Arthritis, Rheumatic Diseases, Autoimmune Diseases, Systemic Lupus Erythematosus, Transaldolase Deficiency
Rheumatology, Immunology, Physician-Scientist Training
Genes and Viruses Predisposing to Autoimmunity, Genetics, Apoptosis, Endogenous Retroviruses, Transaldolase
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Andras Perl – Summary of Research
Overview of Contribution to Science. My research has been focused on the contribution of genetic and environmental factors in shaping immune response with a focus on autoimmunity. In search of potential genetic interactions between the host and the environment, we identified HRES-1, a human T-cell leukemia virus-related endogenous retrovirus (1), mapped it to chromosome 1q42 (2) and identified Rab4a as its gene product that confers modulates susceptibility HIV infection via increased recycling of surface receptors, such as CD4 and transferrin receptor (CD71) (3). Polymorphic haplotypes of the HRES-1 endogenous retrovirus are associated with development and disease manifestations of in patients with SLE (4). The overexpression of Rab4A gene product of HRES-1, which is detectable in T cells of SLE patients and in all lupus-prone strains prior to disease onset, also contributes to oxidative stress and mTOR activation by inhibiting mitochondrial turnover via autophagy, also called mitophagy (5). This newly uncovered pathway to lupus pathogenesis can also be exploited for therapeutic intervention through blocking the enzymatic activity of the Rab GTPases, such as Rab4A using 3-PEHPC (5). The above discoveries have been published in 170 original peer-reviewed papers, authored chapters in rheumatology and immunology textbooks. Our work has been widely cited, credited, inspired a recent explosion of research on the role of metabolic pathways in the pathogenesis of lupus (6-9) and other rheumatic diseases (10,11).
My laboratory has opened up the field of metabolic control of T-cell activation and lineage specification which underlie disease development both in murine models and patients with SLE (12,13). We have originally identified and cloned transaldolase, an enzyme of the pentose phosphate pathway (14), as a regulator of glutathione (GSH) metabolism (15,16) and a newly described metabolic checkpoint of T-cell activation and death signal processing: elevation of the mitochondrial transmembrane potential or, as newly termed, mitochondrial hyperpolarization (MHP) (17). As we also uncovered, persistent MHP is a critical metabolic defect in lupus T cells, which characterizes mitochondrial dysfunction and ATP depletion and predisposes to cell death by necrosis (18). The increased production of necrotic materials from T cells is an important activator of B cells and dendritic cells and leads to inflammation in SLE (19). As we have also unveiled, the depletion of intracellular glutathione (GSH) underlies mitochondrial dysfunction and MHP in lupus T cells (18). To translate these new laboratory findings into clinical practice, we directly targeted the metabolic checkpoint of GSH depletion with N-acetylcysteine (NAC), an amino acid precursor of GSH, within the context of an FDA-approved double-blind placebo-controlled interventional trial (20). Relative to placebo, orally administered NAC reversed GSH depletion and showed remarkable safety, and it reduced disease activity in SLE patients (20,21). The clinical efficacy of NAC was mediated via blockade of complex 1 of the mechanistic target of rapamycin (mTOR), which serves as a sensor of MHP and effector of pro-inflammatory T cell lineage specification in SLE. As recently reviewed (13,22), the significance of mTOR activation is relevant for autoimmune diseases beyond SLE, it effects inflammation and overall lifespan. Based on our discovery of mTOR activation in SLE (23), we have also evaluated the clinical efficacy of rapamycin and found it to be a remarkably effective therapeutic intervention in SLE patients with resistance or intolerance to immunosuppressive medications, which has been repeatedly documented (22,24). Our findings on clinical efficacy of rapamycin have been corroborated by several recent publication, as recently reviewed (25).
