Chronic demodicosis in patients with immune dysregulation: An unexpected infectious manifestation of Signal transducer and activator of transcription (STAT)1 gain-of-function.

Signal transducer and activator of transcription (STAT)1 heterozygous gain-of-function (GOF) mutations are known to induce immune dysregulation and chronic mucocutaneous candidiasis (CMCC). Previous reports suggest an association between demodicosis and STAT1 GOF. However, immune characterization of these patients is lacking. Here, we present a retrospective analysis of patients with immune dysregulation and STAT1 GOF who presented with facial and ocular demodicosis. In-depth immune phenotyping and functional studies were used to characterize the patients. We identified five patients (three males) from two non-consanguineous Jewish families. The mean age at presentation was 11.11 (range = 0.58-24) years. Clinical presentation included CMCC, chronic demodicosis and immune dysregulation in all patients. Whole-exome and Sanger sequencing revealed a novel heterozygous c.1386C>A; p.S462R STAT1 GOF mutation in four of the five patients. Immunophenotyping demonstrated increased phosphorylated signal transducer and activator of transcription in response to interferon-α stimuli in all patients. The patients also exhibited decreased T cell proliferation capacity and low counts of interleukin-17-producing T cells, as well as low forkhead box protein 3+ regulatory T cells. Specific antibody deficiency was noted in one patient. Treatment for demodicosis included topical ivermectin and metronidazole. Demodicosis may indicate an underlying primary immune deficiency and can be found in patients with STAT1 GOF. Thus, the management of patients with chronic demodicosis should include an immunogenetic evaluation.

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 RELMα-expressing eosinophils. We further illustrate that the development of these suppressive dermal cells is dependent upon IL-4Rα 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.

Quantification of immuno-regulatory cytokine and toll-like receptors gene expression in dogs with generalized demodicosis.

The proliferation of Demodex mites is mainly controlled by host immunity; however, the precised mechanism of host-mite interplay and host immune response in the cutaneous microenvironment of dogs with generalized demodicosis (GD) are not yet established. In the present study, we envisaged the alterations in the expression of toll-like receptors (TLRs) and immuno-regulatory cytokine gene in the skin lesions and peripheral blood mononuclear cells (PBMCs) of dogs with GD. The expression of TLR2, TLR6, IFN-γ, TGF-ß and IL-10 genes in the skin lesions and PBMCs of 15 dogs with GD was quantified by qRT-PCR. Compared to healthy dogs, significantly elevated expression of TLR2 (P = 0.048), TGF-ß (P = 0.04) and IL-10 (P = 0.012) were found in the PBMCs of dogs with GD. Conversely, there was significantly reduced expression of TLR6 gene (P = 0.021) in the PBMCs of these dogs. The infested dogs also revealed significantly elevated expression of TLR2 gene (P = 0.034) in the skin lesions, while, the expression of the TLR6 gene was found to be significantly (P = 0.004) reduced. Interestingly, significant alterations in TGF-ß (P = 0.105) and IL-10 (P = 0.162) genes expression were not observed in the skin lesions of diseased dogs. Our findings suggest that Demodex mites contribute to a different systemic and cutaneous immune response in dogs for their proliferation, and consequently the development of GD. Therefore, Demodex mites might be inducing the immunosuppression through activating the systemic over-expression of immunosuppressive cytokines; however, in the cutaneous lesions, the expression of immunosuppressive cytokines remained unaltered. Both systemic and local over-expression of TLR2 and reduced expression of TLR6 genes might be responsible for the inflammatory signs of canine demodicosis and helping to the mite to escape the host immunity.

Cutaneous cytokine gene expression and cellular responses in lambs infested with the louse, Bovicola ovis, and following intradermal injection of crude louse antigen.

The present study was undertaken to investigate further the immunological responses in the skin of lambs to natural louse infestation and following intradermal allergen challenge. Bovicola ovis-infested (n=7) and naïve (n=7) Romney lambs received four intradermal injections each of crude louse Ag and diluent control solutions on the dorso-lateral chest. From each lamb, skin samples were obtained from untreated skin and, at 4, 24, 48 and 72 h following injection, from one each of the Ag- and diluent-injected skin sites. Levels of acetylcholinesterase-positive Langerhans and MHC II(+) cells in the epidermis as well as MHC II(+), CD1b(+), T19(+) and IgE(+) cells, eosinophils, and diffuse IgE staining in the dermis were significantly elevated in infested compared to naïve lambs (all p< or =0.01). Additionally, gene expression of interleukin-4 (IL-4), IL-5, IL-13 (all p< or =0.001) and IL-10 (p< or =0.05) was significantly higher in the skin of infested compared to naïve lambs while TNF-alpha and IFN-gamma gene expression were not significantly different between the two groups. Intradermal injection of louse Ag led to immediate and late phase responses in the infested lambs while the naïve lambs showed only minimal responses. Levels of dermal MHC II(+), CD1b(+), T19(+)and IgE(+) cells, eosinophils and diffuse IgE staining in infested lambs following injection of louse Ag were similar to or exceeded those in untreated skin and, with few exceptions, were higher than in naïve lambs. Additionally, cytokine gene expression of IL-4, IL-5, IL-13 and IL-10 increased to peak levels 4 h following Ag injection in the infested lambs (p< or =0.001, < or =0.05, < or =0.05 and < or =0.001 respectively compared to untreated controls) and remained significantly elevated compared to that observed in the naïve controls for the duration of the experiment. Significant elevations of MHC II(+) cells and IL-4, IL-5, IL-13 and IL-10 gene expression were observed in the louse-naïve lambs following injection of louse Ag but were much less pronounced than in the infested lambs. These results indicated that louse infestation in lambs elicited a highly skewed Th2 immuno-inflammatory response with many characteristics similar to those seen with other parasitic infections and also in atopic dermatitis.

