Imbalanced expression of functional surface molecules in regulatory and effector T cells in systemic lupus erythematosus

Júnior, Danilo Mesquita; Cruvinel, W.M.; Araújo, Júlio Antônio Pereira; Salmazi, Karina Carvalho; Kallas, Esper G.; Andrade, Luís Eduardo Coelho

doi:10.1590/1414-431x20143483

Cited by 7 publications

(6 citation statements)

References 37 publications

(46 reference statements)

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“…Consistent with observations from conditions where there is [97][98][99][100][101][102][103] Increased endothelial expression in kidney biopsies from lupus nephritis patients with the appearance of glomerular positivity [97] OX40 on infiltrating perivascular leucocytes in lupus nephritis [97] Increased peripheral sOX40L, with further elevations in those with nephritis [99] More activated phenotype with increased PI3/Akt activation (see Fig. 4…”

Section: Ox40 Is Upregulated On Peripheral Circulating Lymphocytes Insupporting

confidence: 83%

“…in SLE [97][98][99][100][101][102][103]. Disease-ameliorating interventions can reduce proportions of circulating lymphocytes expressing OX40 such as natalizumab in multiple sclerosis or may correlate with other measures of severity: in myasthenia gravis there is a correlation with acetylcholine receptor antibody titer [104,105].…”

Section: Colitis Expression Increased On Lamina Propria Lymphocytes Imentioning

confidence: 99%

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OX40, OX40L and Autoimmunity: a Comprehensive Review

Webb

Hirschfield

Lane

2015

Clinic Rev Allerg Immunol

191

159

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The tumour necrosis factor receptor OX40 (CD134) is activated by its cognate ligand OX40L (CD134L, CD252) and functions as a T cell co-stimulatory molecule. OX40-OX40L interactions have been proposed as a potential therapeutic target for treating autoimmunity. OX40 is expressed on activated T cells, and in the mouse at rest on regulatory T cells (Treg). OX40L is found on antigen-presenting cells, activated T cells and others including lymphoid tissue inducer cells, some endothelia and mast cells. Expression of both molecules is increased after antigen presentation occurs and also in response to multiple other pro-inflammatory factors including CD28 ligation, CD40L ligation and interferon-gamma signaling. Their interactions promote T cell survival, promote an effector T cell phenotype, promote T cell memory, tend to reduce regulatory function, increase effector cytokine production and enhance cell mobility. In some circumstances, OX40 agonism may be associated with increased tolerance, although timing with respect to antigenic stimulus is important. Further, recent work has suggested that OX40L blockade may be more effective than OX40 blockade in reducing autoimmunity. This article reviews the expression of OX40 and OX40L in health, the effects of their interactions and insights from their under- or over-expression. We then review OX40 and OX40L expression in human autoimmune disease, identified associations of variations in their genes (TNFRSF4 and TNFSF4, respectively) with autoimmunity, and data from animal models of human diseases. A rationale for blocking OX40-OX40L interaction in human autoimmunity is then presented along with commentary on the one trial of OX40L blockade in human disease conducted to date. Finally, we discuss potential problems with clinical use of OX40-OX40L directed pharmacotherapy.

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Section: Ox40 Is Upregulated On Peripheral Circulating Lymphocytes Insupporting

confidence: 83%

Section: Colitis Expression Increased On Lamina Propria Lymphocytes Imentioning

confidence: 99%

OX40, OX40L and Autoimmunity: a Comprehensive Review

Webb

Hirschfield

Lane

2015

Clinic Rev Allerg Immunol

191

159

View full text Add to dashboard Cite

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“…The investigation conducted by Mesquita et al ( 101 ) reported several alterations in the expression of critical surface molecules on Treg and Teff cells in 26 SLE patients with active disease compared to 31 with inactive disease and 26 healthy controls, despite healthy controls and SLE patients showed equivalent Treg cell frequency. More specifically, a higher CD40L + Treg cell frequency, associated with reduced CTLA-4 + Treg and CD28 + Treg cell frequencies, characterized SLE subjects.…”

Section: Evidences Of Pd-1 and Treg Involvement In Autoimmunitymentioning

confidence: 99%

“…The frequency of CD40L + Tregs was positively correlated with the SLE disease activity index. These alterations could play an important role in SLE pathogenesis ( 101 ).…”