Our parallel studies in mouse models led to the discovery of transaldolase (TAL) deficiency, as cause of inflammatory liver disease, which begins with steatohepatitis and progresses to hepatocellular carcinoma (HCC) (26). TAL deficiency has been documented as a cause of liver cirrhosis and cancer in patients as well, as recently reviewed (27). Interestingly, TAL is overexpressed in T cells of SLE patients, which may be related to protection against oxidative stress (23). The involvement of TAL in lupus pathogenesis is further supported by its increased expression in livers and spleen of MRL/lpr mice (28). Therefore, we examined whether oxidative stress, which emanates from the liver, can activate mTORC1 and thus predispose to aPL. Mitochondria from liver of mice lacking TAL (TAL-/-) exhibited increased electron transport chain (ETC) activity and activation of mTORC1. In accordance with an underlying role for oxidative stress and mTORC1 activation in the liver, the production of antiphospholipid antibodies (aPL) is increased in TAL-/- mice relative to TAL+/+ controls matched for age and gender. Importantly, rapamycin treatment abrogated the production of both anti-cardiolipin antibodies (ACLA) and anti-β2 glycoprotein I autoantibodies (anti-β2GPI) in TAL-/- mice. Likewise, aPL production was also blocked by rapamycin in lupus-prone mice (28).The remarkable efficacy of rapamycin in abrogating aPL production has immense relevance for treatment of patients with APS who currently require life-long anticoagulation (29).
Importantly, mild liver disease, defined as ≥2-fold elevation of aspartate aminotransferase or alanine aminotransferase, is associated with the production of aPL in our SLE cohort (30) as well as in previous meta-analyses (31,32). Along these lines, HCC develops in the liver following chronic inflammation, which is driven by mitochondrial oxidative stress (26,27) and responds to treatment with rapamycin (33). The growing evidence that mTORC1 blockade by rapamycin extends life expectancy (34) argues for the overall safety and benefit of this intervention. Given that aPL may precede clinical disease in patients with SLE (35,36), the underlying role of liver disease and preventative treatment via blockade of mTORC1 clearly open additional new avenues of research and patient care.
Of note, TAL is a rate-limiting enzyme of the pentose phosphate pathway (27). Deficiency of another PPP enzyme, glucose 6-phosphate dehydrogenase (G6PD), represents the most common genetic defect in humans, which affects 400 million people globally (37). Deficiency of G6PD elicits the depletion of NADPH in red cells and predisposes to oxidative stress-induced hemolytic anemia (37). The high prevalence of G6PD deficiency is attributed to its protective effects against malaria (38). In contrast to G6PD, TAL is not expressed in red cells, which lack mitochondria (39), and TAL deficiency does not cause hemolytic anemia in men or mice. However, the protozoan replicates in the liver, causes hepatitis(40,41) and induces aPL production (42). Therefore, the potential roles of TAL and the PPP as protectors from malaria would be important to determine.
As described in the above overview, my research has been dedicated to 1) uncovering the molecular basis of immune health, autoimmunity, and lupus pathogenesis and 2) identifying metabolic checkpoints of regulatory impact which can be validated in mechanistic clinical trials. To present specific discoveries and ongoing efforts, I have grouped them into four focused categories:
1. Discovery of the HRES-1 human endogenous retrovirus and the impact of its HRES-1/Rab4 gene product on T-cell activation and lupus pathogenesis
We have identified the HRES-1, the first human endogenous retrovirus (1) which is expressed on the RNA (1) and protein levels (43), exhibits polymorphic alleles conferring susceptibility to human lupus (44). HRES-1 is centrally located within the 1q42 locus associated with lupus susceptibility in 4 independent genome-wide screens of lupus families. Polymorphic haplotypes of HRES-1 are associated with the development of glomerulonephritis in SLE (4). The impact of HRES-1 on altered T cell signaling in SLE is mediated through the HRES-1/Rab4 protein that regulates surface expression of CD4 via endocytic recycling (3). HRES-1/Rab4 regulates assembly and recycling of key components of the T-cell synapse, including T-cell receptor/CD3ζ, and corresponds to the lupus susceptibility gene at 