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CILJ ISTRAŽIVANJA: Procijeniti mogući proupalni učinak hiperbaričnog tretmana u štakora određujući izražaj biljega CD11b i CD15s na leukocitima. Opisati promjene u izražaju biljega CD77 na štakorskim endotelnim (CD34+) stanicama bubrega, pluća i srca nakon izlaganja hiperbaričnom tlaku. MATERIJALI I METODE: Eksperimentalno istraživanje provedeno je na Katedri za medicinsku kemiju i biokemiju Medicinskog fakulteta u Splitu. Mužjaci štakorskog soja Sprague-Dawley, starosti 4 tjedna bili su podijeljeni u 2 skupine: ispitivanu skupinu koja je podvrgnuta hiperbaričnom tretmanu (n=9) i netretiranu kontrolnu skupinu (n=5). Štakori su podvrgnuti hiperbaričnom tlaku smjese zraka koji odgovara dubini zarona od 65 m, u trajanju od 30 min. Tijekom tri dana, nakon izlaganja hiperbariji, štakorima je uzet uzorak krvi za određivanje leukocitnih biljega CD15s i CD11b protočnom citometrijom. Trećeg dana životinje su žrtvovane produljenom anestezijom dietileterom te su im nakon toga izvađeni bubrezi, srce i pluća. Pripremljene stanice bubrega, pluća i srca obilježene su protutijelima za CD34 i CD77 te su analizirane protočnom citometrijom. Za statističku obradu korišten je neparametrijski Mann Whitney U test. REZULTATI: Postotci CD15s+CD11b- leukocita i ukupnih CD15s leukocita bili su značajno povišeni u skupini tretiranih štakora naspram kontrolne skupine. Postotak CD77+CD34- stanica bubrega štakora u ispitivanoj (HB) skupini bio je značajno manji nego u kontrolnoj skupini, kao i udio ukupnih CD77+ stanica. Uočeno je značajno smanjenje % CD77+CD34+ bubrežnih stanica u HB skupini u odnosu na kontrolnu skupinu. Ukupni udio CD34+ bubrežnih stanica bio je značajno povišen u odnosu na kontrolu. Postotak CD77+CD34-, % ukupnih CD77+, % CD77+CD34+, kao i % ukupnih CD34+ stanica pluća štakora u HB skupini bio je značajno viši nego u kontrolnoj skupini. Postotak ukupnih CD77+, % ukupnih CD34+, % CD77+CD34+, kao i % CD77-CD34+ stanica srca štakora u HB skupini bio je značajno viši nego u kontrolnoj skupini. ZAKLJUČAK: Rezultati povećanog postotka leukocita koji imaju izražen CD15s, ligand za endotelni selektin, nakon hiberbaričnog tretmana, ukazuju na njegovu ulogu u prevenciji oštećenja endotela. Rezultati ovog istraživanja ukazuju na moguću ulogu CD77 u mehanizmu odgovornim za razvoj hiperbarične diureze. Hiperbarični tretman značajno je povećao postotak plućnih i srčanih endotelnih stanica što može biti dio mehanizma popravka hiperoksijom ozlijeđenog endotela., AIM OF RESEARCH: To estimate the potential pro-inflammatory effect of hyperbaric treatment in rats by determination of CD11b and CD15s on leukocytes. To describe the changes in the expression of CD77 in rat's kidney, pulmonary and cardiac endotelial (CD34+) cells. MATHERIALS AND METHODS: Experimental research was conducted at Department for Medical Chemistry and Biochemistry, University of Split School of Medicine. Male Sprague-Dawley rats, 4 weeks old, were divided into 2 groups: the examination group, that undergone hyperbaric treatment (n=9) and untreated control group (n=5). The rats were exposed to hyperbaric pressure of air composition that equals the depth of immersion of 65 m, in duration of 30 min. During three days, after the treatment, a blood sample was collected from the rats for determination of leukocyte CD11b and CD15s markers. By the end of the third day from the beginning of hyperbaric treatment rats were sacrified in prolonged anesthesia with diethylether and their kidneys, lungs and heart were extracted afterwards. Furthermore, prepared isolated renal, pulmonary and cardiac cells were incubated with antibodies for CD34 and CD77, and were analysed by flow cytometry. For statistical analysis non-parametric Mann Whitney U test was used. RESULTS: The percentage of CD15s+CD11b- leukocytes and total CD15s leukocytes were significantly increased in examination group compared to control group. The percentage of CD77+CD34+ kidney cells in examination group was significantly lower compared to control group, as well as the percentage of total CD77+ cells. A significant decrease in % CD77+CD34+ kidney cells was observed in examination group compared to control group. Total share of CD34+ kidney cells was significantly higher compared to control group. The percentage of CD77+CD34-, % of total CD77+, % CD77+CD34+, as well as the % of totalCD34+ pulmonary cells in examination group was significantly higher compared to control group. The percentage of total CD77+, % of total CD34+, % of CD77+CD34+, as well as % of CD77-CD34+ cardiac cells in examination group was significantly higher compared to control group. CONCLUSION: The results of increased percentage of leukocytes that have CD15s, ligand for endothelial selectin, after hyperbaric treatment, suggest its role in the prevention of endothelial damage. The results of this experiment indicate a possible role of CD77 in the mechanism responsible for hyperbaric diuresis. Hyperbaric treatment significantly increased the percentage of pulmonary and cardiac endothelial cells which may be a part of hyperoxia-induced endothelial damage repair mechanism.

