Abstract
The tight junction proteins (TJPs) are major determinants of endothelial cells comprising physiological vascular barriers such as the blood–brain barrier, but little is known about their expression and role in immune cells. In this study we assessed TJP expression in human leukocyte subsets, their induction by immune activation and modulation associated with autoimmune disease states and therapies. A consistent expression of TJP complexes was detected in peripheral blood leukocytes (PBLs), predominantly in B and T lymphocytes and monocytes, whereas the in vitro application of various immune cell activators led to an increase of claudin 1 levels, yet not of claudin 5. Claudins 1 and 5 levels were elevated in PBLs of multiple sclerosis (MS) patients in relapse, relative to patients in remission, healthy controls and patients with other neurological disorders. Interestingly, claudin 1 protein levels were elevated also in PBLs of patients with type 1 diabetes (T1D). Following glucocorticoid treatment of MS patients in relapse, RNA levels of JAM3 and CLDN5 and claudin 5 protein levels in PBLs decreased. Furthermore, a correlation between CLDN5 pre-treatment levels and clinical response phenotype to interferon-β therapy was detected. Our findings indicate that higher levels of leukocyte claudins are associated with immune activation and specifically, increased levels of claudin 5 are associated with MS disease activity. This study highlights a potential role of leukocyte TJPs in physiological states, and autoimmunity and suggests they should be further evaluated as biomarkers for aberrant immune activity and response to therapy in immune-mediated diseases such as MS.
Highlights
Autoimmune diseases are associated with aberrant activity and enhanced migratory capacity of immune cells [1, 2]
In a preliminary screen for TJ genes expressed in leukocytes using a qualitative RT-PCR assay, we discovered that several claudin genes are consistently expressed in leukocytes from healthy and multiple sclerosis (MS) affected individuals
Lack of commercial anti-claudin antibodies at the time experiments were performed excluded the use of flow cytometry for co-expression analyses, and use of immunofluorescence staining allowed the additional advantage of observing the cellular localization of the TJ protein expression
Summary
Autoimmune diseases are associated with aberrant activity and enhanced migratory capacity of immune cells [1, 2]. TJs between endothelial and epithelial cells form the structural basis of physiological barriers such as the BBB, which serves as a physical and metabolic barrier between the CNS and the systemic circulation. They are composed of the membranal TJPs occludin, claudins and the junctional adhesion molecules (JAMs), as well as various scaffold and cytoplasmic proteins such as the zonula occludens (ZO) proteins [10]. Expression of TJPs in brain endothelia appears to be regulated by interactions with surrounding cells such as pericytes [32] These multiple regulation pathways converge to effectively determine and modulate barrier properties of the BBB and other endothelial layers. Our findings indicate that the levels of claudin 5 prior to IFN treatment are associated with the drug response phenotype in MS
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