. Bhattacharya, C. J. Angel, D. Furman, S. Shen-Orr, C. L. Dekker, G. E. Swan, A. J. Butte, et al. 2015. Variation in the human immune system is largely driven by non-heritable influences. Cell 160: 37-47.
36. Martinelli, S., M. Urosevic, A. Daryadel, P. A. Oberholzer, C. Baumann, M. F. Fey, R. Dummer, H. U. Simon, and S. Yousefi. 2004. Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation. J. Biol. Chem. 279: 44123-44132.
37. Cowland, J. B., and N. Borregaard. 1999. The individual regulation of granule protein mRNA levels during neutrophil maturation explains the heterogeneity of neutrophil granules. J. Leukoc. Biol. 66: 989-995.
38. Fouret, P., R. M. du Bois, J. F. Bernaudin, H. Takahashi, V. J. Ferrans, and R. G. Crystal. 1989. Expression of the neutrophil elastase gene during human bone marrow cell differentiation. J. Exp. Med. 169: 833-845.
39. Gaudillière, B., G. K. Fragiadakis, R. V. Bruggner, M. Nicolau, R. Finck, M. Tingle, J. Silva, E. A. Ganio, C. G. Yeh, W. J. Maloney, et al. 2014. Clinical recovery from surgery correlates with single-cell immune signatures. Sci. Transl. Med. 6: 255ra131.
40. Elghetany, M. T. 2002. Surface antigen changes during normal neutrophilic development: A critical review. Blood Cells Mol. Dis. 28: 260-274.
41. Martinez-Moczygemba, M., and D. P. Huston. 2003. Biology of common beta receptor-signaling cytokines: IL-3, IL-5, and GM-CSF. J. Allergy Clin. Immunol. 112: 653-665, quiz 666.
42. Gomez-Cambronero, J., J. Horn, C. C. Paul, and M. A. Baumann. 2003. Granulocyte-macrophage colony-stimulating factor is a chemoattractant cytokine for human neutrophils: involvement of the ribosomal p70 S6 kinase signaling pathway. J. Immunol. 171: 6846-6855.
43. Villanueva, E., S. Yalavarthi, C. C. Berthier, J. B. Hodgin, R. Khandpur, A. M. Lin, C. J. Rubin, W. Zhao, S. H. Olsen, M. Klinker, et al. 2011. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J. Immunol. 187: 538-552.
44. Lood, C., L. P. Blanco, M. M. Purmalek, C. Carmona-Rivera, S. S. De Ravin, C. K. Smith, H. L. Malech, J. A. Ledbetter, K. B. Elkon, and M. J. Kaplan. 2016. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22: 146-153.
45. Jamieson, D. J., R. N. Theiler, and S. A. Rasmussen. 2006. Emerging infections and pregnancy. Emerg. Infect. Dis. 12: 1638-1643.
46. Kourtis, A. P., J. S. Read, and D. J. Jamieson. 2014. Pregnancy and infection. N. Engl. J. Med. 371: 1077.
47. Bammann, B. L., C. B. Coulam, and N. S. Jiang. 1980. Total and free testosterone during pregnancy. Am. J. Obstet. Gynecol. 137: 293-298.
48. Makieva, S., P. T. Saunders, and J. E. Norman. 2014. Androgens in pregnancy: roles in parturition. Hum. Reprod. Update 20: 542-559.
49. Wegmann, T. G., H. Lin, L. Guilbert, and T. R. Mosmann. 1993. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol. Today 14: 353-356.
50. Gold, S. M., and R. R. Voskuhl. 2016. Pregnancy and multiple sclerosis: from molecular mechanisms to clinical application. Semin. Immunopathol. 38: 709-718.
51. Kay, A. W., J. Fukuyama, N. Aziz, C. L. Dekker, S. Mackey, G. E. Swan, M. M. Davis, S. Holmes, and C. A. Blish. 2014. Enhanced natural killer-cell and T-cell responses to influenza A virus during pregnancy. Proc. Natl. Acad. Sci. USA 111: 14506-14511.
52. Mak, T. K., P. Mangtani, J. Leese, J. M. Watson, and D. Pfeifer. 2008. Influenza vaccination in pregnancy: current evidence and selected national policies. Lancet Infect. Dis. 8: 44-52.
53. Rasmussen, S. A., D. J. Jamieson, and T. M. Uyeki. 2012. Effects of influenza on pregnant women and infants. Am. J. Obstet. Gynecol. 207(Suppl.)S3-S8.