International audience; We present a new, rapid method for producing blood platelets in vitro from cultured megakaryocytes based on a microfluidic device. This device consists in a wide array of VWF-coated micropillars. Such pillars act as anchors on megakaryocytes, allowing them to remain trapped in the device and subjected to hydrodynamic shear. The combined effect of anchoring and shear induces the elongation of megakaryocytes and finally their rupture into platelets and proplatelets. This process was observed with megakaryocytes from different origins and found to be robust. This original bioreactor design allows to process megakaryocytes at high throughput (millions per hour). Since platelets are produced in such a large amount, their extensive biological characterisation is possible and shows that platelets produced in this bioreactor are functional. Platelets are small anucleate cells that circulate in blood and are responsible for the arrest of bleeding. Platelets are formed by fragmentation of larger cells called megakaryocytes (MKs). Thrombocytopenia (insufficient platelet count) is a major condition, often requiring platelet transfusions. High collection costs, donor shortage, immuno-genicity, risk of contamination and storage issues represent the main limits of this therapeutic approach. People have tried to make artificial platelets but these objects seem promising for drug targeting rather than for therapy

Fundamento y objetivo Tras un infarto de miocardio (IM), las celulas progenitoras endoteliales (CPE) procedentes de la medula osea son movilizadas hacia sangre periferica. El objetivo de nuestro trabajo fue estudiar los factores que influyen en dicha movilizacion celular espontanea. Pacientes y metodo En este estudio se han analizado en 47 pacientes con IM extenso (definido por una fraccion de eyeccion ventricular izquierda [FEVI]

Hematopoietic progenitor cells are the progeny of hematopoietic stem cells that coordinate the production of precise numbers of mature blood cells of diverse functional lineages. Identification of cell-surface antigen expression associated with hematopoietic lineage restriction has allowed prospective isolation of progenitor cells with defined hematopoietic potential. To clarify further the cellular origins of megakaryocyte commitment, we assessed the in vitro and in vivo megakaryocyte and platelet potential of defined progenitor populations in the adult mouse bone marrow. We show that megakaryocytes arise from CD150 + bipotential progenitors that display both platelet- and erythrocyte-producing potential in vivo and that can develop from the Flt3 − fraction of the pregranulocyte-macrophage population. We define a bipotential erythroid-megakaryocyte progenitor population, the CD150 + CD9 lo endoglin lo fraction of Lin − cKit + IL7 receptor alpha − FcγRII/III lo Sca1 − cells, which contains the bulk of the megakaryocyte colony-forming capacity of the bone marrow, including bipotential megakaryocyte-erythroid colony-forming capacity, and can generate both erythrocytes and platelets efficiently in vivo. This fraction is distinct from the CD150 + CD9 hi endoglin lo fraction, which contains bipotential precursors with characteristics of increased megakaryocytic maturation, and the CD150 + CD9 lo endoglin hi fraction, which contains erythroid lineage-committed cells. Finally, we demonstrate that bipotential erythroid-megakaryocyte progenitor and CD150 + CD9 hi endoglin lo cells are TPO-responsive and that the latter population specifically expands in the recovery from thrombocytopenia induced by anti-platelet serum.

