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1.
Exp Dermatol ; 32(12): 2072-2083, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37726950

RESUMO

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune skin disease which occurs independently and in conjunction with systemic lupus erythematosus. Drug development for CLE is severely lacking. Anandamide (AEA) is a primary endocannabinoid which exhibits immunomodulatory effects through mixed cannabinoid receptor agonism. We evaluated AEA as topical treatment for CLE and assessed benefits of nanoparticle encapsulation (AEA-NP) on cutaneous drug penetration, delivery and biological activity. Compared to untreated controls, AEA-NP decreased IL-6 and MCP-1 in UVB-stimulated keratinocytes (p < 0.05) in vitro. In BALB/c mice, AEA-NP displayed improved cutaneous penetration, extended release and persistence of AEA in the follicular unit extending to the base after 24 h. Utilizing the MRL-lpr lupus murine model, twice weekly treatment of lesions with topical AEA-NP for 10 weeks led to decreased clinical and histologic lesion scores compared to unencapsulated AEA and untreated controls (p < 0.05). Prophylactic application of AEA-NP to commonly involved areas on MRL-lpr mice similarly resulted in decreased clinical and histologic scores when compared to controls (p < 0.05), and reduced C3 and IBA-1 in lesional tissue (p < 0.05). The demonstrated clinical and immunomodulatory effects of treatment with AEA support its potential as therapy for CLE. This work also suggests that encapsulation of AEA improves penetration and treatment efficacy. Future studies will be conducted to assess full therapeutic potential.


Assuntos
Lúpus Eritematoso Cutâneo , Lúpus Eritematoso Sistêmico , Camundongos , Animais , Citocinas , Endocanabinoides/farmacologia , Endocanabinoides/uso terapêutico , Modelos Animais de Doenças , Camundongos Endogâmicos MRL lpr , Lúpus Eritematoso Cutâneo/tratamento farmacológico
2.
J Clin Invest ; 132(1)2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-34981775

RESUMO

T cells are central to the pathogenesis of lupus nephritis (LN), a common complication of systemic lupus erythematosus (SLE). CD6 and its ligand, activated leukocyte cell adhesion molecule (ALCAM), are involved in T cell activation and trafficking. Previously, we showed that soluble ALCAM is increased in urine (uALCAM) of patients with LN, suggesting that this pathway contributes to disease. To investigate, uALCAM was examined in 1038 patients with SLE and LN from 5 ethnically diverse cohorts; CD6 and ALCAM expression was assessed in LN kidney cells; and disease contribution was tested via antibody blockade of CD6 in murine models of SLE and acute glomerulonephritis. Extended cohort analysis offered resounding validation of uALCAM as a biomarker that distinguishes active renal involvement in SLE, irrespective of ethnicity. ALCAM was expressed by renal structural cells whereas CD6 expression was exclusive to T cells, with elevated numbers of CD6+ and ALCAM+ cells in patients with LN. CD6 blockade in models of spontaneous lupus and immune-complex glomerulonephritis revealed significant decreases in immune cells, inflammatory markers, and disease measures. Our data demonstrate the contribution of the CD6/ALCAM pathway to LN and SLE, supporting its use as a disease biomarker and therapeutic target.


Assuntos
Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Moléculas de Adesão Celular Neuronais/imunologia , Proteínas Fetais/imunologia , Rim/imunologia , Nefrite Lúpica/imunologia , Ativação Linfocitária , Linfócitos T/imunologia , Animais , Feminino , Humanos , Rim/patologia , Nefrite Lúpica/patologia , Camundongos , Linfócitos T/patologia
3.
Nat Commun ; 12(1): 4447, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290243

RESUMO

Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-L-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-γ mediated STAT1/NF-κΒ pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1ß, IFN-γ, and IL-17 production, and inhibiting generation of effector CD8+ T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction. Overall, we propose that this biogenic amine is a crucial component of tryptophan-mediated immune tolerance.


Assuntos
Aminas Biogênicas/farmacologia , Imunomodulação/efeitos dos fármacos , Cinurenina/análogos & derivados , Animais , Aminas Biogênicas/metabolismo , Aminas Biogênicas/uso terapêutico , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Células Endoteliais , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Inflamação , Interferon gama/farmacologia , Cinurenina/metabolismo , Cinurenina/farmacologia , Cinurenina/uso terapêutico , Camundongos , NF-kappa B/metabolismo , Nefrite/tratamento farmacológico , Nefrite/imunologia , Psoríase/tratamento farmacológico , Psoríase/imunologia , Triptofano/metabolismo
4.
J Transl Autoimmun ; 4: 100075, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33409482