1q42 (23).HRES-1/Rab4A (recently designated by NCBI as Rab4A: http://www.ncbi.nlm.nih.gov/gene/5867) is markedly overexpressed in lupus T cells: 3.7-fold in CD4 T cells of SLE patients (23) as well as 3.6-fold in NZB/WF1 mice and 4.7-fold in MRL/lpr mice at 4 weeks of age, before the appearance of ANA or any sign of disease (5). As a member of the Ras-like Rab small GTPase family, HRES-1/Rab4regulates endosome recycling. In particular it targets the surface proteins CD4 (3), CD71 (transferrin receptor) (3), CD2AP, and CD3ζ (23) and the intracellular protein dynamin-related protein 1 (Drp1) for lysosomal degradation (5). Drp1 plays an essential role in triggering mitochondrial fission and mitochondrial autophagy (mitophagy) (45). Therefore, the HRES-1/Rab4-mediated depletion of Drp1 causes the accumulation of mitochondria, which generate oxidative stress, both in patients and mice with SLE (5). Of note, treatment with Rab GTPase inhibitor 3-PEHPC, which inactivates Rab4A in vitro, reverses the accumulation of mitochondria, blocks ANA production and nephritis in MRL/lpr mice in vivo (5). HRES-1/Rab4 increases the very formation of autophagosomes (46). It is proposed that HRES-1/Rab4-mediated blockade of autophagy prevents the restoration of T-cell activation-induced metabolic changes in lupus T cells (47). Activation of endogenous retroviral elements, such as HRES-1 and LINE elements, contribute to the pathogenic interferon response in SLE (48). Such activation involves the accumulation of oxidative stress-generating mitochondria (5), oligomerization of the mitochondrial antiviral signaling protein (9), or sensing of retroviral RNA (48). Thus, pharmacological inactivation of Rab4A may represent a novel, mechanistic target for treatment of SLE.
2. Discovery of mitochondrial and metabolic dysfunction and the activation of the mammalian target of rapamycin (mTOR) in SLE
We have identified (first) mitochondrial hyperpolarization (MHP) as a novel checkpoint of T cell activation and death (17) and persistent mitochondrial hyperpolarization and increased mitochondrial biogenesis in lupus T cells which are associated with ATP depletion and predisposition to cell death by necrosis (18). The release of necrotic materials is pro-inflammatory in SLE through potent activation of B cells and dendritic cells (19). We discovered (first) that T-cell activation-induced MHP is caused by nitric oxide (NO) which is synthesized by NO synthase isoforms eNOS and nNOS in human T cells (49). Persistent MHP and increased mitochondrial biogenesis are caused by glutathione depletion (18) and enhanced NO production and underlie abnormal T cell activation in SLE (50). Since the mammalian target of rapamycin (mTOR) is a sensor of the Δψm in the outer mitochondrial membrane of T cells, we begun to use rapamcyin for treatment of SLE patients resistant or intolerant to conventional immunosuppressants (24). Rapamycin effectively controls disease activity in SLE normalizing CD3/CD28-induced calcium fluxing without influencing MHP in lupus T cells (24). This suggested that altered calcium fluxing is downstream or independent of mitochondrial dysfunction. Our most recent studies indicate a role for increased mTOR pathway activity in T cell dysfunction in SLE, by connecting mitochondrial dysfunction to enhanced calcium fluxing and altered formation of the immunological synapse (23). mTOR is a component of two interacting signaling complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). While mTORC1 is activated (5,20,23), mTORC2 is inhibited in lupus T cells (51). Such skewing may account for depletion of Tregs and expansion of effector T cells that produce IL-4 and IL-17 in SLE patients (22,51). mTORC1 activation contributes to the pathogenesis of SLE and related autoimmune diseases (13). Rapamycin elicits rapid, progressive, and sustained improvement of disease activity via correcting abnormal T-cell lineage specification in patients with active SLE. In particular, rapamycin blocked the activity of mTOR complex 1 in all T cells, expanded CD4+CD25+FoxP3+ regulatory, CD4+ central-memory (CD62L+CD197+), and CD8+ effector-memory (CD62L–CD197–) T cells and inhibited the pro-inflammatory necrosis and IL-4 production of CD4–CD8– double-negative T cells after 12 months. (http://acrabstracts.org/abstract/rapamycin-elicits-rapid-and-lasting-improvement-of-disease-activity-through-blocking-pro-inflammatory-t-cell-lineage-specification-in-patients-with-active-sle/).
