Identification of LCK mutation in a family with atypical epidermodysplasia verruciformis with T-cell defects and virus-induced squamous cell carcinoma.

BACKGROUND: Inherited epidermodysplasia verruciformis (EV) is a rare skin disorder characterized by susceptibility to specific types of human papilloma virus (HPV) and is strongly associated with skin carcinomas. Inactivating mutations in EVER1/EVER2 account for most cases of EV. However, more phenotypes related to but distinct from EV have been reported with an immunodeficiency state but without EVER1/EVER2 mutation, and the genetic basis for these atypical EV cases is poorly understood. OBJECTIVES: To identify the causative gene responsible for three siblings affected by atypical EV but without EVER1/EVER2 mutation. METHODS: Whole-exome sequencing followed by Sanger sequencing was performed to identify the gene responsible for the patients with atypical EV enrolled in our study. RESULTS: A homozygous splicing mutation was detected in LCK (c.188-2A>G). This mutation resulted in an exon 3 deletion T lymphocyte-specific protein tyrosine kinase isoform, which further led to frameshift mutation and subsequent mRNA decay. CONCLUSIONS: We demonstrate a novel mutation in LCK in a family affected by atypical EV with T-cell defects, HPV infection and virus-induced malignancy, providing new clues in the understanding of host defences against HPV and better genetic counselling of patients with the EV phenotype.

Immunosuppressive human anti-CD83 monoclonal antibody depletion of activated dendritic cells in transplantation.

Current immunosuppressive/anti-inflammatory agents target the responding effector arm of the immune response and their nonspecific action increases the risk of infection and malignancy. These effects impact on their use in allogeneic haematopoietic cell transplantation and other forms of transplantation. Interventions that target activated dendritic cells (DCs) have the potential to suppress the induction of undesired immune responses (for example, graft versus host disease (GVHD) or transplant rejection) and to leave protective T-cell immune responses intact (for example, cytomegalovirus (CMV) immunity). We developed a human IgG1 monoclonal antibody (mAb), 3C12, specific for CD83, which is expressed on activated but not resting DC. The 3C12 mAb and an affinity improved version, 3C12C, depleted CD83(+) cells by CD16(+) NK cell-mediated antibody-dependent cellular cytotoxicity, and inhibited allogeneic T-cell proliferation in vitro. A single dose of 3C12C prevented human peripheral blood mononuclear cell-induced acute GVHD in SCID mouse recipients. The mAb 3C12C depleted CMRF-44(+)CD83(bright) activated DC but spared CD83(dim/-) DC in vivo. It reduced human T-cell activation in vivo and maintained the proportion of CD4(+) FoxP3(+) CD25(+) Treg cells and also viral-specific CD8(+) T cells. The anti-CD83 mAb, 3C12C, merits further evaluation as a new immunosuppressive agent in transplantation.

Determination and use of Rohrschneider-McReynolds constants for chiral stationary phases used in capillary gas chromatography.

The overall polarity of 22 chiral stationary phases (CSPs) used in capillary open tubular gas chromatography columns was estimated using the first five Rohrschneider-McReynolds constants. Most of the columns (i.e., 18) were wall-coated, and four were of the wall-immobilized or of the so-called "bonded" type. A wall-coated capillary squalane column was specially prepared as a polarity reference column. All but two of the CSPs were based on derivatized cyclodextrins (CDs) of different sizes. The overall properties of the CSPs are discussed in terms of the five Rohrschneider-McReynolds constants and their average values. It was found that the derivatized cyclodextrin CSP polarity increased with the CD ring size. The bonded CSPs were significantly less polar than their coated homologues due to the apolar polymer used to immobilize the CD rings. The retention behavior of 14 compounds was studied at 100 degrees C on the capillary columns. Retention parameters are clearly related to the McReynolds constants. Conversely, the enantiomeric resolution capability of a given stationary phase is not related to the constants. The enantioselective resolution mechanism critically depends on the solute structure and on the nature of the CSP.