Biomedical subjects

J D Mountz

Publications and source records attributed to J D Mountz.

At least 55 records · Page 3Linked to original sources

PubMed1998

Reduction of arthritis and pneumonitis in motheaten mice by soluble tumor necrosis factor receptor.

OBJECTIVE: To determine the effects of anti-tumor necrosis factor (anti-TNF) therapy in the inflammatory and autoimmune disease in motheaten (me/me) mice, which exhibit a Fas apoptosis signaling defect. METHODS: Arthritis, pneumonitis, and mortality were analyzed in me/me mice treated with a novel, soluble, dimeric TNF receptor I (sTNFRI) molecule capable of high-affinity binding and neutralization of TNFalpha. RESULTS: Soluble TNFRI reduced serum levels of TNFalpha and led to a 2-fold increase in the lifespan of me/me mice, compared with the control treatment group. The treatment also reduced the development of the "motheaten" skin patches and alleviated pneumonitis and inflammatory lesions in the extremities of me/me mice compared with controls. However, the serum levels of IgM and IgM anti-double-stranded DNA autoantibody were comparable to those of untreated control mice. CONCLUSION: TNFalpha is an important cytokine involved in the pathogenesis of inflammatory disease in me/me mice, resulting in tissue damage and early mortality. Therapies directed at blocking TNF/TNFR interactions, such as the sTNFRI used in these experiments, may be effective in diseases associated with apoptosis defects leading to overutilization of the TNF/TNFR pathway.

Alopecia↗

PubMed1998

Murine cytomegalovirus induces a Sjögren's syndrome-like disease in C57Bl/6-lpr/lpr mice.

OBJECTIVE: To analyze Fas and tumor necrosis factor receptor I (TNFRI) apoptosis pathways in salivary gland inflammatory disease induced by murine cytomegalovirus (MCMV) infection. METHODS: Four different strains of mice (C57BI/6 [B6]-+/+, Fas-deficient B6-lpr/lpr, TNFRI-deficient B6-tnfr1(0/0), and B6-tnfr1(0/0)-lpr/lpr mice) were infected intraperitoneally with the Smith strain of MCMV (1 x 10(5) plaque-forming units). Viral load was determined by a plaque assay, inflammation and apoptosis by immunohistochemistry and staining with terminal dUTP nickend labeling, and autoantibodies by enzyme-linked immunosorbent assay. RESULTS: Infectious MCMV was not detectable by day 100. Although all MCMV-infected mice developed acute sialadenitis by day 28, a chronic (>100 days), severe salivary gland inflammation and anti-Ro and anti-La antibodies developed only in the B6-lpr/lpr mice. Apoptotic cells were detected during the acute, but not the chronic, phase of inflammation. CONCLUSION: Both Fas- and TNFRI-mediated apoptosis contribute to the clearance of MCMV-infected cells in the salivary glands. However, because Fas-mediated apoptosis is necessary for the down-modulation of the immune response, a defect in this process can lead to a postinfection, chronic inflammatory response that resembles Sjögren's syndrome.

Animals↗

PubMed1998

Calmodulin antagonists inhibit apoptosis of CD4+ T-cells from patients with AIDS.

Recent studies indicate that Fas and Fas ligand are involved in apoptosis of T-cells in HIV-infected patients. We have demonstrated that calcium/calmodulin is involved in Fas-mediated apoptosis in human T-cell lines transfected with HIV recombinant cDNA. In the present study, we examined spontaneous apoptosis of T-cells in vitro in peripheral blood obtained from 11 patients with AIDS and 8 HIV-seronegative normal donors and the effect of the calmodulin antagonists, trifluoperazine (TFP) or tamoxifen (TMX), on apoptosis. The results show that: (1) levels of spontaneous apoptosis were higher in PBMCs obtained from patients with AIDS than HIV-negative normal controls and the levels of apoptosis correlated with the severity of disease. (2) The accelerated apoptosis occurred predominantly in CD4+ cells in patients with AIDS. (3) Calmodulin antagonists inhibited the spontaneous apoptosis of CD4+ T-cells from patients with AIDS, which resulted in an increase in the ratio of CD4+ to CD8+ T-cells. (4) The inhibitory effect of calmodulin antagonists on apoptosis was more significant in patients with advanced disease (CDC category C) compared to less severe disease (CDC category B). These results indicate that calmodulin antagonists inhibit HIV-associated apoptosis of CD4+ T-cells, and imply that the calcium/calmodulin play important roles in mediating apoptosis of CD4+ T-cells induced by HIV infection.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Induction of specific T-cell tolerance by adenovirus-transfected, Fas ligand-producing antigen presenting cells.

