scholarly journals Niclosamide Suppresses the Expansion of Follicular Helper T Cells and Alleviates Disease Severity in Two Murine Models of Lupus via STAT3

2020 ◽  
Author(s):  
Se Gwang Jang ◽  
Jaeseon Lee ◽  
Seung-Min Hong ◽  
Young-Seok Song ◽  
Min Jun Kim ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Plasma Cells ◽  
Immune Cell ◽  
Parasitic Infections ◽  
Therapeutic Effects ◽  
Murine Models ◽  
Autoantibody Production ◽  
Follicular Helper ◽  
Dsdna Antibody ◽  
Models Of Lupus

Abstract Background. Autoantibody production against endogenous cellular components is pathogenic feature of systemic lupus erythematosus (SLE). Follicular helper T (TFH) cells aid in B cell differentiation into autoantibody-producing plasma cells (PCs). The IL-6 and IL-21 cytokine-mediated STAT3 signaling are crucial for the differentiation to TFH cells. Niclosamide is an anti-helminthic drug used to treat parasitic infections but also exhibits a therapeutic effect on autoimmune diseases due to its potential immune regulatory effects. In this study, we examined whether Niclosamide treatment could relieve lupus-like autoimmunity by modulating the differentiation of TFH cells in two murine models of lupus.Methods. 10-week-old MRL/lpr mice were orally administered with 100 mg/kg of Niclosamide or with 0.5% methylcellulose (MC, vehicle) daily for 7 weeks. TLR7 agonist, resiquimod was topically applied to an ear of 8-week-old C57BL/6 mice 3 times a week for 5 weeks. And they were orally administered with 100 mg/kg of Niclosamide or with 0.5% MC daily for 5 weeks. Every mouse was analyzed for lupus nephritis, proteinuria, autoantibodies, immune complex, immune cell subsets at the time of the euthanization.Results. Niclosamide treatment greatly improved proteinuria, anti-dsDNA antibody levels, immunoglobulin subclass titers, histology of lupus nephritis, and C3 deposition in MRL/lpr and R848-induced mice. In addition, Niclosamide inhibited the proportion of TFH cells and PCs in the spleens of these animals, and effectively suppressed differentiation of TFH-like cells and expression of associated genes in vitro.Conclusions. Niclosamide exerted therapeutic effects on murine lupus models by suppressing TFH cells and plasma cells through STAT3 inhibition.

scholarly journals Niclosamide suppresses the expansion of follicular helper T cells and alleviates disease severity in two murine models of lupus via STAT3

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Se Gwang Jang ◽  
Jaeseon Lee ◽  
Seung-Min Hong ◽  
Young-Seok Song ◽  
Min Jun Kim ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Plasma Cells ◽  
Immune Cell ◽  
Parasitic Infections ◽  
Therapeutic Effects ◽  
Murine Models ◽  
Autoantibody Production ◽  
Follicular Helper ◽  
Dsdna Antibody ◽  
Models Of Lupus

Abstract Background Autoantibody production against endogenous cellular components is pathogenic feature of systemic lupus erythematosus (SLE). Follicular helper T (TFH) cells aid in B cell differentiation into autoantibody-producing plasma cells (PCs). The IL-6 and IL-21 cytokine-mediated STAT3 signaling are crucial for the differentiation to TFH cells. Niclosamide is an anti-helminthic drug used to treat parasitic infections but also exhibits a therapeutic effect on autoimmune diseases due to its potential immune regulatory effects. In this study, we examined whether niclosamide treatment could relieve lupus-like autoimmunity by modulating the differentiation of TFH cells in two murine models of lupus. Methods 10-week-old MRL/lpr mice were orally administered with 100 mg/kg of niclosamide or with 0.5% methylcellulose (MC, vehicle) daily for 7 weeks. TLR7 agonist, resiquimod was topically applied to an ear of 8-week-old C57BL/6 mice 3 times a week for 5 weeks. And they were orally administered with 100 mg/kg of niclosamide or with 0.5% MC daily for 5 weeks. Every mouse was analyzed for lupus nephritis, proteinuria, autoantibodies, immune complex, immune cell subsets at the time of the euthanization. Results Niclosamide treatment greatly improved proteinuria, anti-dsDNA antibody levels, immunoglobulin subclass titers, histology of lupus nephritis, and C3 deposition in MRL/lpr and R848-induced mice. In addition, niclosamide inhibited the proportion of TFH cells and PCs in the spleens of these animals, and effectively suppressed differentiation of TFH-like cells and expression of associated genes in vitro. Conclusions Niclosamide exerted therapeutic effects on murine lupus models by suppressing TFH cells and plasma cells through STAT3 inhibition.

