Adjacent Keratinocytes Research Articles

Slac2-a/Melanophilin Contains Multiple PEST-like Sequences That Are Highly Sensitive to Proteolysis

Slac2-a/Melanophilin Contains Multiple PEST-like Sequences That Are Highly Sensitive to Proteolysis

Lack of plakophilin 1 increases keratinocyte migration and reduces desmosome stability.

Ablation of the desmosomal plaque component plakophilin 1 underlies the autosomal recessive genodermatosis, skin fragility-ectodermal dysplasia syndrome (OMIM 604536). Skin from affected patients is thickened with increased scale, and there is loss of adhesion between adjacent keratinocytes, which exhibit few small, poorly formed desmosomes. To investigate further the influence of plakophilin 1 on keratinocyte adhesion and desmosome morphology, we compared plakophilin 1-deficient keratinocytes (vector controls) with those expressing recombinant plakophilin 1 introduced by retroviral transduction. We found that plakophilin 1 increases desmosomal protein content within the cell rather than enhancing transcriptional levels of desmosomal genes. Re-expression of plakophilin 1 in null cells retards cell migration but does not alter keratinocyte cell growth. Confluent sheets of plakophilin 1-deficient keratinocytes display fewer calcium-independent desmosomes than do plakophilin 1-deficient keratinocytes expressing recombinant plakophilin 1 or keratinocytes expressing endogenous plakophilin 1. In addition electron microscopy studies show that re-expression of plakophilin 1 affects desmosome size and number. Collectively, these results demonstrate that restoration of plakophilin 1 function in our culture system influences the transition of desmosomes from a calcium-dependent to a calcium-independent state and this correlates with altered keratinocyte migration in response to wounding. Thus, plakophilin 1 has a key role in increasing desmosomal protein content, in desmosome assembly, and in regulating cell migration.

Quercetin-induced melanogenesis in a reconstituted three-dimensional human epidermal model.

Quercetin (3,5,7,3',4'-pentahydroxyflavone) is one of the most abundant natural flavonoids. It is present in various common vegetables and fruits. In this report, we examined the effect of quercetin on melanogenesis using a three-dimensional reconstituted human epidermal culture model, MelanoDerm, which is a new commercially-available cultured human epidermis containing functional melanocytes. Treatment with 10 microM quercetin induced an increase of tyrosinase activity in cultured epidermis after 3-5 days in time-dependent manner. In the quercetin-treated epidermis, furthermore, melanin content and tyrosinase expression were markedly increased, as shown by immunohistochemistry after a 7-day culture period. Ultrastructural studies clearly indicated an accumulation of mature melanosomes (stages III and IV) inside the basal layer of the cultured epidermis after the quercetin treatment. In addition, the dendrites of melanocytes extended further towards the adjacent keratinocytes after quercetin treatment. These results suggest that quercetin has an effect on maturation of melanosomes and that quercetin has the potential to induced melanogenesis in human epidermis.

Pathways involved in proliferating, senescent and immortalized keratinocyte cell death mediated by two different TRAIL preparations.