Background/Aims: To investigate the immunophenotype of 46 Chinese patients with T-lineage acute lymphoblastic leukemia (T-ALL) and its association with biological and clinical features. Methods: 46 patients with T-ALL were immunophenotyped by flow cytometry, and 30 cases were also subjected to karyotype analysis by R-banding technology. The clinical and biological characteristics of T-ALL patients between MyAg+ and MyAg– groups were analyzed. Results: Myeloid antigen (MyAg) expression was documented in 41.3% of the 46 T-ALL cases. Abnormal karyotypes were detected in 17 out of 30 (56.7%) cases. Our data showed that the median lowest white blood cell (WBC) count and lowest hemoglobin level, higher CD34 positivity, and a lower proportion of patients with splenomegaly were found to be correlated with MyAg+ T-ALL. No statistical difference was noted in the complete remission (CR) rate, relapse rate, induction death rate or total death rate among MyAg+ and MyAg– patients. In our cohort, none of the antigens tested affected the CR rate after the first induction. Conclusion: Our results indicate that MyAg expression in patients with T-ALL was not associated with adverse presenting clinical and biological features as well as response to induction treatment. The expression of surface antigens had no impact on initial chemotherapy CR achievement.

Subcutaneous panniculitis-like T-cell lymphoma is an uncommon form of CD8-positive cytotoxic T-cell lymphoma of the skin that predominantly affects the subcutaneous tissue and is extremely rare in early childhood (

Resume Introduction Le sarcome d’Ewing (ou tumeur neuro-ectodermique peripherique) est habituellement localise dans l’os. Les localisations extraosseuses sont plus rares, et la localisation cutanee primitive est exceptionnelle. Nous rapportons un nouveau cas de sarcome d’Ewing cutane primitif. Observation Une jeune femme de 21 ans consultait pour une lesion cutanee acquise de l’epaule, evoluant depuis un an. Une exerese etait pratiquee. L’examen histologique de la piece operatoire montrait une proliferation tumorale faite de petites cellules rondes monomorphes envahissant le derme et l’hypoderme. Seul l’immunomarquage CD99 etait positif : le diagnostic de sarcome d’Ewing cutane primitif etait evoque, puis confirme par la mise en evidence du gene de fusion EWSR1 . Le bilan d’extension etait normal. La prise en charge therapeutique retenue etait identique a celle des sarcomes d’Ewing osseux : reprise chirurgicale elargie et polychimiotherapie. Discussion Les sarcomes cutanes posent des difficultes a la fois diagnostiques et therapeutiques. Leur aspect clinique est tres polymorphe, et l’etude histopathologique standard, peu specifique, peut faire evoquer plusieurs diagnostics differentiels. La confirmation du diagnostic par des techniques de biologie moleculaire est donc indispensable. Toute la difficulte pour l’anatomopathologiste est d’evoquer le diagnostic, avant de le confirmer par la recherche de la translocation specifique du gene EWSR1 . Enfin se pose la question des modalites du traitement de ces sarcomes. Actuellement, en l’absence de recommandations specifiques, les sarcomes d’Ewing cutanes sont traites comme des sarcomes d’Ewing osseux (chirurgie elargie, polychimiotherapie, radiotherapie parfois, voire greffe de moelle osseuse). Or, d’apres les donnees de la litterature, les sarcomes d’Ewing cutanes ont une evolution beaucoup plus favorable que les sarcomes d’Ewing osseux. On peut donc se demander si le rapport benefice/risque justifie une attitude therapeutique commune aux formes primitivement cutanees et osseuses.