scholarly journals Basophils and Systemic Lupus Erythematosus in Murine Models and Human Patients

Biology ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 308
Author(s):  
Kuanysh Dossybayeva ◽  
Diyora Abdukhakimova ◽  
Dimitri Poddighe
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Tissue Injury ◽  
Adaptive Immune Response ◽  
Parasitic Infections ◽  
Murine Models ◽  
Systemic Lupus ◽  
Autoantibody Production ◽  
Adaptive Immune ◽  
Models Of Lupus

Basophils are the rarest cell population in the blood. Even though basophils are known to participate in some allergic reactions and immune responses to parasitic infections, their immunological role is still largely elusive. Recent evidence has suggested that in some murine models of systemic lupus erythematosus and lupus-like nephritis, basophils may also be implicated in autoimmunity processes by promoting autoantibody production and tissue injury. We conducted a systematic search to collect the available evidence on basophils’ potential immunomodulatory role in autoimmunity and, particularly, systemic lupus erythematosus. We identified several articles investigating basophils’ role in murine models of lupus (n = 3) and in patients affected with systemic lupus erythematosus (n = 8). Even though the alteration of the “adaptive” immune response is considered the main immunopathological event in systemic lupus erythematosus, the contribution from the mechanisms of “innate” immunity and, particularly, basophils may be relevant as well, by modulating the activation, polarization, and survival of lymphocytes.

scholarly journals Amiselimod (MT-1303), a Novel Sphingosine 1-Phosphate Receptor-1 Modulator, Potently Inhibits the Progression of Lupus Nephritis in Two Murine SLE Models

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Kunio Sugahara ◽  
Yasuhiro Maeda ◽  
Kyoko Shimano ◽  
Mikako Murase ◽  
Sachiko Mochiduki ◽  
...  
Keyword(s):  
T Cells ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Plasma Cells ◽  
Glomerular Sclerosis ◽  
Therapeutic Effects ◽  
Dsdna Antibody ◽  
Sphingosine 1 Phosphate ◽  
Murine Systemic Lupus Erythematosus ◽  
Antibody Levels

Amiselimod (MT-1303) is a novel and selective sphingosine 1-phosphate receptor-1 (S1P1) modulator with a more favorable cardiac safety profile than other S1P1 receptor modulators. In this study, we evaluated the effects of MT-1303 on the progression of lupus nephritis in two well-known murine systemic lupus erythematosus (SLE) models, MRL/lpr and NZBWF1 mice, compared with those of FK506. Daily oral doses of 0.1 and 0.3 mg/kg MT-1303 not only inhibited the development of lupus nephritis when administered before onset in MRL/lpr and NZBWF1 mice but also improved symptoms of lupus nephritis when administered after onset in MRL/lpr mice. Its efficacy in these models was more potent or comparable to that of FK506 (1 and 3 mg/kg). In histological analysis, treatment with MT-1303 inhibited infiltration of T cells into the kidneys, mesangial expansion, and glomerular sclerosis. MT-1303 treatment resulted in a marked reduction in T cells and B cells in the peripheral blood and significantly inhibited increases in the number of plasma cells in the spleen and T cells in the kidneys. In addition, administration of MT-1303 suppressed elevations in serum anti-dsDNA antibody levels in MRL/lpr mice, but not in NZBWF1 mice. Our findings show that MT-1303 exhibits marked therapeutic effects on lupus nephritis in two SLE models, likely by reducing the infiltration of autoreactive T cells into the kidneys. These results suggest that MT-1303 has the potential to be used as a therapeutic agent for patients suffering from SLE, including lupus nephritis.