The role of mitochondrial dysfunction in pathogenesis of autoimmunity has been supported by linking non-synonymous genetic mutations in mitochondrial DNA to disease susceptibility in patients with SLE and multiple sclerosis (52). The susceptibility gene Sle1c2 was identified by estrogen-related receptor gamma (ESRRG) which is a transcription factor that regulates mitochondrial biogenesis and mediates CD4 T-cell hyper-reactivity in lupus-prone mice (6). Mitochondrial oxidative stress induces oligomerization of the mitochondrial antiviral signaling protein (MAVS) which triggers interferon production in patients with SLE (9).
Comprehensive metabolome analyses revealed an accumulation of pentose phosphate pathway (PPP) metabolites, depletion of cysteine, and the accumulation of kynurenine in lymphocytes of lupus patients relative to matched healthy controls (47). Kynurenine was identified as a metabolic trigger of mTORC1 activation and expansion of DN T cells (47). We are interested to better define the cross-talk between the accumulation of oxidative stress-generating mitochondria and activation of mTOR in human and murine models, including newly developed mice lacking HRES-1/Rab4 and the PPP enzyme, transaldolase.
Dysfunction of mitochondria due to blocked electron transport chain activity (53) and their accumulation due to inhibited mitophagy (5) lead to oxidative stress in lupus T cells (12). In turn, oxidative stress activates mTORC1 (23,54,55) which can be effectively targeted for therapeutic intervention in SLE. We initiated two mechanistic clinical trials which are aimed at blocking the activation of mTOR complex 1 (mTORC1), directly by using rapamycin (22) and indirectly by using the antioxidant, N-acetylcysteine (20). Mitochondrial dysfunction and mTORC1 activation is also detectable in the liver of lupus-prone mice, which has been identified as an early event of disease pathogenesis that triggers the production of antiphospholipid autoantibodies (28). Given that mTOR activation has emerged as a biomarker and central pathway to autoimmune disorders, cancer, obesity and aging, personalized mTOR blockade holds promise to extend life span through preventing and foiling these conditions (56).
3. Discovery of transaldolase and its role in metabolic control of apoptosis, inflammation, autoimmunity, and progressive liver disease
Human transaldolase (TAL) was originally discovered and cloned in our laboratory (14) and identified as a metabolic regulator of programmed cell death via controlling the mitochondrial transmembrane potential (15-17). Expression of transaldolase is controlled by an interplay between the transcription factors ZNF143 and AP2 (57). Transaldolase modulates the tissue-specific activity of the pentose phosphate pathway (27,57). The recently discovered genetic deficiency of transaldolase due to deletion of serin171 causes degradation of the enzyme in the proteasome (58). Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homeostasis, and apoptosis signal processing in human B cells (59). Transaldolase is cleaved and inactivated by granzyme B that may sensitize target cells to apoptosis induced by cytotoxic T cells (60). We have developed transaldolase-deficient mice that exhibit mitochondrial dysfunction in the sperm and some other cell types. Transaldolase-deficient male mice are infertile due to sperm dysmotility resulting from the loss of the mitochondrial transmembrane potential and diminished ATP production (61). Transaldolase-deficient mice spontaneously develop non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC) (26). NASH, cirrhosis, and HCC but not NAFLD are preventable by life-long treatment with N-acetylcysteine (26). These findings are relevant for the pathogenesis of chronic liver disease progressing from NAFLD to NASH, cirrhosis, and HCC in humans since transaldolase deficiency has already been documented in ten children, all with liver disease of varying severity. Mice deficient in transaldolase are also predisposed to acetaminophen/Tylenol-induced liver necrosis (26), the leading cause of acute liver failure in the US. Due to mitochondrial dysfunction and activation of mTORC1, Transaldolase deficiency predisposes to the production of antiphospholipid autoantibodies (28). Transaldolase-deficient mice are also susceptible to other autoimmune inflammatory diseases, which are currently being characterized (62).
