Destruction Of Epithelial Cells Research Articles

Lichen planopilaris is characterized by immune privilege collapse of the hair follicle's epithelial stem cell niche

Lichen planopilaris (LPP) is a chronic inflammatory disease of unknown pathogenesis that leads to permanent hair loss. Whilst destruction of epithelial hair follicle stem cells (eHFSCs) that reside in an immunologically protected niche of the HF epithelium, the bulge, is a likely key event in LPP pathogenesis, this remains to be demonstrated. We have tested the hypotheses that bulge immune privilege (IP) collapse and inflammation-induced eHFSC death are key components in the pathogenesis of LPP. Biopsies of lesional and non-lesional scalp skin from adult LPP patients (n = 42) were analysed by quantitative (immuno)histomorphometry, real-time quantitative polymerase chain reaction (qRT-PCR), laser capture microdissection and microarray analysis, or skin organ culture. At both the protein and transcriptional level, lesional LPP HFs showed evidence for bulge IP collapse (ie increased expression of MHC class I and II, β2microglobulin; reduced TGFβ2 and CD200 expression). This was accompanied by a Th1-biased cytotoxic T cell response (ie increased CD8(+) GranzymeB(+) T cells and CD123(+) plasmacytoid dendritic cells, with increased CXCR3 expression) and increased expression of interferon-inducible chemokines (CXCL9/10/11). Interestingly, lesional LPP eHFSCs showed both increased proliferation and apoptosis in situ. Microarray analysis revealed a loss of eHFSC signatures and increased expression of T cell activation/binding markers in active LPP, while bulge PPARγ transcription was unaltered compared to non-lesional LPP HFs. In organ culture of non-lesional LPP skin, interferon-γ (IFNγ) induced bulge IP collapse. LPP is an excellent model disease for studying and preventing immune destruction of human epithelial stem cells in situ. These novel findings raise the possibility that LPP represents an autoimmune disease in whose pathogenesis IFNγ-induced bulge IP collapse plays an important role. Therapeutically, bulge IP protection/restoration may help to better manage this highly treatment-resistant cicatricial alopecia.

The critical role of Th1 cytokine polarization in murine primary biliary cirrhosis. (P4154)

Abstract Primary biliary cirrhosis (PBC) is a female predominant organ specific autoimmune disease with specific destruction of intrahepatic small biliary epithelial cells (BECs). Patients develop a multilineage response to the E2 component of pyruvate dehydrogenase (PDC-E2) involving autoantibody. We previously reported that IL-12p40 deficiency eliminated biliary disease in dnTGFβRII mice, suggesting that IL-12 and IL-23 are important in the development of biliary disease. IL-12 induced Th1 and IL-23 induces Th17, which express both IFN-\#933; and IL-17, but the role of IL-12p40 in PBC remains unidentified. To further investigate the role of the IL-12p40 in this murine model of autoimmune biliary disease, we immunized IL-12p40-/-, IFN-\#933;-/- and IL-17-/- mice with a xenobiotic mimic of PDC-E2 , 2-octynoic acid (2-OA), coupled to bovine serum albumin. The PBC-related autoepitope of PDC-E2 contains lipoic acid, and previous work has demonstrated that mimics of lipoic acid following immunization of mice lead to a PBC-like disease. Importantly IL-12p40-/- and IFN-\#933;-/- mice immunized with 2-OA did not manifest autoimmune biliary disease. In contrast to IL-12p40-/- and IFN-\#933;-/- mice, IL-17-/- mice developed autoimmune biliary disease. These data suggest that signaling by way of Th1 polarizaion via IL-12p40 is an essential requirement for the development of autoimmune cholangitis. These data have implications for the biologic therapy of patients with primary biliary cirrhosis.