A major problem associated with adenovirus gene therapy is the T cell-mediated immune response, which is elicited by inoculation of the adenovirus vector and leads to rapid clearance of the virus and loss of transgene expression. In this study, the immune response to adenovirus was prevented by induction of specific T-cell tolerance by pretreatment with adenovirus-infected antigen-presenting cells (APC) that express Fas ligand. Compared with control-treated mice, the tolerized mice showed prolonged expression of lacZ upon administration of AdCMVlacZ 1 week after tolerance induction. In contrast to the control mice, the tolerized mice did not display proliferation of CD3+ T cells in the spleen in response to AdCMVlacZ. Tolerance induction also was indicated by the lower production of interferon-gamma and interleukin-2 by peripheral T cells isolated from AdCMVlacZ-challenged tolerized mice than by AdCMVlacZ-challenged control-treated mice. The T-cell tolerance was specific for the adenovirus as the T-cell responses to irrelative murine cytomegalovirus remained unimpaired. Our results indicate that adenovirus-specific T-cell tolerance can be induced by APCs that coexpress Fas ligand and adenovirus antigens. We propose that this new strategy can be used to induce tolerance to adenovirus vector gene therapy with resultant prolonged expression of the transgene.

Adenoviridae↗

PubMed1998

Imaging and tissue biodistribution of 99mTc-labeled adenovirus knob (serotype 5).

Hepatic sequestration of systemically administered adenoviral vectors reduces the number of viral particles available for delivery to other tissues. The biological basis of this phenomenon was investigated using a new in vivo technique which permitted imaging in real time. Recombinant adenovirus serotype 5 knob (Ad5K) was radiolabeled with the gamma-emitter 99mTc (half-life = 6 h). Scatchard analysis of the 99mTc-Ad5K showed specific, high-affinity binding to U293 cells (Kd = 1.4 +/- 0.5 nM), demonstrating that the radiolabeling process had no effect on receptor binding. In vivo dynamic imaging with an Anger gamma camera revealed that the liver binding followed an exponential rise to maximum, with a measured 100% extraction efficiency. Initially, the liver binding capacity was 3.1 +/- 0.4 micrograms Ad5K, equivalent to approximately 17,000 Ad5K molecules per liver cell. Liver binding was blocked by preincubation of Ad5K with neutralizing anti-Ad5K antibody; a 50% reduction in liver uptake was demonstrated by imaging. Unlabeled Ad5K was more effective in blocking liver uptake of 99mTc-Ad5K, whereas irrelevant unlabeled Ad3K had no effect. Imaging data for the liver uptake studies were in agreement with biodistribution determined by removing and measuring tissues. These data demonstrated that in vivo imaging is a sensitive tool for measuring changes to liver tropism. Similar imaging techniques can be applied to adenovirus vectors to measure specific targeting for gene therapy.

Adenoviridae↗

PubMed1998

Application of a Fas ligand encoding a recombinant adenovirus vector for prolongation of transgene expression.