scholarly journals THU0236 EFFICACY AND SAFETY OF NON-MITOGENIC ANTICD3 ANTIBODY ADMINISTRATION IN THE TREATMENT OF LUPUS-PRONE MICE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 345.1-345
Author(s):  
M. Morita ◽  
S. Masuyama ◽  
M. Mizui ◽  
Y. Isaka
Keyword(s):  
T Cells ◽  
Antibody Titer ◽  
Cell Function ◽  
Cell Subpopulation ◽  
Target Cells ◽  
Therapeutic Effects ◽  
Autoantibody Production ◽  
Rate Of Increase ◽  
Dsdna Antibody ◽  
The Difference

Background:Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the production of autoantibody and systemic tissue damages including glomerulonephritis. Immune responses mediated by autoreactive T-cells, as well as by autoantibody, is involved in the development and progression of end-organ damages1. Biologic agents which manipulate T-cell function such as CTLA4-Ig and anti-CD40L have been revisited and tried to treat human SLE, however, both of them failed to demonstrate efficacy.A mouse specific anti-CD3ε mAb, clone 145-2C11 (2C11) is known to be immunosuppressive by down-modulation of TCR and depletion of T-cells2. Administration of Fc-deleted 145-2C11 F(ab’)2to lupus-prone mice was reported to reduce lymphadenopathy and prolong survival, but had no significant effect on anti-DNA antibody titer3. The mechanisms by which 2C11 ameliorates lupus are still unclear.In this study, we used non-mitogenic Fc-modified silent 145-2c11 (2C11S), which disables interaction between target cells and Fc receptor-bearing cells, abolishes antibody directed cytotoxicity, and has longer half-life than F(ab’)2. 2C11S is expected to exert its effect in safe and stable as compared with functional parent-2C11 (2C11P) antibody.Objectives:The purpose of our study is to clarify the difference between 2C11S and 2C11P and to examine their therapeutic effects against murine lupus-prone (NZB/W F1) mice.Methods:20 μg of 2C11P (absolute antibody), 2C11S (absolute antibody), or isotype control immunoglobulin G1 κ (IC)(BioLegend) were administered intraperitoneally to C57BL6 mice. The difference of their action on T-cells were evaluated in a time series from peripheral blood. Plasma cytokine levels were measured within 24 hours after antibody administration.In NZB/W F1 mice from weeks 10 or 20, 2C11P, 2C11S, and IC were administered (100 μg / week, 4 times, intraperitoneally). Plasma anti-dsDNA antibody titer, spleen and kidney blood cell subpopulation, and histology of renal tissue were evaluated before and/or after treatment.Results:Duration of reduced TCR expression in 2C11S group was approximately twice as long as that in 2C11P group, and the levels of plasma TNF-α was not increased in 2C11S group while significant increase was observed in 2C11P group (IC; mean 48.3 ± SD 16.7 pg/ml, 2C11S; 57.9 ± 6.12, 2C11P; 168 ± 50.6, IC VS 2C11S; p>0.99, IC VS 2C11P; p=0.03, ANOVA).In NZB/W F1 mice, the number of follicular helper T (Tfh) cells in spleen significantly decreased in 2C11S group (IC; median 9.0*104[interquartile range 8.5*104], 2C11S; 1.8*104[1.0*104], 2C11P; 1.0*105[9.4*104], IC VS 2C11S; p=0.03, IC VS 2C11P; p>0.99, Kruskal-Wallis). The number of germinal center B (GCB) cells in spleen also decreased in 2C11S group (IC; 1.2*105[1.7*105], 2C11S; 9.0*103[2.3*104], 2C11P; 8.0*104[2.3*105], IC VS 2C11S; p=0.03, IC VS 2C11P; p>0.99). The number of infiltrating CD4+T-cells in kidney significantly reduced in 2C11S group (IC; 3.4*103[1.0*104], 2C11S; 6.4*102[8.8*102], 2C11P; 1.2*103[4.4*103], IC VS 2C11S; p=0.048, IC VS 2C11P; p=0.23). In addition, the rate of increase in anti-dsDNA IgG titers significantly decreased in 2C11S group (IC; 2.3 [1.3], 2C11S; 0.9 [1.0], 2C11P; 1.3 [1.4], IC VS 2C11S; p=0.03, IC VS 2C11P; p=0.24). Finally, glomerular hypercellularity was markedly alleviated only in 2C11S group (IC; 4.4*10 [8.4], 2C11S; 3.8*10 [1.1], 2C11P; 3.9*10 [8.2], IC VS 2C11S; p=0.02, IC VS 2C11P; p=0.57).Conclusion:2C11S did not induce cytokine release with maintaining longer effect on TCR down-modulation. 2C11S reduced autoantibody production by suppressing GCB differentiation, possibly through down-regulation of Tfh cell number. Consequently, 2C11S ameliorated lupus nephritis. On the other hand, 2C11P did not show therapeutic effect.References:[1]George C Tsokos. et al. Nat. Rev. Rheum (2016) 12: 716-730.[2]Kuhn C. et al. Immunotherapy (2016) 8: 889-906.[3]Henrickson M. et al. Arthritis Rheum (1994) 37: 587-589.Disclosure of Interests: :None declared