54. Ostensen, M., F. Förger, J. L. Nelson, A. Schuhmacher, G. Hebisch, and P. M. Villiger. 2005. Pregnancy in patients with rheumatic disease: antiinflammatory cytokines increase in pregnancy and decrease post partum. Ann. Rheum. Dis. 64: 839-844.
55. Puga, I., M. Cols, C. M. Barra, B. He, L. Cassis, M. Gentile, L. Comerma, A. Chorny, M. Shan, W. Xu, et al. 2011. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat. Immunol. 13: 170-180.
56. Soehnlein, O. 2009. An elegant defense: how neutrophils shape the immune response. Trends Immunol. 30: 511-512.
57. Yang, D., G. de la Rosa, P. Tewary, and J. J. Oppenheim. 2009. Alarmins link neutrophils and dendritic cells. Trends Immunol. 30: 531-537.
58. van Gisbergen, K. P., T. B. Geijtenbeek, and Y. van Kooyk. 2005. Close encounters of neutrophils and DCs. Trends Immunol. 26: 626-631.
59. Tillack, K., P. Breiden, R. Martin, and M. Sospedra. 2012. T lymphocyte priming by neutrophil extracellular traps links innate and adaptive immune responses. J. Immunol. 188: 3150-3159.
60. Sagiv, J. Y., J. Michaeli, S. Assi, I. Mishalian, H. Kisos, L. Levy, P. Damti, D. Lumbroso, L. Polyansky, R. V. Sionov, et al. 2015. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 10: 562-573.
61. Carmona-Rivera, C., and M. J. Kaplan. 2013. Low-density granulocytes: A distinct class of neutrophils in systemic autoimmunity. Semin. Immunopathol. 35: 455-463.
62. Bowers, N. L., E. S. Helton, R. P. Huijbregts, P. A. Goepfert, S. L. Heath, and Z. Hel. 2014. Immune suppression by neutrophils in HIV-1 infection: role of PDL1/PD-1 pathway. PLoS Pathog. 10: e1003993.
63. Dumitru, C. A., K. Moses, S. Trellakis, S. Lang, and S. Brandau. 2012. Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology. Cancer Immunol. Immunother. 61: 1155-1167.
64. Brandau, S., S. Trellakis, K. Bruderek, D. Schmaltz, G. Steller, M. Elian, H. Suttmann, M. Schenck, J. Welling, P. Zabel, and S. Lang. 2011. Myeloidderived suppressor cells in the peripheral blood of cancer patients contain a subset of immature neutrophils with impaired migratory properties. J. Leukoc. Biol. 89: 311-317.
65. Ssemaganda, A., L. Kindinger, P. Bergin, L. Nielsen, J. Mpendo, A. Ssetaala, N. Kiwanuka, M. Munder, T. G. Teoh, P. Kropf, and I. Muller. 2014. Characterization of neutrophil subsets in healthy human pregnancies. PLoS One 9: e85696.
66. Nelson, J. L., and M. Ostensen. 1997. Pregnancy and rheumatoid arthritis. Rheum. Dis. Clin. North Am. 23: 195-212.
67. Confavreux, C., M. Hutchinson, M. M. Hours, P. Cortinovis-Tourniaire, and T. Moreau, Pregnancy in Multiple Sclerosis Group. 1998. Rate of pregnancyrelated relapse in multiple sclerosis. N. Engl. J. Med. 339: 285-291.
68. Agret, F., J. Cosnes, Z. Hassani, J. M. Gornet, J. P. Gendre, M. Lémann, and L. Beaugerie. 2005. Impact of pregnancy on the clinical activity of Crohn's disease. Aliment. Pharmacol. Ther. 21: 509-513.
69. Cloke, T., M. Munder, P. Bergin, S. Herath, M. Modolell, G. Taylor, I. Muller, and P. Kropf. 2013. Phenotypic alteration of neutrophils in the blood of HIV seropositive patients. PLoS One 8: e72034.
70. Köstlin, N., K. Hofstädter, A. L. Ostermeir, B. Spring, A. Leiber, S. Haen, H. Abele, P. Bauer, J. Pollheimer, D. Hartl, et al. 2016. Granulocytic myeloidderived suppressor cells accumulate in human placenta and polarize toward a Th2 phenotype. J. Immunol. 196: 1132-1145.
71. Kö stlin, N., H. Kugel, B. Spring, A. Leiber, A. Marmé, M. Henes, N. Rieber, D. Hartl, C. F. Poets, and C. Gille. 2014. Granulocytic myeloid derived suppressor cells expand in human pregnancy and modulate T-cell responses. Eur. J. Immunol. 44: 2582-2591.
