The role of experience in prioritizing hippocampal replay.

During sleep, recent memories are replayed by the hippocampus, leading to their consolidation, with a higher priority given to salient experiences. To examine the role of replay in the selective strengthening of memories, we recorded large ensembles of hippocampal place cells while male rats ran repeated spatial trajectories on two linear tracks, differing in either their familiarity or number of laps run. We observed that during sleep, the rate of replay events for a given track increased proportionally with the number of spatial trajectories run by the animal. In contrast, the rate of sleep replay events decreased if the animal was more familiar with the track. Furthermore, we find that the cumulative number of awake replay events occurring during behavior, influenced by both the novelty and duration of an experience, predicts which memories are prioritized for sleep replay, providing a more parsimonious neural correlate for the selective strengthening of memories.

Xeroderma pigmentosum complementation group G patient with a novel homozygous missense mutation and no neurological abnormalities.

We describe an unusual xeroderma pigmentosum (XP) patient with a mutation in XP complementation group G, representing only the third reported Japanese XP-G patient. A 40-year-old men (XP3HM), born from consanguineous parents experienced sun sensitivity and pigmentary changes of sun-exposed skin since childhood. He developed a squamous cell carcinoma on his lower lip at the age of 40. He has neither neurological abnormalities nor Cockayne syndrome. The primary fibroblasts of the patient were hypersensitive to killing by UV (D(0) = 0.6 J/m(2)) and the post-UV unscheduled DNA synthesis was 8% of normal. Host cell reactivation complementation analysis implicated XP complementation group G. We identified a novel homozygous mutation (c.194T>C) in a conserved portion of the XPG(ERCC5) gene, resulting in a predicted amino acid change; p.L65P. We confirmed that this genetic change reduced DNA repair thus linking this mutation to increased skin cancer.

Experience-driven rate modulation is reinstated during hippocampal replay.

Replay, the sequential reactivation within a neuronal ensemble, is a central hippocampal mechanism postulated to drive memory processing. While both rate and place representations are used by hippocampal place cells to encode behavioral episodes, replay has been largely defined by only the latter - based on the fidelity of sequential activity across neighboring place fields. Here, we show that dorsal CA1 place cells in rats can modulate their firing rate between replay events of two different contexts. This experience-dependent phenomenon mirrors the same pattern of rate modulation observed during behavior and can be used independently from place information within replay sequences to discriminate between contexts. Our results reveal the existence of two complementary neural representations available for memory processes.

How do our brains store memories? We now know that this is a complex and dynamic process, involving multiple regions of the brain. A brain region, called the hippocampus, plays an important role in memory formation. While we sleep, the hippocampus works to consolidate information, and eventually creates stable, long-term memories that are then stored in other parts of the brain. But how does the hippocampus do this? Neuroscientists believe that it can replay the patterns of brain activity that represent particular memories. By repeatedly doing this while we sleep, the hippocampus can then direct the transfer of this information to the rest of the brain for storage. The behaviour of nerve cells in the brain underpins these patterns of brain activity. When a nerve cell is active, it fires tiny electrical impulses that can be detected experimentally. The brain thus represents information in two ways: which nerve cells are active and when (sequential patterns); and how active the nerve cells are (how fast they fire electrical impulses or firing rate). For example, when an animal moves from one location to another, special place cells in the hippocampus become active in a distinct sequence. Depending on the context, they will also fire faster or slower. We know that the hippocampus can replay sequential patterns of nerve cell activity during memory consolidation, but whether it can also replay the firing rates associated with a particular experience is still unknown. Tirole, Huelin Gorriz et al. set out to determine if the hippocampus could also preserve the information encoded by firing rate during replay. In the experiments, rats explored two different environments that they had not seen before. The activity of the rats' place cells was recorded before and after they explored, and also later while they were sleeping. Analysis of the recordings revealed that during replay, the rats' hippocampi could indeed reproduce both the sequential patterns of activity and the firing rate of the place cells. It also confirmed that each environment was associated with unique firing rates ­ in other words, the firing rates were memory-specific. These results contribute to our understanding of how the hippocampus represents and processes information about our experiences. More broadly, they also shed new light on how the brain lays down memories, by revealing a key part of the mechanism that it uses to consolidate that information.

Promiscuous interaction between gold-specific T cells and APCs in gold allergy.

