Laboratory of Holly H. Birdsall, M.D., Ph.D.
Transendothelial Migration of Leukocytes in Inflammation; AIDS Dementia; Ischemia; Virus:leukocyte interactions
Our goal is to identify mechanisms influencing the translocation of mononuclear leukocytes (MNLs) across vascular endothelial barriers in the context of viral infections like HIV. Over 40% of HIV-infected patients develop dementia. HIV-1 in the CNS is found primarily amidst perivascular leukocytic infiltrates, which are a potential source of diverse products that contribute to neurologic dysfunction.
Our hypothesis is that the activation of MNLs in association with HIV-1 infection increases their ability to migrate across vascular endothelium and produce factors that stimulate additional MNLs to migrate across the same vascular endothelium.
We use a model of cultured umbilical vein and brain microvascular endothelium grown over collagen to study the adhesive and transendothelial migratory behavior of MNLs. HIV-infected MNLs are obtained from the peripheral blood of HIV-infected patients or by infecting normal donor MNLs with HIV in vitro. Flow cytometric analyses identify and classify the MNLs that migrate through the endothelial barrier and are also used to measure cytokine production by these migratory MNLs.
We have demonstrated that HIV-1 infection stimulates expression of specific integrins and other yet uncharacterized cell surface molecules that facilitate adhesive interactions with both endothelium and cultured neural cells.
In a subset of HIV-infected subjects, we observed that significantly increased numbers of T lymphocytes spontaneously migrate across these endothelial monolayers in comparison with MNLs from normal donors. These migratory lymphocytes appear to be able to enhance subsequent migration of additional leukocytes into the same perivascular focus.
- Rossen RD, Rubio JA, Porter WJ, Trial J, Orson FM, Rodriguez-Barradas MC, Birdsall HH. Monocyte CD49e and 110-120 kDa fibronectin fragments: HIV prognostic indicators independent of viral load and CD4 T-cell counts. AIDS 2009;23:2247-53.
- Green DM, Noble PC, Bocell JR Jr, Ahuero JS, Poteet BA, Birdsall HH. Effect of early full weight-bearing after joint injury on inflammation and cartilage degradation. J Bone Joint Surg Am 2006;88:2201-9.
- Green DM, Noble PC, Ahuero JS, Birdsall HH. Cellular events leading to chondrocyte death after cartilage impact injury. Arthritis Rheum 2006;54:1509-17.
- Birdsall HH, Porter WJ, Trial J, Rossen RD. Monocytes stimulated by 110-kDa fibronectin fragments suppress proliferation of anti-CD2-activated T cells. J Immunol 2005;175:3347-53.
- Birdsall HH, Porter WJ, Green DM, Rubio J, Trial J, Rossen RD. Impact of fibronectin fragments on the transendothelial migration of HIV-infected leukocytes and the development of subendothelial foci of infectious leukocytes. J Immunol 2004;173:2746-54.
- Trial J, Rubio JA, Birdsall HH, Rodriguez-Barradas M, Rossen RD. Monocyte activation by circulating fibronectin fragments in HIV-1-infected patients. J Immunol 2004;173:2190-8.
- Birdsall HH, Siwak EB, Trial J, Rodriguez-Barradas M, White AC Jr, Wietgrefe S, Rossen RD. Transendothelial migration of leukocytes carrying infectious HIV-1: an indicator of adverse prognosis. AIDS 2002;16:5-12.
- Trial J, Baughn RE, Wygant JN, McIntyre BW, Birdsall HH, Youker KA, Evans A, Entman ML, Rossen RD. Fibronectin fragments modulate monocyte VLA-5 expression and monocyte migration. J Clin Invest 1999;104:419-30.
- Green DM, Trial J, Birdsall HH. TNF-alpha released by comigrating monocytes promotes transendothelial migration of activated lymphocytes. J Immunol 1998;161:2481-9.
- Youker KA, Birdsall HH, Frangogiannis NG, Kumar AG, Lindsey ML, Ballantyne CM, Smith CW, Rossen RD, Entman ML. Phagocytes in ischemia injury. Ann N Y Acad Sci 197;832:243-65.
- Birdsall HH, Trial J, Lin HJ, Green DM, Sorrentino GW, Siwak EB, de Jong AL, Rossen RD. Transendothelial migration of lymphocytes from HIV-1-infected donors: a mechanism for extravascular dissemination of HIV-1. J Immunol 1997;158:5968-77.
- Kumar AG. Ballantyne CM. Michael LH. Kukielka GL. Youker KA. Lindsey ML. Hawkins HK. Birdsall HH. MacKay CR. LaRosa GJ. Rossen RD. Smith CW. Entman ML. Induction of monocyte chemoattractant protein-1 in the small veins of the ischemic and reperfused canine myocardium. Circulation 1997; 95:693-700.
- Birdsall HH. Green DM. Trial J. Youker KA. Burns AR. MacKay CR. LaRosa GJ. Hawkins HK. Smith CW. Michael LH. Entman ML. Rossen RD. Complement C5a, TGF-beta 1, and MCP-1, in sequence, induce migration of monocytes into ischemic canine myocardium within the first one to five hours after reperfusion. Circulation 1997; 95:684-92.
- de Jong AL. Green DM. Trial JA. Birdsall HH. Focal effects of mononuclear leukocyte transendothelial migration: TNF-alpha production by migrating monocytes promotes subsequent migration of lymphocytes. J Leuko Biol 1996;60:129-36.
- Kapadia S. Lee J. Torre-Amione G. Birdsall HH. Ma TS. Mann DL. Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration. J Clin Invest 1995; 96:1042-52.
- Trial J. Birdsall HH. Hallum JA. Crane ML. Rodriguez-Barradas MC. de Jong AL. Krishnan B. Lacke CE. Figdor CG. Rossen RD. Phenotypic and functional changes in peripheral blood monocytes during progression of human immunodeficiency virus infection. Effects of soluble immune complexes, cytokines, subcellular particulates from apoptotic cells, and HIV-1-encoded proteins on monocytes phagocytic function, oxidative burst, transendothelial migration, and cell surface phenotype. J Clin Invest 1995; 95:1690-701.
- Birdsall HH. Trial J. Hallum JA. de Jong AL. Green LK. Bandres JC. Smole SC. Laughter AH. Rossen RD. Phenotypic and functional activation of monocytes in HIV-1 infection: interactions with neural cells. J J Leuko Biol 1994;56:310-7.
- Birdsall HH. Ozluoglu LN. Lew HL. Trial J. Brown DP. Wofford MJ. Jerger JF. Rossen RD. Auditory P300 abnormalities and leukocyte activation in HIV infection. Otolaryngol Head Neck Surg 1994;110:53-9.
- Birdsall HH. Lane C. Ramser MN. Anderson DC. Induction of VCAM-1 and ICAM-1 on human neural cells and mechanisms of mononuclear leukocyte adherence. J Immunol 1992;148:2717-23.
- Birdsall HH. Induction of ICAM-1 on human neural cells and mechanisms of neutrophil-mediated injury. Am J Pathol 1991;139:1341-50.
- Birdsall HH. Baughn RE. Jenkins HA. The diagnostic dilemma of otosyphilis. A new western blot assay. Arch Otolaryngol Head Neck Surg 1990;116:617-21.