RESUMO

Engagement of Fcγ receptor IIb (FcγRIIb) suppresses B cell activation and represents a promising target for therapy in autoimmunity. Obexelimab is a non-depleting anti-human CD19 mAb with an Fc region engineered to have high affinity for human FcγRIIb, thereby co-engaging BCR and FcγRIIb. To assess its ability to suppress B cell activation in vivo, we generated non-autoimmune-prone C57BL/6 (B6) and SLE-prone NZM 2328 (NZM) mice in which the human FcγRIIb extracellular domain was knocked into the mouse Fcgr2b locus (B6.hRIIb and NZM.hRIIb mice, respectively, the latter retaining features of SLE). XENP8206, a mAb which bears the same FcγRIIb-enhanced human Fc domain as does obexelimab but which recognizes murine CD19 rather than human CD19, inhibited in vitro BCR-triggered activation of B cells from both B6.hRIIb and NZM.hRIIb mice. Following administration of XENP8206 to B6.hRIIb or NZM.hRIIb mice, B cell numbers in the spleen and lymph nodes remained stable but became hyporesponsive to BCR-triggered activation for at least 14 days. These findings demonstrate proof-of-principle that pharmacologic co-engagement of BCR and human FcγRIIb inhibits B cell activation in non-autoimmune and SLE-prone hosts while preserving B cell numbers. These observations lay a strong foundation for clinical trials in human SLE with agents that co-engage BCR and FcγRIIb. Moreover, B6.hRIIb and NZM.hRIIb should serve as powerful in vivo models in the elucidation of the cellular and molecular underpinnings of the changes induced by BCR/FcγRIIb co-engagement.

5.
Clin Immunol ; 223: 108640, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33296718

RESUMO

Lupus nephritis (LN) is a serious end organ complication of systemic lupus erythematosus. Nephrotoxic serum nephritis (NTN) is an inducible model of LN, which utilizes passive transfer of pre-formed nephrotoxic antibodies to initiate disease. In previous studies, we demonstrated that the Bruton's tyrosine kinase inhibitor, BI-BTK-1, prevents the development of nephritis in NTN when treatment was started prior to nephrotoxic serum transfer, and reverses established proteinuria as well. We manipulated the initiation and duration of BI-BTK-1 therapy in NTN to study its delayed therapeutic effects when treatment is given later in the disease course, as well as to further understand what effect BI-BTK-1 is having to prevent initiation of nephritis with early treatment. Early treatment and remission induction each correlated with decreased inflammatory macrophages, CD4+ and CD8+ T cells, and decreased B220+ B cells. Additionally, an increased proportion of resident macrophages within the CD45+ population favored a delay of disease onset and remission induction. We also studied the cellular processes involved in reactivation of nephritis by withdrawing BI-BTK-1 treatment at different time points. Treatment cessation led to either early or later onset of renal flares inversely dependent on the initial duration of BTK inhibition, as assessed by increased proteinuria and BUN levels and worse renal pathology. These flares were associated with an increase in kidney CD45+ infiltrates, including myeloid cell populations. IL-6, CD14, and CCL2 were also increased in mice developing late flares. These analyses point to the role of macrophages as an important contributor to the pathogenesis of immune mediated nephritis, and further support the therapeutic potential of BTK inhibition in this disease and related conditions.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Rim/patologia , Nefrite Lúpica/tratamento farmacológico , Macrófagos/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Humanos , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Camundongos da Linhagem 129 , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteinúria
6.
Front Med (Lausanne) ; 7: 471, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32974370

RESUMO

A growing body of evidence demonstrates that asymptomatic and pre-symptomatic transmission of SARS-CoV-2 is a major contributor to the COVID-19 pandemic. Frontline healthcare workers in COVID-19 hotspots have faced numerous challenges, including shortages of personal protective equipment (PPE) and difficulties acquiring clinical testing. The magnitude of the exposure of healthcare workers and the potential for asymptomatic transmission makes it critical to understand the incidence of infection in this population. To determine the prevalence of asymptomatic SARS-CoV-2 infection amongst healthcare workers, we studied frontline staff working in the Montefiore Health System in New York City. All participants were asymptomatic at the time of testing and were tested by RT-qPCR and for anti-SARS-CoV-2 antibodies. The medical, occupational, and COVID-19 exposure histories of participants were recorded via questionnaires. Of the 98 asymptomatic healthcare workers tested, 19 (19.4%) tested positive by RT-qPCR and/or ELISA. Within this group, four (4.1%) were RT-qPCR positive, and four (4.1%) were PCR and IgG positive. Notably, an additional 11 (11.2%) individuals were IgG positive without a positive PCR. Two PCR positive individuals subsequently developed COVID-19 symptoms, while all others remained asymptomatic at 2-week follow-up. These results indicate that there is considerable asymptomatic infection with SARS-CoV-2 within the healthcare workforce, despite current mitigation policies. Furthermore, presuming that asymptomatic staff are not carrying SARS-CoV-2 is inconsistent with our results, and this could result in amplified transmission within healthcare settings. Consequently, aggressive testing regiments, such as testing frontline healthcare workers on a regular, multi-modal basis, may be required to prevent further spread within the workforce and to patients.

