Epidermal keratinocytes initiate wound healing and pro-inflammatory immune responses following percutaneous schistosome infection

Keratinocytes constitute the majority of cells in the skin’s epidermis, the first line of defence against percutaneous pathogens. Schistosome larvae (cercariae) actively penetrate the epidermis to establish infection, however the response of keratinocytes to invading cercariae has not been investigated. Here we address the hypothesis that cercariae activate epidermal keratinocytes to promote the development of a pro-inflammatory immune response in the skin. C57BL/6 mice were exposed to Schistosoma mansoni cercariae via each pinna and non-haematopoietic cells isolated from epidermal tissue were characterised for the presence of different keratinocyte sub-sets at 6, 24 and 96 h p.i. We identified an expansion of epidermal keratinocyte precursors (CD45−, CD326−, CD34+) within 24 h of infection relative to naïve animals. Following infection, cells within the precursor population displayed a more differentiated phenotype (α6integrin−) than in uninfected skin. Parallel immunohistochemical analysis of pinnae cryosections showed that this expansion corresponded to an increase in the intensity of CD34 staining, specifically in the basal bulge region of hair follicles of infected mice, and a higher frequency of keratinocyte Ki67+ nuclei in both the hair follicle and interfollicular epidermis. Expression of pro-inflammatory cytokine and stress-associated keratin 6b genes was also transiently upregulated in the epidermal tissue of infected mice. In vitro exposure of keratinocyte precursors isolated from neonatal mouse skin to excretory/secretory antigens released by penetrating cercariae elicited IL-1α and IL-1β production, supporting a role for keratinocyte precursors in initiating cutaneous inflammatory immune responses. Together, these observations indicate that S. mansoni cercariae and their excretory/secretory products act directly upon epidermal keratinocytes, which respond by initiating barrier repair and pro-inflammatory mechanisms similar to those observed in epidermal wound healing.This project was funded by a Project Grant from the Wellcome Trust, UK, awarded to APM (Grant number: 092745/Z/10/Z) which supported CDB and CTP. DES was funded by COLFUTURO, Colombia and the Departamento Administrativo de Ciencia, Tecnologia e Innovacion de la Republica de Colombia (COLCIENCIAS), Colombia. CDB was also supported by a University of York, UK, Summer Studentship Award for Research Associates and RH was funded by a Wellcome Trust, UK, Biomedical Vacation Scholarship

Stronger evidence for own-age effects in memory for older as compared to younger adults

Three studies examined whether younger and older adults better recall information associated with their own than information related to another age group. All studies compared young and older adults with respect to incidental memory for previously presented stimuli (Studies 1 and 2: everyday objects; Study 3: vacation advertisements) that had been randomly paired with an age-related cue (e.g., photo of a young or an old person; the word "young" or "old"). All three studies found the expected interaction of participants' age and age-associated information. Studies 1 and 2 showed that the memory bias for information arbitrarily associated with one's own as compared to another age group was significant for older adults only. However, when age-relevance was introduced in a context of equal importance to younger and older adults (information about vacations paired either with pictures of young or older adults), the memory bias for one's own age group was clearly present for both younger and older adults (Study 3)

CD207(+) Langerhans cells constitute a minor population of skin-derived antigen-presenting cells in the draining lymph node following exposure to Schistosoma mansoni

Infectious cercariae of Schistosoma mansoni gain entry to the mammalian host through the skin where they induce a transient inflammatory influx of mononuclear cells. Some of these cells have antigen-presenting cell function (MHCII(+)) and have been reported to migrate to the skin-draining lymph nodes (sdLN) where they have the potential to prime CD4(+) cells of the acquired immune response. Here, in mice exposed to vaccinating radiation-attenuated schistosome larvae, which induce high levels of protective immunity to challenge infection, we describe the parasite-induced migration of Langerhans cells (LCs) from the epidermal site of immunisation to the sdLN using a specific monoclonal antibody that recognises langerin (CD207). CD207(+) cells with dendritic morphology were abundant in the epidermis at all times and their migration into the dermis was detected soon after vaccination. All CD207(+) LCs were MHCII(+) but not all MHCII(+) cells in the skin were CD207(+). LCs migrated from the dermis in enhanced numbers after vaccination, as detected in dermal exudate populations recovered after in vitro culture of skin biopsies. Elevated numbers of CD207(+) LCs were also detected in the sdLN from 24 h to 4 days after vaccination. However, compared with other dermal-derived antigen-presenting cells that were CD207(−)MHCII(+) or CD207(−)CD11c(+), the relative numbers of CD207(+) cells in the dermal exudate population and in the sdLN were very small. Furthermore, the migration of CD207(+) cells after exposure to ‘protective’ radiation-attenuated, compared with ‘non-protective’ normal cercariae, was similar in terms of numbers and kinetics. Together, these studies suggest that CD207(+) LCs are only a minor component of the antigen-presenting cell population that migrates from the epidermis and they are unlikely to be important in the priming of protective CD4(+) cells in the sdLN

Multiple helminth infection of the skin causes lymphocyte hypo-responsiveness mediated by Th2 conditioning of dermal myeloid cells

Infection of the mammalian host by schistosome larvae occurs via the skin, although nothing is known about the development of immune responses to multiple exposures of schistosome larvae, and/or their excretory/secretory (E/S) products. Here, we show that multiple (4x) exposures, prior to the onset of egg laying by adult worms, modulate the skin immune response and induce CD4(+) cell hypo-responsiveness in the draining lymph node, and even modulate the formation of hepatic egg-induced granulomas. Compared to mice exposed to a single infection (1x), dermal cells from multiply infected mice (4x), were less able to support lymph node cell proliferation. Analysis of dermal cells showed that the most abundant in 4x mice were eosinophils (F4/80(+)MHC-II(-)), but they did not impact the ability of antigen presenting cells (APC) to support lymphocyte proliferation to parasite antigen in vitro. However, two other cell populations from the dermal site of infection appear to have a critical role. The first comprises arginase-1(+), Ym-1(+) alternatively activated macrophage-like cells, and the second are functionally compromised MHC-II(hi) cells. Through the administration of exogenous IL-12 to multiply infected mice, we show that these suppressive myeloid cell phenotypes form as a consequence of events in the skin, most notably an enrichment of IL-4 and IL-13, likely resulting from an influx of RELMa-expressing eosinophils. We further illustrate that the development of these suppressive dermal cells is dependent upon IL-4Ra signalling. The development of immune hypo-responsiveness to schistosome larvae and their effect on the subsequent response to the immunopathogenic egg is important in appreciating how immune responses to helminth infections are modulated by repeated exposure to the infective early stages of development