An adenovirus vector encoding murine Fas ligand (mFasL) under an inducible control was derived. In vivo ectopic expression of mFasL in murine livers induced an inflammatory cellular infiltration. Furthermore, ectopic expression of mFasL by myocytes did not allow prolonged vector-mediated transgene expression. Thus, ectopic expression of functional mFasL in vector-transduced cells does not appear to confer, by itself, an immunoprivileged site sufficient to mitigate adenovirus vector immunogenicity.

Adenoviridae↗

PubMed1998

Familial painful restless legs syndrome correlates with pain dependent variation of blood flow to the caudate, thalamus, and anterior cingulate gyrus.

To understand the relationship of caudate, thalamic, and anterior cingulate perfusion to pain states, we investigated familial restless legs syndrome in a father and daughter during the state of pain induced by immobility using semiquantitative regional cerebral blood flow (rCBF) brain single photon emission computed tomography (SPECT). The father underwent 4 brain SPECT scans using the rCBF tracer 99mTc-HMPAO several weeks apart, at different pain levels and after treatment with L-dopa. Caudate, thalamic, and anterior cingulate rCBF indices were measured. The caudate nuclei showed a 13% reduction in rCBF with increasing pain. The thalami and anterior cingulate showed a 7 and 6.6% increase in rCBF, respectively, with increasing pain. Compared to normal controls at rest, there was a decrease in caudate rCBF by 13% and an increase in thalamic rCBF by 3%. Linear regression for the caudate nuclei revealed a significant reduction in rCBF (p < 0.05), as pain increased. The daughter underwent an identical rCBF brain SPECT scan procedure at a high pain level induced by immobilization. Her scan showed a 12% reduction in caudate rCBF and a 1.2% increase in the anterior cingulate rCBF compared to healthy controls. The study supports the association between pain and decreased regional cerebral blood flow to the caudate nucleus as reported in fibromyalgia syndrome. There is increase in anterior cingulate rCBF with increasing pain. Our findings also corroborate that there is increased thalamic rCBF with pain stimulation.

Adult↗

PubMed1997

Increased lymphocyte apoptosis in Fas ligand transgenic mice.

Fas ligand (fasL) transgenic (Tg) mice were produced by introducing a murine fasL cDNA under the control of a TCR beta-chain enhancer minigene. Higher levels of fasL expression with increased biologic activity were observed in the Tg mice compared with non-Tg mice. Numbers of CD4+ CD8+ T cells in the thymus and T cells in the lymph node and spleen were lower in the fasL Tg mice compared with the non-Tg mice. This is consistent with a reduction in the size of the T cell areas in fasL Tg mice compared with non-Tg mice. Conversely, in fasL Tg mice, there was an increase in the number and size of apoptotic foci associated with phagocytic cells, as determined by in vivo TUNEL (TdT-mediated dUTP nick-end labeling) staining. Stimulation of non-Tg mice in vivo with anti-CD3 Ab for 3 days resulted in greatly increased apoptosis of CD4+ CD8+ thymocytes and lymph node T cells. Surviving thymocytes and T cells of lymph node and spleen expressed Fas at low levels. After similar stimulation of fasL Tg mice, however, a discreet population of surviving cells expressed high levels of Fas, indicating that a novel population of Fas apoptosis-resistant cells develops in these mice. These results indicate that high levels of fasL can result in both increased Fas-mediated apoptosis and the development of T cells that express high levels of Fas, but are resistant to Fas-mediated apoptosis.

Animals↗

PubMed1997

Increased acute-phase response and renal amyloidosis in aged CD2-fas-transgenic mice.