7.
Front Immunol ; 11: 1476, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32765512

RESUMO

Objective: In systemic lupus erythematosus (SLE), widespread T cell infiltration into target organs contributes to inflammation and organ damage. Autoreactive T cells become aberrantly activated in this disease due to dysfunctional T cell receptor signaling that lowers the activation threshold. Characterizing the T cell repertoire can provide further insight into the specific homing and proliferation of these T cells into lupus target organs. In the spontaneous lupus model, MRL/lpr, the TCR repertoire has not been fully elucidated, especially for T cells infiltrating the brain. Our aim was to investigate and compare the TCR repertoire between MRL/lpr mice and its congenic controls, MRL/MpJ, and within MRL/lpr tissues. Methods: Spleen, salivary gland, and brain choroid plexus were isolated from female MRL/lpr mice and MRL/MpJ mice. The TCRß CDR3 region was analyzed by multiplex PCRs and sequencing. Results: Significant differences were seen not only between the MRL/lpr and MRL/MpJ spleens, but also between MRL/lpr tissues. The TCR repertoire in MRL/lpr choroid plexus tissues had significantly increased clonality and sequence homology compared to MRL/lpr spleen and salivary gland. The consensus sequence, CASSQDWGGYEQYFF, was identified in the MRL/lpr choroid plexus repertoire. Conclusions: The TCR repertoire in lupus prone mice is not uniform between target organs, and suggests that T cells are specifically recruited into the choroid plexus of MRL/lpr mice. Further studies are needed to determine the antigen specificities for these infiltrating T cells in target organs of lupus mice, and their possible contribution to the pathogenesis of neuropsychiatric disease and other lupus manifestations.


Assuntos
Encéfalo/imunologia , Plexo Corióideo/imunologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/genética , Camundongos , Camundongos Endogâmicos MRL lpr , Transdução de Sinais
8.
Arthritis Rheumatol ; 72(2): 292-302, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31493335

RESUMO

OBJECTIVE: To determine whether systemic lupus erythematosus (SLE) can develop in the absence of BAFF in an SLE-prone host. METHODS: Starting with C57BL/6 mice that express a human BCL2 transgene (Tg) in their B cells (thereby rendering B cell survival largely independent of BAFF-triggered signals), we introgressed this Tg into NZM 2328 mice genetically deficient in BAFF (NZM.Baff-/- ) to generate NZM.Baff-/- .Bcl2Tg mice. Expression of human Bcl-2 and lymphocyte profiles were assessed by fluorescence-activated cell sorting, and serologic profiles were determined by enzyme-linked immunosorbent assay. Immunofluorescence and histologic analyses were performed to assess renal immunopathologic features in the mice, and clinical disease was assessed according to the outcomes of severe proteinuria and death. RESULTS: In comparison to their non-Tg NZM.Baff-/- littermates (n ≥ 7), NZM.Baff-/- .Bcl2Tg mice (n ≥ 8) overexpressed Bcl-2 in their B cells and developed significantly increased percentages and numbers of B cells and plasma cells, serum levels of IgG autoantibodies, glomerular deposition of IgG and C3, and severity of glomerular and tubulointerstitial inflammation, culminating in severe proteinuria and death (all P < 0.05 versus NZM.Baff-/- littermates). The time course for development of SLE-like features in NZM.Baff-/- .Bcl2Tg mice was more rapid than has been previously observed in NZM 2328 wild-type mice (median age at death 4.5 months versus 7.5 months). NZM.Baff-/- .Bcl2Tg mice remained responsive to BAFF, since reintroduction of the Baff gene into these mice further accelerated the course of disease (median age at death 3 months). CONCLUSION: The role of BAFF in the development of SLE-like disease may be dispensable as long as B cell survival is preserved via a BAFF-independent pathway. This may help explain the limited and variable clinical success with BAFF antagonists in human SLE. Thus, NZM.Baff-/- .Bcl2Tg mice may serve as a powerful murine model for the study of BAFF-independent SLE.