Effects of Free Fatty Acids on Human Salivary Gland Epithelial Cells

Obesity and type 2 diabetes (T2D) are characterized by decreased insulin sensitivity and higher concentrations of free fatty acids (FFAs) in plasma. Among FFAs, saturated fatty acids (SFAs), such as palmitate, have been proposed to promote inflammatory responses. Primary Sjögren’s syndrome (SS) is an autoimmune disease characterized by inflammatory mononuclear cell infiltration and destruction of epithelial cells in the salivary and lacrimal glands. IL-6 production and α-fodrin degradation are increased in salivary gland epithelial cells of patients with primary SS. Although previous studies have shown a link between SS and either dyslipidemia or T2D, little is known about the clinical significance of FFAs in primary SS. Here we report that SFAs, but not unsaturated fatty acids, induced IL-6 production via NF-κB and p38 MAPK activation in human salivary gland epithelial cells. Moreover, palmitate induced apoptosis and α-fodrin degradation by caspase-3 activation. Unlike salivary gland epithelial cells, induction of IL-6 production and the degradation of α-fodrin in response to palmitate were undetectable in squamous carcinoma cells and keratinocytes. Taken together, SFAs induced IL-6 production and α-fodrin degradation in salivary gland epithelial cells, implicating a potential link between the pathogenesis of primary SS and SFAs level in plasma.

Protective effects of osthole, a natural derivative of coumarin, against intestinal ischemia-reperfusion injury in mice

Intestinal ischemia/reperfusion (I/R) injury is considered to be associated with high morbidity and mortality rates. Osthole, a natural derivative of coumarin, has been shown to exert a variety of pharmacological and therapeutic effects under physiological and pathological conditions. In the present study, to investigate the protective effects of osthole against intestinal I/R injury, various doses of osthole (5, 10, 25 and 50 mg/kg) were pre-administered to mice subjected to intestinal I/R injury. A dose-dependent increase in the survival rate was observed in the osthole-treated mice. Pre-treatment with osthole (50 mg/kg) attenuated the destruction of epithelial cells within the villi induced by intestinal I/R injury, and suppressed oxidative stress, neutrophil infiltration and modulated nitric oxide (NO) levels. Moreover, the increased IκBα phosphorylation and nuclear factor (NF)-κB nuclear translocation induced by I/R injury were significantly decreased following pre-treatment with osthole. Taken together, our data demonstrate that osthole exerts protective effects against intestinal I/R injury in mice by suppressing oxidative stress, neutrophil infiltration and NO levels, partly through the inhibition of NF-κB nuclear translocation. Hence, the findings of the present study provide insight into the mechanisms through which osthole exerts its protective effects against intestinal I/R injury.

Human Implantation: A Tale of Mutual Maternal and Fetal Attraction1

Implantation in humans has been conceptualized largely on the basis of mouse models [1]. It is viewed as a stepwise process involving apposition and adherence of a blastocyst to the endometrium, followed by breaching of the luminal epithelium and, finally, invasion of maternal tissues. This process seems analogous to an invading cancer, with the embryo driving the destruction of endometrial epithelial cells, the enzymatic digestion of stromal matrix, and finally, the invasion of the maternal decidua and inner myometrium (Fig. 1a). Within this context, the role of the maternal decidua is to both tolerate and control the invading semiallogeneic fetal trophoblast. Excessive trophoblast invasion of the uterus presents clinically as placenta accreta or choriocarcinoma, conditions associated with considerable maternal morbidity and, occasionally, death. Conversely, inadequate or deregulated invasion of trophoblast compromises the survival of the fetus and causes a spectrum of pregnancy complications, including miscarriage, intrauterine growth restriction, preeclampsia, and stillbirth. Hence, both excessive and inadequate implantation can have disastrous consequences.

Histopathological effects and determination of the putative receptor of Bacillus thuringiensis Cry1Da toxin in Spodoptera littoralis midgut

Bacillus thuringiensis subsp. aizawai strain HD133, known by its effectiveness against Spodoptera species, produces many insecticidal proteins including Cry1Ab, Cry1Ca and Cry1Da. In the present study, the insecticidal activity of Cry1Da against Spodoptera littoralis was investigated. It showed toxicity with an LC50 of 224.4ng/cm2 with 95% confidence limits of (178.61–270.19) and an LC90 of 467.77ng/cm2 with 95% confidence limits of (392.89–542.65). The midgut histopathology of Cry1Da fed larvae showed vesicle formation in the apical region, vacuolization and destruction of epithelial cells. Biotinylated-activated Cry1Da toxin bound protein of about 65kDa on blots of S. littoralis brush border membrane preparations. This putative receptor differs in molecular size from those recognized by Cry1C and Vip3A which are active against this polyphagous insect. This difference in midgut receptors strongly supports the use of Cry1Da as insecticidal agent, particularly in case of Cry and/or Vip-resistance management.