Gold compounds clinically used as immunomodulators have high potential to evoke hypersensitivity reactions as an adverse effect. To explore the mechanism of gold allergy, we immunologically characterized T cells infiltrating skin rashes and generated 44 gold-specific T cell clones and lines from a rheumatoid arthritis patient who developed skin rashes and systemic symptoms after gold treatment. CD4(+) and CD8(+) cells predominantly infiltrating the skin rashes and some of the T cell clones and lines shared common Vbetas. These cells exhibited Th0-like, Th2-like, and Tc1-like cytokine profiles, and showed chemotactic activities for thymus and activation-regulated chemokine and IFN-gamma-inducible protein-10 corresponding to the cytokine profiles. T cell recognition of gold consisted of MHC-restricted and MHC-independent pathways. Blocking studies with anti-MHC Abs indicated that the groove of MHC in APCs, where Ags should ordinarily be settled, did not serve as a conjugating site of gold for these T cells in certain cases. These observations raise the possibility that gold-specific CD4(+) and CD8(+) T cells and APCs promiscuously interact under stimulation with gold, resulting in various clinical manifestations in gold allergy.

In vitro propagation and dynamics of T cells from skin biopsies by methods using interleukins-2 and -4 or anti-CD3/CD28 antibody-coated microbeads.

In order to explore the mechanisms of inflammatory skin disorders, we established two methods of expanding skin-derived lymphocytes, one using high levels of interleukin (IL)-2 and IL-4 (method A) and the other using low levels of cytokines and anti-CD3/CD28 microbeads (method B). Both methods provide advantages for functional studies. With either of these two, we could obtain more than 10(7) cells/ from a 3 mm skin biopsy in 21 days from 23 out of 26 biopsies of various skin diseases. The relevance of these cells was confirmed by shifted T-cell receptor beta chain variable region (TCR-Vbeta) repertoire and antigen-dependent proliferation in antigen-driven skin disorders. The propagation of skin-resident lymphocytes, seen especially in method A, seems to be mediated by a functional defect of regulatory T cells residing in skin sequentially expanding under the conditions of our methods.

A randomized double-blind trial of intravenous immunoglobulin for pemphigus.

BACKGROUND: Pemphigus is a rare life-threatening intractable autoimmune blistering disease caused by IgG autoantibodies to desmogleins. It has been difficult to conduct a double-blind clinical study for pemphigus partly because, in a placebo group, appropriate treatment often must be provided when the disease flares. OBJECTIVE: A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of a single cycle of high-dose intravenous immunoglobulin (400, 200, or 0 mg/kg/d) administered over 5 consecutive days in patients relatively resistant to systemic steroids. METHODS: We evaluated efficacy with time to escape from the protocol as a novel primary end point, and pemphigus activity score, antidesmoglein enzyme-linked immunosorbent assay scores, and safety as secondary end points. RESULTS: We enrolled 61 patients with pemphigus vulgaris or pemphigus foliaceus who did not respond to prednisolone (> or =20 mg/d). Time to escape from the protocol was significantly prolonged in the 400-mg group compared with the placebo group (P < .001), and a dose-response relationship among the 3 treatment groups was observed (P < .001). Disease activity and enzyme-linked immunosorbent assay scores were significantly lower in the 400-mg group than in the other groups (P < .05 on day 43, P < .01 on day 85). There was no significant difference in the safety end point among the 3 treatment groups. LIMITATION: Prednisolone at 20 mg/d or more may not be high enough to define steroid resistance. CONCLUSION: Intravenous immunoglobulin (400 mg/kg/d for 5 d) in a single cycle is an effective and safe treatment for patients with pemphigus who are relatively resistant to systemic steroids. Time to escape from the protocol is a useful indicator for evaluation in randomized, placebo-controlled, double-blind studies of rare and serious diseases.

Induction of therapeutically relevant cytotoxic T lymphocytes in humans by percutaneous peptide immunization.

Percutaneous peptide immunization (PPI) is a simple and noninvasive immunization approach to induce potent CTL responses by peptide delivery via skin with the stratum corneum removed. After such a barrier disruption in human skin, epidermal Langerhans cells, although functionally matured through the up-regulation of HLA expression and costimulatory molecules, were found to emigrate with a reduced number of dendrites. CD8(+) populations binding to MHC-peptide tetramers/pentamers and producing IFN-gamma appeared in the blood after PPI with HLA class I-restricted antigenic peptides. PPI with melanoma-associated peptides reduced the lesion size and suppressed further development of tumors in four of seven patients with advanced melanoma. These beneficial effects were accompanied by the generation of circulating CTLs with in vitro cytolytic activity and extensive infiltration of tetramer/pentamer-binding cells into regressing lesions. PPI elicited neither local nor systemic toxicity or autoimmunity, except for vitiligo, in patients with melanoma. Therefore, PPI represents a novel therapeutic intervention for cancer in the clinical setting.

