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https://portlandpress.com/clinsci/article/doi/10.1042/CS20200799/226127/Myeloid-derived-suppressor-cells-shift-Th17-Treg

https://www.ncbi.nlm.nih.gov/pubmed/32808653?dopt=Abstract

Myeloid-derived suppressor cells shift Th17/Treg ratio and promote systemic lupus erythematosus progression through arginase-1/miR-322-5p/TGF-β pathway.

Clin Sci (Lond). 2020 Aug 18;:

Authors: Pang B, Zhen Y, Hu C, Ma Z, Lin S, Yi H

Abstract

Immune cells play important roles in systemic lupus erythematosus (SLE). We previously found that myeloid-derived suppressor cell (MDSC)-derived arginase-1 (Arg-1) promoted Th17 cell differentiation in SLE. In this study, we performed RNA-chip to identify the microRNA regulation network between MDSCs and Th17 cells. miR-542-5p in humans, as the homologous gene of miR-322-5p in mice was significantly upregulated in the Th17+MDSC group compared to Th17 cells cultured alone and downregulated in the Th17+MDSC+Arg-1 inhibitor group compared to the Th17+MDSC group. We further evaluated the miR-322-5p and Th17/Treg balance in mice and found that the proportions of both Th17 cells and Tregs were elevated and that miR-322-5p overexpression activated the transforming growth factor-β pathway. Moreover, although miR-322-5p expression was higher in SLE mice, it decreased after treatment with an Arg-1 inhibitor. The proportion of Th17 cells and Th17/Treg ratio correlated with miR-322-5p levels. In conclusion, MDSC-derived Arg-1 and mmu-miR-322-5p not only promote Th17 cell and Treg differentiation, but also shift the Th17/Treg ratio in SLE. The Arg-1/miR-322-5p axis may serve as a novel treatment target for SLE.

PMID: 32808653 [PubMed – as supplied by publisher]

PubMed:32808653

Date Found:
08/19/20 06:00AM

https://ojs.ptbioch.edu.pl/index.php/abp/article/view/5416

https://www.ncbi.nlm.nih.gov/pubmed/32730703?dopt=Abstract

Dendritic cells’ characteristics in patients with treated systemic lupus erythematosus.

Acta Biochim Pol. 2020 Jul 30;:

Authors: Wardowska A, Smoleńska Ż, Lisowska KA, Zdrojewski Z, Pikuła M

Abstract

The systemic lupus erythematosus (SLE) is a chronic autoimmune disease related to a loss of immune tolerance against autoantigens that leads to tissue inflammation and organ dysfunction. Constant stimulation of dendritic cells (DC) with autoantigens is hypothesized to increase the B cells’ activity which are involved in production of autoantibodies that play an essential role in the SLE development. We focused our study on detecting alterations in DCs at the cellular and molecular levels in patients with treated SLE, depending on the disease activity and treatment. In order to phenotype subpopulations of DCs, multicolor flow cytometry was used. Transcriptional changes were identified with quantitative PCR, while soluble cytokine receptors were assessed with the Luminex technology. We show that SLE patients display a higher percentage of activated myeloid DCs (mDCs) when compared to healthy people. Both, the mDCs and plasmacytoid DCs (pDCs) of SLE patients were characterized by changes in expression of genes associated with their maturation, functioning and signalling, which was especially reflected by low expression of regulatory factor ID2 and increased expression of IRF5. pDCs of SLE patients also showed increased expression of IRF1. There were also significant changes in the expression of APRIL, MBD2, and E2-2 in mDCs that significantly correlated with some serum components, i.e. anti-dsDNA antibodies or complement components. However, we did not find any significant differences depending on the disease activity. While the majority of available studies focuses mainly on the role of pDCs in the disease development, our results show significant disturbances in the functioning of mDCs in SLE patients, thus confirming mDCs’ importance in SLE pathogenesis.

PMID: 32730703 [PubMed – as supplied by publisher]

PubMed:32730703

Date Found:
07/31/20 06:01AM

https://www.frontiersin.org/articles/10.3389/fimmu.2020.01572/full

https://www.ncbi.nlm.nih.gov/pubmed/32793221?dopt=Abstract

Related Articles

Targeting the Protective Arm of the Renin-Angiotensin System to Reduce Systemic Lupus Erythematosus Related Pathologies in MRL-lpr Mice.