Popular and unpopular infectious agents linked to primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterized by the autoimmune destruction of the biliary epithelial cells of the small and medium-size bile ducts. The disease affects middle aged women and usually affects more than one member within a family. The pathognomonic serological hallmark of the disease is the presence of circulating anti-mitochondrial antibodies, and disease-specific anti-nuclear antibodies. Susceptibility genes and environmental risk factors such as infections and smoking have been reported as important for the development of the disease. Among the environmental agents, infectious triggers are the best studied. Most of the work published so far has investigated the role of infections caused by Novosphingobium aromaticivorans and Escherichia coli. This review will discuss the popular and unpopular infectious agents causatively linked to PBC. It will also examine reports investigating the epidemiological aspects of the disease and their direct or indirect implications to bacterial-induced PBC.

Uso de vacinas no controle da coccidiose aviária

The genus Eimeria belonging to the Subphylum Apicomplexa, Family Eimeriidae, have seven recognized species infecting chickens: E.acervulina, E. maxima, E.tenella, E.brunetti, E.necatrix, E.mitis and E.praecox. It’s an obligate intracellular parasite that causes disease by the destruction of intestinal epithelial cells in the replication process. The indiscriminate use of anticoccidial drugs has resulted in the selection of drug-resistant strains, which reduce de effectiveness of various anticoccidial drugs used currently in control of the disease. As in many countries legislation prohibits the use of thes products continuously until slaughter withdrawal periods have been required, which increases the risk of infection at the end of the growing season. Thus, vaccines are essential as a tool for controlling these parasites. There are several types of vaccines, but only attenuated live vaccines are marketed for the control of avian coccidiosis, with the exception of recombinant vaccine CoxAbic®. Nevertheless, its use is still mild compared to the use of anticoccidial drugs, possibly due to its lower cost and greater effectiveness. Thus, it is important that control of avian coccidiosis is extremely complex, and that further studies should be encouraged to develop effective methods, including the use of vaccines for the production of chicken meat free of medication.

Intraepithelial lymphocytes in celiac disease immunopathology

Celiac disease is a T cell-mediated immune disorder induced by dietary gluten that is characterized by the development of an inflammatory anti-gluten CD4 T cell response, anti-gluten antibodies, and autoantibodies against tissue transglutaminase 2 and the activation of intraepithelial lymphocytes (IELs) leading to the destruction of the intestinal epithelium. Intraepithelial lymphocytes represent a heterogeneous population of T cells composed mainly of cytotoxic CD8 T cells residing within the epithelial layer, whose main role is to maintain the integrity of the epithelium by eliminating infected cells and promoting epithelial repair. Dysregulated activation of IELs is a hallmark of CD and is critically involved in epithelial cell destruction and the subsequent development of villous atrophy. In this review, we compare and contrast the phenotype and function of human and mouse small intestinal IELs under physiological conditions. Furthermore, we discuss how conditions of epithelial distress associated with overexpression of IL-15 and non-classical MHC class I molecules induce cytotoxic IELs to become licensed killer cells that upregulate activating NKG2D and CD94/NKG2C natural killer receptors, acquiring lymphokine killer activity. Pathways leading to dysregulated IEL activation could eventually be targeted to prevent villous atrophy and treat patients who respond poorly to gluten-free diet.