scholarly journals High-Dimensional Immunophenotyping of Murine T-cell and B-cell Subsets

2020 ◽  
Author(s):  
Kyle T. Mincham ◽  
Jacob D. Young ◽  
Deborah H. Strickland
Keyword(s):  
T Cell ◽  
B Cell ◽  
Plasma Cells ◽  
Effector Memory ◽  
High Dimensional ◽  
Cell Populations ◽  
Lymphoid Tissues ◽  
Murine Models ◽  
Follicular Helper ◽  
B Cell Subsets

Purpose and appropriate sample typesThis 19-parameter, 18-colour flow cytometry panel was designed and optimised to enable the comprehensive and simultaneous immunophenotyping of distinct T-cell and B-cell subsets within murine lymphoid tissues (Table 1). Cellular populations identified by employing this OMIP include 4 major subsets of B-cells (memory, activated, plasma cells and plasmablasts) and 7 major subsets of CD4+ T-cells (naïve, central memory, effector memory, helper, regulatory, follicular helper and follicular regulatory). Staining was performed on freshly isolated splenocytes from 21-day-old neonatal BALB/c mice, however due to the omission of mouse strain-specific markers, this OMIP can be implemented across a range of murine models where in-depth immunophenotyping of the diverse repertoire of T-cell and B-cell populations localised within lymphoid tissues is required.

scholarly journals Differential immune cell infiltrations between healthy periodontal and chronic periodontitis tissues

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Wei Li ◽  
Zheng Zhang ◽  
Zuo-min Wang
Keyword(s):  
T Cells ◽  
B Cells ◽  
Mast Cells ◽  
Plasma Cells ◽  
Immune Cell ◽  
Memory T Cells ◽  
Host Immunity ◽  
Memory B Cells ◽  
Helper T Cells ◽  
Follicular Helper

Abstract Background Host immunity plays an important role against oral microorganisms in periodontitis. Methods This study assessed the infiltrating immune cell subtypes in 133 healthy periodontal and 210 chronic periodontitis tissues from Gene Expression Omnibus (GEO) datasets using the CIBERSORT gene signature files. Results Plasma cells, naive B cells and neutrophils were all elevated in periodontitis tissues, when compared to those in healthy controls. In contrast, memory B cells, resting dendritic, mast cells and CD4 memory cells, as well as activated mast cells, M1 and M2 macrophages, and follicular helper T cells, were mainly present in healthy periodontal tissues. Furthermore, these periodontitis tissues generally contained a higher proportion of activated CD4 memory T cells, while the other subtypes of T cells, including resting CD4 memory T cells, CD8 T cells, follicular helper T cells (TFH) and regulatory T cells (Tregs), were relatively lower in periodontitis tissues, when compared to healthy tissues. The ratio of dendritic and mast cells and macrophages was lower in periodontitis tissues, when compared to healthy tissues. In addition, there was a significant negative association of plasma cells with most of the other immune cells, such as plasma cells vs. memory B cells (γ = − 0.84), plasma cells vs. resting dendritic cells (γ = − 0.64), plasma cells vs. resting CD4 memory T cells (γ = 0.50), plasma cells versus activated dendritic cells (γ = − 0.46), plasma cells versus TFH (γ = − 0.46), plasma cells versus macrophage M2 cells (γ = − 0.43), or plasma cells versus macrophage M1 cells (γ = − 0.40), between healthy control and periodontitis tissues. Conclusion Plasma cells, naive B cells and neutrophils were all elevated in periodontitis tissues. The infiltration of different immune cell subtypes in the periodontitis site could lead the host immunity against periodontitis.