Front Immunol. 2020;11:1572

Authors: Soto M, Delatorre N, Hurst C, Rodgers KE

Abstract

Patients with Systemic Lupus Erythematosus (SLE) suffer from a chronic inflammatory autoimmune disease that results from the body’s immune system targeting healthy tissues which causes damage to various organ systems. Patients with lupus are still in need of effective therapies to treat this complex, multi-system disease. Because polymorphisms in ACE are associated with the activity of SLE and lupus nephritis and based on well-documented renal-protective effects of Renin Angiotensin System (RAS)-modifying therapies, ACE-I are now widely used in patients with SLE with significant efficacy. Our research explores alternate ways of modifying the RAS as a potential for systemic therapeutic benefit in the MRL-lpr mouse model of SLE. These therapeutics include; angiotensin (1-7) [A(1-7)], Nor-Leu-3 Angiotensin (1-7) (NorLeu), Losartan (ARB), and Lisinopril (ACE-I). Daily systemic treatment with all of these RAS-modifying therapies significantly reduced the onset and intensity in rash formation and swelling of the paw. Further, histology showed a corresponding decrease in hyperkeratosis and acanthosis in skin sections. Important immunological parameters such as decreased circulating anti-dsDNA antibodies, lymph node size, and T cell activation were observed. As expected, the development of glomerular pathologies was also attenuated by RAS-modifying therapy. Improved number and health of mesenchymal stem cells (MSCs), as well as reduction in oxidative stress and inflammation may be contributing to the reduction in SLE pathologies. Several studies have already characterized the protective role of ACE-I and ARBs in mouse models of SLE, here we focus on the protective arm of RAS. A(1-7) in particular demonstrates several protective effects that go beyond those seen with ACE-Is and ARBs; an important finding considering that ACE-Is and ARBs are teratogenic and can cause hypotension in this population. These results offer a foundation for further pharmaceutical development of RAS-modifying therapies, that target the protective arm, as novel SLE therapeutics that do not rely on suppressing the immune system.

PMID: 32793221 [PubMed – in process]

PubMed:32793221

Date Found:
08/15/20 06:04AM

https://www.frontiersin.org/articles/10.3389/fimmu.2020.01477/full

https://www.ncbi.nlm.nih.gov/pubmed/32793202?dopt=Abstract

Related Articles

Immunomodulatory Effects of Diet and Nutrients in Systemic Lupus Erythematosus (SLE): A Systematic Review.

Front Immunol. 2020;11:1477

Authors: Islam MA, Khandker SS, Kotyla PJ, Hassan R

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement, including the skin, joints, kidneys, lungs, central nervous system and the haematopoietic system, with a large number of complications. Despite years of study, the etiology of SLE remains unclear; thus, safe and specifically targeted therapies are lacking. In the last 20 years, researchers have explored the potential of nutritional factors on SLE and have suggested complementary treatment options through diet. This study systematically reviews and evaluates the clinical and preclinical scientific evidence of diet and dietary supplementation that either alleviate or exacerbate the symptoms of SLE. For this review, a systematic literature search was conducted using PubMed, Scopus and Google Scholar databases only for articles written in the English language. Based on the currently published literature, it was observed that a low-calorie and low-protein diet with high contents of fiber, polyunsaturated fatty acids, vitamins, minerals and polyphenols contain sufficient potential macronutrients and micronutrients to regulate the activity of the overall disease by modulating the inflammation and immune functions of SLE.

PMID: 32793202 [PubMed – in process]

PubMed:32793202

Date Found:
08/15/20 06:04AM

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381321/

https://www.frontiersin.org/articles/10.3389/fmed.2020.00316/full

https://www.ncbi.nlm.nih.gov/pubmed/32754605?dopt=Abstract

Related Articles

B Cell Therapy in Systemic Lupus Erythematosus: From Rationale to Clinical Practice.

Front Med (Lausanne). 2020;7:316

Authors: Parodis I, Stockfelt M, Sjöwall C

Abstract

B cell hyperactivity and breach of tolerance constitute hallmarks of systemic lupus erythematosus (SLE). The heterogeneity of disease manifestations and relatively rare prevalence of SLE have posed difficulties in trial design and contributed to a slow pace for drug development. The anti-BAFF monoclonal antibody belimumab is still the sole targeted therapy licensed for SLE, lending credence to the widely accepted notion that B cells play central roles in lupus pathogenesis. However, more therapeutic agents directed toward B cells or B cell-related pathways are used off-label or have been trialed in SLE. The anti-CD20 monoclonal antibody rituximab has been used to treat refractory SLE during the last two decades, and the anti-type I IFN receptor anifrolumab is currently awaiting approval after one phase III clinical trial which met its primary endpoint and one phase III trial which met key secondary endpoints. While the latter does not directly affect the maturation and antibody production activity of B cells, it is expected to affect the contribution of B cells in proinflammatory cytokine excretion. The proteasome inhibitor bortezomib, primarily directed toward the plasma cells, has been used in few severe cases as an escape regimen. Collectively, current clinical experience and primary results of ongoing clinical trials prophesy that B cell therapies of selective targets will have an established place in the future personalized therapeutic management of lupus patients.

PMID: 32754605 [PubMed]

PubMed:32754605

Date Found:
08/06/20 07:09AM

https://www.nature.com/articles/s41467-020-15224-w

Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory

https://www.tandfonline.com/doi/abs/10.1080/14737159.2019.1665511?journalCode=iero20

https://www.ncbi.nlm.nih.gov/pubmed/31516059?dopt=Abstract

Role of anti-DNA auto-antibodies as biomarkers of response to treatment in systemic lupus erythematosus patients: hypes and hopes. Insights and implications from a comprehensive review of the literature.

