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Harlequin ichthyosis (HI) is one of the most devastating genodermatoses. Recently, ABCA12 mutations were identified as the cause of HI. A newborn Japanese male demonstrated the typical features of HI. The patient was treated with oral etretinate and his general condition has been good (now aged 1.5 years). This patient with moderate clinical severity was compound heterozygous for a novel de novo missense mutation 1160G > A (S387N) in exon 10 and a maternal deletion mutation 4158_4160delTAC (T1387del) in exon 28 of ABCA12. T1387del was a deletion of a highly conserved threonine residue within the first adenosine 5' triphosphate-binding domain and is thought to seriously affect the function of the ABCA12 protein. Conversely, the residue 387 is located outside the known active sites of ABCA12 and S387N is predicted not to lead to a serious functional deficiency in ABCA12. Electron microscopy revealed abnormal lamellar granules in the granular layer cells and a moderate number of lipid vacuoles in the cornified cells. Disturbed glucosylceramide transport was confirmed in the cultured keratinocytes from the patient. No de novo mutation in ABCA12 has yet been reported either in HI or lamellar ichthyosis. The present case suggested that a de novo ABCA12 mutation might underlie HI.

Severe hypersensitivity to mosquito bites (HMB) is characterized by intense local skin reactions and systemic symptoms such as high fever, lymphadenopathy, and hepatosplenomegaly. Patients with HMB often have natural killer (NK) cell lymphocytosis associated with Epstein-Barr virus (EBV) infection. Here we investigated whether mosquito bites have any influence on the oncogenesis of EBV-infected NK cells. We examined six HMB patients with EBV-infected NK cell lymphocytosis. We first demonstrated that CD4+ T cells, but not NK cells, proliferated well in response to mosquito salivary gland extracts (SGE), especially to SGE of Aedes albopictus. When NK cells were cocultured with autologous CD4+ T cells stimulated by mosquito SGE, the expression of viral oncogene latent membrane protein 1 (LMP1) was remarkably enhanced. Next, we stimulated mononuclear cells of the patients with mosquito SGE, and NK cell counts were monitored for 28 d. The counts changed little from initial levels in the culture with mosquito SGE, whereas they decreased steadily in the culture without the extracts. Furthermore, we detected LMP1 mRNA in the skin lesion induced by mosquito SGE. These results suggest that mosquito bites can induce expression of the viral oncogene LMP1 in NK cells via mosquito antigen-specific CD4+ T cells, which is involved in the oncogenesis of NK cells in vivo.

Our laboratory has previously demonstrated that ultraviolet B radiation impairs contact hypersensitivity induction in ultraviolet B susceptible mice through a tumor necrosis factor-alpha-dependent mechanism, involving calcitonin gene related peptide and cutaneous mast cells. This study was designed to test directly whether mast cells are the source of tumor necrosis factor-alpha, to account for the ultra-violet B-susceptible phenotype. As dermal mast cells seem to release tumor necrosis factor-alpha following exposure to ultraviolet B, we investigated whether tumor necrosis factor-alpha released by mast cells could mediate impairment of contact hypersensitivity in a manner similar to that found with ultraviolet B radiation treatment. First, we loaded Fcepsilon receptors of mast cells of ultraviolet B-susceptible (C3H/HeN), ultraviolet B-resistant (C3H/HeJ), and mast-cell deficient (Sl/Sld) mice by intradermal injections of anti-dinitrophenyl immunoglobulin E antibodies. Twenty-four hours later, dinitrophenyl was injected intravenously, and within 30 min oxazolone was painted on injected skin sites. Contact hypersensitivity induction was impaired in ultraviolet B-susceptible mice, but not in ultraviolet B-resistant or Sl/Sld mice, and treatment with anti-tumor necrosis factor-alpha antibodies was able to reverse this impairment of contact hypersensitivity. Second, we have found that ultraviolet B radiation did not impair contact hypersensitivity induction when haptens were painted on irradiated skin of mast cell deficient mice. As ultraviolet B radiation impairs contact hypersensitivity induction through a tumor necrosis factor-alpha-dependent mechanism, we conclude that ultraviolet B radiation triggers the prompt release of tumor necrosis factor-alpha from dermal mast cells, and that mast cell-derived tumor necrosis factor-alpha interferes with generation of the hapten-specific signal required for contact hypersensitivity induction. In addition, we are providing data that indicate that tumor necrosis factor-alpha levels released from mast cells as well as sensitivity of Langerhans cells to tumor necrosis factor-alpha contribute in defining the phenotypes of resistance versus sensitivity to ultra-violet B radiation.

