The use of pentoxifylline as adjuvant therapy with praziquantel downregulates profibrogenic cytokines, collagen deposition and oxidative stress in experimental schistosomiasis mansoni

This study investigates the possible use of pentoxifylline (PTX), with antifibrotic and anti-inflammatory properties, as adjuvant in treatment of schistosomal liver fibrosis through determination of some profibrogenic cytokines, oxidative stress and collagen deposition. Animals were classified into seven groups: normal control (i), Schistosoma mansoni-infected untreated (ii), infected treated with praziquantel (PZQ) curative, 1000 mg/kg (iii) or sub curative, 200 mg/kg dose (iv), infected treated with PTX alone (10 mg/kg/day; 5 days/wk) for 8 weeks starting from the 2nd to the 10th week post infection (v), or in addition to curative (vi) or sub curative dose of PZQ (vii). Serum transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), matrix metalloproteinases-2 (MMP-2) and hepatic hydroxyproline (Hyp) content, glutathione related antioxidant enzymes and malondialdehyde (MDA) were determined. Results showed that S. mansoni infection produced remarkable elevations in the serum levels of TGF-β1, TNF-α, MMP-2 and the hepatic contents of Hyp, glutathione reductase (GR), MDA with significant reduction in reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and superoxide dismutase (SOD) when compared with their corresponding normal controls. Treatment of infected mice with PTX in addition to PZQ curative rather than its sub curative dose produced the best results evidenced by complete normalization in the previously mentioned serum and hepatic parameters. Conclusion: PTX could attenuate liver fibrosis in early stages of S. mansoni infection through downregulation of profibrogenic cytokines, oxidative stress and collagen deposition.     

TNF-α is involved in the abnormal thymocyte migration during experimental Trypanosoma cruzi infection and favors the export of immature cells

Previous studies revealed a significant production of inflammatory cytokines together with severe thymic atrophy and thymocyte migratory disturbances during experimental Chagas disease. Migratory activity of thymocytes and mature T cells seem to be finely tuned by cytokines, chemokines and extracellular matrix (ECM) components. Systemic TNF-α is enhanced during infection and appears to be crucial in the response against the parasite. However, it also seems to be involved in disease pathology, since it is implicated in the arrival of T cells to effector sites, including the myocardium. Herein, we analyzed the role of TNF-α in the migratory activity of thymocytes in Trypanosoma cruzi (T. cruzi) acutely-infected mice. We found increased expression and deposition of TNF-α in the thymus of infected animals compared to controls, accompanied by increased co-localization of fibronectin, a cell migration-related ECM molecule, whose contents in the thymus of infected mice is also augmented. In-vivo studies showed an enhanced export of thymocytes in T. cruzi-infected mice, as ascertained by intrathymic injection of FITC alone or in combination with TNF-α. The increase of immature CD4(+)CD8(+) T cells in secondary lymphoid organs was even more clear-cut when TNF-α was co-injected with FITC. Ex-vivo transmigration assays also revealed higher number of migrating cells when TNF-α was added onto fibronectin lattices, with higher input of all thymocyte subsets, including immature CD4(+)CD8(+). Infected animals also exhibit enhanced levels of expression of both mRNA TNF-α receptors in the CD4(+)CD8(+) subpopulation. Our findings suggest that in T. cruzi acute infection, when TNF-α is complexed with fibronectin, it favours the altered migration of thymocytes, promoting the release of mature and immature T cells to different compartments of the immune system. Conceptually, this work reinforces the notion that thymocyte migration is a multivectorial biological event in health and disease, and that TNF-α is a further player in the process.     

