Upregulation of CD74 and its potential association with disease severity in subjects with ischemic stroke

Abstract

Macrophage migration inhibitory factor (MIF) is a key cytokine/chemokine in the activation and recruitment of inflammatory T lymphocytes known to exacerbate experimental stroke severity. MIF effects are mediated through its primary cellular receptor, CD74, the MHC class II invariant chain present on all class II expressing cells, including monocytes, macrophages and dendritic cells (DC). We demonstrated previously that partial MHC class II/peptide constructs (pMHC) can effectively treat mice with experimental stroke, in part through their ability to competitively inhibit MIF/CD74 interactions and downstream signaling. However, the role of MIF and CD74 in human ischemic stroke is not yet well established. To evaluate the therapeutic potential for pMHC, we assessed MIF and CD74 expression levels and their association with disease outcome in subjects with ischemic stroke. MIF levels were assessed in blood plasma by ELISA and CD74 expression was quantified by flow cytometry and qRT-PCR in peripheral blood mononuclear cells (PBMCs) obtained from subjects with ischemic stroke and age and sex-matched healthy controls (HC). MIF levels were increased in plasma and the number of CD74+ cells and CD74 mRNA expression levels were significantly increased in PBMC of subjects with ischemic stroke versus HC, mainly on CD4+ T cells, monocytes and DC. Greater increases of CD74+ cells were seen in subjects with cortical vs. subcortical infarcts and the number of CD74+ cells in blood correlated strongly with infarct size and neurological outcomes. However, differences in MIF and CD74 expression were not affected by age, gender or lesion laterality. Increased CD74 expression levels may serve as a useful biomarker for worse stroke severity and predicted outcomes in subjects with ischemic stroke and provide a rationale for potential future treatment with pMHC constructs.

Brain–Heart Interaction

“…SIRS is indicated by abnormal leukocyte counts, high respiratory and heart rate (>90 bmp), and abnormal body temp, and can increase the risk of developing vasospasm and secondary complications 117 . In ischemic stroke patients, the number of CD74 + cells (the MHC class II invariant chain present on all class II expressing cells, including monocytes, macrophages and dendritic cells) were significantly increased in peripheral blood mononuclear cells compared to healthy controls 118 . The increased CD74 positive cells were mainly on CD4 + T cells, monocytes and dendritic cells 118 .…”

“…In ischemic stroke patients, the number of CD74 + cells (the MHC class II invariant chain present on all class II expressing cells, including monocytes, macrophages and dendritic cells) were significantly increased in peripheral blood mononuclear cells compared to healthy controls 118 . The increased CD74 positive cells were mainly on CD4 + T cells, monocytes and dendritic cells 118 . In heart diseases such as myocardial infarction, elevation of circulating blood monocytes is associated with poor cardiac function and predicts poor recovery of left ventricular systolic function at 3 months post injury 119 .…”

A novel neurotherapeutic for multiple sclerosis, ischemic injury, methamphetamine addiction, and traumatic brain injury

“…In addition, partial MHC class II constructs were shown to reverse stroke-associated splenic atrophy and promote a protective anti-inflammatory macrophage/microglia phenotype in the CNS which contributes to tissue repair and recovery after stroke [59, 60]. A recent study has also demonstrated increased expression of CD74 on T cells and antigen-presenting cells that directly correlate with infarct size and neurological deficits in people with ischemic stroke [61].…”

“…* p < 0.05, ** p < 0.01. Reprinted by permission from RightsLink: Springer, Translational Stroke Research, DRα1-MOG-35-55 treatment reduces lesion volumes and improves neurological deficits after traumatic brain injury, Yang et al, copyright 2017 [61]…”

Old Dog New Tricks; Revisiting How Stroke Modulates the Systemic Immune Landscape

“…These monocytes, also through their increased secretion of IL-10 and downregulation of human leukocyte antigen-DR isotype (HLA-DR) thus acquire an immune suppressed state (16, 17, 33, 46, 52–54). That said, CD74, the invariant polypeptide chain associated with the HLA complex is upregulated in the peripheral blood mononuclear cells of patients (55). Despite being capable of processing and transporting antigens, monocytes, nevertheless, are not professional antigen-presenting cells (56, 57).…”