Because substance p (SP) has been reported to be released from cutaneous sensory nerve endings after hapten application, we determined whether SP participates in contact hypersensitivity (CH) induction by using a SP agonist, GR73632 or delta-Aminovaleryl [Pro9, N-Me-Leu10]-substance P(7-11) and a SP antagonist, spantide I. When injected intradermally, SP agonist enhanced CH induced by conventional, but not optimal, sensitizing doses of hapten. By contrast, SP antagonist inhibited the induction of CH by optimal sensitizing doses of hapten. Moreover, SP agonist promoted CH induction and prevented tolerance when hapten was painted on skin exposed to acute, low-dose ultraviolet-B radiation. Intradermally injected SP agonist altered neither the density nor the morphology of epidermal Langerhans cells, implying that SP agonist enhanced the generation of hapten-specific immunogenic signals from the dermis. It is proposed that SP is a natural "adjuvant" that promotes the induction of CH within normal skin. Although exogenous SP agonist can prevent impaired CH and tolerance after ultraviolet-B radiation, the susceptibility of native SP to local neuropeptidases renders the neuropeptide unable to prevent the deleterious effects of ultraviolet-B radiation on cutaneous immunity.

Because interleukin (IL)-10 is an immunoregulatory cytokine that is produced by keratinocytes exposed to UVB radiation (UVR), we determined whether IL-10 participates in either failed contact hypersensitivity (CH) induction or tolerance after acute, low-dose UVR. Murine recombinant IL-10 (200 ng) was injected intradermally on shaved abdominal skin. To assess the effects of IL-10 on CH induction, dinitrofluorobenzene (DNFB, 185 microg) was painted on the skin within 30 min after IL-10 was injected, and the mice were assayed 5 d later by ear challenge with dilute DNFB. To assess tolerance, DNFB (185 microg) was painted a second time on normal body-wall skin 14 d after DNFB was first painted on IL-10-injected skin; CH was then assayed on day 19. We found that mice that received DNFB on IL-10-injected skin developed CH comparable in intensity to that observed in PBS-injected controls. Thus, this dose of IL-10 did not prove to be deleterious to CH induction if hapten was painted on the injected site within 30 min. By contrast, mice that first experienced DNFB within 30 min, 1 d, or 3 d after IL-10 had been injected intracutaneously displayed hapten-specific tolerance. Moreover, intraperitoneally injected anti-IL-10 antibody prevented UVR- and cis-urocanic acid-dependent tolerance; anti-IL-10 antibody had no effect on TNF-alpha-induced tolerance and failed to restore CH induction after UVR exposures. These data indicate that IL-10 is an important mediator of the tolerance induced when hapten is painted on the skin of animals exposed to acute, low-dose UVR.

Tyrosinase-negative oculocutaneous albinism, the most severe subtype of a heterogeneous group of albinism, is an autosomal recessive trait caused by mutations in the tyrosinase gene. Prenatal diagnosis had been made previously only by evaluating fetal skin obtained by biopsy, an invasive procedure that cannot be performed earlier than 19 weeks of gestation. A pregnant mother of a 9-year-old Japanese boy with tyrosinase-negative oculocutaneous albinism wanted a prenatal diagnosis. Polymerase chain reaction amplification and allele-specific oligonucleotide hybridization revealed that the child is homozygous and the parents heterozygous for the pathologic mutation of the tyrosinase gene in exon 2 (single base insertion) but not for the one in exon 1. Prenatal diagnosis was made by analyzing the tyrosinase gene in fetal cells obtained by amniocentesis at 14 weeks of gestation, which demonstrated that the fetus was heterozygous for mutant tyrosinase gene. Pregnancy was therefore continued and a normal male infant was born. This procedure, the analysis of the fetal genomic tyrosinase DNA, is a rapid and reliable approach to the prenatal diagnosis of oculocutaneous albinism at a relatively early stage of pregnancy and is safer and less invasive than previous methods using fetal skin biopsy.