We previously demonstrated that increased Fas expression in T cells of aged CD2-fas transgenic (Fas-Tg) CD-1 mice results in an increased immune response and T cell apoptosis. Surprisingly, despite prevention of T cell immune senescence, the average life span of Fas-Tg mice is comparable with that of nontransgenic (non-Tg) mice. Histopathologic evaluation of tissue sections showed that nearly 50% of the aged (>18-mo-old) Fas-Tg mice developed renal amyloid A amyloidosis, whereas no amyloid deposition was observed in aged non-Tg mice. The amyloid A deposition was observed primarily in glomeruli by using immunohistochemical stains and electron microscopy. The full-length amino acid coding sequence of serum amyloid A2 cDNA in CD-1 mice was identical to that of amyloid A amyloidosis-susceptible BALB/c mice. Although there was no significant difference in steady-state serum amyloid A level in the serum of aged non-Tg and Fas-Tg mice, challenging mice with staphylococcal enterotoxin B resulted in significantly higher serum levels of serum amyloid A on day 2 and IL-6 on days 1 and 2 and a higher magnitude of weight loss on day 7 in aged Fas-Tg mice compared with young mice. These parameters, at the indicated time points, were equivalent between young and aged non-Tg mice. Taken together, our data suggest that prevention of T cell senescence in Fas-Tg mice may be a factor in induction of an excessive acute-phase response triggered by T cell activation. The Fas-Tg mice are a novel model for understanding the immunologic mechanisms leading to secondary amyloidosis.

Acute-Phase Reaction↗

PubMed1997

Increased apoptosis of CD45RO- T cells with aging.

Increasing susceptibility to infectious and autoimmune phenomena have long been recognized to accompany advancing age in otherwise healthy individuals. Recently animal models of aging have suggested that age-associated immune dysfunction may correlate with defects in T cell apoptosis. We have examined activation-induced apoptosis defects in human peripheral T cells from young individuals (mean age = 31 +/- 3 years old) compared to aged individuals (mean age = 67 +/- 8 years old). Following in vitro activation of T cells with PHA and IL-2, apoptosis was measured in T cell subsets using 7-amino actinomycin D (7-AAD) staining and analysis via three colour flow cytometry. There was no significant difference in apoptosis of the total CD3+ T cell population at early and late time points. Interestingly, increased apoptosis in the CD3+ CD45RO- T cell population of older adults was observed by culture day 6. While the total number of CD3+ CD45RO- cells was not different between young (< 33 years) and old (> 65 years) individuals, 32% of these cells did not undergo apoptosis in younger individuals while only 10% of these cells avoided this fate in older individuals. These results suggest that accumulation of CD45RO+ T cells may occur in aged subjects due in part to preferential elimination of CD45RO- cells with activation. Furthermore, as new or continued immune response requires differentiation of CD45RO+ T cells to CD45RO+ T cells after activation, increased apoptosis instead of survival in aged individuals could lead to observed T cell immune deficiency.

Adult↗

PubMed1997

Kinetics of Fas-induced apoptosis in thymic organ culture.

Although most thymocytes express high levels of Fas antigen (CD95), the role of Fas in apoptosis signaling during thymocyte maturation has not been defined. Fas apoptosis occurs primarily in the CD4+CD8+ subpopulations of thymocytes. Fas expression and apoptosis function were investigated in the CD4-8-, CD4+8+, and CD4+ and CD8 single positive thymocyte subpopulations by in vivo injection of anti-Fas and in vitro incubation of Fas with thymic organ cultures. Fas was first expressed on CD4-8- thymocytes coincident with expression of IL-2R and CD44. In Fas mutant lpr/lpr mice, defective Fas expression correlated with overproduction of late-stage CD4-8(-)-thymocytes. Fas was highly expressed on CD3dull and CD3bright thymocytes. CD4+8+CD3dull thymocytes were sensitive to Fas apoptosis, whereas more mature CD4+8+CD3bright thymocytes were resistant to Fas apoptosis. Anti-Fas incubation with established thymic organ culture for 24 hr resulted in apoptosis of approximately 25% of thymocytes. Continued incubation of thymic organ culture with anti-Fas resulted in an apoptosis rate of 25% of CD4+CD8+ thymocytes per day for the first 3 days of culture. Continued culture for further time points up to 6 days did not result in further apoptosis of the CD4+CD8+ thymocytes. These results suggest that CD4-CD8-CD44+ IL-2R+ thymocytes express Fas and there is overpopulation of the subsequent developmental stage of thymocytes in Fas mutant lpr mice. Also, early-stage CD4+8+ thymocytes are susceptible to Fas apoptosis, whereas Fas apoptosis resistance is required after 3 days of thymic organ culture. We conclude that these two populations of thymocytes are susceptible to Fas ligand-mediated apoptosis during T cell development in the thymus.