Human milk oligosaccharides reduceEntamoeba histolyticaattachment and cytotoxicityin vitro

Human milk oligosaccharides (HMO), complex sugars that are highly abundant in breast milk, block viral and bacterial attachment to the infant's intestinal epithelium and lower the risk of infections. We hypothesised that HMO also prevent infections with the protozoan parasite Entamoeba histolytica, as its major virulence factor is a lectin that facilitates parasite attachment and cytotoxicity and binds galactose (Gal) and N-acetyl-galactosamine. HMO contain Gal, are only minimally digested in the small intestine and reach the colon, the site of E. histolytica infection. The objective of the present study was to investigate whether HMO reduce E. histolytica attachment and cytotoxicity. Our in vitro results show that physiological concentrations of isolated, pooled HMO detach E. histolytica by more than 80 %. In addition, HMO rescue E. histolytica-induced destruction of human intestinal epithelial HT-29 cells in a dose-dependent manner. The cytoprotective effects were structure-specific. Lacto-N-tetraose with its terminal Gal rescued up to 80 % of the HT-29 cells, while HMO with fucose α1-2-linked to the terminal Gal had no effect. Galacto-oligosaccharides (GOS), which also contain terminal Gal and are currently added to infant formula to mimic some of the beneficial effects of HMO, completely abolished E. histolytica attachment and cytotoxicity at 8 mg/ml. Although our results need to be confirmed in vivo, they may provide one explanation for why breast-fed infants are at lower risk of E. histolytica infections. HMO and GOS are heat tolerant, stable, safe and in the case of GOS, inexpensive, which could make them valuable candidates as alternative preventive and therapeutic anti-amoebic agents.

Primary Biliary Cirrhosis: Bad Genes, Bad Luck

Primary biliary cirrhosis (PBC) is considered a model for autoimmune disease based upon its hallmark autoantibodies serologic response, the focused target destruction of biliary epithelial cells (BEC), and the clinical homogeneity among patients [1]. PBC is also overwhelmingly a disease of middle-aged and older females, being virtually absent in the pediatric or adolescent population. True pediatric PBC is indeed highly rare, and likely represents an etiopathogenesis that is extremely atypical compared to the classical PBC in adults. PBC also has one of the latest ages of onset out of all autoimmune diseases [2]. The etiology remains enigmatic, although various genetic and environmental factors have been implicated in the disease development and progression, many of which also provide insight as to why females are more prone to PBC [3, 4]. Both genetic and environmental factors may well contribute to the decline of an already ageing immune system, a phenomenon termed immunosenescence [5], through recurrent infections and inflammation, as well as oxidative damage. Immunosenescence is known to begin in approximately the fifth decade of life, and is characterized by a progressive decline in immunological functioning [5–8]. It is likely that the immune system may then reach a critical stage where tolerance to self is lost, thus contributing to the development of autoimmune diseases. A number of studies showing immunosenescence have provided additional evidence as to why middle age presentation often occurs in PBC. For example, changes in T cell signaling such as the decreased expression of the co-stimulatory receptor CD28, have been largely described [7, 11]. In PBC, an age-related progressive increase number of immune-related circulating cells carrying only one X chromosome, that is with monosomy X, was reported [9, 10]. Again, several phenotypical and functional changes have been also noted in the CD4 and CD8 T lymphocytes of PBC patients [1]. Of interest is for example the increased CD127 (marker of effector cells), reduced CD39 (marker of normal Treg function) expression of the CD8 Treg, and that CD8?CD28-cells from PBC patients failed to display a regulatory immune response after incubation with IL-10 [12]. A growing number of evidences suggest that not only immunosenescence but also senescence of the target organ, that is of BEC, has a role in the development of PBC. Senescence is a well-known delayed stress response induced by factors such as oxidative stress, telomere shortening, DNA damage, and autophagy [13]. First, several studies have demonstrated that oxidative stress is an inducer of cell senescence in the BEC of PBC patients [14– 16]. Sasaki et al. [14] notes that cellular senescence in early-stage PBC was associated with an infiltration of myeloperoxidase-positive inflammatory cells, indicating oxidative stress. Another study by the same group showed that Bmi1 (a suppressor of oxidative stress) was significantly reduced in damaged BEC of PBC patients [16]. Second, shortened telomere length with associated cellular senescence has been demonstrated in a study by Sasaki and colleagues [17]. In particular, they examined telomere length using quantitative fluorescent in situ hybridization of 13 patients with PBC and 13 controls and showed a significant decrease in telomere length in damaged BEC from PBC patients, in comparison to histologically normal P. Invernizzi Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano, Italy

Role for mycobacterial infection in pathogenesis of primary biliary cirrhosis?

