Autoimmunity, Apoptosis Defects and Retroviruses View Full Text


Ontology type: schema:Chapter     


Chapter Info

DATE

1995

AUTHORS

J. D. Mountz , J. Cheng , X. Su , J. Wu , T. Zhou

ABSTRACT

Autoimmune disease in both mice and humans is associated with increased expression of endogenous retroviruses in the thymus and T cells, and loss of self-tolerance by T cells. The basic genetic defect underlying autoimmune disease has been identified as a mutation of the Fas apoptosis antigen in MRL-lpr/lpr mice or a mutation of the Fas ligand in C3H-gld/gld mice. In MRL-lpr/lpr mice, the lpr mutation results from a 5.3 kb insertion of the ETn retrotransposon in the second intron of the Fas gene. In contrast to normal mice, which express a 2.2 kb normal size Fas cDNA, MRL-lpr/lpr mice express multiple Fas RNA transcripts ranging from 2-10.5 kb. In addition, a 5.7 kb full-length ETn transcript is highly expressed in the thymus of younger MRL-lpr/lpr mice. To determine if high ETn expression was dependent on abnormal Fas expression, CD2-fas transgenic mice were produced using the full-length murine Fas cDNA under the regulation of the CD2 promoter and enhancer. This resulted in normalization of Fas expression and also elimination of expression of the ETn retrotransposon. The ETn regulatory sequence contains potential DNA binding sites found in the enhancers of many genes activated during early T cell development in the thymus including enhancer regions for the TCR, CD3 and IL-2 genes. Therefore we propose that ETn expression is increased during early T cell development in the thymus, or after T cell activation, and that the integration of ETn in the Fas apoptosis gene leads to abnormal T cell apoptosis or development.Human autoimmune disease has also been found to result from production of a soluble inhibitor of apoptosis. The full-length cDNA and genomic clones for human Fas were cloned and sequenced. Patients with SLE produced high levels of an alternatively spliced soluble Fas (sFas) RNA lacking the transmembrane (exon 6) resulting in high circulating levels of the Fas molecule. This human sFas molecule was able to inhibit apoptosis in vitro at levels found in serum of SLE patients (200 ng/ml). The same levels of mouse sFas were able to inhibit apoptosis in vivo in mice resulting in a 3-fold increase in spleen size, and altered thymocyte maturation consisting of increased production of CD4-CD8- T cells and decreased CD4+CD8+ T cells. Regulation of Fas signaling in human T cells also plays a role in abnormal apoptosis. Fas signaling is mediated by the hematopoietic stem cell phosphatase, (Hcph) and is inhibited in the Hcph deficient Molt-4 T cell, the phosphatase deficient motheaten (me/me) mice and by the tyrosine phosphatase inhibitor pervanadate. Multiple pathways of Fas apoptosis were also shown to exist, as Fas induced apoptosis is increased in the liver of me/me mice, and signaling likely also involves an sphingomylinaseceramide activated kinase pathway as utilized by the TNF-R.Fas ligand has been recently cloned in mice and humans, and is homologous to TNF-a. The Fas ligand defect in autoimmune C3H-gld/gld mice is due to a point mutation resulting in a single amino acid change in the hydrophobic region of the Fas ligand trimer. These results indicate that T cell apoptosis can be dramatically increased or decreased by cellular interactions which in turn regulate either the levels of production or signaling activity of the Fas and Fas ligand. Retroviruses and their products can influence apoptosis by altering expression of Fas or Fas-L, or altering apoptotic signaling after Fas/Fas-L interactions. Further insights into the regulation of apoptosis molecules will be important in normalizing this activity when it is decreased as in the case of autoimmune disease, or when it is in excess, as is the case with HIV disease. More... »

PAGES

183-201

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/978-1-4615-1995-9_16

DOI

http://dx.doi.org/10.1007/978-1-4615-1995-9_16

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1008068393

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/7572392


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82 cases
83 cell activation
84 cell apoptosis
85 cell development
86 cell phosphatase
87 cells
88 cellular interactions
89 changes
90 clones
91 contrast
92 defect underlying autoimmune disease
93 defects
94 deficient Molt-4 T cell
95 development
96 disease
97 elimination
98 elimination of expression
99 endogenous retroviruses
100 enhancer
101 enhancer region
102 excess
103 expression
104 expression of Fas
105 fa/fa
106 full-length ETn transcript
107 full-length cDNA
108 full-length murine Fas cDNA
109 further insight
110 genes
111 genetic defect underlying autoimmune disease
112 genomic clones
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115 high ETn expression
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117 human Fas
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119 human sFas molecule
120 humans
121 hydrophobic region
122 increase
123 induced apoptosis
124 inhibitor pervanadate
125 inhibitors
126 insertion
127 insights
128 integration
129 integration of ETn
130 interaction
131 introns
132 kb
133 kb full-length ETn transcript
134 kb insertion
135 kb normal size Fas cDNA
136 kinase pathway
137 level of production
138 levels
139 ligand defect
140 ligand trimer
141 ligands
142 liver
143 loss
144 lpr mice
145 lpr mutation
146 maturation
147 mice
148 molecules
149 motheaten mice
150 mouse sFas
151 multiple Fas RNA transcripts
152 multiple pathways
153 murine Fas cDNA
154 mutations
155 normal mice
156 normal size Fas cDNA
157 normalization
158 pathway
159 patients
160 pervanadate
161 phosphatase
162 phosphatase inhibitor pervanadate
163 point mutations
164 potential DNA
165 production
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167 promoter
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169 regulation
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171 regulatory sequences
172 results
173 retrotransposons
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178 sequence
179 serum
180 signaling
181 single amino acid change
182 sites
183 size
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185 soluble Fas (sFas) RNA
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187 sphingomylinaseceramide
188 spleen size
189 stem cell phosphatase
190 thymocyte maturation
191 thymus
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195 trimer
196 turn
197 tyrosine phosphatase inhibitor pervanadate
198 underlying autoimmune disease
199 vivo
200 young MRL-lpr/lpr mice
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