4. Clinical research
To test the clinical relevance of our basic research findings, we have begun developing mechanistic clinical trials. We described first that rapamycin may be an effective treatment for lupus. We received investigator-initiated grant support from Wyeth, now Pfizer, to study prospectively the impact of rapamycin on global gene expression and activation of T cells and clinical outcomes in an open-label trial of 40 lupus patients (clinicaltrials.gov: IND No. 101,566). We are currently in discussion with NIAID about a follow-up randomized, placebo controlled trial with rapamycin in SLE. In addition, mTORC1 blockade with rapamycin may also benefit rheumatic diseases other than SLE (13). Our double-blind placebo-controlled study supported by NIH will determine the effect of NAC on glutathione depletion, mitochondrial hyperpolarization, and calcium signaling in lupus T cells and the clinical outcomes in SLE patients (clinicaltrials.gov: IND No 101,320). The 1st phase of our study double-blind placebo-controlled randomized study shows improved disease activity in NAC-treated SLE patients, relative to placebo, by reversing glutathione depletion and mTORC1 activation in T lymphocytes (20). Within the context of this trial we also discovered that SLE patients exhibit elevated attention deficit and hyperactivity disorder symptoms that respond to treatment with NAC (21). NAC may be beneficial for other co-morbidities of SLE, such as anti-phospholipid syndrome (63) and liver disease (30). To support the continuation of this study, a clinical trial center grant (UO1) and multicenter planning grant (U34) have been submitted to NIH. A grant award for planning of the multicenter trial has been issued by NIAMS for the period of 8/1/2016-7/31/2018.
I have been extremely blessed having been continuously supported by the National Institutes of Health (NIH) and numerous private foundations in the United States. Currently, my research is funded by three NIH grants, two is focused on basic research and a third one is to plan a follow-up phase II clinical trial in patients with SLE. One of the basic research project is entitled “Metabolic Control of T-cell Lineage Specification in SLE” (Grant number R01 AI072648; Period: 2015-2020) which represents a competitive continuation of studies on “Metabolic control of systemic autoimmunity”. The second basic research grant is entitled “Endocytic Control of Autophagosome Formation in Lupus T cells” which is built on our discovery of dysregulated autophagy in SLE patients and lupus-prone mice (Grant number R01 AI122176; Period: 2016-2021). The recently awarded planning grant is to develop a mechanistic multicenter clinical trial of NAC treatment in patients with SLE (Title: “Treatment of Systemic Lupus Erythematosus (SLE) with N-acetylcysteine (NAC)”; Grant number R34 AR068052; Period: 2016-2018). This trial is expected to translate our basic research findings of glutathione (GSH) depletion and oxidative stress into clinical practice by assessing the safety of replenishing GSH in 12-month clinical trial in 200 patients with SLE. Our recently (12/2015) completed “Prospective Study of Rapamycin for the Treatment of Systemic Lupus Erythematosus” has been supported by an Investigator-Initiated Research Grant P0468X1-4470/WS1234172 from Pfizer. Promising results of this study will be presented at the November 2016 Meeting of the American College of Rheumatology (http://acrabstracts.org/abstract/rapamycin-elicits-rapid-and-lasting-improvement-of-disease-activity-through-blocking-pro-inflammatory-t-cell-lineage-specification-in-patients-with-active-sle/). Approval of a follow-up mechanistic trial by NIH is pending.