Expert Rev Mol Diagn. 2019 Sep 13;:1-10

Authors: Bragazzi NL, Watad A, Damiani G, Adawi M, Amital H, Shoenfeld Y

Abstract

Introduction: Due to the polymorphic clinical presentations and manifestations of systemic lupus erythematosus (SLE), biomarkers with enough diagnostic and prognostic value are of paramount importance. Recently, anti-double stranded DNA (anti-dsDNA) auto-antibodies have been proposed to monitor the response to different therapies. It has also been suggested that they should be employed as entry markers in trial studies. However, their clinical use remains still debated and, sometimes, controversial, due to conflicting findings reported. Areas covered: Through an extensive literature review, we evaluated changes in anti-dsDNA auto-antibodies levels before and after the administration of the treatment (either biological or non-biological). Expert opinion: Anti-dsDNA auto-antibodies related findings are still difficult to compare mainly because of the different detecting methods employed, even though in most studies included in this review a consistent decreasing pattern after the treatment seems to emerge. Hence, if properly standardized, anti-dsDNA auto-antibody profile may be a reliable biomarker to monitor the effectiveness of biologics as well as of non-biological drugs, especially if grouped in composite outcomes scores, such as the ‘Lupus Multivariable Outcome Score’ (LUMOS) or measured with other biomarkers, such as anti-nucleosome auto-antibodies. We recommend the assessment of anti-dsDNA auto-antibodies levels in both daily practice and research settings.

PMID: 31516059 [PubMed – as supplied by publisher]

PubMed:31516059

https://www.nature.com/articles/s41584-019-0272-0

https://www.ncbi.nlm.nih.gov/pubmed/31399711?dopt=Abstract

Related Articles

Cutaneous lupus erythematosus: new insights into pathogenesis and therapeutic strategies.

Nat Rev Rheumatol. 2019 Aug 09;:

Authors: Wenzel J

Abstract

Cutaneous lupus erythematosus (CLE) is an autoimmune disease that can present as an isolated skin disease or as a manifestation within the spectrum of systemic lupus erythematosus. The clinical spectrum of CLE is broad, ranging from isolated discoid plaques to widespread skin lesions. Histologically, skin lesions present as interface dermatitis (inflammation of the skin mediated by anti-epidermal responses), which is orchestrated by type I and type III interferon-regulated cytokines and chemokines. Both innate and adaptive immune pathways are strongly activated in the formation of skin lesions owing to continuous re-activation of innate pathways via pattern recognition receptors (PRRs). These insights into the molecular pathogenesis of skin lesions in CLE have improved our understanding of the mechanisms underlying established therapies and have triggered the development of targeted treatment strategies that focus on immune cells (for example, B cells, T cells or plasmacytoid dendritic cells), as well as immune response pathways (for example, PRR signalling, Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signalling and nuclear factor-κB signalling) and their cytokines and chemokines (for example, type I interferons, CXC-chemokine ligand 10 (CXCL10), IL-6 and IL-12).

PMID: 31399711 [PubMed – as supplied by publisher]

PubMed:31399711

https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/kez306/5543451

https://www.ncbi.nlm.nih.gov/pubmed/31377780?dopt=Abstract

Anti-apolipoprotein A-1 autoantibodies correlate with disease activity in systemic lupus erythematosus.

Rheumatology (Oxford). 2019 Aug 03;:

Authors: Nigolian H, Ribi C, Courvoisier DS, Pagano S, Alvarez M, Trendelenburg M, Huynh-Do U, Vuilleumier N, Dayer JM, Chizzolini C, Roux-Lombard P

Abstract

OBJECTIVES: Apolipoprotein A-1 (ApoA-1) is a protein fraction of the high-density lipoproteins with anti-inflammatory and antioxidant properties that play a major role in reverse cholesterol transport. The presence of anti-ApoA-1 IgG has been reported in SLE to be variably associated with disease activity or cardiovascular events (CVEs). We assessed the clinical performance of anti-ApoA-1 IgG and of antibodies directed against its immunodominant F3L1 peptide (F3L1 IgG) in a well-characterized Swiss SLE cohort study.

METHODS: A total of 354 biological samples and interviews from 176 individuals were studied. SLEDAI, clinical characteristics, anamnestic CVEs and therapy details were recorded. Sera were tested for the presence of anti-ApoA-1 IgG, anti-F3L1 IgG, anti-dsDNA IgG and aPL.

RESULTS: Anti-ApoA-1 and anti-F3L1 IgG positivity was associated with higher SLEDAI, mostly due to concomitant positivity of dsDNA IgG and low complement. Variations in time of anti-ApoA-1 IgG correlated positively with variations of anti-dsDNA IgG and inversely to variations of C3 levels. No cross-reactivity was found between anti-ApoA-1 and anti-dsDNA IgG. Positivity for anti-Apo-A1 IgG was more frequent in individuals receiving 10 mg/day or more of prednisone. We did not find any significant association between anti-ApoA-1 IgG positivity and CVEs.

CONCLUSION: Anti-ApoA-1 and anti-F3L1 IgG in SLE correlate strongly with laboratory markers of activity, particularly with the presence and titre of dsDNA IgG. These results confirm and extend previous findings and support the use of anti-ApoA1 IgG in the clinical setting. Their role in CVEs deserves further investigation.