Assuntos
Fator Ativador de Células B/genética , Modelos Animais de Doenças , Lúpus Eritematoso Sistêmico/genética , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL
9.
Lupus Sci Med ; 6(1): e000313, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31168399

RESUMO

BACKGROUND/OBJECTIVE: Treatment with immune checkpoint inhibitors (ICIs) in oncology patients is increasing. Although ICIs trigger rheumatic immune-related adverse events, development of SLE features has been rare. Whether long-term treatment with ICIs would promote SLE features remains unknown. To begin to address this, we generated SLE-prone NZM 2328 mice with lifelong reduction in CTLA-4 expression. METHODS: Since CTLA-4-deficient (Ctla4- /-) NZM mice developed a lethal lymphoproliferative disorder by 3-6 weeks of age, development of SLE in these mice could not be studied. Ctla4 haploinsufficient NZM.Ctla4+ / - mice were assessed in parallel with littermate female NZM.Ctla4+ / + mice. Evaluations included CTLA-4 expression and lymphocyte profiles, assessed by fluorescence-activated cell sorting; serological profiles, assessed by ELISA; renal immunopathology, assessed by histology and immunofluorescence; and clinical courses, assessed by mortality. RESULTS: CTLA-4 expression was lower in NZM.Ctla4+ / - mice than in NZM.Ctla4+ / + mice. Spleen mononuclear cells, B cells, plasma cells, CD4+ cells, recently activated CD4+ cells and CD4+ T regulatory (Treg) cells were increased in NZM.Ctla4+ / - mice (p≤0.042). The serological profile, degree of renal immunopathology and mortality in NZM.Ctla4+ / - mice remained unaffected. CONCLUSION: Lifelong reduction in CTLA-4 expression in NZM mice neither accelerated nor aggravated SLE. Expansion in Treg cells may have played a protective role. Our observations raise the hope that long-term treatment of patients with SLE with an anti-CTLA-4 agent, should the need arise, would not adversely affect SLE disease activity.

10.
J Autoimmun ; 98: 33-43, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30612857

RESUMO

Immune-mediated glomerulonephritis is a serious end organ pathology that commonly affects patients with systemic lupus erythematosus (SLE). A classic murine model used to study lupus nephritis (LN) is nephrotoxic serum nephritis (NTN), in which mice are passively transferred nephrotoxic antibodies. We have previously shown that macrophages are important in the pathogenesis of LN. To further investigate the mechanism by which macrophages contribute to the pathogenic process, and to determine if this contribution is mediated by NF-κB signaling, we created B6 mice which had RelA knocked out in myeloid cells, thus inhibiting classical NF-κB signaling in this cell lineage. We induced NTN in this strain to assess the importance of macrophage derived NF-κB signaling in contributing to disease progression. Myeloid cell RelA knock out (KO) mice injected with nephrotoxic serum had significantly attenuated proteinuria, lower BUN levels, and improved renal histopathology compared to control injected wildtype B6 mice (WT). Inhibiting myeloid NF-κB signaling also decreased inflammatory modulators within the kidneys. We found significant decreases of IL-1a, IFNg, and IL-6 in kidneys from KO mice, but higher IL-10 expression. Flow cytometry revealed decreased numbers of kidney infiltrating classically activated macrophages in KO mice as well. Our results indicate that macrophage NF-κB signaling is instrumental in the contribution of this cell type to the pathogenesis of NTN. While approaches which decrease macrophage numbers can be effective in immune mediated nephritis, more targeted treatments directed at modulating macrophage signaling and/or function could be beneficial, at least in the early stages of disease.


Assuntos
Rim/metabolismo , Macrófagos/imunologia , Fator de Transcrição RelA/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Rim/patologia , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Ativação de Macrófagos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Fator de Transcrição RelA/genética
11.
Clin Immunol ; 197: 205-218, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30339790