Properly regulated keratinocyte cell death is fundamentally important to maintain structural integrity and homeostatic function of epidermis. Moreover, from an oncological perspective, therapeutic approaches selectively targeting apoptosis of malignant cell types while sparing normal keratinocytes in surrounding skin is desirable. Apo2Ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) has been observed to preferentially induce cytopathic effects on transformed/malignant cell types compared with their non-neoplastic counterparts. In this report, two different biologically active preparations of Apo2L/TRAIL, a non-tagged version, NT-Apo2L/TRAIL, and a leucine zipper fusion protein, LZ-Apo2L/TRAIL, were examined for their ability to trigger apoptosis in normal human keratinocytes, and in an immortalized cell line (HaCaT cells). Differences between these preparations were observed, including: NT-Apo2L/TRAIL induced less keratinocyte apoptosis compared with LZ-Apo2L/TRAIL; NT-Apo2L/TRAIL also induced less apoptosis of HaCaT cells compared with LZ-Apo2L/TRAIL; LZ-Apo2L/TRAIL but not NT-Apo2L/TRAIL induced cytotoxic effects when keratinocytes became growth arrested due to undergoing spontaneous replicative senescence--a biological state previously observed to be resistant to UV-light-induced apoptosis. Similarities between preparations included: an enhanced ability for both Apo2L/TRAIL preparations to kill a greater relative percentage of HaCaT cells compared with keratinocytes; enhanced cytotoxicity towards keratinocytes that had their NF-B activity inhibited; a dependence of both Apo2L/TRAIL preparations on FADD and caspase activation; triggering of the same caspase cascades including caspase 8 and 3; and an ability to induce apoptosis even when HaCaT cells and keratinocytes were transduced to overexpress either Bcl-2 or Bcl-x(L) (survival factors that reduce susceptibility to UV-light-induced apoptosis). These results indicate that while both preparations of Apo2L/TRAIL possess biological activity, there are important differences as regards their ability to induce apoptosis in normal and immortalized keratinocytes. Moreover, the death receptor pathway triggered by LZ-Apo2L/TRAIL can overcome the apoptotic resistance normally observed in response to UV-light mediated by Bcl-2/Bcl-x(L), as well as by the state of cellular senescence. Unraveling the molecular basis for these differential biological effects may reveal a new strategic role for these death receptor/ligands linked to apoptosis in maintaining the dynamic balance of keratinocyte proliferation, differentiation, and cell death necessary to achieve a homeostatic thickness and function of normal skin. In addition, it may be possible to utilize these Apo2L/TRAIL preparations for the treatment of various sun-induced skin cancers as they can differentially trigger apoptosis of transformed keratinocytes, or keratinocytes with abnormal NF-kappaB signaling, while sparing adjacent normal keratinocytes.

Mechanisms of desmosome assembly and disassembly.

In skin, desmosomes constitute critical adhesion complexes between adjacent keratinocytes that help maintain an intact epidermis. However, individual keratinocytes need to migrate and differentiate and therefore desmosomes must have an inherent dynamic capacity to assemble and disassemble. This review highlights the role of the different structural junctional components involved in desmosome formation and turnover, as well as the possible signalling processes and pathways that may be implicated in desmosome homeostasis. Clues to the intricate nature of desmosome assembly and disassembly have been derived from human inherited and acquired blistering skin diseases as well as animal models and basic cell biology studies. The key implications for understanding desmosome dynamics from these findings are summarized in this review.

Oral pigmented lesions

Melanocytes have their embryologic origin in the neural crest and, during fetal life, migrate to the basal layer of the skin and mucosa through the peripheral nerves. They exhibit dendritic processes that extend to adjacent keratinocytes, where they transfer pigment. Melanocytes synthesize melanin in specialized granules, that is, the melanosomes, which deliver the pigment to the surrounding keratinocytes and sometimes to the macrophages. Genetic constitution, hormone production, and sun exposure usually influence the amount of pigment production. Oral pigmentations represent a group of several entities ranging from physiologic pigmentation to malignant melanoma. The clinical appearance of oral pigmentation ranges from brown to black, depending on the amount of melanin production and depth of the pigment location (usually brown lesions are related to a superficial pigment location and black/gray lesions to deep pigment location). Oral pigmented lesions are due to:

Keratinocyte adhesion and the missing link: from Dowling–Meara to Hay–WellsSt John's Hospital Dermatological Society Annual Oration 2000

Maintaining a protective barrier against the environment is an essential function of normal skin. Critical to this role are several structural proteins and glycoproteins that contribute to adhesive junctions linking adjacent keratinocytes and basal keratinocytes to the underlying dermis, as well as other regulatory proteins involved in aspects of epidermal development, differentiation and proliferation. Inherited abnormalities in the genes that encode these components may give rise to a range of genodermatoses, many of which are characterized structurally by a 'missing' or perturbed adhesive link and clinically by congenital skin blistering. This oration reviews some of the original clinical descriptions and observations made in this field, as well as providing an update on the corresponding recent molecular discoveries. The emphasis is on contributions made by past and present members of the St John's Hospital Dermatological Society.