Green tea extract attenuates hepatic steatosis by decreasing adipose lipogenesis and enhancing hepatic antioxidant defenses in ob/ob mice

Excess hepatic lipid accumulation and oxidative stress contribute to nonalcoholic fatty liver disease (NAFLD). Thus, we hypothesized that the hypolipidemic and antioxidant activities of green tea extract (GTE) would attenuate events leading to NAFLD. Obese mice (ob/ob; 5 weeks old, n=38) and their lean littermates (n=12) were fed 0%, 0.5% or 1% GTE for 6 weeks. Then, hepatic steatosis, oxidative stress and inflammatory markers were measured. Obese mice, compared to lean controls, had greater hepatic lipids and serum alanine aminotransferase (ALT). GTE at 1% lowered (P<.05) hepatic lipids and ALT in obese mice. The GTE-mediated attenuation in hepatic steatosis was accompanied by decreased mRNA expression of adipose sterol regulatory element-binding protein-1c, fatty acid synthase, stearoyl CoA desaturase-1, and hormone-sensitive lipase and decreased serum nonesterified fatty acid concentrations. Immunohistochemical data indicated that steatotic livers from obese mice had extensive accumulation of tumor necrosis factor-α (TNF-α), whereas GTE at 1% decreased hepatic TNF-α protein and inhibited adipose TNF-α mRNA expression. Hepatic total glutathione, malondialdehyde and Mn- and Cu/Zn-superoxide dismutase activities in obese mice fed GTE were normalized to the levels of lean littermates. Also, GTE increased hepatic catalase and glutathione peroxidase activities, and these activities were inversely correlated with ALT and liver lipids. Collectively, GTE mitigated NAFLD and hepatic injury in ob/ob mice by decreasing the release of fatty acids from adipose and inhibiting hepatic lipid peroxidation as well as restoring antioxidant defenses and decreasing inflammatory responses. These findings suggest that GTE may be used as an effective dietary strategy to mitigate obesity-triggered NAFLD.     

Tumor necrosis factor alpha induced by Trypanosoma cruzi infection mediates inflammation and cell death in the liver of infected mice

Trypanosoma cruzi (T. cruzi) infected C57BL/6 mice developed a progressive fatal disease due to an imbalance in the profile of circulating related compounds accompanying infection like tumor necrosis factor alpha (TNFα). TNFα has been proposed as an important effector molecule in apoptosis. In this work, we evaluate inflammation and the proteins involved in apoptotic process in liver of infected mice and the role of TNFα. C57BL6/mice were infected subcutaneously with 100 viable trypomastigotes of Tulahuén strain of T cruzi. One set of these animals were treated with 375 μg of antihuman TNFα blocking antibody. Animals were sacrificed at 14 days post-infection (p.i).The analyses of Bcl-2 family proteins revealed an increase of the pro-apoptotic proteins Bax and tBid in T. cruzi-infected mice. Compared with control animals, cytochrome c release was increased. Apoptosis was also induced in infected mice. Anti-TNFα treatment decreases hepatic apoptosis. Our results suggest that T. cruzi infection induces programmed cell death in the host liver by increase of TNFα production, associated with TNF-R1 over-expression, that set in motion the Bid cleavage and mitochondrial translocation, Bax mitochondrial translocation, cytochrome c release, and ultimately apoptosis induction.     

Effect of honey on mRNA expression of TNF-α, IL-1β and IL-6 following acute toxoplasmosis in mice

This study analyzed the mRNA expression of tumor necrosis factor (TNF-α), interleukin 1 beta (IL-1β) and interleukin 6 (IL-6) in mice experimentally infected with T. gondii undergoing honey treatment. Thirty male mice were divided in groups: pre-treatment/infected (1), infected/non-treated (2), infected/treated (3), non-infected/treated (4) and control (5). Honey was applied for groups 1, 3, 4 by gavage and the mice in group 1–3 were infected by T. gondii tissue cysts. The parasite load and the level of mRNA expression of the aforementioned cytokines in the brains of mice were assessed by qPCR. The mean number of T. gondii tachyzoite in 1 mg brain tissue was 32, 73 and 59 in groups one, two and three, respectively. The mRNA expression of TNF-α increased in group 1, 2 and 3, about 49.1%, 307.3% and 63.2%, respectively but it was down-regulated by 53% in group 4. The mRNA expression of IL-1β and IL-6 was also up-regulated in all groups except group 2. The mRNA level of TNF-α was reduced by 2.7-fold and 1.18-fold in pre-treated/infected (group 1) and infected/treated (group 3) compared with infected/non-treated (group 2). The mRNA level of IL-1β and IL-6 were increased in these groups. The current study demonstrated that honey can stimulate or suppress the mRNA expression of some pro-inflammatory cytokines in mice brains. Furthermore, honey suppresses the TNF-α mRNA expression in the presence of T. gondii infection but it stimulates the IL-1β and IL-6 mRNA expression. Treatment of the mice with honey reduces parasite multiplication in the brain.     