The current status and future direction of percutaneous peptide immunization against melanoma.

Dendritic cell (DC)-based tumor immunotherapy is widely known to elicit protective anti-tumor immune responses, although the safety and effectiveness have yet to be thoroughly explored. We reported that a disruption in the stratum corneum barrier resulted in enhanced permeability and alterations in the skin immune system in such a way that epidermal Langerhans cells (LCs) functioned as vigorous antigen presenters for T helper (Th) cells and cytotoxic T lymphocytes (CTLs). In both human and murine models, topical application of melanoma-associated antigen peptides onto stratum corneum barrier-disrupted skin, specifically induced tumoricidal immune responses in vivo and in vitro accompanying an increased expression of MHC and co-stimulatory molecules on LCs. In addition, for reasons of simplicity, safety and effectiveness, percutaneous peptide application has demonstrated a certain degree of feasibility in clinical approach in patients with melanoma. In the future, resolution of some of the outstanding issues concerning the selection of the most effective adjuvants in combination with barrier disruption and depletion of regulatory T (Treg) cell-mediated immune suppression would appear as essential to improve percutaneous melanoma immunotherapy.

Primary cutaneous anaplastic large cell lymphoma with fatal leukemic outcome in association with CLA and CCR4-negative conversion.

A 70-year-old Japanese male presented with a 1-year history of skin tumors, which were diagnosed as primary cutaneous anaplastic large cell lymphoma (ALCL) because of the CD3(low+), CD4(+), CD25(+), CD30(+), CD45RO(+), CD71(+), HLA-DR(+), CD8(-), CD56(-), and NPM/ALK(-) phenotype and monoclonal T-cell receptor-rearranged property of tumor cells as well as the absence of systemic involvement. At this time, the tumor cell was positive for cutaneous lymphocyte-associated antigen (CLA) and TH(2) chemokine receptor CCR4. The eruption had repeatedly appeared and spontaneously regressed or regressed by virtue of several therapeutic modalities, including radiotherapy, interferon-alpha and chemotherapy, until the tumor cell invaded the gastric mucosa and spread to the peripheral blood 5 years later. Upon progression to the fatal leukemic change, the skin lesions inversely disappeared. Flow cytometric monitoring of the phenotype of peripheral blood and skin-infiltrating lymphocytes disclosed that the expression of CLA and CCR4 on the tumor cells was converted from positive to negative in association with the leukemic change. The altered expression of skin-homing receptors might change its clinical behavior.

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma with a CD15(+)CD30(-) phenotype.

Primary cutaneous aggressive epidermotropic CD8(+) T-cell lymphoma (CD8(+)TCL) is an extremely rare entity with distinct clinicopathological features. While the CD15 antigen is typically associated with classic Hodgkin's lymphoma, aggressive peripheral T-cell lymphomas, including advanced stage cutaneous T-cell lymphomas, rarely express this molecule. We report a case of primary cutaneous aggressive epidermotropic CD8(+)TCL, in which lymphoma cells are CD15(+)CD30(-) with a medium-to-large pleomorphic phenotype. Although the functional characteristics of CD15 expression in the cutaneous lymphomas are not fully understood, the poor prognosis of primary cutaneous aggressive epidermotropic CD8(+)TCL might be associated with the presence of this molecule in our case.

Efficacy and safety of preprandial versus postprandial administration of low-dose cyclosporin microemulsion (Neoral) in patients with psoriasis vulgaris.

A study of therapeutic drug monitoring indicated that cyclosporin administered before meals produces higher blood concentrations than an equivalent dose administered after meals. Our objective was to compare the efficacy of cyclosporin administered before and after meals, respectively, in psoriasis vulgaris patients. We performed an open trial study. Patients were randomly assigned to receive cyclosporin before (group B, n = 20) or after meals (group A, n = 17), and were followed up in 10 dermatology clinics. The difference between groups was evaluated in severity. The percent reduction in psoriasis area and severity index score from baseline was 29.8% in group A and 75.4% in group B (A vs B, P = 0.00005). Two patients in each group withdrew due to abnormality of laboratory data. Short-term, low-dose treatment with cyclosporin before rather than after meals is suggested as a new effective treatment regimen for psoriasis, with the added advantage of lowering costs.

Chemokine receptor expression in cutaneous T cell and NK/T-cell lymphomas: immunohistochemical staining and in vitro chemotactic assay.