Leukaemia Inhibitory Factor (LIF) Expression in Skin from Amyotrophic Lateral Sclerosis Patients Compared with Skin from Normal Individuals: What is the Function of LIF in the Skin?

Leukaemia Inhibitory Factor (LIF) Expression in Skin from Amyotrophic Lateral Sclerosis Patients Compared with Skin from Normal Individuals: What is the Function of LIF in the Skin?

ACTH4-12 is the minimal message sequence required to induce the differentiation of mouse epidermal melanocytes in serum-free primary culture

It is well known that alpha-melanocyte stimulating hormone (MSH) induces the differentiation of mouse epidermal melanocytes in vivo and in vitro. Although adrenocorticotropic hormone (ACTH) possesses the same amino acid sequence as MSH does, it is not clear whether the peptide and its fragments induce the differentiation of mouse epidermal melanocytes. In this study, the differentiation-inducing potencies of human ACTH and its fragments were investigated by adding them into a culture medium (0.001-1,000 nM) from the initiation of primary culture of epidermal cell suspensions. Their potencies were compared with the potency of alpha-MSH. After 2-4 days of primary cultures with ACTH(1-13), ACTH(1-17), ACTH(1-24), ACTH(1-39), ACTH(4-12), ACTH(4-13), and alpha-MSH, pigment granules appeared in the cytoplasms and dendrites of melanoblasts that were in contact with the adjacent keratinocyte colonies. By 14 days, cultures contained mostly pigmented melanocytes. The order of potencies of ACTH fragments and alpha-MSH shown by the ED(50) value was as follows: alpha-MSH = ACTH(1-13) = ACTH(1-17) = ACTH(4-12) = ACTH(4-13) > ACTH(1-24) > ACTH(1-39). The length of their peptide chains was inversely proportional to the potency. On the contrary, ACTH(1-4), ACTH(11-24), and ACTH(18-39) failed to induce the differentiation of melanocytes. In contrast, ACTH(1-10), ACTH(4-10), ACTH(4-11), and ACTH(5-12) possessed a weak potency at high doses only (100 and 1,000 nM). These results suggest that ACTH(4-12) is the minimal message sequence required to induce the differentiation of mouse epidermal melanocytes in culture completely. The amino acids of Met(4) and Pro(12) are suggested to be important for its potency.

Strong expression of the lymphoattractant C-X-C chemokine Mig is associated with heavy infiltration of T cells in human malignant melanoma.

Human malignant melanoma (MM) is a highly aggressive tumour which is particularly prone to specific local immune responses. To determine the microanatomical location and the species of chemokines possibly involved in the intricate control of cell migration and positioning of immune effector cells in primary and metastatic MM lesions, the expression of those chemokines with lymphocyte and/or macrophage chemoattractant properties was analysed by in situ hybridization. GROalpha (growth-related oncogene) and IL-8 (interleukin 8) were expressed at low levels by single melanoma cells, adjacent keratinocytes, and infiltrating leukocytes. In contrast, the lymphocyte-specific chemokine Mig (monokine induced by interferon-gamma) was strongly expressed by mononuclear cells (mainly macrophages) infiltrating the tumour margin in primary MM lesions, whereas expression was less intense in MM metastasis. IP-10 (interferon-gamma inducible protein 10) was expressed in the same loci at lower intensity. Marked infiltration of T cells was exclusively detected in those areas which exhibited strong Mig expression, whereas areas in the vicinity of tumour cells devoid of Mig expression were not infiltrated. In contrast to Mig, expression of MCP-1 (macrophage chemotactic protein-1) was weaker and mainly detected in lesional basal keratinocytes, occasionally at sites of macrophage infiltration, as well as in single melanoma cells. MIP-1alpha (macrophage inflammatory protein 1alpha) showed similar, albeit weaker expression compared with MCP-1. Other chemokines relevant for the recruitment of monocytes and lymphocytes, such as RANTES (regulated on activation, normal T cells expressed and secreted) and MIP-1beta, were barely detectable. In summary, the chemokine expression profiles support the notion that particularly in heavily infiltrated primary MM lesions, Mig and to a lesser extent IP-10 are important mediators of an IFN-gamma-dependent pathway. Due to their lymphoattractant properties and the known inhibitory effects on the tumour vasculature, both chemokines may be critical for the control of local melanoma tumour growth.

