HTLV-I induced myeloneuropathy in WKAH rats: apoptosis and local activation of the HTLV-I pX and TNF-alpha genes implicated in the pathogenesis.
To investigate the pathogenesis of HTLV-I associated diseases, we established a rat model for HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in WKAH rats. In the spinal cords of WKAH rats carrying HTLV-I, chronological histopathology revealed the occurrence of apoptotic cell death starting at 9 months after the infection, followed by demyelination, macrophage infiltration, and the activation of astrocytes starting at 12, 15 and 20 months, respectively. Apoptosis of the Schwann cells was also observed in the peripheral nerves of these rats. By RT-PCR, pX mRNA of HTLV-I was selectively expressed in the diseased spinal cords and peripheral nerves, but not in the unaffected cerebra, cerebella, even though provirus DNAs were consistently identified in these tissues. Among several cytokines examined, mRNA expression and production of TNF-alpha were frequently detected in the spinal cord and the cerebrospinal fluid. The collective evidence suggests that the selective activation of HTLV-I, in particular Tax expression, and/or the production of TNF-alpha in target spinal cord and peripheral nerves are causally related to apoptotic death of the oligodendrocytes and Schwann cells, a major pathogenetic pathway of HTLV-I induced myeloneuropathy in the WKAH rat.
Ohya
O
O
Department of Pathology, Hokkaido University School of Medicine, Sapporo, Japan.
Tomaru
U
U
Yamashita
I
I
Kasai
T
T
Morita
K
K
Ikeda
H
H
Wakisaka
A
A
Yoshiki
T
T
D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004279:DNA, Viral / Q000096:biosynthesis; D005786:Gene Expression Regulation; D015368:Human T-lymphotropic virus 1 / Q000302:isolation & purification* / Q000502:physiology; D009186:Myelin Sheath / Q000473:pathology; D015493:Paraparesis, Tropical Spastic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011533:Proviruses / Q000302:isolation & purification; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D015682:Retroviridae Proteins, Oncogenic / Q000096:biosynthesis* / Q000235:genetics; D012583:Schwann Cells / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D014157:Transcription Factors; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000134:cerebrospinal fluid / Q000235:genetics; D054334:Viral Regulatory and Accessory Proteins; D014779:Virus Replication
D004279:DNA, Viral; D012333:RNA, Messenger; D015682:Retroviridae Proteins, Oncogenic; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D054334:Viral Regulatory and Accessory Proteins; C072343:pX protein, Human T-lymphotropic virus 1