PMID: 31377780 [PubMed – as supplied by publisher]

PubMed:31377780

https://www.sciencedirect.com/science/article/pii/S0142961219305071?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31394431?dopt=Abstract

Atializumab, a humanized anti-aminoacyl-tRNA synthetase-interacting multifunctional protein-1 (AIMP1) antibody significantly improves nephritis in (NZB/NZW) F1 mice.

Biomaterials. 2019 Aug 02;220:119408

Authors: Mun CH, Kim JO, Ahn SS, Yoon T, Kim SJ, Ko E, Noh HD, Park YB, Jung HJ, Kim TS, Lee SW, Park SG

Abstract

Aminoacyl-tRNA synthetase (ARS)-interacting multifunctional protein 1 (AIMP1) enhances the expression of proinflammatory cytokines. In our previous study, we have shown that serum AIMP1 in patients with SLE was significantly higher than that of healthy controls. To address whether neutralization of AIMP1 could ameliorate nephritis in lupus-prone mice, we generated atializumab, a humanized antibody against AIMP1 and investigated its therapeutic efficacy. ELISA showed that serum AIMP1 at 23 weeks old was significantly higher than that at 13 weeks old in lupus-prone mice. Therefore, lupus-prone mice were randomly assigned to 5 groups (vehicle, methylprednisolone and 0.5, 2, and 5 mg/kg atializumab). After treatment, disease severity was assessed using a variety of phenotypes, including proteinuria, histological damages, renal deposition of immune-complex. In addition, serum cytokines, anti-dsDNA and IgG subclasses were determined. T cell subsets were analyzed using a fluorescence-activated cell sorter. Atializumab significantly diminished proteinuria, improved glomerular and tubular damages and reduced the renal deposition of immune-complexes. Moreover, atializumab significantly decreased serum interferon (IFN)-γ, interleukin (IL)-17A, and IL-6, whereas it increased serum IL-10. Similarly, atializumab reduced the numbers of TH1, TH2 and TH17 cells in a dose-dependent manner, while atializumab enhanced the number of regulatory T (Treg) cells. Furthermore, atializumab decreased not only splenic plasma cells and serum anti-dsDNA but also pathogenic IgG subclasses for nephritis. It suppressed NF-κB activation by inhibiting IκBα degradation in a dose-dependent manner in vitro. Atializumab alleviated nephritis by inhibiting autoreactive T, B, and plasma cells and decreasing NF-κB-related proinflammatory cytokines in lupus-prone mice. These results suggest that treatment targeting AIMP1 could be a novel and highly immune-modulating therapeutic strategy in lupus nephritis.

PMID: 31394431 [PubMed – as supplied by publisher]

PubMed:31394431

https://stm.sciencemag.org/content/11/502/eaaw1736

https://www.ncbi.nlm.nih.gov/pubmed/31341059?dopt=Abstract

Related Articles

Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain.

Sci Transl Med. 2019 Jul 24;11(502):

Authors: Burke JR, Cheng L, Gillooly KM, Strnad J, Zupa-Fernandez A, Catlett IM, Zhang Y, Heimrich EM, McIntyre KW, Cunningham MD, Carman JA, Zhou X, Banas D, Chaudhry C, Li S, D’Arienzo C, Chimalakonda A, Yang X, Xie JH, Pang J, Zhao Q, Rose SM, Huang J, Moslin RM, Wrobleski ST, Weinstein DS, Salter-Cid LM

Abstract

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.

PMID: 31341059 [PubMed – in process]

PubMed:31341059

https://www.hindawi.com/journals/bmri/2019/8142368/

https://www.ncbi.nlm.nih.gov/pubmed/31396534?dopt=Abstract

Related Articles

Biologics in the Treatment of Lupus Erythematosus: A Critical Literature Review.

Biomed Res Int. 2019;2019:8142368

Authors: Samotij D, Reich A

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease affecting multiple organ systems that runs an unpredictable course and may present with a wide variety of clinical manifestations. Advances in treatment over the last decades, such as use of corticosteroids and conventional immunosuppressive drugs, have improved life expectancy of SLE sufferers. Unfortunately, in many cases effective management of SLE is still related to severe drug-induced toxicity and contributes to organ function deterioration and infective complications, particularly among patients with refractory disease and/or lupus nephritis. Consequently, there is an unmet need for drugs with a better efficacy and safety profile. A range of different biologic agents have been proposed and subjected to clinical trials, particularly dedicated to this subset of patients whose disease is inadequately controlled by conventional treatment regimes. Unfortunately, most of these trials have given unsatisfactory results, with belimumab being the only targeted therapy approved for the treatment of SLE so far. Despite these pitfalls, several novel biologic agents targeting B cells, T cells, or cytokines are constantly being evaluated in clinical trials. It seems that they may enhance the therapeutic efficacy when combined with standard therapies. These efforts raise the hope that novel drugs for patients with refractory SLE may be available in the near future. This article reviews the current biological therapies being tested in the treatment of SLE.

