Andras Perl profile picture
Accepting New Patients
315 464-3836

Andras Perl, MD, PhD


Distinguished Professor of Medicine
Division Chief of Rheumatology
Co-Director, MD/PhD Program


Internal Medicine






Biochemistry and Molecular Biology
Biomedical Sciences Program
Microbiology and Immunology


Genes and Viruses Predisposing to Autoimmunity, Genetics, Apoptosis, Endogenous Retroviruses, Transaldolase


Rheumatology, Immunology, Physician-Scientist Training


American Association for the Advancement of Science (AAAS)
American Association for the Study of Liver Diseases (AASLD)
American Association of Immunologists (AAI)
American College of Rheumatology (ACR), Fellow
American Society for Biochemistry and Molecular Biology (ASBMB)
Federation of Clinical Immunology Societies Center of Excellence, Director
Henry Kunkel Society


Fellowship: University of Rochester Medical Center, 1988, Rheumatology/Immunology
PhD: Semmelweis Medical University, Budapest, Hungary, 1984
Residency: Semmelweis Medical School, Budapest, 1982
MD: Semmelweis Medical University, Budapest, Hungary, 1979


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:

Research Projects

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: 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 dysfunction and activation of the mechanistic target of rapamycin (mTOR) as mediators of pro-inflammatory T-cell development 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 rapamycin 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 (52). 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 (52). Unlike effector cells, Tregs of SLE patients exhibit deficient autophagy due to activation of an mTORC1/IL-21 positive feedback loop. Importantly, rapamycin treatment reverses deficient autophagy and facilitates the development and function of Tregs is patients with SLE (53).

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 (54). 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 (55) and their accumulation due to inhibited mitophagy (5) lead to oxidative stress in lupus T cells (12). In turn, oxidative stress activates mTORC1 (23,56,57) 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 (58).

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 (59). Transaldolase modulates the tissue-specific activity of the pentose phosphate pathway (27,59). The recently discovered genetic deficiency of transaldolase due to deletion of serin171 causes degradation of the enzyme in the proteasome (60). Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homeostasis, and apoptosis signal processing in human B cells (61). Transaldolase is cleaved and inactivated by granzyme B that may sensitize target cells to apoptosis induced by cytotoxic T cells (62). 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 (63). 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 (64).

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 ( 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 ( 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 (65) 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. Application for planning a phase II mechanistic clinical trial to confirm preliminary results (52) is pending.

Reference List

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 Rheumatol. 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.

31. Asherson, R. A., R. Cervera, J. C. Piette, J. Font, J. T. Lie, A. Burcoglu, K. Lim, F. J. Munoz-Rodriguez, R. A. Levy, F. Boue, J. Rossert, and M. Ingelmo. 1998. Catastrophic Antiphospholipid Syndrome: Clinical and Laboratory Features of 50 Patients. Medicine (Baltimore) 77:195-207.

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.

37. Nkhoma, E. T., C. Poole, V. Vannappagari, S. A. Hall, and E. Beutler. 2009. The global prevalence of glucose-6-phosphate dehydrogenase deficiency: A systematic review and meta-analysis. Blood Cell. Molec. Dis. 42:267-278.

38. Sorenson, R. C., C. L. Bisgaier, M. Aviram, C. Hsu, S. Billecke, and B. N. La Du. 1999. Human Serum Paraoxonase/Arylesterase's Retained Hydrophobic N-Terminal Leader Sequence Associates With HDLs by Binding Phospholipids : Apolipoprotein A-I Stabilizes Activity. Arterioscler. Thromb. Vasc. Biol. 19:2214-2225.

39. Geminard, C., A. de Gassart, and M. Vidal. 2002. Reticulocyte maturation: mitoptosis and exosome release. [Review] [90 refs]. Biocell 26:205-215.

40. Bhalla, A., V. Suri, and V. Singh. 2006. Malarial hepatopathy. J Postgrad Med 52:315-320.

41. Anand, A. C., and P. Puri. 2005. Jaundice in malaria. Journal of Gastroenterology & Hepatology 20:1322-1332.

42. Consigny, P. H., B. Cauquelin, P. Agnamey, E. Comby, P. Brasseur, J. J. Ballet, and C. Roussilhon. 2002. High prevalence of co-factor independent anticardiolipin antibodies in malaria exposed individuals. Clin Exp Immunol 127:158-164.

43. Banki, K., J. Maceda, E. Hurley, E. Ablonczy, D. H. Mattson, L. Szegedy, C. Hung, and A. Perl. 1992. Human T-cell lymphotropic virus (HTLV)-related endogenous sequence, HRES-1, encodes a 28-kDa protein: a possible autoantigen for HTLV-I gag-reactive autoantibodies. Proc. Natl. Acad. Sci. USA 89:1939-1943.

44. Magistrelli, C., E. Samoilova, R. K. Agarwal, K. Banki, P. Ferrante, A. Vladutiu, P. E. Phillips, and A. Perl. 1999. Polymorphic genotypes of the HRES-1 human endogenous retrovirus locus correlate with systemic lupus erythematosus and autoreactivity. Immunogenetics 49:829-834.

45. Gomes, L. C., G. D. Benedetto, and L. Scorrano. 2011. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13:589-598.