Scientific community leadership: I have served in various leadership positions including Co-Director of the Foundation of the National Institutes of Health Inflammation and Immunity Steering Committee (United States), Chair of the Arthritis Foundation Cell Biology Grant Review Committee (United States), Member of the Board of Directors of the Arthritis Foundation, Lupus Alliance of Northern New York, Scientific Review Boards of the Lupus Research Institute and the Alliance of Lupus Research. I have served numerous study sections for the National Institutes of Health (NIH) including as permanent member the Arthritis Connective Tissue and Skin Diseases Committee (4 years) and the Hypersensitivity, Allergy and Immunology Committee (2012-2018). I have served on review panels of international scientific organizations, such Agence Nationale de la Recherche (France); Arthritis Research Campaign (U.K.); Australian Grant Fund; Deutsche Forschungsgemeinschaft (German Research Foundation); Hungarian Science Foundation; Israel Science Foundation; I am currently serving as editor or member of the editorial boards of over 20 journals including Arthritis and Rheumatology, Autoimmunity, and Clinical Immunology. I earlier served as editorial board member and reviewer of top medical journals, including Journal of Immunology and Journal of Autoimmunity. Currently, I am serving as one of the Associate Editors of Arthritis and Rheumatology.
1. Perl, A., J. D. Rosenblatt, I. S. Chen, J. P. DiVincenzo, R. Bever, B. J. Poiesz, and G. N. Abraham. 1989. Detection and cloning of new HTLV-related endogenous sequences in man. Nucl. Acids Res. 17:6841-6854.
2. Perl, A., C. M. Isaacs, R. L. Eddy, M. G. Byers, S. N. Sait, and T. B. Shows. 1991. The human T-cell leukemia virus-related endogenous sequence (HRES1) is located on chromosome 1 at q42. Genomics 11:1172-1173.
3. Nagy, G., J. Ward, D. D. Mosser, A. Koncz, P. Gergely, C. Stancato, Y. Qian, D. Fernandez, B. Niland, C. E. Grossman, T. Telarico, K. Banki, and A. Perl. 2006. Regulation of CD4 Expression via Recycling by HRES-1/RAB4 Controls Susceptibility to HIV Infection. J. Biol. Chem. 281:34574-34591.
4. Pullmann, R. Jr., E. Bonilla, P. E. Phillips, F. A. Middleton, and A. Perl. 2008. Haplotypes of the HRES-1 endogenous retrovirus are associated with development and disease manifestations of systemic lupus erythematosus. Arthritis Rheum. 58:532-540.
5. Caza, T. N., D. Fernandez, G. Talaber, Z. Oaks, M. Haas, M. P. Madaio, Z.-W. Lai, G. Miklossy, R. R. Singh, D. M. Chudakov, W. Malorni, F. A. Middleton, K. Banki, and A. Perl. 2014. HRES-1/RAB4-Mediated Depletion of DRP1 Impairs Mitochondrial Homeostasis and Represents a Target for Treatment in SLE. Ann. Rheum. Dis. 73:1887-1897.
6. Perry, D. J., Y. Yin, T. Telarico, H. V. Baker, I. Dozmorov, A. Perl, and L. Morel. 2012. Murine Lupus Susceptibility Locus Sle1c2 Mediates CD4+ T Cell Activation and Maps to Estrogen-Related Receptor gamma. J. Immunol. 189:793-803.
7. Srinivas, S., T. Watanabe, C. S. Lin, C. M. William, Y. Tanabe, T. M. Jessell, and F. Costantini. 2001. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol 1:4.
8. Lood, C., L. P. Blanco, M. M. Purmalek, C. Carmona-Rivera, S. S. De Ravin, C. K. Smith, H. L. Malech, J. A. Ledbetter, K. B. Elkon, and M. J. Kaplan. 2016. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med 22:146-153.