The Physiology of Pigmented Nevi

Melanocytes are pigment-producing cells derived from the neural crest. These specialized exocrine cells produce melanin, which is packaged and dispersed to neighboring keratinocytes in organelles called melanosomes. Within the melanocyte, tyrosine is converted to dopa, and then dopaquinone via the bifunctional enzyme tyrosinase. Dopaquinone is oxidized further to form the pigment melanin. Each epidermal melanocyte secretes melanosomes to approximately 36 adjacent keratinocytes, forming an epidermal melanin unit. Genetically programmed constitutive skin color is determined by the amount of cutaneous melanin pigmentation. The common mole or acquired melanocytic nevus (AMN) is a collection of nevomelanocytes grouped into nests located in the epidermis (junctional nevus), dermis (dermal nevus), or both (compound nevus). It is hypothesized that nevomelanocytes are derived from either epidermal melanoblasts or dermal Schwann cells. AMN first appear at approximately 1 year of age, peaking in number during the second or third decades of life, and disappearing by the seventh to ninth decades. AMN may appear suddenly or become more prominent in response to sun exposure, cortisone and corticotropin, blistering diseases, chemotherapy, immunosuppression, and other factors that are not well-defined. Reports of AMN increasing in size and darkening in color during puberty and pregnancy have been reported but not quantitated systematically.melanocytes, keratinocytes, acquired melanocytic nevi.

Cell Interactions Control the Fate of Malignant Keratinocytes in an Organotypic Model of Early Neoplasia

The role of cell interactions during early neoplastic progression in human skin is not well understood. We report that the fate and behavior of low-grade malignant cells in stratified epithelium is dependent on their interactions with neighboring cells and with extracellular matrix during the early events in neoplastic progression. We utilized an organotypic tissue model which mimics premalignancy to monitor malignant cells (II-4) genetically marked with beta-gal and grown in the context of either normal human keratinocytes or the immortalized cell line HaCaT. HaCaT cells were permissive for clonal expansion of II-4 cells at ratios of 4:1, 12:1, and 50:1 (HAC:II-4) when compared with coculture with normal human keratinocytes. This II-4 cell expansion was associated with the failure of neighboring HaCaT cells to induce differentiation and cell cycle withdrawal of II-4, as had been seen in the context of normal human keratinocytes. When 12:1 mixtures (NHK:II-4) were stripped of all suprabasal cells and regrown, all beta-gal cells were lost showing that these normal human keratinocyte-suppressed II-4 cells had been actively sorted to a suprabasal position where their clonal expansion was limited. These growth-suppressive effects of normal human keratinocytes were found to be conditional on direct cell-cell contact, as II-4 formed colonies when trypsinized from 12:1 (NHK:II-4) mixtures and grown at clonal density in submerged culture. The distribution and behavior of low-grade malignant cells was therefore dependent on the state of transformation of adjacent keratinocytes and on cell-matrix interactions. These results demonstrate that alterations in the cellular microenvironment are central to the induction of clonal expansion and early neoplastic progression in stratified epithelium.