Animals↗

PubMed1997

Lymphoid cell accumulation in salivary glands of autoimmune MRL mice can be due to impaired apoptosis.

MRL-lpr mice and the congenic strain MRL +/+ exhibit pathological abnormalities in the salivary glands similar to Sjögren's syndrome in humans. The lpr genotype has been identified as a mutation in the gene encoding Fas which is a cell surface protein that mediates apoptosis. The mutation is leaky, allowing for low levels of the APO-1/Fas (CD95) receptor and partial activity of Fas/Fas ligand-mediated programmed cell death in this strain. To examine the expression of Fas in situ, the authors analysed thymus, lymph node and salivary gland tissue from BALB/c, MRL +/+ and MRL-lpr mice by an immunohistochemical technique (ABC-immunoperoxidase) using an anti-Fas (Jo2) antibody. For detection of apoptotic cells the authors used the terminal deoxynucleotidyl-transferase-mediated dUTP-digoxigenin nick end labelling (TUNEL) method. Thymus from MRL +/+ and normal BALB/c mice showed a higher frequency of Fas expression than was seen in the lpr mice, but the +/+ mice had similar expression of Fas in lymph nodes as lpr mice. The Fas protein was detected among infiltrating mononuclear cells in the salivary glands of both lpr and +/+ mice. Apoptotic cells were found in the thymus with similar frequency in all three strains, while in the lymph nodes only BALB/c mice showed apoptosis. There was no, or very low, frequency of apoptosis among infiltrating mononuclear cells in salivary glands of both MRL strains. In conclusion, despite mutation of the Fas gene in the MRL-lpr strain, there was nevertheless an expression of the apoptosis-related Fas protein in lymphoid tissue and salivary glands of these mice. Based on analysis of apoptotic activity, the impaired Fas in autoimmune MRL mice seems to affect primarily the peripheral organs.

Animals↗

PubMed1997

Cell death and longevity: implications of Fas-mediated apoptosis in T-cell senescence.

Two prominent features of immune senescence are altered T-cell phenotype and reduced T-cell response. We have previously shown that T-cell senescence is greatly reduced in CD2-fas transgenic mice, in which the Fas apoptosis molecule is constantly expressed on T cells. Using a different experimental approach, the relationship between T-cell senescence and apoptosis was analyzed on human peripheral blood mononuclear cells. The results indicate that there was increased apoptosis of CD45RO- (CD45RA+) T cells upon activation. We propose that this could account for the increase in CD45RO+ "memory" T cells with aging in humans. T-cell responsiveness remained high in CD2-fas transgenic aged mice, but there was no increase in overall life span of these mice. Increased T-cell responsiveness was associated with an increased acute-phase response and serum amyloid A deposition in the glomerulus of aged CD2-fas transgenic mice. Therefore, restoration of the T-cell immune function using a CD2-fas transgene produced undesirable side-effects to aged transgenic mice. In addition to its role in activation-induced cell death, Fas-mediated apoptosis may be important in deleting T cells in response to DNA damage. It may also inhibit cell-cycle progression by cleaving various kinases and DNA repair enzymes. We observed that cell lines derived from human premature aging diseases have a higher sensitivity to Fas-mediated apoptosis. The implications of these observations are discussed.

Acute-Phase Reaction↗

PubMed1996

Intracellular IL-1beta is an inhibitor of Fas-mediated apoptosis.