RESUMO

Lupus nephritis is a common disease manifestation of SLE, in which immune complex deposition and macrophage activation are important contributors to disease pathogenesis. Bruton's tyrosine kinase (BTK) plays an important role in both B cell and FcgammaR mediated myeloid cell activation. In the current study, we examined the efficacy of BI-BTK-1, a recently described irreversible BTK inhibitor, in the classical NZB × NZW F1 (NZB/W) and MRL/lpr spontaneous mouse models of SLE. NZB/W mice were randomly assigned to a treatment (0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg) or control group and began treatment at 22 weeks of age. The experimental setup was similar in MRL/lpr mice, but with a single treated (10 mg/kg, beginning at 8-9 weeks of age) and control group. A separate experiment was performed in the MRL/lpr strain to assess the ability of BI-BTK-1 to reverse established kidney disease. Early treatment with BI-BTK-1 significantly protected NZB/W and MRL/lpr mice from the development of proteinuria, correlating with significant renal histological protection, decreased anti-DNA titers, and increased survival in both strains. BI-BTK-1 treated mice displayed a significant decrease in nephritis-associated inflammatory mediators (e.g. LCN2 and IL-6) in the kidney, combined with a significant inhibition of immune cell infiltration and accumulation. Importantly, BI-BTK-1 treatment resulted in the reversal of established kidney disease. BTK inhibition significantly reduced total B cell numbers and all B cell subsets (immature, transitional, follicular, marginal zone, and class switched) in the spleen of NZB/W mice. Overall, the significant efficacy of BI-BTK-1 in ameliorating multiple pathological endpoints associated with kidney disease in two distinct murine models of spontaneous lupus nephritis provides a strong rationale for BTK inhibition as a promising treatment approach for lupus nephritis.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Rim/efeitos dos fármacos , Nefrite Lúpica/patologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Anticorpos Antinucleares/efeitos dos fármacos , Anticorpos Antinucleares/imunologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , DNA/imunologia , Modelos Animais de Doenças , Interleucina-6/imunologia , Interleucina-6/metabolismo , Rim/imunologia , Rim/metabolismo , Rim/patologia , Lipocalina-2/efeitos dos fármacos , Lipocalina-2/imunologia , Lipocalina-2/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/imunologia , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Endogâmicos NZB , Proteinúria/imunologia , Distribuição Aleatória , Baço/citologia , Baço/efeitos dos fármacos
12.
Arthritis Res Ther ; 20(1): 10, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29370834

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects different end organs, including skin and brain. We and others have previously shown the importance of macrophages in the pathogenesis of cutaneous and neuropsychiatric lupus. Additionally, autoantibodies produced by autoreactive B cells are thought to play a role in both the skin and central nervous system pathologies associated with SLE. METHODS: We used a novel inhibitor of Bruton's tyrosine kinase (BTK), BI-BTK-1, to target both macrophage and B cell function in the MRL-lpr/lpr murine model of SLE, and examined the effect of treatment on skin and brain disease. RESULTS: We found that treatment with BI-BTK-1 significantly attenuated the lupus associated cutaneous and neuropsychiatric disease phenotypes in MRL/lpr mice. Specifically, BI-BTK-1 treated mice had fewer macroscopic and microscopic skin lesions, reduced cutaneous cellular infiltration, and diminished inflammatory cytokine expression compared to control mice. BTK inhibition also significantly improved cognitive function, and decreased accumulation of T cells, B cells, and macrophages within the central nervous system, specifically the choroid plexus. CONCLUSIONS: Directed therapies may improve the response rate in lupus-driven target organ involvement, and decrease the dangerous side effects associated with global immunosuppression. Overall, our results suggest that inhibition of BTK may be a promising therapeutic option for cutaneous and neuropsychiatric disease associated with SLE.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Encefalopatias/prevenção & controle , Inibidores Enzimáticos/farmacologia , Lúpus Eritematoso Sistêmico/complicações , Dermatopatias/prevenção & controle , Tirosina Quinase da Agamaglobulinemia/imunologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Encefalopatias/etiologia , Encefalopatias/imunologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos MRL lpr , Dermatopatias/etiologia , Dermatopatias/imunologia
13.
Clin Immunol ; 185: 100-108, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-27570219

RESUMO

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that can affect multiple end organs. Kidney and brain are two of the organs most commonly involved in SLE. Past studies have suggested the importance of macrophages in the pathogenesis of lupus nephritis (LN). Furthermore, as the immune effectors of the brain, microglia have been implicated in pathways leading to neuropsychiatric SLE (NPSLE). We depleted macrophages and microglia using GW2580, a small colony stimulating factor-1 receptor (CSF-1R) kinase inhibitor, in MRL-lpr/lpr (MRL/lpr) mice, a classic murine lupus model that displays features of both LN and NPSLE. Treatment was initiated before the onset of disease, and mice were followed for the development of LN and neurobehavioral dysfunction throughout the study. Treatment with GW2580 significantly ameliorated kidney disease, as evidenced by decreased proteinuria, BUN, and improved renal histopathology, despite equivalent levels of IgG and C3 deposition in the kidneys of treated and control mice. We were able to confirm macrophage depletion within the kidney via IBA-1 staining. Furthermore, we observed specific improvement in the depression-like behavioral deficit of MRL/lpr mice with GW2580 treatment. Circulating antibody and autoantibody levels were, however, not affected. These results provide additional support for the role of macrophages as a potentially valuable therapeutic target in SLE. Inhibiting CSF-1 receptor signaling would be more targeted than current immunosuppressive therapies, and may hold promise for the treatment of renal and neuropsychiatric end organ disease manifestations.