46. Talaber, G., G. Miklossy, Z. Oaks, Y. Liu, S. A. Tooze, D. M. Chudakov, K. Banki, and A. Perl. 2014. HRES-1/Rab4 promotes the formation of LC3+ autophagosomes and the accumulation of mitochondria during autophagy. PLoS ONE 9:e84392.

47. Perl, A., R. Hanczko, Z.-W. Lai, Z. Oaks, R. Kelly, R. Borsuk, J. M. Asara, and P. E. Phillips. 2015. Comprehensive metabolome analyses reveal N-acetylcysteine-responsive accumulation of kynurenine in systemic lupus erythematosus: implications for activation of the mechanistic target of rapamycin. Metabolomics 11:1157-1174.

48. Perl, A. 2016. Editorial: LINEing Up to Boost Interferon Production: Activation of Endogenous Retroviral DNA in Autoimmunity. Arthritis Rheumatol 68:2568-2570.

49. Nagy, G., A. Koncz, and A. Perl. 2003. T cell activation-induced mitochondrial hyperpolarization is mediated by Ca2+- and redox-dependent production of nitric oxide . J. Immunol. 171:5188-5197.

50. Nagy, G., M. Barcza, N. Gonchoroff, P. E. Phillips, and A. Perl. 2004. Nitric Oxide-Dependent Mitochondrial Biogenesis Generates Ca2+ Signaling Profile of Lupus T Cells. J. Immunol. 173:3676-3683.

51. Kato, H., and A. Perl. 2014. MTORC1 expands Th17 and IL-4+ DN T cells and contracts Tregs in SLE. J. Immunol. 192:4134-4144.

52. Lai, Z., R. Kelly, T. Winans, I. Marchena, A. Shadakshari, J. Yu, M. Dawood, R. Garcia, H. Tily, L. Francis, S. V. Faraone, P. E. Phillips, and A. Perl. 2018. Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial. Lancet 391:1186-1196.

53. Kato, H., and A. Perl. 2018. The IL-21-mTOR axis blocks Treg differentiation and function by suppression of autophagy in patients with systemic lupus erythematosus. Arthritis Rheumatol. 70:427-438.

54. Vyshkina, T., A. Sylvester, S. Sadiq, E. Bonilla, J. A. Canter, A. Perl, and B. Kalman. 2008. Association of common mitochondrial DNA variants with multiple sclerosis and systemic lupus erythematosus. Clin Immunol 129:31-35.

55. Doherty, E., Z. Oaks, and A. Perl. 2014. Increased Mitochondrial Electron Transport Chain Activity at Complex I is Regulated by N-acetylcysteine in Lymphocytes of Patients with Systemic Lupus Erythematosus. Antiox. Redox Signal. 21:56-65.

56. Sarbassov, d. D., and D. M. Sabatini. 2005. Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex. J. Biol. Chem. 280:39505-39509.

57. Yoshida, S., S. Hong, T. Suzuki, S. Nada, A. M. Mannan, J. Wang, M. Okada, K. L. Guan, and K. Inoki. 2011. Redox Regulates Mammalian Target of Rapamycin Complex 1 (mTORC1) Activity by Modulating the TSC1/TSC2-Rheb GTPase Pathway. J. Biol. Chem. 286:32651-32660.

58. Perl, A. 2015. mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging. Ann. NY Acad. Sci. 1346:33-44.

59. Grossman, C. E., Y. Qian, K. Banki, and A. Perl. 2004. ZNF143 Mediates Basal and Tissue-specific Expression of Human Transaldolase. J. Biol. Chem. 279:12190-12205.

60. Grossman, C. E., C. Stancato, B. Niland, N. M. Verhoeven, M. S. van der Knaap, C. Jakobs, L. M. Brown, S. Vajda, and A. Perl. 2004. Deletion of serine 171 causes misfolding, proteasome-mediated degradation, and complete deficiency of human transaldolase. Biochem. J. 382:725-731.

61. Qian, Y., S. Banerjee, C. E. Grossman, W. Amidon, G. Nagy, M. Barcza, B. Niland, D. R. Karp, F. A. Middleton, K. Banki, and A. Perl. 2008. Transaldolase deficiency influences the pentose phosphate pathway, mitochondrial homoeostasis and apoptosis signal processing. Biochem. J. 415:123-134.

62. Niland, B., G. Miklossy, K. Banki, W. E. Biddison, L. Casciola-Rosen, A. Rosen, D. Martinvalet, J. Lieberman, and A. Perl. 2010. Cleavage of Transaldolase by Granzyme B Causes the Loss of Enzymatic Activity with Retention of Antigenicity for Multiple Sclerosis Patients. J. Immunol. 184:4025-4032.

63. 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.

64. Perl, A., A. Bartos, B. Niland, and D. Fernandez. 2012. Transaldolase Deficiency Enhances the Development of Experimental Autoimmune Encephalomyelitis., pp.

65. Lai, Z.-W., I. Marchena-Mendez, and A. Perl. 2015. Oxidative stress and Treg depletion in lupus patients with anti-phospholipid syndrome. Clin. Immunol. 158:148-152.


Link to PubMed (Opens new window. Close the PubMed window to return to this page.)