Human Melanocytes and Keratinocytes Exposed to UVB or UVA In Vivo Show Comparable Levels of Thymine Dimers

Epidemiology shows a relationship between solar exposure and all types of skin cancer. Understanding the mechanisms of skin cancer requires knowledge of the photomolecular events that occur within the relevant epidermal cell types in vivo. Studies to date have focused on UVR-induced DNA lesions in keratinocytes, the majority epidermal cell population which gives rise to most skin cancers. Malignant melanoma, arising from melanocytes (5%-10% of epidermal cells), accounts for most skin cancer deaths. We report on new techniques to detect DNA photolesions in human epidermal melanocytes in situ. Previously nonexposed buttock skin of volunteers of skin types I/II was exposed to clinically relevant doses of narrow bandwidth UVB (300 nm) and UVA (320 nm, 340 nm, 360 nm) radiation. Biopsies were taken immediately afterwards and processed for routine histology. Microscope sections were prepared and double-stained with fluorescent-tagged monoclonal antibodies for thymine dimers and melanocytes. UVR dose-response curves for dimer levels within melanocyte nuclei were determined by image analysis and compared with dimer levels in adjacent basal cell keratinocytes. Our data show that UVB and UVA readily induce thymine dimers in melanocytes at levels that are comparable with those found in adjacent keratinocytes. This new technique will enable melanocyte specific studies, such as DNA repair kinetics, to be done in vivo.

Partial albinism with immunodeficiency: Griscelli syndrome: Report of a case and review of the literature

Partial albinism with immunodeficiency (Griscelli syndrome) is an uncommon disorder characterized by pigmentary dilution and variable immunodeficiency. Features include a silvery-gray sheen to the hair, large clumped melanosomes in hair shafts, and prominent mature melanosomes in cutaneous melanocytes with sparse pigmentation of adjacent keratinocytes. Immunologic abnormalities most often include impaired natural killer cell activity, absent delayed-type hypersensitivity, and impaired responses to mitogens. Impaired helper T cell function and hypogammaglobulinemia have also been described. The syndrome can be differentiated from Chediak-Higashi syndrome by pathognomonic light and electron microscopic features in skin and hair, and absence of consistent granulocyte abnormalities, but similarly carries a poor prognosis without bone marrow transplantation. We describe a patient with Griscelli syndrome who presented with hepatosplenomegaly, hepatitis, pancytopenia, and silvery hair in the newborn period. (J Am Acad Dermatol 1998;38:295-300.)

In situ and in vitro expression of protein kinase C alpha in human melanocytes.

Protein kinase C (PKC) is a multigene family of at least 12 isoforms involved in the transduction of extracellular signals. We investigated whether PKC-alpha, a major isoform known to be relatively abundant in brain tissue, is increased in human melanocytes relative to keratinocytes in vitro and in situ. Immunohistochemical staining for PKC-alpha in frozen neonatal human foreskin exhibited intermittent 2-3 + staining along the basal cell layer consistent with melanocytes, and 0-1 + staining of keratinocytes (on a scale of 0-3). Microscopic densitometry of the intermittent cellular staining was at least 3-fold greater than that of adjacent keratinocyte cell cytoplasm. Sequential frozen sections revealed similar intermittent cell staining with PKC-alpha and Mel-5 (tyrosinase related protein-1), known to specifically react with melanocytes. Northern blot analysis with a specific cDNA probe for PKC-alpha showed strong PKC-alpha mRNA expression in cultured melanocytes, whereas PKC-alpha mRNA in cultured non-stratifying keratinocytes was expressed at low levels. Western blot analysis revealed a prominent PKC-alpha band at approximately 80 kDa in melanocytes as opposed to a weak band in keratinocytes. Densitometry of the northern and western blots revealed that melanocytes had at least 10-fold more PKC-alpha mRNA and approximately 6-fold more PKC-alpha protein expression than keratinocytes. Total PKC activity measured in vitro revealed that melanocytes had 5-fold more activity than keratinocytes. The marked difference in melanocyte and keratinocyte expression of PKC-alpha provides further evidence for cell type specificity in the balance of PKC-alpha expression and may implicate differential PKC isoform signaling pathways in neuro-ectodermally derived cells.

Differentiation of cultured keratinocytes promotes the adherence of Streptococcus pyogenes.