Assuntos
Anisóis/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Vasculite Associada ao Lúpus do Sistema Nervoso Central/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Pirimidinas/uso terapêutico , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Animais , Anisóis/farmacologia , Anticorpos Antinucleares/imunologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Cromatina/imunologia , Proteínas do Sistema Complemento/imunologia , Citocinas/imunologia , Depressão/tratamento farmacológico , Depressão/imunologia , Depressão/patologia , Modelos Animais de Doenças , Feminino , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Locomoção/efeitos dos fármacos , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Nefrite Lúpica/psicologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/patologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/psicologia , Macrófagos/imunologia , Camundongos Endogâmicos MRL lpr , Pirimidinas/farmacologia , Memória Espacial/efeitos dos fármacos
14.
Autoimmun Rev ; 15(9): 890-5, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27389531

RESUMO

The central nervous system manifestations of SLE (neuropsychiatric lupus, NPSLE) occur frequently, though are often difficult to diagnose and treat. Symptoms of NPSLE can be quite diverse, including chronic cognitive and emotional manifestations, as well as acute presentations, such as stroke and seizures. Although the pathogenesis of NPSLE has yet to be well characterized, B-cell mediated damage is believed to be an important contributor. B-cells and autoantibodies may traverse the blood brain barrier promoting an inflammatory environment consisting of glia activation, neurodegeneration, and consequent averse behavioral outcomes. This review will evaluate the various suggested roles of B-cells and autoantibodies in NPSLE, as well as therapeutic modalities targeting these pathogenic mediators.


Assuntos
Autoanticorpos/imunologia , Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Autoanticorpos/metabolismo , Barreira Hematoencefálica/metabolismo , Humanos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Fosfolipídeos/imunologia , Receptores de N-Metil-D-Aspartato/imunologia
15.
Exp Dermatol ; 25(12): 969-976, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27305603

RESUMO

The cytokine TNF-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 are involved in cell survival and cytokine production. The TWEAK/Fn14 pathway plays a role in the pathogenesis of spontaneous cutaneous lesions in the MRL/lpr lupus strain; however, the role of TWEAK/Fn14 in disease induced by ultraviolet B (UVB) irradiation has not been explored. MRL/lpr Fn14 knockout (KO) was compared to MRL/lpr Fn14 wild-type (WT) mice following exposure to UVB. We found that irradiated MRL/lpr KO mice had significantly attenuated cutaneous disease when compared to their WT counterparts. There were also fewer infiltrating immune cells (CD3+ , IBA-1+ and NGAL+ ) in the UVB-exposed skin of MRL/lpr Fn14KO mice, as compared to Fn14WT. Furthermore, we identified several macrophage-derived proinflammatory chemokines with elevated expression in MRL/lpr mice after UV exposure. Depletion of macrophages, using a CSF-1R inhibitor, was found to be protective against the development of skin lesions after UVB exposure. In combination with the phenotype of the MRL/lpr Fn14KO mice, these findings indicate a critical role for Fn14 and recruited macrophages in UVB-triggered cutaneous lupus. Our data strongly suggest that TWEAK/Fn14 signalling is important in the pathogenesis of UVB-induced cutaneous disease manifestations in the MRL/lpr model of lupus and further support this pathway as a possible target for therapeutic intervention.


Assuntos
Lúpus Eritematoso Sistêmico/complicações , Transtornos de Fotossensibilidade/etiologia , Pele/efeitos da radiação , Receptor de TWEAK/metabolismo , Raios Ultravioleta/efeitos adversos , Animais , Apoptose , Quimiocinas/metabolismo , Citocina TWEAK/metabolismo , Feminino , Lipocalina-2/metabolismo , Camundongos Knockout , Transtornos de Fotossensibilidade/metabolismo , Pele/imunologia , Pele/metabolismo
16.
Sci Rep ; 6: 26164, 2016 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-27192942