72. Bronte, V., S. Brandau, S. H. Chen, M. P. Colombo, A. B. Frey, T. F. Greten, S. Mandruzzato, P. J. Murray, A. Ochoa, S. Ostrand-Rosenberg, et al. 2016. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7: 12150.
73. Scapini, P., and M. A. Cassatella. 2014. Social networking of human neutrophils within the immune system. Blood 124: 710-719.
74. Gabrilovich, D. I., and S. Nagaraj. 2009. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9: 162-174.
75. Andric, S. A., M. M. Janjic, N. J. Stojkov, and T. S. Kostic. 2010. Testosteroneinduced modulation of nitric oxide-cGMP signaling pathway and androgenesis in the rat Leydig cells. Biol. Reprod. 83: 434-442.
76. Kropf, P., D. Baud, S. E. Marshall, M. Munder, A. Mosley, J. M. Fuentes, C. R. Bangham, G. P. Taylor, S. Herath, B. S. Choi, et al. 2007. Arginase activity mediates reversible T cell hyporesponsiveness in human pregnancy. Eur. J. Immunol. 37: 935-945.
77. Chuang, K. H., S. Altuwaijri, G. Li, J. J. Lai, C. Y. Chu, K. P. Lai, H. Y. Lin, J. W. Hsu, P. Keng, M. C. Wu, and C. Chang. 2009. Neutropenia with impaired host defense against microbial infection in mice lacking androgen receptor. J. Exp. Med. 206: 1181-1199.
78. Pikwer, M., A. Giwercman, U. Bergström, J. A. Nilsson, L. T. Jacobsson, and C. Turesson. 2014. Association between testosterone levels and risk of future rheumatoid arthritis in men: A population-based case-control study. Ann. Rheum. Dis. 73: 573-579.
79. Marin, D. P., A. P. Bolin, Rde. C. dos Santos, R. Curi, and R. Otton. 2010. Testosterone suppresses oxidative stress in human neutrophils. Cell Biochem. Funct. 28: 394-402.
80. Malkin, C. J., P. J. Pugh, R. D. Jones, D. Kapoor, K. S. Channer, and T. H. Jones. 2004. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J. Clin. Endocrinol. Metab. 89: 3313-3318.
81. Liva, S. M., and R. R. Voskuhl. 2001. Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. J. Immunol. 167: 2060-2067.
82. Cassatella, M. A., L. Meda, S. Bonora, M. Ceska, and G. Constantin. 1993. Interleukin 10 (IL-10) inhibits the release of proinflammatory cytokines from human polymorphonuclear leukocytes. Evidence for an autocrine role of tumor necrosis factor and IL-1 beta in mediating the production of IL-8 triggered by lipopolysaccharide. J. Exp. Med. 178: 2207-2211.
83. Roilides, E., H. Katsifa, S. Tsaparidou, T. Stergiopoulou, C. Panteliadis, and T. J. Walsh. 2000. Interleukin 10 suppresses phagocytic and antihyphal activities of human neutrophils. Cytokine 12: 379-387.
84. Marzi, M., A. Vigano, D. Trabattoni, M. L. Villa, A. Salvaggio, E. Clerici, and M. Clerici. 1996. Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy. Clin. Exp. Immunol. 106: 127-133.
85. Thaxton, J. E., and S. Sharma. 2010. Interleukin-10: A multi-faceted agent of pregnancy. Am. J. Reprod. Immunol. 63: 482-491.
86. Huizinga, T. W., M. W. van der Linden, V. Deneys-Laporte, and F. C. Breedveld. 1999. Interleukin-10 as an explanation for pregnancy-induced flare in systemic lupus erythematosus and remission in rheumatoid arthritis. Rheumatology (Oxford) 38: 496-498.
87. Torcia, M. G., L. Nencioni, A. M. Clemente, L. Civitelli, I. Celestino, D. Limongi, G. Fadigati, E. Perissi, F. Cozzolino, E. Garaci, and A. T. Palamara. 2012. Sex differences in the response to viral infections: TLR8 and TLR9 ligand stimulation induce higher IL10 production in males. PLoS One 7: e39853.
88. Orr, Y., J. M. Taylor, P. G. Bannon, C. Geczy, and L. Kritharides. 2005. Circulating CD10-/CD16low neutrophils provide a quantitative index of active bone marrow neutrophil release. Br. J. Haematol. 131: 508-519.