Fas-mediated apoptosis has been shown to be mediated by the IL-1beta converting enzyme (ICE) pathway. To determine the relationship between ICE and its substrate IL-1beta, we examined six human cell lines for susceptibility to Fas-mediated apoptosis and Fas induction of ICE-like activity. The human B lymphoblastoid cell line SKW6.4 and the human T lymphoma cell lines Jurkat, CEM-6, H-9, and MOLT4 were susceptible to Fas-mediated apoptosis, whereas the human promyelocytic leukemia cell line HL-60 was resistant to Fas-mediated apoptosis. ICE mRNA was highly expressed in SKW6.4, H-9, and HL-60 cells, and ICE-like activity increased during Fas-mediated apoptosis in SKW6.4 cells. In contrast, IL-1beta mRNA was highly expressed only in HL-60 cells. Acetyl-Tyr-Val-Ala-Asp-chloromethylketone, a tetrapeptidyl inhibitor of ICE, prevented Fas-mediated apoptosis strongly in SKW6.4 and H-9 cells but weakly or marginally in other cells. To examine whether intracellular IL-1beta is a proteolytic substrate or an endogenous competitive inhibitor against other substrates for Fas-ICE-mediated apoptosis in SKW6.4 cells, we established precursor IL-1beta transfectant clones using SKW6.4 cells. We demonstrated that stably transfected SKW6.4 cells expressing precursor IL-1beta, but not cells transfected with the empty vector, exhibited resistance to Fas-mediated apoptosis due to competitive inhibition of ICE-like activity, which was associated with increased cleavage of precursor IL-1beta to mature IL-1beta. These results suggest that Fas-mediated apoptosis is mediated by ICE cleavage of proteolytic substrates other than IL-1beta and that IL-1beta is an endogenous inhibitor of Fas-mediated apoptosis.

Amino Acid Chloromethyl Ketones↗

PubMed1996

Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease.

The pathogenesis of systemic lupus erythematosus (SLE) is multifactorial and multigenetic. The apoptosis genes, fas and fas ligand (fasL), are candidate contributory genes in human SLE, as mutations of these genes result in autoimmunity in several murine models of this disease. In humans, fas mutations result in a familial autoimmune lymphoproliferative syndrome, but defects in FasL have not yet been identified. In this study, DNA from 75 patients with SLE was screened by single-stranded conformational polymorphism analysis for potential mutations of the extracellular domain of FasL. A heterozygous single-stranded conformational polymorphism for FasL, was identified in one SLE patient, who exhibited lymphadenopathy. Molecular cloning and sequencing indicated that the genomic DNA of this patient contained an 84-bp deletion within exon 4 of the fasL gene, resulting in a predicted 28 amino acid in-frame deletion. Analysis of PBMC from this patient revealed decreased FasL activity, decreased activation-induced cell death, and increased T cell proliferation after activation. This is the first report of defective FasL-mediated apoptosis related to a mutation of the human Fasl, gene in a patient with SLE and suggests that fasL mutations are an uncommon cause of the disease.

Amino Acid Sequence↗

PubMed1996

Inhibition of superantigen-induced proinflammatory cytokine production and inflammatory arthritis in MRL-lpr/lpr mice by a transcriptional inhibitor of TNF-alpha.