RESUMO

Lupus nephritis (LN) is a potentially dangerous end organ pathology that affects upwards of 60% of lupus patients. Bruton's tyrosine kinase (BTK) is important for B cell development, Fc receptor signaling, and macrophage polarization. In this study, we investigated the effects of a novel, highly selective and potent BTK inhibitor, BI-BTK-1, in an inducible model of LN in which mice receive nephrotoxic serum (NTS) containing anti-glomerular antibodies. Mice were treated once daily with vehicle alone or BI-BTK-1, either prophylactically or therapeutically. When compared with control treated mice, NTS-challenged mice treated prophylactically with BI-BTK-1 exhibited significantly attenuated kidney disease, which was dose dependent. BI-BTK-1 treatment resulted in decreased infiltrating IBA-1+ cells, as well as C3 deposition within the kidney. RT-PCR on whole kidney RNA and serum profiling indicated that BTK inhibition significantly decreased levels of LN-relevant inflammatory cytokines and chemokines. Renal RNA expression profiling by RNA-seq revealed that BI-BTK-1 dramatically modulated pathways related to inflammation and glomerular injury. Importantly, when administered therapeutically, BI-BTK-1 reversed established proteinuria and improved renal histopathology. Our results highlight the important role for BTK in the pathogenesis of immune complex-mediated nephritis, and BTK inhibition as a promising therapeutic target for LN.


Assuntos
Complexo Antígeno-Anticorpo/metabolismo , Inibidores Enzimáticos/administração & dosagem , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/prevenção & controle , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Animais , Análise Química do Sangue , Complemento C3/análise , Citocinas/análise , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Rim/patologia , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/patologia , Camundongos , Análise de Sequência de RNA , Resultado do Tratamento
17.
J Neuroinflammation ; 13(1): 73, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27055816

RESUMO

BACKGROUND: Neuropsychiatric lupus (NPSLE) can be one of the earliest clinical manifestations in human lupus. However, its mechanisms are not fully understood. In lupus, a compromised blood-brain barrier may allow for the passage of circulating autoantibodies into the brain, where they can induce neuropsychiatric abnormalities including depression-like behavior and cognitive abnormalities. The purpose of this study was to determine the role of B cells and/or autoantibodies in the pathogenesis of murine NPSLE. METHODS: We evaluated neuropsychiatric manifestations, brain pathology, and cytokine expression in constitutively (JhD/MRL/lpr) and conditionally (hCD20-DTA/MRL/lpr, inducible by tamoxifen) B cell-depleted mice as compared to MRL/lpr lupus mice. RESULTS: We found that autoantibody levels were negligible (JhD/MRL/lpr) or significantly reduced (hCD20-DTA/MRL/lpr) in the serum and cerebrospinal fluid, respectively. Nevertheless, both JhD/MRL/lpr and hCD20-DTA/MRL/lpr mice showed profound depression-like behavior, which was no different from MRL/lpr mice. Cognitive deficits were also observed in both JhD/MRL/lpr and hCD20-DTA/MRL/lpr mice, similar to those exhibited by MRL/lpr mice. Furthermore, although some differences were dependent on the timing of depletion, central features of NPSLE in the MRL/lpr strain including increased blood-brain barrier permeability, brain cell apoptosis, and upregulated cytokine expression persisted in B cell-deficient and B cell-depleted mice. CONCLUSIONS: Our study surprisingly found that B cells and/or autoantibodies are not required for key features of neuropsychiatric disease in murine NPSLE.


Assuntos
Autoanticorpos/imunologia , Linfócitos B/imunologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/imunologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Animais , Comportamento Animal , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Humanos , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos MRL lpr , Reação em Cadeia da Polimerase em Tempo Real
18.
Discov Med ; 20(108): 43-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26321086

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease which results in multiple different end organ pathologies, including the kidney. Lupus nephritis (LN) is one of the most serious complications of SLE, and a leading cause of morbidity and mortality. Current treatment options are suboptimal, involving non-specific immunosuppression which exposes patients to potentially serious side effects with no guarantee of remission. More targeted therapeutic approaches may improve treatment results. Many studies have implicated macrophages as actively contributing to LN pathogenesis in both human and murine disease. Indeed, various studies have shown that depletion of macrophage populations, inhibition of macrophage recruitment, and disruption of inflammatory macrophage activation and polarization have significantly ameliorated nephritis in several different murine LN models. The current literature explores targeting macrophages by several different means, including the CSF-1/CSF-1R signaling axis, the CX3CL1/CX3CR1 signaling axis, the CCL2/CCR2 signaling axis, and Bruton's Tyrosine Kinase (BTK), all of which hold promise as targets for future LN treatments. These studies highlight the potential benefit of targeting macrophages in LN, and emphasize the need for future investigations to discern the ideal mean(s) for targeting macrophages in LN.