Thalidomide decreases intrahepatic resistance in cirrhotic rats

Increased intrahepatic resistance (IHR) within cirrhotic liver is caused by increased endotoxemia, cytokines tumor necrosis factor-α (TNF-α), vasoconstrictor thromboxane A₂ (TXA₂), and disrupted microvasculatures. We evaluated the effects of thalidomide-related inhibition of TNF-α upon the hepatic microcirculation of cirrhosis in rats. Portal venous pressure (PVP), hepatic TNF-α, expression of thromboxane synthase (TXS), and leukocyte common antigen (LCA) were measured in bile-duct-ligated (BDL) rats receiving 1 month of thalidomide (BDL-thalido rats). Portal perfusion pressure (PPP), IHR, and hepatic TXA₂ production were measured in the isolated liver perfusion system. Intravital microscopy was used to examine hepatic microvascular disruptions. In BDL-thalido rats, PVP, PPP, IHR, hepatic TXA₂ and TNF-α, hydroxyproline content, expression of TXS and LCA, and LPS-induced leukocyte recruitment were significantly decreased. Conversely, hepatic microvascular density and perfused sinusoids were significantly increased. Thalidomide decreased PVP and IHR by reducing hepatic TXA₂ and improving hepatic microvascular disruptions in rats with biliary cirrhosis.     

Cellular therapy by allogeneic macrophages against visceral leishmaniasis: Role of TNF-α

Tumor necrosis factor α (TNF-α) is an essential player in infection with Leishmania, controlling inflammatory lesion and parasite killing. We recently have shown the leishmanicidal activity of transmembrane form of TNF (mTNF) derived from allogeneic natural killer (NK) cells in experimental visceral leishmaniasis. Allogeneic macrophages and human monocytes derived mTNF has significantly higher antileishmanial activity compared to allogeneic NK cells. Unlike NK cells, syngeneic macrophages also possess antileishmanial activity, although degree of activity is significantly less compared to allogeneic macrophages. Cellular therapy by intravenous transfer of allogeneic macrophages enhances leishmanicidal effect against the established infection in susceptible animal by reducing the splenic parasite burden to 28.3 ± 4.71 × 10⁵ compared to 256.00 ± 17.36 × 10⁵ in control group. In vivo treatment with anti-mouse TNF-α reduces the therapeutic efficacy of the allogeneic macrophages by increasing the parasite load in spleen of infected mice. These results demonstrated that allogeneic and xenogeneic macrophages induce cytokine mediated protective mechanism against infected macrophages via TNF-α in vitro and, possibly in vivo. The macrophage mediated protective role in absence of T cell help demonstrate an unique property of the mononuclear phagocytes in controlling infection and inflammation in visceral leishmaniasis, despite being acts as a host cell for the same parasite.     

细菌及其毒素诱发小鼠胸腺细胞凋亡的机制初探

给ＢＡＬＢ／ｃ小鼠腹腔注射产肠毒素Ｂ金黄色葡萄球菌（ＳＥＢＳ）、绿脓杆菌（ＰＡ）或葡萄球菌肠毒素Ｂ（ＳＥＢ）,均可引起小鼠胸腺萎缩,呈现胸腺重量减轻、胸腺细胞数减少、胸腺细胞存活率降低。实验发现,在这些细菌或毒素作用下,胸腺细胞发生了具有细胞凋亡的特征性形态学和生化学变化。进一步研究表明,小鼠胸腺细胞凋亡的机制可能与这些细菌或毒素诱导宿主产生ＴＮＦ－α、ＩＦＮｒ和ＩＬ－６等细胞因子有关。     