Based on a consideration of the histopathology of nonbullous impetigo that shows localization of Streptococcus pyogenes to highly differentiated, subcorneal keratinocytes, we hypothesized that adherence of an impetigo strain of S. pyogenes would be promoted by terminal differentiation of keratinocytes. An assay was developed in which S. pyogenes adhered via pilus-like projections from the cell wall to the surface of cultured human keratinocytes in a time- and inoculum-dependent manner suggestive of a receptor-mediated process. Terminal differentiation of keratinocytes was induced by increasing the calcium concentration in the growth medium, and was confirmed by morphologic analysis using electron microscopy. Adherence of S. pyogenes was three and fourfold greater to keratinocytes differentiated in 1.0 and 1.5 mM calcium, respectively, compared with undifferentiated keratinocytes in 0.15 mM calcium. The presence of calcium during the adherence assay further enhanced adherence nearly twofold. Adherence occurred preferentially to sites of contact between adjacent keratinocytes, suggesting that the keratinocyte receptor may be a molecule involved in cell-to-cell adhesion. In contrast, nonpathogenic Streptococcus gordonii adhered poorly to keratinocytes regardless of their state of terminal differentiation, and adherence of a pharyngeal strain of S. pyogenes was twofold greater to undifferentiated than differentiated keratinocytes. This is the first report of in vitro adherence of S. pyogenes to keratinocytes in a manner that emulates human impetigo. Adherence of only the impetigo strain, and not the pharyngeal strain of S. pyogenes or the nonpathogenic S. gorgonii isolate, was promoted by keratinocyte differentiation. This result provides a model system for investigating the molecular pathogenesis of streptococcal skin infections.

An immunocytochemical study of MHC class I expression on human Langerhans cells and melanocytes.

Classical MHC class I glycoproteins (HLA-A, B, and C) present endogenous cytosolic peptide antigen fragments to CD8-positive T-cells. CD8-positive T-cell recognition and destruction of virus-infected cells are dependent on adequate cellular MHC class I expression. Constitutive MHC class I expression is ubiquitous, but known to be deficient on specific differentiated cell types which include hepatocytes, neurones, chondrocytes and myocytes. Although enabling assessment of MHC class I expression on individual cells, limitations of immunocytochemistry were encountered with this assessment on Langerhans cells and melanocytes. These dispersed intraepidermal cells were obscured by adjacent keratinocytes in sections immunostained for MHC class I glycoproteins. Initiatives designed to resolve the issue have included immunoelectron microscopy, cell culture techniques, and animal bone marrow chimera models. Despite the elegance of these techniques, the issue of MHC class I expression on Langerhans cells and melanocytes remains unresolved. In this immunocytochemical study, an alternative strategy was based upon the recognized deficiency of epithelial MHC class I expression within pilosebaceous adnexal units. Langerhans cells and melanocytes were therefore studied within this microenvironment of deficient MHC class I expression, using monomorphic and polymorphic MHC markers. Langerhans cells and melanocytes were demonstrated within pilosebaceous units of scalp skin by immunocytochemistry. Differentiation markers OKT6 (CD1a) and TMH1 defined Langerhans cells and melanocytes, respectively. Monomorphic MHC markers W6/32 and TAL IB5 defined invariant epitopes of HLA class I and II, respectively. Polymorphic MHC class I markers defined the HLA-Bw4 and HLA-Bw6 supertypic determinants. Constitutive MHC class I expression was shown to be deficient on Langerhans cells and melanocytes.

Langerhans Cells Express Inducible Nitric Oxide Synthase and Produce Nitric Oxide