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterized by the immune-mediated destruction of biliary epithelial cells in small intrahepatic bile ducts. The disease is characterized by circulating antimitochondrial antibodies (AMAs) as well as disease-specific antinuclear antibodies, cholestatic liver function tests, and characteristic histological features, including granulomas. A variety of organisms are involved in granuloma formation, of which mycobacteria are the most commonly associated. This has led to the hypothesis that mycobacteria may be involved in the pathogenesis of PBC, along with other infectious agents. Additionally, AMAs are found in a subgroup of patients with mycobacterial infections, such as leprosy and pulmonary tuberculosis. Antibodies against species-specific mycobacterial proteins have been reported in patients with PBC, but it is not clear whether these antibodies are specific for the disease. In addition, data in support of the involvement of the role of molecular mimicry between mycobacterial and human mitochondrial antigens as triggers of cross-reactive immune responses leading to the loss of immunological tolerance, and the induction of pathological features have been published. Thus, antibodies against mycobacterial heat shock protein appear to cross-recognize AMA-specific autoantigens, but it is not clear whether these autoantibodies are mycobacterium-species-specific, and whether they are pathogenic or incidental. The view that mycobacteria are infectious triggers of PBC is intriguing, but the data provided so far are not conclusive.

Reduced production of polymeric immunoglobulin receptor in murine dextran sodium sulfate-induced colitis

Polymeric immunoglobulin receptor (pIgR) plays an intrinsic role in protecting the intestinal tract from invading pathogens. In the present study, we observed a decrease in pIgR in colon lysate from mice with dextran sodium sulfate (DSS) colitis. A decrease in pIgR was detected in both mRNA and protein levels. Histologic examinations revealed marked destruction of intestinal epithelial cells (IECs), and only a small number of regenerating IECs expressed pIgR. These results suggest that the decrease in pIgR was due to the destruction of IECs. Because activation of toll-like receptor 3 slows the progression of DSS colitis, we injected polyriboinosinic: polyribocytidylic acid (poly I:C) intraperitoneally and observed the correlation between pIgR level and severity of DSS colitis. Poly I:C markedly decreased progression of DSS colitis, and pIgR levels significantly recovered. Furthermore, we found that expressions of IFN-γ and TNF-α were higher in DSS colitis. These results indicate that the decrease in pIgR was not compensated for by increased expression of these cytokines. In sum, our findings show that pIgR levels vary according to the severity of DSS colitis and that these changes might be useful as a biomarker of the severity of inflammatory bowel disease.

Magnetic nanoparticle-based hyperthermia for head & neck cancer in mouse models.

In this study, magnetic iron oxide nanoparticle induced hyperthermia is applied for treatment of head and neck cancer using a mouse xenograft model of human head and neck cancer (Tu212 cell line). A hyperthermia system for heating iron oxide nanoparticles was developed by using alternating magnetic fields. Both theoretical simulation and experimental studies were performed to verify the thermotherapy effect. Experimental results showed that the temperature of the tumor center has dramatically elevated from around the room temperature to about 40oC within the first 5-10 minutes. Pathological studies demonstrate epithelial tumor cell destruction associated with the hyperthermia treatment.

Injection of Acanthaster planci with thiosulfate-citrate-bile-sucrose agar (TCBS). II. Histopathological changes

We assessed histological changes in the tissues of the crown-of-thorns starfish Acanthaster planci (COTS) after injection of thiosulfate-citrate-bile-sucrose agar (TCBS) which was used as a disease inducer (potential outbreak control method), by conventional and scanning electron microscopy. Digestive glands were processed and stained with hematoxylin and eosin to describe the histological architecture of the intestinal epithelium. Subsequently comparison of healthy versus infected tissues and Gram stains were carried out to confirm bacterial occurrence on infected tissues, characterize the structural changes induced by bacterial communities in COTS tissues, and to determine if the histopathological changes of intestinal tissues were consistent with vibrio infection. TCBS injections induced marked epithelial desquamation, hypertrophy and hypersecretion of glandular cells, epithelial cell destruction, pyknosis, reduction of thickness and disorganization of connective tissue and associated nerve plexus, presence of bacterial colonies, irregular eosinophilic foci in glandular cells, brush border disruption, atrophy and detachment of intestinal microvilli and cell debris in the lumen. All these changes were attributed to a fulminating systemic dysbiosis and were consistent with vibrio infections.

