scholarly journals CXCL13 Neutralization Attenuates Neuropsychiatric Manifestations in Lupus-Prone Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Michelle W. Huang ◽  
Ariel D. Stock ◽  
Chaim Putterman
Keyword(s):  
Disease Progression ◽  
Lupus Erythematosus ◽  
Lymphoid Follicle ◽  
Beneficial Effects ◽  
Brain Gene Expression ◽  
Potential Contributor ◽  
Neuropsychiatric Manifestations ◽  
Tertiary Lymphoid Structures ◽  
Neurobehavioral Manifestations ◽  
Lymphoid Structures

Neuropsychiatric lupus (NPSLE), the nervous system presentation of systemic lupus erythematosus (SLE), remains challenging to treat due to its unclear pathogenesis and lack of available targeted therapies. A potential contributor to disease progression is brain tertiary lymphoid structures (TLS); these ectopic lymphoid follicles that can develop tissue-targeted antibodies have recently been described in the MRL/lpr lupus mouse strain, a classic model for studying NPSLE. The brains of MRL/lpr mice show a significant increase of CXCL13, an important chemokine in lymphoid follicle formation and retention that may also play a role in the disease progression of NPSLE. The aim of the present study was to inhibit CXCL13 and examine the effect of this intervention on lymphoid formation and the development of neurobehavioral manifestations in lupus mice. Female MRL/lpr mice were injected with an anti-CXCL13 antibody, an IgG1 isotype-matched antibody, or PBS either three times a week for 12 weeks intraperitoneally (IP) starting at 6-8 weeks of age, or continuously intracerebroventricularly (ICV) with an osmotic pump over a two-week period starting at 15 weeks of age. Cognitive dysfunction and depression-like behavior were assessed at the end of treatment. When treatment was delivered IP, anti-CXCL13 treated mice showed significant improvement in cognitive function when compared to control treated mice. Depression-like behavior was attenuated as well. Furthermore, mice that received anti-CXCL13 by the ICV route showed similar beneficial effects. However, the extent of lymphocyte infiltration into the brain and the general composition of the aggregates were not substantively changed by anti-CXCL13 irrespective of the mode of administration. Nevertheless, analysis of brain gene expression in anti-CXCL13 treated mice showed significant differences in key immunological and neuro-inflammatory pathways that most likely explained the improvement in the behavioral phenotype. Our results indicate that CXCL13 affects the behavioral manifestations in the MRL/lpr strain and is important to the pathogenesis of murine NPSLE, suggesting it as a potential therapeutic target.

scholarly journals A Standardized Analysis of Tertiary Lymphoid Structures in Human Melanoma: Disease Progression- and Tumor Site-Associated Changes With Germinal Center Alteration

2021 ◽  
Vol 12 ◽  
Author(s):  
Franziska Werner ◽  
Christine Wagner ◽  
Martin Simon ◽  
Katharina Glatz ◽  
Kirsten D. Mertz ◽  
...  
Keyword(s):  
Spatial Distribution ◽  
Disease Progression ◽  
Germinal Center ◽  
Human Melanoma ◽  
Melanoma Tumor ◽  
Invasive Tumor ◽  
Evaluation Approach ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
And Function

There is increasing evidence that tertiary lymphoid structures (TLS) control not only local adaptive B cell responses at melanoma tumor sites but also the cellular composition and function of other immune cells. In human melanoma, however, a comprehensive analysis of TLS phenotypes, density and spatial distribution at different disease stages is lacking. Here we used 7-color multiplex immunostaining of whole tissue sections from 103 human melanoma samples to characterize TLS phenotypes along the expression of established TLS-defining molecular and cellular components. TLS density and spatial distribution were determined by referring TLS counts to the tissue area within defined intra- and extratumoral perimeters around the invasive tumor front. We show that only a subgroup of primary human melanomas contains TLS. These TLS rarely formed germinal centers and mostly located intratumorally within 1 mm distance to the invasive tumor front. In contrast, melanoma metastases had a significantly increased density of secondary follicular TLS. They appeared preferentially in stromal areas within an extratumoral 1 mm distance to the invasive tumor front and their density varied over time and site of metastasis. Interestingly, secondary follicular TLS in melanoma often lacked BCL6+ lymphatic cells and canonical germinal center polarity with the formation of dark and light zone areas. Our work provides an integrated qualitative, quantitative and spatial analysis of TLS in human melanoma and shows disease progression- and site-associated changes in TLS phenotypes, density and spatial distribution. The frequent absence of canonical germinal center polarity in melanoma TLS highlights the induction of TLS maturation as a potential additive to future immunotherapy studies. Given the variable evaluation strategies used in previous TLS studies of human tumors, an important asset of this study is the standardized quantitative evaluation approach that provides a high degree of reproducibility.

scholarly journals Anti-IFNAR treatment does not reverse neuropsychiatric disease in MRL/lpr lupus mice

Lupus ◽  
2019 ◽  
Vol 28 (13) ◽  
pp. 1510-1523 ◽  
Author(s):  
M W Huang ◽  
A D Stock ◽  
E V Mike ◽  
L Herlitz ◽  
R Kolbeck ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Treatment Schedule ◽  
Type I ◽  
Neuropsychiatric Lupus ◽  
Type I Ifn ◽  
Neuropsychiatric Disease ◽  
Beneficial Effects ◽  
Neuropsychiatric Manifestations ◽  
And Control

