Partial <scp>MHC</scp> class <scp>II</scp> constructs inhibit <scp>MIF</scp>/<scp>CD</scp>74 binding and downstream effects

Benedek, Gil; Meza-Romero, Roberto; Andrew, Shayne F.; Leng, Lin; Burrows, Gregory G.; Bourdette, Dennis; Offner, Halina; Bucala, Richard; Vandenbark, Arthur A.

doi:10.1002/eji.201243162

Cited by 52 publications

(68 citation statements)

References 42 publications

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“…We evaluated stored PMBC samples from a cohort of eight HLA-DR2 positive MS subjects from our previous clinical study vs. eight HLA-DR2 positive, age and gender-matched healthy controls (HC) and found significantly higher expression levels of CD74 on CD11b + monocytes in MS subjects vs. HC donors. These data correlate with the data obtained from the mouse MS model (Benedek et al 2013) (Figure 1C). …”

Section: Cd74 Expression Is Up-regulated In Eae and Mssupporting

confidence: 88%

“…We recently demonstrated enhanced CD74 cell surface expression on monocytes in mice with EAE and subjects with MS, which implicates its involvement in the disease course (Benedek et al 2013)[10]. CD74 was shown to be up-regulated in peripheral blood monocytes by 3 hours after EAE induction, ~10 days before the appearance of definite clinical signs.…”

Section: Cd74 Expression Is Up-regulated In Eae and Msmentioning

confidence: 99%

“…Blocking of MIF binding, by partial MHC class II construct, either to immunoprecipitated mouse CD74 or to human PBMC was detected by western blot or by flow cytometry, respectively, using Alexa-488 labeled recombinant MIF protein. This inhibition of MIF binding resulted in profound downstream effects on EAE, including inhibition of cell migration to the CNS, secretion of pro-inflammatory cytokines and enhanced survival of activated monocytes (Benedek et al 2013; Meza-Romero et al 2014). …”

Section: Partial Mhc Class II Constructs Down Regulate Cd74 Expressiomentioning

confidence: 99%

“…The use of flow cytometry based assays enabled us to identify the predominant cell population that bind these constructs and to follow the changes in the partial MHC class II native cell surface receptor, the class II invariant chain (CD74), during the course of EAE and correlate the treatment response with this potential disease biomarker (Benedek et al 2013). We further identified the DRα1 domain, but not the DR2β1 domain as the RTL component that binds and down-regulates CD74 (Meza-Romero et al 2014; Vandenbark et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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The use of flow cytometry to assess a novel drug efficacy in multiple sclerosis

et al. 2014

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Applying different technologies to monitor disease activity and treatment efficacy are essential in a complex disease such as multiple sclerosis. Combining current assays with flow cytometry could create a powerful tool for such analyses. The cell surface expression level of CD74, the MHC class II invariant chain, is a potential disease biomarker that could be monitored by FACS analysis in order to assess disease progression and the clinical efficacy of partial MHC class II constructs in treating MS. These constructs, which can bind to and down-regulate CD74 cell-surface expression on monocytes and inhibit macrophage migration inhibitory factor (MIF) effects, can reverse clinical and histological signs of EAE. These properties of partial class II constructs are highly compatible with a flow cytometry approach for monitoring CD74 expression as a possible biomarker for disease activity/progression and as a treatment response marker.

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Section: Cd74 Expression Is Up-regulated In Eae and Mssupporting

confidence: 88%

Section: Cd74 Expression Is Up-regulated In Eae and Msmentioning

confidence: 99%

Section: Partial Mhc Class II Constructs Down Regulate Cd74 Expressiomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The use of flow cytometry to assess a novel drug efficacy in multiple sclerosis

et al. 2014

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“…MIF engagement of CD74 leads to the recruitment and activation of CD44 and CXCR2/4 to initiate signaling pathways necessary for MAPK activation and cell motility(3–5). We recently demonstrated enhanced CD74 cell surface expression on monocytes in mice with experimental autoimmune encephalomyelitis (EAE) and subjects with multiple sclerosis (MS), which implicates its involvement in the disease course(6). …”

Section: Introductionmentioning

confidence: 99%

HLA-DRα1 Constructs Block CD74 Expression and MIF Effects in Experimental Autoimmune Encephalomyelitis

Meza-Romero

Benedek

et al. 2014

The Journal of Immunology

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CD74, the cell surface form of the MHC class II invariant chain, is a key inflammatory factor that is involved in various immune mediated diseases as part of the Macrophage Migration Inhibitory Factor (MIF) binding complex. However, little is known about the natural regulators of CD74 in this context. In order to study the role of the HLA-DR molecule in regulating CD74, we utilized the HLA-DRα1 domain, which was shown to bind to and downregulate CD74 on CD11b+ monocytes. We found that DRα1 directly inhibited binding of MIF to CD74 and blocked its downstream inflammatory effects in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE). Potency of the DRα1 domain could be destroyed by trypsin digestion but enhanced by addition of a peptide extension (MOG-35–55 peptide) that provided secondary structure not present in DRα1. These data suggest a conformationally-sensitive determinant on DRα1-MOG that is responsible for optimal binding to CD74 and antagonism of MIF effects, resulting in reduced axonal damage and reversal of ongoing clinical and histological signs of EAE. These results demonstrate natural antagonist activity of DRα1 for MIF that was strongly potentiated by the MOG peptide extension, resulting in a novel therapeutic, DRα1-MOG-35–55,that within the limitations of the EAE model may have the potential to treat autoimmune diseases such as multiple sclerosis.

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Bioinformatics analysis of the wheel treadmill test on motor function recovery after spinal cord injury

Wang

Fang

et al. 2021

Ibrain

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This study aimed to explore the possible target and mechanism of the wheel treadmill (WTM) test for motor function recovery of spinal cord injury (SCI).Rats were divided into sham, control and WTM groups to establish an SCI mode. Rats in the WTM group were trained on the WTM test, and Basso-Beattie-Bresnahan (BBB) scores were determined. The samples were collected, and mRNA sequencing was conducted to determine the changes in gene expression. The coexpressed genes were screened to construct a protein-protein interaction (PPI), followed by the Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology function enrichment analysis, and the differentially expressed genes (DEGs) volcano map and hub gene expression heat map were constructed using R language. The BBB scores in the control and WTM groups increased with time, with the WTM group scoring higher than the control group. The results of rat spinal cord tissue sequencing showed that a total of 1679 DEGs were screened in the sham and control groups; 928 DEGs and 731 overlapping genes were screened in the WTM and control groups. The key genes were identified by PPI analysis. One hundred and thirty-three genes were found to be overlapping by combined analysis of spinal cord sequencing data and BBB scores of rats at Week 7. The top 10 DEGs from high to low were Tyrobp,

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Partial MHC class II constructs inhibit MIF/CD74 binding and downstream effects

Cited by 52 publications

References 42 publications

The use of flow cytometry to assess a novel drug efficacy in multiple sclerosis

The use of flow cytometry to assess a novel drug efficacy in multiple sclerosis

HLA-DRα1 Constructs Block CD74 Expression and MIF Effects in Experimental Autoimmune Encephalomyelitis

Bioinformatics analysis of the wheel treadmill test on motor function recovery after spinal cord injury

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