The impact of the Bacillus subtilis SPB1 biosurfactant on the midgut histology of Spodoptera littoralis (Lepidoptera: Noctuidae) and determination of its putative receptor

SPB1 is a Bacillus subtilis strain producing a lipopeptide biosurfactant. The insecticidal activity of this biosurfactant was evaluated against the Egyptian cotton leaf worm ( Spodoptera littoralis). It displayed toxicity with an LC 50 of 251 ng/cm 2. The histopathological changes occurred in the larval midgut of S. littoralis treated with B. subtilis SPB1 biosurfactant were vesicle formation in the apical region, cellular vacuolization and destruction of epithelial cells and their boundaries. Ligand-blotting experiments with S. littoralis brush border membrane vesicles showed binding of SPB1 biosurfactant to a protein of 45 kDa corresponding to its putative receptor. The latter differs in molecular size from those recognized by Bacillus thuringiensis Vip3A and Cry1C toxins, commonly known by their activity against S. littoralis. This result wires the application of B. subtilis biosurfactant for effective control of S. littoralis larvae, particularly in the cases where S. littoralis will develop resistance against B. thuringiensis toxins.

Interactions of Lymphocytes, Thyrocytes and Fibroblasts in Hashimoto’s Thyroiditis: An Immunohistochemical and Ultrastructural Study

Background: The mechanism of autoimmune reaction, a diffuse process consisting of a combination of epithelial cell destruction, lymphoid cellular infiltration, and fibrosis in Hashimoto’s thyroiditis, is not well known. The aim of this study was to analyse the cell subsets in thyroid tissue of patients with Hashimoto’s thyroiditis. Methods: We studied paraffin-embedded thyroid specimens obtained from children with Hashimoto’s thyroiditis and children without an autoimmune thyroid disease. Mononuclear T cells were detected by means of CD3+, CD4+, CD8+ antibodies, B cells by CD79 alpha+ antibodies, and antigen-presenting cells by CD1a+ antibodies, and they were counted in every 1,000 cells. The specimens from each patient were routinely estimated and investigated under the electron microscope. Results: In Hashimoto’s thyroiditis, we observed a statistically significant increase in T suppressor/cytotoxic cells CD8+ (20.54 ± 0.68%) in comparison to the control group (0.65 ± 0.30%), simple goitre (4.01 ± 5.54%) and nodular goitre (8.53 ± 2.37%), and a statistically significant increase in plasma CD79 alpha+ cells (31.65 ± 9.11%) in comparison to the control group (4.11 ± 1.94%), simple goitre (1.83 ± 0.64%) and nodular goitre (5.22 ± 1.63%). Simultaneously, we observed a low number of CD4+ T helper cells in the thyroid gland (0.93 ± 0.99%) in Hashimoto’s thyroiditis (0.19 ± 0.05% in the control group, 1.05 ± 2.71% in simple goitre, 2.03 ± 1.06% in nodular goitre). The ultrastructural investigations showed interactions between T cells, plasmocytes, fibrocytes and thyrocytes leading to apoptosis of thyrocytes. An immunological synapse between T cells, plasmocytes and thyrocytes in the thyroid gland was noticed. Conclusions: In Hashimoto’s thyroiditis, autoantigen presentation in combination with a low number of CD4+ T helper cells and a high number of CD8+ cells and plasmocytes caused the development of a cytotoxic reaction against thyrocytes, leading to apoptosis of the thyrocytes.

