Tight junction proteins expression and modulation in immune cells and multiple sclerosis

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.

Appearance of claudin-5+ leukocytes in the central nervous system during neuroinflammation: a novel role for endothelial-derived extracellular vesicles

“…The present work extends the report of Mandel et al [20, 21], which noted an increase in CLN-5 + leukocytes in blood from MS patients who experienced disease relapse. Our findings corroborated the presence of CLN-5 + leukocytes in blood during EAE, an animal model of MS [54–56], and further demonstrated their appearance in the CNS.…”

“…Specifically, Mandel et al [20] observed TJ proteins of the claudin (CLN) family—notably CLN-1 (CLN-1 + ) and CLN-5 (CLN-5 + )—in peripheral blood leukocytes (PBLs) from both healthy individuals and those affected with the neuroinflammatory condition multiple sclerosis (MS). They further noted an increase in CLN-1 and CLN-5 protein expression by PBLs from MS patients experiencing disease relapse, compared to healthy controls or patients in remission.…”

Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus

“…30 Consistent expression of tight junction proteins was also reported in human leucocytes, primarily in lymphocytes and monocytes, and they were suggested to play a role in immune activity and autoimmunity. 31 Tight junction proteins (eg, CLDN19) were also proposed among possible biomarkers for refractory lupus nephritis. 32 SGK223 (http:// www.…”

Gene Expression Profiling of the Response to Interferon Beta in Epstein-Barr-Transformed and Primary B Cells of Patients with Multiple Sclerosis

“…RT-PCR analyses were performed using the FastStart Universal SYBR Green Master-Rox (Roche) on the AB 7300 sequence detection system in duplicates. The ubiquitin-conjugating enzyme E2 D2 ( UBE2D2 ) gene was used as a reference gene as in previous and the present studies its levels were unaffected by IFN-β [38]. Relative quantification of mRNA expression was calculated using the comparative CT method and is shown as fold change of expression (2 −ΔΔ C T ) [39].…”