Platelets are crucial for preventing excessive blood loss at sites of injury by plugging holes in damaged blood vessels through thrombus formation. Platelet thrombi can, however, cause heart attack or stroke by blocking diseased vessels upon rupture of atherosclerotic plaques. Current anti-platelet therapy is not effective in all patients and carries a risk of bleeding. As such, a major goal in platelet research is to identify new drug targets to specifically inhibit platelets in disease processes. Tetraspanins are potential candidates because of their capacity to regulate other proteins in microdomains, and their defined roles in cell adhesion and signalling. In the last 6 years, analyses of tetraspanin-deficient mice have suggested that tetraspanins are indeed important for fine-tuning platelet responses. The future characterization of novel regulatory mechanisms in tetraspanin microdomains may lead to new drug targets for the prevention and treatment of heart attack and stroke.

Tetherin represents an important barrier for successful cross-species transmissions of primate lentiviruses. HIV-1 overcame this obstacle by using Vpu as a countermeasure. However, Kluge and collaborators now show that HIV-1 group O uses Nef to antagonize tetherin, and that this activity may have contributed to its spread in West-Central Africa.

B7-H1 is expressed in vestibular schwannomas.Little is known about how benign human vestibular schwannomas interact with antibody-mediated or cell-mediated immunity. We report on the aberrant expression of a novel T-cell coregulatory molecule, B7 homolog 1 (B7-H1), in vestibular schwannomas and discuss the implications of B7-H1 expression and tumor aggressiveness and a potential regulator of B7-H1 expression.Immunohistochemical staining for B7-H1, CD8+, CD3+, and CD4+ lymphocytes were performed on 48 fresh-frozen vestibular schwannoma tissue specimens. A clinical review of patient presenting symptoms and tumor characteristics was performed. Real-time polymerase chain reaction was used to determine if there was differential expression of B7-H1 messenger RNA and microRNA-513, a known regulator of B7-H1, in several strongly positive and negative B7-H1 vestibular schwannomas.Nine (19%) of 48 tumors were negative, 23 (48%) tumors were 1+ mildly positive (20% section area), and 16 (33%) stained 2+ strongly positive (or=20% section area) for B7-H1. The average number of CD8 cells per high-power field was 2.1 for positive-staining tumors and 1.0 for negative tumors (p = 0.16). Failure of tumor control with stereotactic radiation (p = 0.029) was significantly greater in the strongly positive B7-H1 tumors. Real-time polymerase chain reaction did not show significant differential expression of microRNA-513 (p = 0.62) or B7-H1 messenger RNA (p = 0.35) between the tumors showing strong and negative immunohistochemical staining for B7-H1 protein.Vestibular schwannoma tumors express B7-H1, which has been associated with immune tolerance and adverse disease characteristics in several malignancies. Growing tumors that were surgically removed after failed stereotactic radiation therapy were significantly more likely to strongly express B7-H1 protein, which lends some credibility to the hypothesis that immuno-evasion may play some role in their continued growth. Although clinical trends were seen, greater statistical power is required to evaluate whether B7-H1 expression correlates with more aggressive tumor growth or poorer hearing class. B7-H1 seems to be expressed in equal amounts at the RNA level in all vestibular schwannoma tumors that suggests that differential protein expression is occurring at the posttranscriptional level. However, microRNA-513 does not regulate B7-H1 protein expression in these tumors.

T cell large granular lymphocyte leukemia (T-LGL) is a chronic disease covering a wide spectrum of clinical presentations in the border-land between reactive autoimmunity and overt leukemia [1-2]. ...

Rendu-Osler-Weber disease, also known as hereditary hemorrhagic telangiectasia (HHT), is an autosomal dominant inherited disorder characterized by an aberrant vascular development. The reported prevalence is approximately 1 per 5,000-10,000. The clinical manifestations consist of recurrent spontaneous nosebleeds, telangiectasias characteristically at the lips, oral cavity, fingers, and nose, and visceral arteriovenous malformations. Timely recognition of this syndrome makes screening for complications, preventive measurements, and genetic counselling possible. The important role of the dental profession in the recognition of this genetic disease is emphasized. In addition, a brief overview of the current literature is presented.