Interactions between chemokines and chemokine receptors are involved in migration and invasion of lymphoma cells. We investigated expression profiles of CXCR3 and CCR4 by immunohistochemistry and flow cytometry, and their biologic behaviors by real-time horizontal chemotaxis assay in cutaneous T cell and NK/T-cell lymphomas (TCLs). Tumor cells in mycosis fungoides (MF) constantly expressed CXCR3 at the patch stage, and expressed CCR4 at the tumor stage and in the folliculotropic variant of MF. Neoplastic cells at the plaque stage expressed CXCR3 and/or CCR4. Sezary cells in the dermis and circulation were positive for CCR4. Epidermotropic atypical cells in pagetoid reticulosis expressed CXCR3. CD30 cells exclusively expressed CCR4 in anaplastic large-cell lymphoma, and CXCR3 and/or CCR4 in lymphomatoid papulosis. In CD8TCL and extranodal NK/TCL characterized by extensive epidermotropism, tumor cells were positive for CXCR3. These data demonstrated preferential expression of CXCR3 in epidermotropic tumor cells, and of CCR4 in dermis-based lymphomas. In chemotaxis assays, CCR4 tumor cells in MF and CXCR3 tumor cells in CD8TCL migrated to thymus and activation-regulated chemokine and inducible protein-10, respectively. Therefore, spatial and temporal interactions between chemokine receptors and their ligands seem to dictate recruitment and retention of lymphoma cells in the skin.

Anxiety in allergy and atopic dermatitis.

PURPOSE OF REVIEW: Individuals suffering from allergies often exhibit a specific psychological profile characterized by anxiety, depression and emotional excitability. Emotional stress precipitates allergic symptoms not only by heightening anxiety levels but also by dysregulating immune-cell functions. The primary objective of this report is to review recent findings of the relationship between anxiety and hypersensitivity responses in the context of psychoneuroimmunology in allergic individuals, notably patients with atopic dermatitis. RECENT FINDINGS: Atopic subjects with emotional problems develop a vicious cycle between anxiety and clinical symptoms. Acute stresses, which repeatedly and chronically affect patients with atopic dermatitis, raise anxiety in general more preferentially than anxiety at present. This psychological failure enhances Th2-type responses due to dysregulation of the neuroimmune system, leading to worsening of allergic symptoms. Tandospirone, a 5-hydroxytryptamine 1A receptor agonist with anxiolytic and antidepressant effects, attenuates itching through successful control of emotional difficulties. These data suggest the efficacy of administrating drugs with anxiolytic effects as part of the management strategy of stress-associated itching in patients with atopic dermatitis. SUMMARY: Psychological interventions such as periodic monitoring of anxiety levels in the context of immune functions and skin conditions are fundamental in therapy of allergic patients with emotional problems.

Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol.

The skin and its major appendages are prominent target organs and potent sources of key players along the classical hypothalamic-pituitary axis, such as corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and alpha melanocyte stimulating hormone (alpha-MSH), and even express key steroidogenic enzymes. Therefore, it may have established local stress response systems that resemble the hypothalamic-pituitary-adrenal (HPA) axis. However, functional evidence that this is indeed the case in normal human skin in situ has still been missing. We show that microdissected, organ-cultured human scalp hair follicles respond to CRH stimulation by up-regulating proopiomelanocortin (POMC) transcription and immunoreactivity (IR) for ACTH and alpha-MSH, which must have been processed from POMC. CRH, alpha-MSH, and ACTH also modulate expression of their cognate receptors (CRH-R1, MC1-R, MC2-R). In addition, the strongest stimulus for adrenal cortisol production, ACTH, also up-regulates cortisol-IR in the hair follicles. Isolated human hair follicles secrete substantial levels of cortisol into the culture medium, and this activity is further up-regulated by CRH. CRH also modulates important functional hair growth parameters in vitro (hair shaft elongation, catagen induction, hair keratinocyte proliferation, melanin production). Finally, human hair follicles display HPA axis-like regulatory feedback systems, since the glucocorticoid receptor agonist hydrocortisone down-regulates follicular CRH expression. Thus, even in the absence of endocrine, neural, or vascular systemic connections, normal human scalp hair follicles directly respond to CRH stimulation in a strikingly similar manner to what is seen in the classical HPA axis, including synthesis and secretion of cortisol and activation of prototypic neuroendocrine feedback loops.

Decreased gene expression responsible for post-ultraviolet DNA repair synthesis in aging: a possible mechanism of age-related reduction in DNA repair capacity.