scholarly journals Intermittent Fasting Aggravates Lupus Nephritis through Increasing Survival and Autophagy of Antibody Secreting Cells in MRL/lpr Mice

2020 ◽  
Vol 21 (22) ◽  
pp. 8477
Author(s):  
Seung-Min Hong ◽  
Jaeseon Lee ◽  
Se Gwang Jang ◽  
Youngseok Song ◽  
Minjun Kim ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Lupus Nephritis ◽  
Immune Complex ◽  
Lupus Erythematosus ◽  
Plasma Cells ◽  
Clinicopathological Parameters ◽  
Control Group ◽  
Intermittent Fasting ◽  
Glomerular Injury ◽  
Dsdna Antibody

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the main contributors to organ damage are antibodies against autoantigens, such as double-stranded DNA (dsDNA). Calorie restriction and intermittent fasting (IF) have been shown to improve autoimmune disease symptoms in patients and animal models. Here, we tested the hypothesis that IF might improve symptoms in MRL/lpr mice, which spontaneously develop an SLE-like disease. Groups of mice were fed every other day (IF) or provided food ad libitum (controls), and various lupus-associated clinicopathological parameters were analyzed for up to 28 weeks. Contrary to expectations, anti-dsDNA antibody levels, immune complex deposition in the kidney, and glomerular injury were higher in the IF group than the control group, although there were no differences in spleen and lymph node weights between groups. Proteinuria was also worsened in the IF group. IF also increased the abundance of B cells, plasmablasts, and plasma cells and elevated autophagy in plasma cells in the spleen and lymph nodes. Secretion of anti-dsDNA antibody by splenocytes in vitro was reduced by chloroquine-induced inhibition of autophagy. These results suggest that IF exacerbates lupus nephritis in MRL/lpr mice by increasing autoantibody immune complex formation.

scholarly journals Recent advances in the understanding of renal inflammation and fibrosis in lupus nephritis

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 874 ◽  
Author(s):  
Susan Yung ◽  
Desmond YH Yap ◽  
Tak Mao Chan
Keyword(s):  
Lupus Nephritis ◽  
Treatment Options ◽  
Critical Role ◽  
Fibrous Tissue ◽  
Kidney Injury ◽  
High Dose ◽  
Renal Cells ◽  
Autoantibody Production ◽  
Recent Advances ◽  
Dsdna Antibody

Lupus nephritis is a potentially reversible cause of severe acute kidney injury and is an important cause of end-stage renal failure in Asians and patients of African or Hispanic descent. It is characterized by aberrant exaggerated innate and adaptive immune responses, autoantibody production and their deposition in the kidney parenchyma, triggering complement activation, activation and proliferation of resident renal cells, and expression of pro-inflammatory and chemotactic molecules leading to the influx of inflammatory cells, all of which culminate in destruction of normal nephrons and their replacement by fibrous tissue. Anti-double-stranded DNA (anti-dsDNA) antibody level correlates with disease activity in most patients. There is evidence that apart from mediating pathogenic processes through the formation of immune complexes, pathogenic anti-dsDNA antibodies can bind to resident renal cells and induce downstream pro-apoptotic, pro-inflammatory, or pro-fibrotic processes or a combination of these. Recent data also highlight the critical role of macrophages in acute and chronic kidney injury. Though clinically effective, current treatments for lupus nephritis encompass non-specific immunosuppression and the anti-inflammatory action of high-dose corticosteroids. The clinical and histological impact of novel biologics targeting pro-inflammatory molecules remains to be investigated. Insight into the underlying mechanisms that induce inflammatory and fibrotic processes in the kidney of lupus nephritis could present opportunities for more specific novel treatment options to improve clinical outcomes while minimizing off-target untoward effects. This review discusses recent advances in the understanding of pathogenic mechanisms leading to inflammation and fibrosis of the kidney in lupus nephritis in the context of established standard-of-care and emerging therapies.