The importance of nitric oxide (NO) in mediating macrophage functions has been demonstrated, but production of this potent gas has not been examined in Langerhans cells (LC). Using murine LC purified from epidermal cell suspensions and the recently established LC-like cell line derived from newborn BALB/c epidermis (XS-52), it was shown with reverse transcriptase (RT)-PCR that inducible nitric oxide synthase (iNOS) message is present in these cells. Murine keratinocytes did not contain iNOS message. iNOS mRNA was increased in a concentration-dependent manner by lipopolysaccharide (LPS) in purified murine LC and XS-52 cells, and immunofluorescence using an antibody to iNOS revealed bright cytoplasmic staining in LPS-treated XS-52 cells. Anti-iNOS antibody brightly stained LC on human neonatal foreskin cryosections. An increase in NO production by LPS-treated XS-52 cells over 16 h, as measured by the determination of nitrite levels in culture supernatants using the Griess Reaction, was observed. Interferon-gamma (IFNgamma) did not affect NO production on its own. In the presence of LPS and IFNgamma, NO production was 3 times more than observed with LPS alone. NO production was inhibited by the NOS inhibitor L-NAME. Western blots with anti-iNOS antibody demonstrated an increase in iNOS expression in LPS-treated XS-52 cells that was suppressed by IL-10. NO produced in LC may affect LC functions such as microbicidal activity, antigen presentation, and cytotoxicity and may affect adjacent keratinocytes and melanocytes.

Tissue distribution of a melanoma-associated antigen immunogenic in patients with melanoma as analyzed by polyclonal antibodies to recombinant peptide antigen.

This study aimed to detect in vivo expression of human melanoma-associated antigen D-1, which was identified by screening an expression cDNA library constructed from mRNA extracted from cultured melanoma cells with sera from patients with melanoma. The tissue distribution of D-1 antigen was then analyzed. Murine anti-D-1 recombinant peptide polyclonal antibodies were raised by immunization of in vitro synthesized D-1 peptide against Balb/c mice and applied immunohistochemically on paraffin-embedded tissue specimens. D-1 antigen was found to be restrictedly expressed on melanoma cells, but not on normal melanocytes, adjacent keratinocytes, fibroblasts, lymphocytes and adnexal structures of skin. The reactivities of anti-D-1 antibodies did not correlate with histogenesis of the lesions, their ability to produce melanin, and/or their primary or metastatic nature. There was no positive reactivity of anti-D-1 antibodies with other skin tumors, including squamous cell carcinoma, basal cell epithelioma, seborrheic keratosis, and nevus cell nevus. Further, cytoplasmic expression of D-1 antigen in melanoma cells was observed only in a certain subgroup of patients with melanoma. This indicates that the cell surface expression of D-1 peptide requires specific transporting proteins, such as HLA molecules.

Partial albinism with immunodeficiency (Griscelli syndrome)

Partial albinism with immunodeficiency is a rare and fatal immunologic disorder characterized by pigmentary dilution and variable cellular immunodeficiency. To define the phenotype, therapy, and outcome, we retrospectively analyzed seven consecutive patients. Primary abnormalities included a silvery-grayish sheen to the hair, large pigment agglomerations in hair shafts, and an abundance of mature melanosomes in melanocytes, with reduced pigmentation of adjacent keratinocytes. Clinical onset occurred between the ages of 4 months and 4 years and was characterized by accelerated phases (lymphohistiocytic infiltration of multiple organs, including the brain and the meninges), triggered by viral and bacterial infections. Characteristic laboratory features included pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and hypoproteinemia. Consistent immunologic abnormalities were characterized by absent delayed-type cutaneous hypersensitivity and impaired natural killer cell function. Some patients had secondary hypogammaglobulinemia, impaired major histocompatibility complex-mediated cytotoxic effects, a decreased capacity of lymphocytes to trigger a mixed lymphocyte reaction, or various functional granulocytic abnormalities. The disease seems to be invariably lethal without bone marrow transplantation; the mean age at the time of death was 5 years. Bone marrow transplantation has been performed in three cases; two patients died in the immediate posttransplantation period of infectious complications, but one patient is cured after a follow-up of 5 years. We conclude that partial albinism with immunodeficiency (Griscelli syndrome) can be differentiated from Chédiak-Higashi syndrome by pathognomonic histologic features. One of the underlying immunologic defects may be a defective function of natural killer cells, predisposing the patient to virus-associated hemophagocytic syndrome or accelerated phases. The prognosis is very poor unless early bone marrow transplantation is carried out. (J P EDIATR 1994;125:886-95)