Deletion of tumor necrosis factor-α receptor type 1 exacerbates insulin resistance and hepatic steatosis in aromatase knockout mice

The relevance of estrogen functions in lipid metabolism has been suggested in patients with estrogen-signaling deficiencies. Their importance was further implied by studies in estrogen-deficient mice (ArKO mice), which progressively developed hepatic steatosis. As circulating tumor necrosis factor (TNF)-α levels are known to positively correlate with disturbances in lipid metabolism, we investigated the impact of the loss of TNF-α signaling on carbohydrate and lipid metabolism in ArKO mice. Histological examinations of the livers of mice at 5 months of age revealed that ArKO male mice lacking the TNF-α receptor type 1 (TNFR1) gene (ArKO/TNFR1KO) or both the TNFR 1 and 2 genes (ArKO/TNFR1&2KO) developed more severe hepatic steatosis than ArKO or ArKO/TNFR2KO mice. Serum analyses demonstrated a clear increase in cholesterol and insulin levels in the ArKO/TNFR1KO mice compared with the ArKO mice. Glucose- and insulin-tolerance tests further revealed exacerbation of the systemic insulin resistant phenotype in the ArKO/TNFR1KO mice. Hepatic expression of lipogenic genes including fatty-acid synthase and stearoyl-Coenzyme A desaturase 1 were more markedly upregulated in the ArKO/TNFR1KO mice than the ArKO mice. These findings indicate that under estrogen-deficient physiological conditions, hepatic lipid metabolism would benefit from TNF-α mediated signaling via TNFR1.     

Effects of Selenium-Enriched Agaricus blazei Murill on Liver Metabolic Dysfunction in Mice,a Comparison with Selenium-Deficient Agaricus blazei Murill and Sodium Selenite

In the present study, we investigated the effects of Se-enriched Agaricus blazei Murill (Se-AbM) on liver injury in mice induced by acute alcohol administration. Mice received ethanol (5 g/kg body weight (BW)) by gavage every 12 h for a total of 3 doses. Se-AbM was administrated before ethanol administration. Subsequent serum alanine aminotransferase (ALT) level, aspartate aminotransaminase (AST) level, maleic dialdehyde (MDA) level, hepatic total antioxidant status (TAOS), nuclear factor kappa B (NF-κB) level, polymorphonuclear cells (PMN) level, interleukin-1β (IL-1β) level, inducible nitric oxide synthase (iNOS) level, tumor necrosis factor-α (TNF-α) level, intercellular adhesion molecule 1 (ICAM-1), and cyclooxygenase-2 (COX-2) were determined by ELISA and immunohistochemistry, respectively. Se-AbM administration markedly (p?<?005) decreased serum ALT, AST, and MDA levels, hepatic IL-1β and TNF-α levels, as well as PMN infiltration and the expression of ICAM-1, COX-2, iNOS, and NF-κB compared with alcohol administration. In conclusion, we observed that Se-AbM supplementation could restrain the hepatic damage caused by acute alcohol exposure.     

Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Infection Induced Apoptosis and Autophagy in Thymi of Infected Piglets

Previously, we demonstrated that the highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) HuN4 strain causes obvious thymic atrophy and thymocytes apoptosis in infected piglets after birth, which is more severe than that induced by classical PRRSV. In this study, we investigated apoptosis and autophagy in the thymus of piglets infected with the HP-PRRSV HuN4 strain, and found that both apoptosis and autophagy occurred in the thymus of piglets infected with HP-PRRSV. In addition to a few virus-infected cells, CD14⁺ cells, the main autophagic cells in the thymus were thymic epithelial cells. These findings demonstrated that HP-PRRSV induces apoptosis in bystander cells, and induces autophagy in both infected and bystander cells in the thymus of infected piglets. Herein, we first present new data on the thymic lesions induced by HP-PRRSV, and show that apoptosis and autophagy are key mechanisms involved in cell survival and determinants of the severity of thymic atrophy in infected piglets. Finally, future studies of the mechanism underlying immune responses are proposed based on our current understanding of PRRSV-host interactions.     