PMID: 31396534 [PubMed – in process]

PubMed:31396534

https://advances.sciencemag.org/content/5/7/eaav9019

Control of TLR7-mediated type I IFN signaling in pDCs through CXCR4 engagement—A new target for lupus treatment

Nikaïa Smith1,2,3,4,*, Mathieu P. Rodero1,2,3, Nassima Bekaddour1,2,3, Vincent Bondet5,6, Yasser B. Ruiz-Blanco7, Mirja Harms4, Benjamin Mayer8, Brigitte Badder-Meunier3,9,10,11, Pierre Quartier3,9,10, Christine Bodemer3,9,12, Véronique Baudouin13, Yannick Dieudonné14,15,16, Frank Kirchhoff4, Elsa Sanchez Garcia7, Bruno Charbit17, Nicolas Leboulanger3,18, Bernd Jahrsdörfer19, Yolande Richard3,20,21, Anne-Sophie Korganow14,15,16, Jan Münch4, Sébastien Nisole22, Darragh Duffy5,6,17 and Jean-Philippe Herbeuval1,2,3,*
See all authors and affiliations

Science Advances 10 Jul 2019:
Vol. 5, no. 7, eaav9019
DOI: 10.1126/sciadv.aav9019

https://www.hindawi.com/journals/dm/2019/7838195/

https://www.ncbi.nlm.nih.gov/pubmed/31360267?dopt=Abstract

Gas6/TAM Receptors in Systemic Lupus Erythematosus.

Dis Markers. 2019;2019:7838195

Authors: Cohen PL, Shao WH

Abstract

Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease associated with impaired immune system regulation. The exact mechanisms of SLE development remain to be elucidated. TAM receptor tyrosine kinases (RTKs) are important for apoptotic cell clearance, immune homeostasis, and resolution of immune responses. TAM deficiency leads to lupus-like autoimmune diseases. Activation of TAM receptors leads to proteolytic cleavage of the receptors, generating soluble forms of TAM. Circulating TAM receptors have an immunoregulatory function and may also serve as biomarkers for disease prognosis. Here, we review the biological function and signaling of TAM RTKs in the development and pathogenesis of lupus and lupus nephritis. Targeting Gas6/TAM pathways may be of therapeutic benefit. A discussion of potential TAM activation and inhibition in the treatment of lupus and lupus nephritis is included.

PMID: 31360267 [PubMed – in process]

PubMed:31360267

https://www.nature.com/articles/s41590-019-0419-9

Epigenetic programming underpins B cell dysfunction in human SLE

https://www.frontiersin.org/articles/10.3389/fimmu.2019.00833/full

https://www.ncbi.nlm.nih.gov/pubmed/31057554?dopt=Abstract

Targeting T Cell Activation and Lupus Autoimmune Phenotypes by Inhibiting Glucose Transporters.

Front Immunol. 2019;10:833

Authors: Li W, Qu G, Choi SC, Cornaby C, Titov A, Kanda N, Teng X, Wang H, Morel L

Abstract

CD4+ T cells have numerous features of over-activated cellular metabolism in lupus patients and mouse models of the disease. This includes a higher glycolysis than in healthy controls. Glucose transporters play an essential role in glucose metabolism by controlling glucose import into the cell from the extracellular environment. We have previously shown that treatment of lupus-prone mice with 2-deoxy-D-glucose, which inhibits the first step of glycolysis was sufficient to prevent autoimmune activation. However, direct targeting of glucose transporters has never been tested in a mouse model of lupus. Here, we show that CG-5, a novel glucose transporter inhibitor, ameliorated autoimmune phenotypes in a spontaneous lupus-prone mouse model, B6.NZM2410.Sle1.Sle2.Sle3 (Triple-congenic, TC), and in a chronic graft- vs. host-disease (cGVHD) model of induced lupus. In vitro, CG-5 blocked glycolysis in CD4+ T cells, and limited the expansion of CD4+ T cells induced by alloreactive stimulation. CG-5 also modulated CD4+ T cell polarization by inhibiting Th1 and Th17 differentiation and promoting regulatory T (Treg) induction. Moreover, CG-5 treatment reduced lupus phenotypes including the expansion of germinal center B (GC B) cells, as well as the production of autoantibodies in both TC mice and cGVHD models. Finally, CG-5 blocked glycolysis in human T cells. Overall, our data suggest that blocking glucose uptake with a small molecule inhibitor ameliorates autoimmune activation, at least partially due to its inhibition of glycolysis in CD4+ T cells.

PMID: 31057554 [PubMed – in process]

PubMed:31057554

https://www.sciencedirect.com/science/article/pii/S1567576919304783?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31002998?dopt=Abstract

Therapeutic advances in the treatment of SLE.