9. Buskiewicz, I., T. Montgomery, E. C. Yasewicz, S. A. Huber, M. P. Murphy, R. C. Hartley, R. Kelly, M. K. Crow, A. Perl, R. C. Budd, and A. Koenig. 2016. Reactive oxygen species induce virus-independent MAVS-oligomerization in systemic lupus erythematosus. Sci. Signal. 29:ra115.
10. Yang, Z., Y. Shen, H. Oishi, E. L. Matteson, L. Tian, J. r. J. Goronzy, and C. M. Weyand. 2016. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Science Translational Medicine 8:331ra38.
11. Tsokos, G. C. 2016. Metabolic control of arthritis: Switch pathways to treat. Sci. Transl. Med. 8:331fs8.
12. Perl, A. 2013. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat Rev Rheumatol 9:674-686.
13. Perl, A. 2016. Mechanistic Target of Rapamycin Pathway Activation in Rheumatic Diseases. Nat. Rev. Rheumatol. 12:169-182.
14. Banki, K., D. Halladay, and A. Perl. 1994. Cloning and expression of the human gene for transaldolase: a novel highly repetitive element constitutes an integral part of the coding sequence. J. Biol. Chem. 269:2847-2851.
15. Banki, K., E. Hutter, E. Colombo, N. J. Gonchoroff, and A. Perl. 1996. Glutathione Levels and Sensitivity to Apoptosis Are Regulated by changes in Transaldolase expression. J. Biol. Chem. 271:32994-33001.
16. Banki, K., E. Hutter, N. J. Gonchoroff, and A. Perl. 1998. Molecular ordering in HIV-induced apoptosis: Oxidative stress, activation of caspases, and cell survival are regulated by transaldolase. J. Biol. Chem. 273:11944-11953.
17. Banki, K., E. Hutter, N. Gonchoroff, and A. Perl. 1999. Elevation of mitochondrial transmembrane potential and reactive oxygen intermediate levels are early events and occur independently from activation of caspases in Fas signaling. J. Immunol. 162:1466-1479.
18. Gergely, P. J., C. Grossman, B. Niland, F. Puskas, H. Neupane, F. Allam, K. Banki, P. E. Phillips, and A. Perl. 2002. Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus. Arthritis Rheum. 46:175-190.
19. Perl, A., P. Gergely, Jr., G. Nagy, A. Koncz, and K. Banki. 2004. Mitochondrial hyperpolarization: a checkpoint of T cell life, death, and autoimmunity. Trends Immunol 25:360-367.
20. Lai, Z.-W., R. Hanczko, E. Bonilla, T. N. Caza, B. Clair, A. Bartos, G. Miklossy, J. Jimah, E. Doherty, H. Tily, L. Francis, R. Garcia, M. Dawood, J. Yu, I. Ramos, I. Coman, S. V. Faraone, P. E. Phillips, and A. Perl. 2012. N-acetylcysteine reduces disease activity by blocking mTOR in T cells of lupus patients. Arthritis Rheum. 64:2937-2946.
21. Garcia, R. J., L. Francis, M. Dawood, Z.-W. Lai, S. V. Faraone, and A. Perl. 2013. Attention Deficit and Hyperactivity Disorder Scores are Elevated and Respond to NAC treatment in patients with SLE. Arthritis Rheum. 65:1313-1318.
22. Lai, Z.-W., R. Borsuk, A. Shadakshari, J. Yu, M. Dawood, R. Garcia, L. Francis, H. Tily, A. Bartos, S. V. Faraone, P. E. Phillips, and A. Perl. 2013. mTOR activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus eryhthematosus. J. Immunol. 191:2236-2246.
23. Fernandez, D. R., T. Telarico, E. Bonilla, Q. Li, S. Banerjee, F. A. Middleton, P. E. Phillips, M. K. Crow, S. Oess, W. Muller-Esterl, and A. Perl. 2009. Activation of mTOR controls the loss of TCR. in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation. J. Immunol. 182:2063-2073.