Naringenin alleviates nonalcoholic steatohepatitis in middle-aged Apoe−/−mice: role of SIRT1

BackgroundNaringenin is naturally isolated from citrus fruits possessing many pharmacological activities. However, little is known about the effect of naringenin on nonalcoholic steatohepatitis (NASH) in the model of metabolic syndrome.PurposeThe present study is aimed to investigate the effect of naringenin on NASH in 12-mo-old male ApoE^−/− mice and its possible underlying mechanism.MethodsIn vivo, 12-mo-old male ApoE^−/− mice were administrated with naringenin by intragastric gavage for 12 weeks. At the end of experiment, the blood samples and liver tissues were collected. Metabolic parameters in serum, levels of triglyceride, cholesterol and hydroxyproline, activities of antioxidant enzymes, and content of inflammatory cytokines (TNF-α and IL-6) in liver were examined by corresponding assay kits. Pathological changes in liver were observed by hematoxylin-eosin, oil red O, masson's trichrome, picro-sirius red and senescence β-galactosidase staining. Dihydroethidium was used for detection of reactive oxygen species (ROS). In vitro, AML-12 cells were treated with oleic acid in the presence or absence of naringenin for 24 h. Transfection of SIRT1 siRNA was also conducted in vitro. Lipid accumulation, cellular ROS generation, malondialdehyde content, antioxidant enzyme activities and secretion levels of TNF-α and IL-6 were examined. Both in vivo and in vitro, gene expressions were detected by real-time PCR or western blot.ResultsNaringenin administration improved metabolic parameters, suppressed hepatic steatosis, regulated expression of genes involved in lipid metabolism (FASN, SCD1, PPARα and CPT1α), reduced hepatic fibrosis and cell senescence, inhibited hepatic inflammation as evidenced by the decreased macrophage recruitment and content of TNF-α and IL-6, and reduced hepatic oxidative stress by suppressing ROS generation and normalizing activities of antioxidant enzymes. Notably, naringenin administration increased hepatic SIRT1 protein expression and activity along with the increased deacetylation of liver kinase B1 (LKB1), PGC1α and NF-κB. In vitro study, the benefits of naringenin on lipid accumulation, oxidative stress and inflammation were diminished by SIRT1 siRNA transfection.ConclusionsThese results indicate that naringenin administration may be a potential curative therapy for NASH treatment and the activation of hepatic SIRT1-mediated signaling cascades is involved in its beneficial effects.     

Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death

Ischemia/reperfusion (I/R) is a pivotal mechanism of liver damage after liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol (CBD), the nonpsychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, and gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor α (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, intercellular adhesion molecule 1 mRNA levels; tissue neutrophil infiltration; nuclear factor κB (NF-κB) activation), stress signaling (p38MAPK and JNK), and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress, and cell death and also attenuated the bacterial endotoxin-triggered NF-κB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecule expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent of classical CB1/2 receptors.     

Genetic ablation of PLA2G6 in mice leads to cerebellar atrophy characterized by Purkinje cell loss and glial cell activation

Infantile neuroaxonal dystrophy (INAD) is a progressive, autosomal recessive neurodegenerative disease characterized by axonal dystrophy, abnormal iron deposition and cerebellar atrophy. This disease was recently mapped to PLA2G6, which encodes group VI Ca(2+)-independent phospholipase A(2) (iPLA(2) or iPLA(2)β). Here we show that genetic ablation of PLA2G6 in mice (iPLA(2)β(-/-)) leads to the development of cerebellar atrophy by the age of 13 months. Atrophied cerebella exhibited significant loss of Purkinje cells, as well as reactive astrogliosis, the activation of microglial cells, and the pronounced up-regulation of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, glial cell activation and the elevation in TNF-α and IL-1β expression occurred before apparent cerebellar atrophy. Our findings indicate that the absence of PLA2G6 causes neuroinflammation and Purkinje cell loss and ultimately leads to cerebellar atrophy. Our study suggests that iPLA(2)β(-/-) mice are a valuable model for cerebellar atrophy in INAD and that early anti-inflammatory therapy may help slow the progression of cerebellar atrophy in this deadly neurodegenerative disease.     