Int Immunopharmacol. 2019 Apr 16;72:218-223

Authors: Mohamed A, Chen Y, Wu H, Liao J, Cheng B, Lu Q

Abstract

In recent years, the research on the pathogenesis of systemic lupus erythematosus (SLE) has been deepened, from the level of histopathology to the cellular and molecular biology, thus promoting the progress of SLE drug therapeutics. In March 2011, the United States Food and Drug Administration (FDA) approved the humanized monoclonal antibody, Belimumab for the treatment of SLE and put an end to the dilemma of no new drug available to SLE for more than half a century. On the other hand, the continuous evidence-based medical information has enabled rheumatologists to have a more comprehensive and depth understanding of the application of SLE traditional therapies, further improve the treatment strategy of SLE and put forward higher requirements for treatment goals. At the same time, advances in therapies have significantly improved survival rate of the patients, and the importance of long-term complications such as early-onset atherosclerosis and cardiovascular events has become increasingly apparent as a new challenge. In view of the hot issues of SLE clinical treatment, this paper introduces the research progress in recent years.

PMID: 31002998 [PubMed – as supplied by publisher]

PubMed:31002998

https://cjasn.asnjournals.org/content/early/2019/04/11/CJN.03230319

https://www.ncbi.nlm.nih.gov/pubmed/30979714?dopt=Abstract

Related Articles

Treatment Options for Refractory Lupus Nephritis.

Clin J Am Soc Nephrol. 2019 Apr 12;:

Authors: Anders HJ, Hiepe F

PMID: 30979714 [PubMed – as supplied by publisher]

PubMed:30979714

https://f1000research.com/articles/8-368/v1

https://www.ncbi.nlm.nih.gov/pubmed/31001416?dopt=Abstract

Related Articles

The central role of nucleic acids in the pathogenesis of systemic lupus erythematosus.

F1000Res. 2019;8:

Authors: Pisetsky DS

Abstract

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease whose pathogenesis can be conceptualized by a model based on a central role for immune complexes (ICs) between antinuclear antibodies and nucleic acids. According to this model, ICs can promote pathogenesis by two main mechanisms: deposition in the tissue to incite local inflammation and interaction with cells of the innate immune system to stimulate the production of cytokines, most prominently type 1 interferon. The latter stimulation results from the uptake of DNA and RNA in the form of ICs into cells and subsequent signaling by internal nucleic acid sensors for DNA and RNA. These sensors are likely important for the response to intracellular infection, although they may also be triggered during cell stress or injury by DNA or RNA aberrantly present in the cytoplasm. For IC formation, a source of extracellular DNA and RNA is essential. The current model of SLE posits that cell death is the origin of the nucleic acids in the ICs and that impairment of clearance mechanisms increases the amount of nuclear material in the extracellular space. This model of SLE is important since it points to new approaches to therapy; agents targeting interferon or the interferon receptor are examples of therapeutic approaches derived from this model. Future studies will explore novel biomarkers to monitor the operation of these mechanisms and to elucidate other steps in pathogenesis that can be targeted for therapy.

PMID: 31001416 [PubMed – in process]

PubMed:31001416

https://www.sciencedirect.com/science/article/pii/S1567576918313936?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/30925322?dopt=Abstract

Depression and its related parameters increased the production of autoantibodies against 16α-hydroxyestrone-albumin complex in systemic lupus erythematosus.

Int Immunopharmacol. 2019 Mar 26;71:215-223

Authors: Khan WA, Zaman GS, Alouffi S, Khan MWA

Abstract

Depression is the common and early symptoms associated with early onset of SLE, 16α-hydroxyestrone (16α-OHE1) levels were found to be significantly higher in serum and urine in patients with SLE. This study was carried out in order to know whether depression and its related parameters in the SLE patients enhanced the production of autoantibodies against 16α-OHE1-albumin (A) complexes. The autoantibodies in the serum of 100 SLE [including 65 depressed SLE (DSLE)] patients and 37 control subjects were detected by using direct binding, inhibition ELISA and quantitative precipitin titration. Autoantibodies from DSLE patients (and also the patients who were taken anti-depressant and with neurological symptoms) showed high binding to 16α-OHE1-A in contrast to SLE (p < 0.05) and control subjects (p < 0.001). Although, SLE sera showed high recognition to 16α-OHE1-A in comparison to A (p < 0.05) or 16α-OHE1 (p < 0.001). The affinity of autoantibodies for 16α-OHE1-A was found to be high for DSLE (1.16 × 10-7 M) and SLE (1.24 × 10-7 M) patients as detected by Langmuir plot. The concentration of 16α-OHE1 (p < 0.05) and inflammatory cytokines (IL-6, p < 0.05 and IL-17, p < 0.001) in the serum of SLE patients was found to be significantly higher than controls. Depression and its related parameters in SLE enhanced the production of autoantibodies against 16α-OHE1-A through the generation of inflammatory conditions. Depression in SLE patients increased the release of pro-inflammatory cytokine (IL-6 and IL-17) that in turn generating more autoantibodies and showed strong recognition to 16α-OHE1-A. PMID: 30925322 [PubMed - as supplied by publisher] PubMed:30925322

https://www.nature.com/articles/s41598-019-41534-1

https://www.ncbi.nlm.nih.gov/pubmed/30914691?dopt=Abstract

Related Articles

Inhibition of IL-17 ameliorates systemic lupus erythematosus in Roquinsan/san mice through regulating the balance of TFH cells, GC B cells, Treg and Breg.