scholarly journals Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells

2017 ◽  
Vol 214 (5) ◽  
pp. 1259-1267 ◽  
Author(s):  
Nike J. Kräutler ◽  
Dan Suan ◽  
Danyal Butt ◽  
Katherine Bourne ◽  
Jana R. Hermes ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Protective Immunity ◽  
Plasma Cells ◽  
Discrete Subset ◽  
Autoantibody Production ◽  
High Affinity ◽  
Tfh Cells ◽  
Follicular Helper

Plasma cells (PCs) derived from germinal centers (GCs) secrete the high-affinity antibodies required for long-term serological immunity. Nevertheless, the process whereby GC B cells differentiate into PCs is uncharacterized, and the mechanism underlying the selective PC differentiation of only high-affinity GC B cells remains unknown. In this study, we show that differentiation into PCs is induced among a discrete subset of high-affinity B cells residing within the light zone of the GC. Initiation of differentiation required signals delivered upon engagement with intact antigen. Signals delivered by T follicular helper cells were not required to initiate differentiation but were essential to complete the differentiation process and drive migration of maturing PCs through the dark zone and out of the GC. This bipartite or two-signal mechanism has likely evolved to both sustain protective immunity and avoid autoantibody production.

Therapeutic potential of DCB-SLE1, an extract of a mixture of Chinese medicinal herbs, for severe lupus nephritis

2011 ◽  
Vol 301 (4) ◽  
pp. F751-F764 ◽  
Author(s):  
Pei-Yi Tsai ◽  
Shuk-Man Ka ◽  
Jia-Ming Chang ◽  
Wen-Liang Chang ◽  
Yuan-Jen Huang ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
B Cell ◽  
Cell Activation ◽  
Acute Onset ◽  
Medicinal Herbs ◽  
Autoimmune Response ◽  
Therapeutic Effects ◽  
Chinese Medicinal Herbs ◽  
Autoantibody Production ◽  
Severe Lupus Nephritis

The pathogenesis of lupus nephritis is mainly attributable to a complex interaction between the innate and adaptive immune systems, including T and B cell function abnormalities. In addition to autoantibody production and immune complex deposition, Th1 and Th17 cytokines may play key roles in the development and progression of lupus nephritis. Acute onset of severe lupus nephritis remains a challenge in terms of prevention and treatment. In the present study, we evaluated the therapeutic effects of DCB-SLE1, an extract of a mixture of four traditional Chinese medicinal herbs ( Atractylodis macrocephalae Rhizoma, Eucommiae cortex , Lonicerae caulis , and Hedyotidis diffusae Herba), on an accelerated severe lupus nephritis model, characterized by acute onset of proteinuria, azotemia, autoantibody production, and development of severe nephritis, induced by twice weekly injection of New Zealand black/white F1 mice with Salmonella -type lipopolysaccharide. DCB-SLE1 was administered daily by gavage starting 2 days after the first dose of induction of lipopolysaccharide, and the mice were euthanized at week 1 or week 5. The results showed that DCB-SLE1 significantly ameliorated the hematuria, proteinuria, renal dysfunction, and severe renal lesions by 1) suppression of B cell activation and decreased autoantibody production; 2) negative regulation of T cell activation/proliferation and natural killer cell activity; 3) suppression of IL-18, IL-6, and IL-17 production and blocking of NF-κB activation in the kidney; and 4) prevention of lymphoid and renal apoptosis. These results show that DCB-SLE1 can protect the kidney from autoimmune response-mediated acute and severe damage through systemic immune modulation and anti-inflammation pathways.

Sign in / Sign up

Export Citation Format

Share Document