Assuntos
Nefrite Lúpica/imunologia , Nefrite Lúpica/terapia , Macrófagos/imunologia , Animais , Quimiocinas/imunologia , Modelos Animais de Doenças , Humanos , Nefrite Lúpica/patologia , Macrófagos/patologia , Camundongos , Receptores de Quimiocinas/imunologia , Transdução de Sinais/imunologia
19.
J Invest Dermatol ; 135(8): 1986-1995, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25826425

RESUMO

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSF12) and its sole receptor Fn14, belonging to the TNF ligand and receptor superfamilies respectively, are involved in cell survival and cytokine production. The role of TWEAK/Fn14 interactions in the pathogenesis of cutaneous lupus has not been explored. TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES via Fn14 and promoted apoptosis. Parthenolide, but not wortmanin or the MAPK inhibitor PD98059, significantly decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-κB signaling. UVB irradiation significantly upregulated the expression of Fn14 on keratinocytes in vitro and in vivo and increased RANTES production. MRL/lpr Fn14 knockout (KO) lupus mice were compared with MRL/lpr Fn14 wild-type (WT) mice to evaluate for any possible differences in the severity of cutaneous lesions and the presence of infiltrating immune cells. MRL/lpr Fn14 KO mice had markedly attenuated cutaneous disease as compared with their Fn14 WT littermates, as evidenced by the well-maintained architecture of the skin and significantly decreased skin infiltration of T cells and macrophages. Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations in the MRL/lpr model of spontaneous lupus and suggest a possible target for therapeutic intervention.


Assuntos
Lúpus Eritematoso Cutâneo/etiologia , Lúpus Eritematoso Cutâneo/fisiopatologia , Receptores do Fator de Necrose Tumoral/fisiologia , Transdução de Sinais/fisiologia , Fatores de Necrose Tumoral/fisiologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular , Quimiocina CCL5/metabolismo , Citocina TWEAK , Modelos Animais de Doenças , Fibroblastos/metabolismo , Técnicas In Vitro , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Lúpus Eritematoso Cutâneo/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Receptores do Fator de Necrose Tumoral/deficiência , Receptores do Fator de Necrose Tumoral/efeitos da radiação , Receptor de TWEAK , Fatores de Necrose Tumoral/farmacologia , Raios Ultravioleta , Regulação para Cima/efeitos da radiação
20.
J Autoimmun ; 57: 42-52, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25554644

RESUMO

Kidney involvement affects 40-60% of patients with lupus, and is responsible for significant morbidity and mortality. Using depletion approaches, several studies have suggested that macrophages may play a key role in the pathogenesis of lupus nephritis. However, "off target" effects of macrophage depletion, such as altered hematopoiesis or enhanced autoantibody production, impeded the determination of a conclusive relationship. In this study, we investigated the role of macrophages in mice receiving rabbit anti-glomerular antibodies, or nephrotoxic serum (NTS), an experimental model which closely mimics the immune complex mediated disease seen in murine and human lupus nephritis. GW2580, a selective inhibitor of the colony stimulating factor-1 (CSF-1) receptor kinase, was used for macrophage depletion. We found that GW2580-treated, NTS challenged mice did not develop the increased levels of proteinuria, serum creatinine, and BUN seen in control-treated, NTS challenged mice. NTS challenged mice exhibited significantly increased kidney expression of inflammatory cytokines including RANTES, IP-10, VCAM-1 and iNOS, whereas GW2580-treated mice were protected from the robust expression of these inflammatory cytokines that are associated with lupus nephritis. Quantification of macrophage related gene expression, flow cytometry analysis of kidney single cell suspensions, and immunofluorescence staining confirmed the depletion of macrophages in GW2580-treated mice, specifically within renal glomeruli. Our results strongly implicate a specific and necessary role for macrophages in the development of immune glomerulonephritis mediated by pathogenic antibodies, and support the development of macrophage targeting approaches for the treatment of lupus nephritis.


Assuntos
Anisóis/imunologia , Anticorpos/imunologia , Nefrite Lúpica/imunologia , Macrófagos/imunologia , Pirimidinas/imunologia , Animais , Anisóis/farmacologia , Modelos Animais de Doenças , Citometria de Fluxo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Glomerulonefrite/imunologia , Glomerulonefrite/prevenção & controle , Proteína HMGB1/genética , Proteína HMGB1/imunologia , Proteína HMGB1/metabolismo , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Rim/efeitos dos fármacos , Rim/imunologia , Rim/metabolismo , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Nefrite Lúpica/prevenção & controle , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/imunologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Proteinúria/imunologia , Proteinúria/prevenção & controle , Pirimidinas/farmacologia , Coelhos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/imunologia , Linfócitos T/metabolismo
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