Keratitis-ichthyosis-deafness syndrome, atypical connexin GJB2 genemutation, and peripheral T-cell lymphoma: more than a random association?

Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital disorder characterized by a variety of skin lesions— that is, palmoplantar keratoderma, thickening of the skin, and erythematous verrucous lesions—neurosensorial hypoacusia, and keratitis with a variable degree of visual impairment. Both sporadic and familial forms of the syndrome have been described, the latter usually showing a dominant pattern of inheritance. The molecular lesion responsible for the syndrome typically involves the connexin 26 (Cx26) gene (GJB2). Most patients display the heterozygous c.148G→A mutation causing the substitution of an aspartic acid for an asparagine at position 50 (p.Asp50Asn), while a few of them show the c.50C→T mutation, implying the substitution of a serine for a phenylalanine at position 17 (p.Ser17Phe). However, even a mutation in the connexin 30 (Cx30) gene (GJB6) has been found in a typical KID patient, thus suggesting a genetic heterogeneity of the syndrome. As connexins are a large family of small integral membrane proteins which influence tissue cornification by modulating the establishment of direct cell-cell communication through gap junction channels, it is likely that defects involving this class of proteins are at the basis of the wellknown increased incidence of squamous cell carcinoma in KID patients

Effects of maternal obesity on Wharton's Jelly mesenchymal stromal cells

Abstract We investigated whether maternal metabolic environment affects mesenchymal stromal/stem cells (MSCs) from umbilical cord’s Wharton’s Jelly (WJ) on a molecular level, and potentially render them unsuitable for clinical use in multiple recipients. In this pilot study on umbilical cords post partum from healthy non-obese (BMI = 19–25; n = 7) and obese (BMI ≥ 30; n = 7) donors undergoing elective Cesarean section, we found that WJ MSC from obese donors showed slower population doubling and a stronger immunosuppressive activity. Genome-wide DNA methylation of triple positive (CD73+CD90+CD105+) WJ MSCs found 67 genes with at least one CpG site where the methylation difference was ≥0.2 in four or more obese donors. Only one gene, PNPLA7, demonstrated significant difference on methylome, transcriptome and protein level. Although the number of analysed donors is limited, our data suggest that the altered metabolic environment related to excessive body weight might bear consequences on the WJ MSCs

Patients with myelodysplastic syndromes show reduced frequencies of CD4⁺ CD8⁺ double-positive T cells

Even though the expression of CD4 and CD8 on thymocytes is considered mutually exclusive, CD4+ CD8+ double-positive T cells (DP) represent a small subset of T lymphocytes that have been described in the peripheral blood of normal individuals, as well as in some pathological conditions. In particular, an agedependent accumulation of monoclonal DP has been shown in elderly healthy subjects. From the functional point of view, DP are able to act as differentiated effector memory cells with specific antiviral functions

Patients with myelodysplastic syndromes display several T-cell expansions, which are mostly polyclonal in the CD4⁺ subset and oligoclonal in the CD8⁺ subset

Objective. Immune dysregulation plays a role in the pathophysiology of myelodysplastic syndromes (MDS), as T-cell clones seem to be involved in the inhibition of hematopoietic precursors. The purpose of this study was to analyze the T-cell receptor (TCR) repertoire of MDS patients, focusing on the third complementarity determining region (CDR3) pattern of their CD4+ and CD8+ lymphocyte expansions. Materials and Methods. The study involved 30 patients and 15 age-matched controls. The β-variable (βV) subfamily flow-cytometry analysis was performed on peripheral CD4+ and CD8+ T-cells. Spectratyping TCR-CDR3 analysis was carried out on isolated helper and cytotoxic T lymphocytes after immunomagnetic separation and reverse-transcriptase polymerase chain reaction. Results. We first identified by flow cytometry an increased frequency of expanded βVs in both CD4+ and CD8+ T-cells in MDS patients. We then showed, by spectratyping, that the CDR3 profile was mostly Gaussian in their CD4+ T cells, whereas CD8+ T cells usually showed skewed or oligoclonal CDR3 regions. When we compared spectratyping and flow-cytometry findings in each patient, we showed that most CD4+ lymphocyte expansions detected by flow cytometry had Gaussian CDR3 profiles, whereas most CD8+ expansions were oligoclonal. Conclusion. We confirm that in MDS patients the TCR-βV repertoire is overall extremely contracted, especially in cytotoxic T cells. This pattern is mainly determined by selective proliferations of both helper and cytotoxic T cells, which are, however, mostly polyclonal in the former and oligoclonal in the latter. Such a difference, possibly related to the different human leukocyte antigen restriction, could reflect the selective involvement of cytotoxic T cells either in the anti-tumor immune surveillance or in an autoreactive aggression toward hematopoietic precursors