A reduction in the post-ultraviolet (UV) DNA repair capacity is associated with aging. To clarify the mechanism of this change, we examined the DNA repair capacity of skin fibroblasts from healthy donors of different ages by the two methods: host cell reactivation (HCR) assay and ELISA of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone (6-4) photoproducts. In HCR assay, cells from elderly donors exhibited significant declines in the ability to restore transfected reporter DNA damaged by UV light. In contrast, the ability to remove DNA damage declined little with age in ELISA. These results imply that the age-sensitive step took place after the damage excision in nucleotide excision repair (NER). The mRNA expression of DNA repair synthesis-related genes (DNA polymerase delta, replication factor C, and proliferating cell nuclear antigen) were markedly decreased in the cells from multiple elderly subjects compared with those from young subjects. Further, the protein level of DNA polymerase delta1, a catalytic subunit of the pivotal factor in repair synthesis, correlated with the mRNA level. These findings suggest that the reduced post-UV DNA repair capacity in aging results from an impairment in the latter step of NER by the decreased expression of factors in repair synthesis.

Immunology of the human nail apparatus: the nail matrix is a site of relative immune privilege.

The nail apparatus is constantly exposed to environmental damage. It requires effective immune responses to combat infection, while avoiding the loss of nail production and regeneration by autoaggressive immunity. By immunohistology, we define here previously unknown characteristics of the normal human nail immune system (NIS). Compared with other regions of nail epithelium, human leukocyte antigen (HLA)-A/B/C expression is prominently down regulated on both keratinocytes and melanocytes of the proximal nail matrix (PNM), whereas HLA-G(+) is upregulated here. Together with the expression of macrophage migration inhibitory factor in PNM, this may serve to inhibit an natural killer (NK) cell attack on major histocompatibility complex (MHC) class Ia-negative PNM. PNM also displays strong immunoreactivity for potent, locally generated immunosuppressants such as transforming growth factor-beta1, alpha-melanocyte stimulating hormone, insulin-like growth factor-1, and adrenocorticotropic hormone, exhibits unusually few CD1a(+), CD4(+), or CD8(+), NK, and mast cells. Finally, MHC class II and CD 209 expression on CD1a(+) cells in and around the PNM is reduced, indicating diminished antigen-presenting capacity. Thus, the NIS strikingly differs from the skin immune system, but shows intriguing similarities to the hair follicle immune system, including the establishment of an area of relative immune privilege in the PNM. This nail immune privilege may offer a relative safeguard against autoimmunity. But, the localized intraepithelial defect of innate and adaptive immunity in the PNM revealed here also may impede effective anti-infection defense.

Anti-allergic Psidium guajava extracts exert an antitumor effect by inhibition of T regulatory cells and resultant augmentation of Th1 cells.

Th1 polarization is one of the mechanisms underlying the therapeutic effects of herbal medicine. The action of anti-allergic agents from Psidium guajava (P. guajava) on T cell immunity in mice was investigated. The addition of P. guajava extracts blocked IL-10-mediated, in vitro induction of T regulatory (Tr) cells from CD4+ splenocytes of C57BL/6 mice, whereas the extracts exerted only a weak or no effect on the development of Th1 and Th2 cells. Accordingly, Tr cells were not induced from splenocytes of mice administered orally with the extracts. Furthermore, P. guajava extracts shifted the Th1/Th2 balance to a Th1 dominant status by directly attenuating Tr cell activity. In a study of tumor immunity, mice pretreated with the extracts exhibited retarded growth of s.c. inoculated B16 melanoma cells. These findings suggest that P. guajava extracts are efficacious for the prevention of tumor development by depressing Tr cells and subsequently shifting to Th1 cells.

Defining early mycosis fungoides.

This editorial review summarizes the results of 5 meetings sponsored by the International Society for Cutaneous Lymphoma at which the clinicopathologic and ancillary features of early mycosis fungoides were critically examined. Based on this analysis, an algorithm was developed for the diagnosis of early mycosis fungoides involving a holistic integration of clinical, histopathologic, immunopathologic, and molecular biological characteristics. A novel aspect of this algorithm is that it relies on multiple types of criteria rather than just one, for example, histopathology. Before its finalization, the proposed diagnostic algorithm will require validation and possibly further refinement at multiple centers during the next several years. It is anticipated that a more standardized approach to the diagnosis of early mycosis fungoides will have a beneficial impact on the epidemiology, prognostication, treatment, and analysis of clinical trials pertaining to this most common type of cutaneous lymphoma.