Angiocentric CD3⁺T-Cell Infiltrates in Human Immunodeficiency Virus Type 1-Associated Central Nervous System Disease in Children

Abstract

A significant proportion of brain tissue specimens from children with AIDS show evidence of vascular inflammation in the form of transmural and/or perivascular mononuclear-cell infiltrates at autopsy. Previous studies have shown that in contrast to inflammatory lesions observed in human immunodeficiency virus type 1 (HIV-1) encephalitis, in which monocytes/macrophages are the prevailing mononuclear cells, these infiltrates consist mostly of lymphocytes. Perivascular mononuclear-cell infiltrates were found in brain tissue specimens collected at autopsy from five of six children with AIDS and consisted of CD3+ T cells and equal or greater proportions of CD68+ monocytes/macrophages. Transmural (including endothelial) mononuclear-cell infiltrates were evident in one patient and comprised predominantly CD3+ T cells and small or, in certain vessels, approximately equal proportions of CD68+monocytes/macrophages. There was a clear preponderance of CD3+ CD8+ T cells on the endothelial side of transmural infiltrates. In active lesions of transmural vasculitis, CD3+ T-cell infiltrates exhibited a distinctive zonal distribution. The majority of CD3+ cells were also CD8+ and CD45RO+. Scattered perivascular monocytes/macrophages in foci of florid vasculitis were immunoreactive for the p24 core protein. In contrast to the perivascular space, the intervening brain neuropil was dominated by monocytes/macrophages, microglia, and reactive astrocytes, containing only scant CD3+ CD8+ cells. Five of six patients showed evidence of calcific vasculopathy, but only two exhibited HIV-1 encephalitis. One patient had multiple subacute cerebral and brainstem infarcts associated with a widespread, fulminant mononuclear-cell vasculitis. A second patient had an old brain infarct associated with fibrointimal thickening of large leptomeningeal vessels. These infiltrating CD3+ T cells may be responsible for HIV-1-associated CNS vasculitis and vasculopathy and for endothelial-cell injury and the opening of the blood-brain barrier in children with AIDS.

Theiler's Virus Infection: a Model for Multiple Sclerosis

“…Disturbances in oxidative metabolism resembling hypoxia-ischemia may be the consequence of vascular factors and/or the production of toxic metabolites typically associated with hypoxia-ischemia. Inflammatory damage of the vessel wall, endothelium, and bloodbrain barrier by T cells and monocytes is tantamount to a vasculitic state, reminiscent of the angiocentric T-cell infiltrates in human immunodeficiency virus type 1-associated CNS disease (197). The latter, compounded by edema and disturbance of the cerebral microcirculation, may culminate in variably pronounced hypoxic-ischemic injury causing damage to myelin, axons, and oligodendrocytes (227).…”

Oligoclonal T cells are infiltrating the brains of children with AIDS: sequence analysis reveals high proportions of identical β-chain T-cell receptor transcripts

“…Although not prevalent in adult patients with AIDS, angiocentric mononuclear cell infiltrates have been found at autopsy in the brains of up to 40% of HIV‐1‐infected children [4–6,14–18]. Sharer et al .…”

“…Katsetos et al . [18] reported angiocentric (perivascular and in certain cases also transmural) mononuclear cell infiltrates in brain tissue specimens collected at autopsy from five of six children with AIDS. Immunohistochemical studies demonstrated that these angiocentric infiltrates mostly consisted of CD3+ CD8+ CD45RO+ T cells and of CD68+ monocyte/macrophages.…”

Cerebrovascular disease in children with HIV‐1 infection

“…Molecular mimicry (cross-recognition of common epitomes on HIV-1 and the host protein) was suggested as a mechanism for the endothelial cell injury, the ensuing vasculopathy, and the subsequent ischaemic stroke in these children. 47 Inflammatory markers correlated with common carotid intima-media thickness in young adults with perinatally acquired HIV-1 infection, considered an increased risk for stroke, and further support an inflammation mediated mechanism. 46…”

“…47 Perivascular and transmural infiltrates of inflammatory cellspredominantly CD3+ and CD8+ T-cellswere detected, with no clinical or immunohistochemical evidence of opportunistic viral infections. 47 The authors proposed that the CD3+ T-cell infiltrates in the CNS of children infected with HIV may represent oligoclonal expansion of cytotoxic T-cells in the context of a vigorous anti-HIV-1 response, even though the viral loads in the CNS during this T-cell perivasculitis were low, raising the possibility of an autoimmune basis for the T-cell response. Molecular mimicry (cross-recognition of common epitomes on HIV-1 and the host protein) was suggested as a mechanism for the endothelial cell injury, the ensuing vasculopathy, and the subsequent ischaemic stroke in these children.…”