Fine phenotypic and functional characterization of effector cluster of differentiation 8 positive T cells in human patients with primary biliary cirrhosis

In primary biliary cirrhosis (PBC), patients develop a multilineage response to a highly restricted peptide of the E2 component of pyruvate dehydrogenase (PDC-E2) involving autoantibody and autoreactive cluster of differentiation (CD)4(+) and CD8(+) T-cell responses. Recent data from murine models have suggested that liver-infiltrating CD8(+) cells play a critical role in biliary destruction in PBC. We hypothesized that chronic antigen stimulation of CD8(+) T cells alters effector memory T cell (T(EM) ) frequency and function similar to that seen with chronic viral infections, including failure to terminally differentiate and relative resistance to apoptosis. We have rigorously phenotyped CD8(+) T-cell subpopulations from 132 subjects, including 76 patients with PBC and 56 controls, and report a higher frequency of T(EM) cells characterized as CD45RO(high) CD57(+) CD8(high), but expressing the gut homing integrin, α4β7, in peripheral blood mononuclear cells of PBC. These CD8(high) T(EM) cells have reduced expression of Annexin V after TCR stimulation. Consistent with a T(EM) phenotype, CD45RO(high) CD57(+) CD8(high) T cells express higher levels of granzyme A, granzyme B, perforin, CCR5 and α4β7, and lower levels of CCR7 and CD28 than other CD8(high) T cells. Furthermore, interleukin (IL)-5 produced by CD8(+) CD57(+) T lymphocytes upon in vitro T-cell receptor stimulation are increased in PBC. Histologically, CD8(+) CD57(+) T cells accumulate around the portal area in PBC. Moreover, CD8(+) CD57(+) T cells respond specifically to the major histocompatibility class I epitope of PDC-E2. In conclusion, our data demonstrate that CD45RO(high) CD57(+) CD8(high) T cells are a subset of terminally differentiated cytotoxic T(EM) cells, which could play a critical role in the progressive destruction of biliary epithelial cells.

Morphological Changes in Rat Tracheal Wall in Experimental Hemorrhagic Stroke

Structure of the tracheal wall of male Wistar rats was studied by histological methods on days 1, 3, and 7 after experimental hemorrhagic stroke. Signs of impaired microcirculation and lymphatic drainage were revealed at all stages of the experiment. In the acute phase of stroke (day 1), these disturbances lead to destruction of epithelial cells and their extensive desquamation, edema of the submucosa, and hemorrhages in the tracheal wall. On days 3 and 7 of the experiment, destructive changes in the mucosa membrane were still present, but swelling of mucosa lamina propria and submucosa of the tracheal wall greatly decreased, probably due to evacuation of tissue fluid excess into the lumen. We can assume that changes in the structure of the tracheal wall in experimental hemorrhagic stroke impair the barrier function of the wall, which can contribute to the development of pneumonia, a serious inflammatory complications of stroke.

Intravenous immunoglobulin in the treatment of childhood Stevens Johnson syndrome

A 12-year-old boy of Polynesian background, who had been previously well, presented with swollen blistering lesions involving his lips and oral mucosa which then progressed to involve his limbs and genitalia over 3 days. He was unable to eat and drink and had difficulty passing urine because of pain. A diagnosis of Stevens Johnson syndrome (SJS) was made. The question of whether intravenous immunoglobulin (IVIG) would be effective in treating this condition was raised. SJS is a severe mucocutaneous reaction characterised by destruction of epithelial cells resulting in widespread blisters with involvement of at least two mucosal membranes. It has a clinical course of up to 6 weeks with a high morbidity and mortality of 5–10%. The current management of SJS is primarily supportive. It involves careful wound care, close monitoring of fluid and electrolyte balance, ophthalmological review and eye care, infection control, pain control and nutritional support. Any inciting drug is discontinued, and causative organism is treated – the most common being Mycoplasma pneumoniae. The use of IVIG for SJS has been controversial. IVIG has been used with reported beneficial effects in various case reports in treating SJS. In 1998, Viard et al. reported that IVIG inhibited Fas-mediated keratinocyte apoptosis in vitro – a key mechanism in the pathogenesis of SJS. This added in vitro evidence to clinical experience.