We have used fas-defective MRL-lpr/lpr mice to study the effects of the staphylococcal enterotoxin superantigens on the development of autoimmune, inflammatory joint disease in animals that are susceptible to the development of rheumatoid arthritis-like disease. We show that systematic administration by a single i.p. injection of staphylococcal enterotoxin B (SEB; 10 micrograms/mouse) caused a mild, inflammatory arthritis +30 days postchallenge in the knee joints of young (< 2-mo-old) MRL-lpr/lpr mice, but not aged-matched MRL +/+ mice. In aged (> 8-mo-old) MRL-lpr/lpr mice, but not in aged MRL +/+ mice, SEB caused a severe, inflammatory arthritis, as assessed histologically, and systemic autoimmune disease, including glomerulonephritis and autoantibody production. Furthermore, in aged MRL-lpr/lpr mice, SEB but not heat-denatured SEB caused acute weight loss and elevated levels of serum proinflammatory cytokines. Compared with highly purified peritoneal macrophages obtained from either aged MRL +/+, young MRL-lpr/lpr, or young MRL +/+, peritoneal macrophages obtained from aged MRL-lpr/lpr mice constitutively expressed 2- to 10-fold greater levels of TNF-alpha, IL-1 beta, IL-6, and IL-10, and produced elevated amounts of these cytokines when treated in vitro with SEB. SEB-challenged aged MRL-lpr/lpr mice treated with anti-TNF mAb (100 micrograms/mouse; every other day), anti-V beta 8 TCR mAb (250 micrograms/mouse; every other day), or orally with the novel TNF-alpha inhibitor MDL 201,449A (9-[(1R, 3R)-trans-cyclopentan-3-ol] adenine; 25 mg/kg/day) exhibited reduced inflammatory arthritis, autoantibody formation, and serum TNF-alpha levels, but not IL-10 levels, after +30 days of treatment. These data suggest that SEB is an extremely potent macrophage-activating factor in vitro and in vivo, enhancing several aspects of autoimmune disease in MRL-lpr/lpr mice, and that anti-TNF therapies may have potential use in inflammatory arthritis.

Aging↗

PubMed1996

Hematopoietic cell protein-tyrosine phosphatase-deficient motheaten mice exhibit T cell apoptosis defect.

We previously demonstrated that hematopoietic cell protein-tyrosine phosphatase is one of the molecules that can transduce Fas-mediated apoptosis signals in lymphoid cells. The present study analyzed the effect of defective Fas signaling on the T cell phenotype and apoptosis function in hematopoietic cell protein-tyrosine phosphatase-deficient motheaten mice. Viable motheaten (me(v)/me(v)) mice exhibited increased T cell proliferation and defective activation-induced apoptosis of Fas+ T cells in the lymph node, which was not ascribed to defective Fas ligand function. Furthermore, the Fas-mediated apoptosis defect in activated T cells from me(v)/me(v) mice was confirmed by their resistance to anti-Fas-induced apoptosis. No protein tyrosine dephosphorylation signal was delivered after anti-Fas cross-linking in the lymph node cells of me(v)/me(v) mice as revealed by 32Pi labeling of protein phosphatase substrates. The defective activation-induced apoptosis of Fas+ T cells in me(v)/me(v) mice led to lymphadenopathy with an accumulation of CD4- CD8- B220+ CD3+ T cells. Pneumonitis in me(v)/me(v) mice was associated with infiltration of cycling T cells detected by bromodeoxyuridine uptake in vivo. Thus, T cells from me(v)/me(v) mice are resistant to Fas-mediated apoptosis which results in lymphoproliferative disease and tissue infiltration.

Animals↗

PubMed1996

Greatly accelerated lymphadenopathy and autoimmune disease in lpr mice lacking tumor necrosis factor receptor I.

Fas and TNF receptor I (TNF-RI) share homology at their cytoplasmic death domain and belong to the same gene family, but utilize different pathways to signal activation-induced cell death. To determine the combined effects of defective TNF-RI and Fas signaling on lymphadenopathy and autoimmune disease, we backcrossed TNF-RI knockout mice (Tnfr1(0/0)) with Fas-deficient C57BL/6-lpr/lpr mice. Tnfr1(0/0)lpr/lpr mice developed greatly accelerated lymphadenopathy and autoantibody production compared with C57BL/6-lpr/ lpr mice. Tnfr1(0/0)-lpr/lpr mice also exhibited high mortality and early onset autoimmune disease characterized by massive mononuclear cell infiltration in liver, kidney, lung, and knee joints. These results indicate that the Fas-mediated apoptosis defect in lpr mice is accelerated in the absence of TNF-RI and that normal expression of TNF-RI might partially compensate for the Fas-mediated apoptosis defect of mononuclear cells in lpr mice.

Animals↗