Sci Rep. 2019 Mar 26;9(1):5227

Authors: Lee SY, Lee SH, Seo HB, Ryu JG, Jung K, Choi JW, Jhun J, Park JS, Kwon JY, Kwok SK, Youn J, Park SH, Cho ML

Abstract

Systemic lupus erythematosus (SLE) is mediated by a chronic and dysregulated inflammatory response. Interleukin (IL)-17, a proinflammatory cytokine, and T helper (Th)17 cells are associated with chronic autoimmune diseases. We hypothesized that inhibition of IL-17 would decrease the numbers of T cell subsets that function as B-cell helpers, as well as B-cell differentiation into plasma cells and autoantibody expression. The IL-17 level was increased markedly in Roquinsan/san mice. Loss of IL-17 in Roquinsan/san mice improved nephritis by downregulating immunoglobulin (Ig)G, IgG1, and IgG2a production. Formation of germinal centers (GCs), and follicular B- and T-cell differentiation was reduced, whereas the number of regulatory T (Treg) cells and immature B cells was increased, by IL-17 deficiency in Roquinsan/san mice. These results suggest that IL-17 inhibition can ameliorate SLE by inhibiting B-cell differentiation into GCs. Therefore, IL-17-producing Th17 cells show promise as a target for development of novel therapeutics for SLE.

PMID: 30914691 [PubMed – in process]

PubMed:30914691

https://www.mdpi.com/1422-0067/20/6/1354

https://www.ncbi.nlm.nih.gov/pubmed/30889825?dopt=Abstract

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Decreased Protein Kinase C-β Type II Associated with the Prominent Endotoxin Exhaustion in the Macrophage of FcGRIIb-/- Lupus Prone Mice is Revealed by Phosphoproteomic Analysis.

Int J Mol Sci. 2019 Mar 18;20(6):

Authors: Ondee T, Jaroonwitchawan T, Pisitkun T, Gillen J, Nita-Lazar A, Leelahavanichkul A, Somparn P

Abstract

Dysfunction of FcGRIIb, the only inhibitory receptor of the FcGR family, is commonly found in the Asian population and is possibly responsible for the extreme endotoxin exhaustion in lupus. Here, the mechanisms of prominent endotoxin (LPS) tolerance in FcGRIIb-/- mice were explored on bone marrow-derived macrophages using phosphoproteomic analysis. As such, LPS tolerance decreased several phosphoproteins in the FcGRIIb-/- macrophage, including protein kinase C-β type II (PRKCB), which was associated with phagocytosis function. Overexpression of PRKCB attenuated LPS tolerance in RAW264.7 cells, supporting the role of this gene in LPS tolerance. In parallel, LPS tolerance in macrophages and in mice was attenuated by phorbol 12-myristate 13-acetate (PMA) administration. This treatment induced several protein kinase C families, including PRKCB. However, PMA attenuated the severity of mice with cecal ligation and puncture on LPS tolerance preconditioning in FcGRIIb-/- but not in wild-type cells. The significant reduction of PRKCB in the FcGRIIb-/- macrophage over wild-type cell possibly induced the more severe LPS-exhaustion and increased the infection susceptibility in FcGRIIb-/- mice. PMA induced PRKCB, improved LPS-tolerance, and attenuated sepsis severity, predominantly in FcGRIIb-/- mice. PRKCB enhancement might be a promising strategy to improve macrophage functions in lupus patients with LPS-tolerance from chronic infection.

PMID: 30889825 [PubMed – in process]

PubMed:30889825

http://www.haematologica.org/content/early/2019/03/11/haematol.2018.209536

https://www.ncbi.nlm.nih.gov/pubmed/30872365?dopt=Abstract

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Interleukin-17/Interleukin-21 and Interferon-g producing T cells specific for β2 Glycoprotein I in atherosclerosis inflammation of systemic lupus erythematosus patients with antiphospholipid syndrome.

Haematologica. 2019 Mar 14;:

Authors: Benagiano M, Borghi MO, Romagnoli J, Mahler M, Della Bella C, Grassi A, Capitani N, Emmi G, Troilo A, Silvestri E, Emmi L, Alnwaisri H, Bitetti J, Tapinassi S, Prisco D, Baldari CT, Meroni PL, D’Elios MM

Abstract

Systemic lupus erythematosus is frequently associated with antiphospholipid syndrome. Patients with lupus-antiphospholipid syndrome are characterized by recurrent arterial/venous thrombosis, miscarriages, and persistent presence of autoantibodies against phospholipid-binding proteins, such as β2-Glycoprotein I. We investigated the cytokine production induced by β2-Glycoprotein I in activated T cells that infiltrate in vivo atherosclerotic lesions of lupus-antiphospholipid syndrome patients. We examined the helper function of β2-Glycoprotein I-specific T cells for the tissue factor production, as well as their cytolytic potential and their helper function for antibody production. Lupus-antiphospholipid syndrome patients harbor in vivo activated CD4+ T cells that recognize β2-Glycoprotein I in atherosclerotic lesions. β2-Glycoprotein I induces T cell proliferation and expression of both Interleukin-17/Interleukin-21 and Interferon-γ in plaque-derived T cell clones. β2-Glycoprotein I-specific T cells display strong help for monocyte tissue factor production, and promote antibody production in autologous B cells. Moreover, plaque-derived β2-Glycoprotein I-specific CD4+ T lymphocytes express both perforin-mediated and Fas/FasLigand-mediated-cytotoxicity. Altogether, our results indicate that β2-Glycoprotein I is able to elicit a local Interleukin-17/Interleukin-21 and Interferon-γ inflammation in lupus-antiphospholipid syndrome patients that might lead, if unabated, to plaque instability and subsequent arterial thrombosis, suggesting that the T helper 17/T helper 1 pathway may represent a novel target for the prevention and treatment of the disease.