Efficiency of ginger (Zingbar officinale) against Schistosoma mansoni infection during host–parasite association

The possible protective effect of ethanolic extract of ginger against infection with Schistosome mansonii was evaluated in mice. The extract was given daily for 45 days beginning at either 2nd day or 45 days post infection. Oral supplementation of ginger extract to infected animals was effective in reducing worm burden and the egg load in the liver and intestine which coincided with the reduction in granuloma diameters. Ginger extract had also the effect to offset liver fibrosis in response to S. mansoni infection indicated by reduced liver hydroxyproline level and serum alpha–fetoprotein (AFP). The extract reduces some inflammatory mediators that play a crucial role in schistosomal liver fibrosis and its complications. These include liver xanthine oxidase (XO); nitric oxide (NO); tumour necrosis factor–alpha (TNF-α); immunoglobins E, G, and M (Ig-E, Ig-G and Ig-M, respectively), and interleukin 4, 10 and 12 (IL-4, IL-10 and IL-12, respectively). Administration of ginger extract ameliorated the infection-induced alterations in serum gamma-glutamyl transferase (GGT), alanine amintransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). It was concluded that oral administration of ginger extract to S. mansoni infected mice could minimize the deleterious effects of this parasite on the vital functions of infected animals.     

Importance of TNF-alpha in the course of acute infection with Trypanosoma cruzi: influence of its inhibition by pentoxifylline treatment

Infection of C3H/He mice with the Peruvian strain of Trypanosoma cruzi (Biodeme type I, Z2b), a macrophagotropic strain, determined severe parasitism of macrophages, necrosis of the spleen, and high host mortality. In the present study, pentoxifylline (PTX), an inhibitor of TNF-alpha was investigated on its action upon splenic necrosis, parasitemia and host survival. Immunohistochemical data suggested the importance of this cytokine in parasite destruction and decreasing of parasitemia, although paradoxically contributing to the high mortality of infected mice. Necrotic lesions involving several organs, specially the heart, in acute Chagas disease, are important aggravating factors, increasing cardiac morbidity. Advantage of inhibiting TNF-alpha action was herein investigated. Infected mice were divided into two groups: untreated (n = 24), and PTX treated mice (n = 25). PTX was administered in two daily doses of 30 mg/kg/bw, by intraperitoneal route. Normal controls either treated with PTX or saline were also included. Histopathology of the spleen and in situ immunolabeling of TNF-alpha, using anti-TNF-alpha monoclonal antibody, were performed. Necrotic areas were evaluated by morphometry. Mice treated with PTX showed a significant decrease of necrotic areas and diminution of TNF-alpha expression in spleen tissue, suggesting that PTX treatment could control TNF-alpha effects, and thus be used as an adjuvant in the treatment of acute Chagas' disease.     

Thymus involution induced by mouse hepatitis virus A59 in BALB/c mice.

Mouse hepatitis virus A59 (MHV-A59) infection of adult BALB/c mice induced a severe, transient atrophy of the thymus. The effect was maximal at 1 week after infection, and thymuses returned to normal size by 2 weeks after infection. There was no effect of glucocorticoids, since thymus atrophy was also found in adrenalectomized, infected mice. In infected thymus, immature CD4+ CD8+ lymphocytes were selectively depleted, and apoptosis of lymphocytes was increased. The MHV receptor glycoprotein MHVR was detected on thymus epithelial cells but not on T lymphocytes. In a small number of stromal epithelial cells, but in very few lymphocytes, the viral genome was detectable by in situ hybridization. These observations suggested that MHV-A59-induced thymic atrophy results not from a generalized lytic infection of T lymphocytes but rather from apoptosis of immature double-positive T cells that might be caused by infection of a small proportion of thymus epithelial cells or from inappropriate secretion of some factor, such as a cytokine.