Objective Many systemic lupus erythematosus patients display a type I interferon (IFN) signature, and IFNα levels positively correlate with disease severity. Previous studies blocking the type I IFN pathway systemically in lupus models showed some beneficial effects. However, its effects on neuropsychiatric manifestations have yet to be carefully assessed, even though IFNα has been associated with induction of depression. Our aim was to investigate whether disrupting the type I IFN pathway would attenuate the development of murine neuropsychiatric lupus. Methods Female MRL/ lpr mice were administered an antitype I IFN receptor (IFNAR) antibody or a control antibody intraperitoneally three times weekly for 12 weeks starting at age 4–5 weeks. Behavior was assessed during and at the end of the treatment schedule. Results No significant differences were seen between the anti-IFNAR– and control-treated mice when assessing for depression-like behavior or cognitive dysfunction, although anti-IFNAR antibody–treated mice displayed significant decreases in levels of IFN-stimulated genes. Anti-IFNAR treatment also did not significantly improve brain histology, cellular infiltration, or blood-brain barrier integrity. Conclusions Surprisingly, our results showed no improvement in neuropsychiatric disease and suggest that the role of IFNAR signaling in the pathogenesis of neuropsychiatric lupus continues to need to be carefully assessed.

scholarly journals Electroencephalography in systemic lupus erythematosus patients with neuropsychiatric manifestations

2020 ◽  
Vol 32 (1) ◽  
Author(s):  
Howaida E. Mansour ◽  
Reem A. Habeeb ◽  
Noran O. El-Azizi ◽  
Heba H. Afeefy ◽  
Marwa A. Nassef ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Epileptiform Activity ◽  
Brain Mri ◽  
Periventricular White Matter ◽  
Normal Brain ◽  
Systemic Lupus ◽  
Specific Test ◽  
Eeg Abnormalities ◽  
Neuropsychiatric Manifestations

Abstract Background Neuropsychiatric manifestations are frequently reported in systemic lupus erythematosus (SLE) patients. This study was done to describe electroencephalographic (EEG) findings in SLE patients with neuropsychiatric manifestation (NPSLE). Results Among 60 SLE patients, there were 50 females (83.3%) and 10 males (16.7%). EEG abnormalities were reported in 12 patients out of 30 (40%) with NPSLE, while all patients with non-NPSLE (n = 30) had no EEG abnormalities; diffuse slowing (20%) was the most common abnormalities, followed by generalized epileptiform activity (13.3%), and lastly temporal epileptiform activity (6.7%). Seizure was the most reported neuropsychiatric disorder in 13 patients (43.3%); 8 of them had abnormal EEG (61.5%). Periventricular white matter lesion (23.3%) followed by infarction (13.3%) were the most common MRI brain findings among 53.3% of NPSLE group. Half of the cases with EEG abnormality had normal brain MRI. SLEDAI score and ACL IgM positivity were higher in the NPSLE group than the non-NPSLE group. EEG is not a sensitive or specific test for detecting NPSLE with sensitivity (37.5%) and specificity (57.1%). Conclusion Not all patients with NPSLE must have abnormal brain MRI or EEG. EEG is a useful assistant tool in the assessment of different manifestations of NPSLE, but it cannot be used as a screening test alone and must be supplemented by neuroimaging studies.

A longitudinal multiethnic study of biomarkers in systemic lupus erythematosus: Launching the GLADEL 2.0 Study Group

Lupus ◽  
2021 ◽  
pp. 096120332098858
Author(s):  
José A Gómez-Puerta ◽  
Guillermo J Pons-Estel ◽  
Rosana Quintana ◽  
Romina Nieto ◽  
Rosa M Serrano Morales ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Renal Disease ◽  
Latin American ◽  
Lupus Erythematosus ◽  
Renal Involvement ◽  
Systemic Lupus ◽  
Original Cohort ◽  
Beneficial Effects ◽  
New Generation ◽  
Methodological Aspects

Introduction: After more than 20 years of sustained work, the Latin American Group for the Study of Lupus (GLADEL) has made a significant number of contributions to the field of lupus, not only in the differential role that race/ethnicity plays in its course and outcome but also in several other studies including the beneficial effects of using antimalarials in lupus patients and the development of consensus guidelines for the treatment of lupus in our region. Methods: A new generation of “Lupus Investigators” in more than 40 centers throughout Latin America has been constituted in order to continue the legacy of the investigators of the original cohort and to launch a novel study of serum and urinary biomarkers in patients with systemic lupus erythematosus. Results: So far, we have recruited 807 patients and 631 controls from 42 Latin-American centers including 339 patients with SLE without renal involvement, 202 patients with SLE with prevalent but inactive renal disease, 176 patients with prevalent and active renal disease and 90 patients with incident lupus nephritis. Conclusions: The different methodological aspects of the GLADEL 2.0 cohort are discussed in this manuscript, including the challenges and difficulties of conducting such an ambitious project.

Sign in / Sign up

Export Citation Format

Share Document