Rescue of anaemia and autoimmune responses in SOD1-deficient mice by transgenic expression of human SOD1 in erythrocytes

Abstract

Oxidative stress has been implicated as a cause of various diseases such as anaemia. We found that the SOD1 [Cu,Zn-SOD (superoxide dismutase)] gene deficiency causes anaemia, the production of autoantibodies against RBCs (red blood cells) and renal damage. In the present study, to further understand the role of oxidative stress in the autoimmune response triggered by SOD1 deficiency, we generated mice that had the hSOD1 (human SOD1) transgene under regulation of the GATA-1 promoter, and bred the transgene onto the SOD1(-/-) background (SOD1(-/-);hSOD1(tg/+)). The lifespan of RBCs, levels of intracellular reactive oxygen species, and RBC content in SOD1(-/-);hSOD1(tg/+) mice, were approximately equivalent to those of SOD1(+/+) mice. The production of antibodies against lipid peroxidation products, 4-hydroxy-2-nonenal and acrolein, as well as autoantibodies against RBCs and carbonic anhydrase II were elevated in the SOD1(-/-) mice, but were suppressed in the SOD1(-/-);hSOD1(tg/+) mice. Renal function, as judged by blood urea nitrogen, was improved in the transgenic mice. These results rule out the involvement of a defective immune system in the autoimmune response of SOD1-deficient mice, because SOD1(-/-);hSOD1(tg/+) mice carry the hSOD1 protein only in RBCs. Metabolomic analysis indicated a shift in glucose metabolism to the pentose phosphate pathway and a decrease in the energy charge potential of RBCs in SOD1-deficient mice. We conclude that the increase in reactive oxygen species due to SOD1 deficiency accelerates RBC destruction by affecting carbon metabolism and increasing oxidative modification of lipids and proteins. The resulting oxidation products are antigenic and, consequently, trigger autoantibody production, leading to autoimmune responses.

Identification of a Lipid Peroxidation Product as the Source of Oxidation-specific Epitopes Recognized by Anti-DNA Autoantibodies*

“…S3). These data were consistent with our previous observations that the SOD1 deficiency causes anemia and autoimmune responses against red blood cells and that the transgenic expression of human SOD1 in erythroid cells rescues them (20). Moreover, we evaluated the presence of the anti-ONE antibodies in SLE patients and observed pronounced increases in them (supplemental Fig.…”

SOD1 deficiency induces the systemic hyperoxidation of peroxiredoxin in the mouse

“…A genotypic analysis of the mice was performed using PCR with specific primers, as previously described [1]. Transgenic mice expressing human SOD1 under the GATA1 promoter have been described previously [24]. The mice were backcrossed to C57BL/6 mice more than eight times before being used in this study.…”

SOD1 deficiency decreases proteasomal function, leading to the accumulation of ubiquitinated proteins in erythrocytes

“…RBCs then leads to an aberrant immune response to RBCs, which results in 45 autoimmune hemolytic anemia (AIHA) [8]. The hypothetical role of oxidative stress in 46 the onset of AIHA are supported by findings that ROS levels are elevated in RBCs from 47 AIHA-prone NZB mice and coincide with AIHA onset [9].…”