Section: Evidences Of Pd-1 and Treg Involvement In Autoimmunitymentioning

confidence: 99%

Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression

2018

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Regulatory T (Treg) cells represent a subpopulation of suppressor CD4+ T cells critically involved in the establishment of peripheral tolerance through the inhibition of effector T (Teff) cells and the suppression of the immune-mediated tissue destruction toward self-antigens. Treg generation, their suppressive properties and also Treg-Teff cell interactions could be modulated at least in part by programmed cell death-1 (PD-1) expression on their surface and through binding between PD-1 and programmed cell death ligand-1 (PD-L1). Defects involving PD-1 and Tregs can lead to the development of pathological conditions, including autoimmune disorders or promote cancer progression by favoring tumor evasion from the host immune response. At the same time, PD-1 and Tregs could represent attractive targets for treatment, as demonstrated by the therapeutic blockade of PD-L1 applied for the management of different cancer conditions in humans. In the present Review, we focus specifically the role of PD-1/PD-L1 on Treg development and activity.

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“…In contrast, Tregs have also been shown to be significantly expanded in patients with active SLE compared to those with inactive disease and HCs ( 10 – 13 ). Some studies suggest that the defects of Tregs are secondary to the imbalance between auto-aggressive T-cells and Tregs in lupus patients, tipping the balance toward Teffector (Teff) activation, clonal expansion, cell survival, cytokine production, and ultimately, autoimmunity ( 8 , 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

Changes in Frequency and Activation Status of Major CD4+ T-Cell Subsets after Initiation of Immunosuppressive Therapy in a Patient with New Diagnosis Childhood-Onset Systemic Lupus Erythematosus

et al. 2017

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BackgroundSeveral studies suggest that defects of regulatory T-cells (Tregs) and impaired cellular immunity are secondary to an imbalance between auto-aggressive T-cells and Tregs in lupus patients. Discrepancies in Tregs and effector T-cells (Teff) in active lupus patients are shown to be restored in patients upon receiving immunosuppressive therapy. Therefore, our main aim was to observe frequencies of these CD4+ T-cell subsets and Tregs/Teff ratio in a new diagnosis of childhood-onset systemic lupus erythematous (cSLE) before and after initiation of therapy. In addition, we monitored T-cell exhaustion status by examining responses to super-antigen staphylococcal enterotoxin B (SEB) and PD-1 expression in this patient.MethodsPhenotyping of CD4+ T-cell subsets was carried out under basal conditions and after SEB stimulation using flow cytometry in one inactive (I-cSLE) and one active cSLE (A-cSLE) patient, as well as a healthy control (HC). The A-cSLE patient was a new diagnosis. Variables were measured at three consecutive time points in the active patient, reflecting various stages of disease activity. Activation status of CD4+ T-cells in the A-cSLE patient was compared to that of the I-cSLE patient and HC. Disease activity was measured by calculating the systemic lupus erythematous disease activity index.ResultsWe found that the A-cSLE patient was not Tregs deficient. The patient had increased frequency of Tregs, and the Tregs/Teff ratio increased when the disease activity became less severe. CD4+ T-cells in the I-cSLE patient and in the A-cSLE patient with milder disease activity had heightened responsiveness to SEB, whereas T-cells were relatively hypo-responsive to SEB in the A-cSLE patient when disease activity was higher. The active patient exhibited higher frequencies of PD-1+ expressing Tregs, Teff, and Tnaïve/mem cells under basal conditions compared to the HC and I-cSLE patient.ConclusionIn the A-cSLE patient, changes in Tregs/Teff ratio correlated better with clinical improvement compared to Tregs frequencies alone and might reflect the restoration of immune homeostasis with therapy. SEB hypo-responsiveness in the A-cSLE patient when disease activity was higher paralleled with findings of greater frequencies of PD-1+ expressing Tregs, Teff, and Tnaïve/mem cells, suggests a possible global exhaustion status of CD4+ T-cells in this patient.

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Imbalanced expression of functional surface molecules in regulatory and effector T cells in systemic lupus erythematosus

Cited by 7 publications

References 37 publications

OX40, OX40L and Autoimmunity: a Comprehensive Review

OX40, OX40L and Autoimmunity: a Comprehensive Review

Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression

Changes in Frequency and Activation Status of Major CD4+ T-Cell Subsets after Initiation of Immunosuppressive Therapy in a Patient with New Diagnosis Childhood-Onset Systemic Lupus Erythematosus

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