The variant Arg110Gln of human IL-13 is associated with an immunologically hyper-reactive form of onchocerciasis (sowda).

Onchocerca volvulus infection usually results in a predominantly immunopermissive reaction called generalized onchocerciasis and characterized by high microfilarial burden and immunological tolerance to the worms. Rarely, however, infection leads to the sowda form of the disease displaying low microfilarial numbers, i.e. microfilarial control, and a T helper 2 (Th2)-type immune response including high immunoglobulin (Ig)E levels, and interleukin (IL)-13 being one of the key cytokines. The aim of this study was to investigate a possible association of a variant of the IL-13 gene, which confers an IgE-independent risk for asthma and atopy, with the immunologically hyper-reactive sowda form of onchocerciasis. Genotyping for the IL-13 variant Arg110Gln revealed a highly significant association of Arg110Gln with the sowda form (relative risk of 2.98, n = 19 patients), whereas the frequency of the variant was significantly lower in patients with generalized onchocerciasis (n = 92 individuals). Sowda patients had higher IgE levels than those with generalized onchocerciasis. Logistic regression analysis revealed that IgE and IL-13 are independent variables, each increasing the relative risk for sowda. Arg110Gln has been suggested to lead to enhanced IL-13 signaling and thus may be involved in shifting the immune reaction towards the hyper-reactivity characteristic for the sowda form, thereby promoting defense mechanisms.

Tokelau Islands Children's Study: scabies infestation in children.

Tokelau children have been examined for scabies infestation in three groups--those living in their home atolls--those living in New Zealand in 1972-73, and those living in New Zealand in 1975. There was less infestation in Tokelau than in New Zealand. In 1975 the rate of infestation in New Zealand had increased since 1972. The manifestation of the mite in children in New Zealand varied from the classical descriptions, in that the mite itself, and its burrows, were seldom found, and the skin lesions were more often seen on the body than on the wrists and hands. A treatment regime which was found satisfactory is described. It was found essential to treat the entire family at the same time.

Fatal disseminated Acanthamoeba lenticulata infection in a heart transplant patient.

We report a fatal case of disseminated acanthamebiasis caused by Acanthamoeba lenticulata (genotype T5) in a 39-year-old heart transplant recipient. The diagnosis was based on skin histopathologic results and confirmed by isolation of the ameba from involved skin and molecular analysis of a partial 18S rRNA gene sequence (DF3).

[Mite dermatitis due to Tyrophagus dimidiatus]. / Milbendermatitis durch Tyrophagus dimidiatus.

This paper describes a small endemic with acarus Tyrophagus dimidiatus in a butcher's family originating from contaminated meat. The morphology and biology of this parasite are discussed.

Suppressive effect of cyclosporin A on the development of Leishmania tropica-induced lesions in genetically susceptible BALB/c mice.

The effect of cyclosporin A (CyA) application on the development of cutaneous lesions was analyzed in genetically susceptible BALB/c mice infected s.c. with Leishmania tropica promastigotes. Daily i.p. injections of CyA, beginning 2 days before or at the day of the infection, dose dependently inhibited the development of parasite-induced lesions; no effect on the lesions was observed, however, if CyA application was started 14 days after the infection. Cessation of CyA administration after having successfully suppressed the cutaneous lesions for a period of 42 days, resulted in the development of lesions within 3 days. CyA had no inhibitory effect on lesions developing in L. tropica infected hypothymic BALB/c nu/nu mice. CyA or CyA-containing mouse serum did not directly affect the viability and the growth rate of L. tropica promastigotes, suggesting that the effect of the agent was imposed on the cells participating in the formation of the cutaneous lesions. Quantitative analysis of the cell distribution in the spleens of infected mice revealed that CyA markedly suppressed the infection-associated numerical increase of splenocytes. Within the Thy-1+ lymphocyte compartment, CyA had its most pronounced effect on the Lyt-1+ T lymphocyte subset. Early in the disease, the frequency of splenic cells proliferating in response to L. tropica antigen in vitro was clearly inhibited by CyA; in the later stages of the infection, however, this effect could not be observed, indicating the presence of L. tropica-inducible T cells being relatively resistant to CyA. Taken together, our findings indicate that CyA reversibly inhibits or delays the parasite-induced expansion of Lyt-1+ splenic T lymphocytes, and thus suppresses the biological function of those T cells that are instrumental for the formation of cutaneous lesions in L. tropica-infected BALB/c mice.