PMID: 30872365 [PubMed – as supplied by publisher]

PubMed:30872365

https://www.dovepress.com/efficacy-and-safety-of-tacrolimus-in-induction-therapy-of-patients-wit-peer-reviewed-article-DDDT

https://www.ncbi.nlm.nih.gov/pubmed/30880918?dopt=Abstract

Efficacy and safety of tacrolimus in induction therapy of patients with lupus nephritis.

Drug Des Devel Ther. 2019;13:857-869

Authors: Zhou T, Lin S, Yang S, Lin W

Abstract

Background: The purpose of this study was to detect the efficacy and safety of tacrolimus (TAC) in induction therapy of patients with lupus nephritis.

Methods: Associated studies were extracted from the PubMed and the Cochrane Library on July 10, 2018, and applicable investigations were pooled and analyzed by meta-analysis. Data on complete remission (CR), total remission (TR; complete plus partial remission), proteinuria levels, urine erythrocyte number, albumin, glomerular filtration rate, negative rate of ds-DNA, C3 levels, C4 levels, systemic lupus erythematosus disease activity index (SLE-DAI), etc, were extracted and pooled using RevMan 5.3.

Results: In the therapeutic regimen of TAC + glucocorticoids (GC) vs cyclophosphamide (CYC) + GC, the results indicated that the TAC group had high values of CR, TR, albumin, and negative rate of ds-DNA, and low values of proteinuria levels and SLE-DAI when compared with those in CYC group (all P<0.05). In the therapeutic regimen comprising TAC + GC vs mycophenolate mofetil (MMF) + GC, the results indicated that the difference of CR, TR, proteinuria levels, and albumin between TAC group and MMF group were not significant (all P>0.05). In the therapeutic regimen comprising TAC + MMF + GC vs CYC + GC, multitarget therapy group showed higher values of CR, TR, urinary protein decline, and rise of serum albumin when compared with CYC group (all P<0.05). Conclusion: TAC is an effective and safe agent in induction therapy of patients with lupus nephritis. PMID: 30880918 [PubMed - in process] PubMed:30880918

https://www.dovepress.com/clinical-efficacy-and-safety-of-rituximab-in-lupus-nephritis-peer-reviewed-article-DDDT

https://www.ncbi.nlm.nih.gov/pubmed/30880917?dopt=Abstract

Clinical efficacy and safety of rituximab in lupus nephritis.

Drug Des Devel Ther. 2019;13:845-856

Authors: Zhong Z, Li H, Zhong H, Zhou T

Abstract

Background: Long-term treatment programs with low toxicity represent a therapeutic challenge in lupus nephritis (LN). Although a therapeutic benefit of rituximab (RTX) has been reported in LN patients who have failed conventional treatment, the results are controversial. We aimed to assess the clinical efficacy and safety of RTX as a new immunosuppressive medicine in the treatment of LN with a meta-analysis.

Methods: Based on predetermined criteria, PubMed, Embase, and Cochrane Library were used to identify the eligible studies. Cochrane Review Manager version 5.3 was applied to pool the data extracted from individual investigations and provide summary effect estimates.

Results: Twenty-four studies with 940 patients were analyzed. In case series trials with specific LN assessment, the complete remission (CR) rate at 12 months was 35.9% (95% CI: 24.2%-49.5%), and total remission (TR: CR plus partial remission) was 73.4% (95% CI: 66.0%-79.7%). In controlled trials, RTX was associated with a higher probability of TR (OR =2.02, 95% CI: 1.23-3.32, P<0.01). The CR in the RTX group was higher than that in the control group, although there was no significant difference between the two groups (OR =1.98, 95% CI: 0.90-4.39, P>0.05). Additionally, RTX treatment significantly decreased proteinuria (mean difference: -2.79, 95% CI: -3.95 to -1.62, P<0.01) as well as the renal activity index in patients with LN (mean difference: -3.46, 95% CI: -4.43 to -2.50, P<0.01). In controlled trials, the relative risks of the adverse events of infection and infusion reaction were not notably different between the two groups. Conclusion: RTX is a promising therapy for the treatment of LN due to significant clinical efficacy and a favorable safety profile. In future studies, larger study populations and longer-term time points may identify additional important patient-centered outcomes. PMID: 30880917 [PubMed - in process] PubMed:30880917

http://stm.sciencemag.org/content/11/482/eaav1648