24. Fernandez, D., E. Bonilla, N. Mirza, B. Niland, and A. Perl. 2006. Rapamycin reduces disease activity and normalizes T-cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum. 54:2983-2988.
25. Oaks, Z., T. Winans, N. Huang, K. Banki, and A. Perl. 2016. Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years. Curr. Rheum. Rep. 18:73.
26. Hanczko, R., D. Fernandez, E. Doherty, Y. Qian, Gy. Vas, B. Niland, T. Telarico, A. Garba, S. Banerjee, F. A. Middleton, D. Barrett, M. Barcza, K. Banki, S. K. Landas, and A. Perl. 2009. Prevention of hepatocarcinogenesis and acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine. J. Clin. Invest. 119:1546-1557.
27. Perl, A., R. Hanczko, T. Telarico, Z. Oaks, and S. Landas. 2011. Oxidative stress, inflammation and carcinogenesis are controlled through the pentose phosphate pathway by transaldolase. Trends Mol. Med. 7:395-403.
28. Oaks, Z., T. Winans, T. Caza, D. Fernandez, Y. Liu, S. K. Landas, K. Banki, and A. Perl. 2016. Mitochondrial dysfunction in the liver and antiphospholipid antibody production precede disease onset and respond to rapamycin in lupus-prone mice. Arthritis Rheum. 68:2728-2739.
29. Lockshin, M. D., and D. Erkan. 2003. Treatment of the Antiphospholipid Syndrome. N. Engl. J. Med. 349:1177-1179.
30. Liu, Y., J. Yu, Z. Oaks, I. Marchena-Mendez, L. Francis, E. Bonilla, P. Aleksiejuk, J. Patel, K. Banki, S. K. Landas, and A. Perl. 2015. Liver injury correlates with biomarkers of autoimmunity and disease activity and represents an organ system involvement in patients with systemic lupus erythematosus. Clin. Immunol. 160:319-327.
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32. Ambrosino, P., R. Lupoli, G. Spadarella, P. Tarantino, A. Di Minno, L. Tarantino, and M. N. D. Di Minno. 2015. Autoimmune liver diseases and antiphospholipid antibodies positivity: A meta-analysis of literature studies. 24:25-34.
33. Finn, R. S. 2012. Current and Future Treatment Strategies for Patients with Advanced Hepatocellular Carcinoma: Role of mTOR Inhibition. Liver Cancer 1:247-256.
34. Harrison, D. E., R. Strong, Z. D. Sharp, J. F. Nelson, C. M. Astle, K. Flurkey, N. L. Nadon, J. E. Wilkinson, K. Frenkel, C. S. Carter, M. Pahor, M. A. Javors, E. Fernandez, and R. A. Miller. 2009. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392-395.
35. Tarr, T., G. Muzes, E. Pitlik, G. Lakos, T. Csepany, P. Soltesz, M. Zeher, G. Szegedi, and E. Kiss. 2005. Is the primary antiphospholipid syndrome a forerunner of SLE? Orv. Hetil. 146:203-207.
36. McClain, M. T., M. R. Arbuckle, L. D. Heinlen, G. J. Dennis, J. Roebuck, M. V. Rubertone, J. B. Harley, and J. A. James. 2004. The Prevalence, Onset, and Clinical Significance of Antiphospholipid Antibodies Prior to Diagnosis of Systemic Lupus Erythematosus. Arthritis Rheum. 50:1226-1232.
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61. Perl, A., Y. Qian, K. R. Chohan, C. R. Shirley, W. Amidon, S. Banerjee, F. A. Middleton, K. L. Conkrite, M. Barcza, N. Gonchoroff, S. S. Suarez, and K. Banki. 2006. Transaldolase is essential for maintenance of the mitochondrial transmembrane potential and fertility of spermatozoa. Proc. Natl. Acad. Sci. USA 103:14813-14818.
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