In this issue of the Journal, Hobbs et al. [ 1 ] present evidence that the severity of herpes simplex virus (HSV) type 1 (HSV-1) infection may be associated with a genotype on human chromosome 21. Their report explicitly addresses a question that is frequently presented to general clinicians and those specializing in infectious diseases and sexually transmitted infections: why is my herpes so bad? Implicit subtexts concern the "normalcy" of the immune system, as well as the possibility of an intervention predicated on the mechanisms behind variations in severity. Although no definitive answers are provided by the current study, these questions are well worth asking and have been approached from several angles in recent years. With exceptions, such as rabies, infections display great variation in disease severity. For chronic infections, such as those caused by herpesviruses, both the primary and recurrent episodes may range in severity from clinically quite significant, leading to doctor visits and time lost from work, to clinically silent, occurring without signs or symptoms [2]. This spectrum is particularly apparent among persons considered to be immunocompetent. Findings of type-specific HSV serological assays have been correlated with clinical histories to demonstrate that

Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in Europe and in North America. It is caused by the neoplastic transformation of a population of B-lymphocytes coexpressing CD5, CD19 and CD23. Although the etiology is not well known there is evidence of the existence of a genetical base. CLL is not only caused by the accumulation of B-lymphocytes due to a failure in the apoptosis. It is also caused by the active proliferation of the B-cells in response to the signs sent by the environment. Its clinical course is variable. One third of CLL patients are affected by an indolent form that does not require treatment. Another third of patients with leukemia will require iterative therapies and a small fraction patients develop Richter syndrome that reduces its overall survival to 5 to 8 months. This variability is due to the heterogeneity of the molecules that participate in the pathogenesis. One of these molecules is CD38. Some studies have demonstrated that the presence of this marker confers a worse prognostic, specially the presence of one polymorphism of CD38, rs6449182. Fluradabine, clyclophosphamide and rituximab (FCR) is considered the gold standard therapy for young patients under 65 years with CLL because achieves high percentage of minimal residual disease (MRD). But it has not been studied if in CLL patients with this polymorphism, FCR continues offering these good results. Objective: To analyze the relationship between the polymorphisms of CD38 and treatment outcomes in CLL patients treated with FCR. Methods: The design is a multicenter prospective cohort study. 338 patients will be recruited during 4 years. We will analyze the presence of the polymorphism and evaluate the minimal residual disease (MRD) after the treatment with FCR

Objectives: In-stent restenosis due to neointima formation is a major limitation following stent implantation. Recently, several studies reported mobilization of primarily extravascular cells to the arterial sites after balloon angioplasty. Therefore, the goal of the present study was to assess the coordinated neointimal expression of endothelial progenitor, dendritic and neural crest-derived cells after stent implantation. Methods: Male minipigs underwent stent implantation in abdominal aortic segments. Animals were sacrificed at 1, 7, 14, 30, 60 or 90 days. Cross sections of the injured vessels were obtained for immunohistochemistry using specific antibodies for the detection of endothelial progenitor (CD133), dendritic (S100) and neural crest-derived cells (GFAP), as well as monocytes/macrophages (CD14) and T lymphocytes (CD3). Results: As a key finding, frequency of CD133, S100, GFAP, CD14 and CD3 (18.5 ± 3.6, 14.9 ± 1.8, 10.6 ± 1.1, 40.2 ± 8.3 and 5.0 ± 0.6%, respectively) in neointima was maximal at day 7. With ongoing neointima enlargement, expression of these cells decreased. In advanced neointima, labeled cells were predominantly localized at luminal and stented sites. Media showed almost no immunoreactivity of the markers studied, whereas adventitial zones of neovascularization revealed some signals. Conclusions: Endothelial progenitor, dendritic, neural crest-derived and inflammatory cells are consistently recruited into arterial neointima, mostly at early time points after stent implantation.

Granulomatous slack skin syndrome is a rare clinical and pathologic disorder. Only 42 patients have been reported, one of whom we described in 1997--the only child so far reported. We now describe the evolution of this patient and the transformation of the disease into a peripheral T-cell lymphoma, and the complications resulting in the child's death.

Ralph Steinman is perhaps best known as a codiscoverer of dendritic cells (DCs) and as a founding father of the research area that these cells have spawned. For his discovery, Steinman was recently awarded the 2007 Albert Lasker Award for Basic Medical Research. Yet the man behind the research holds his praise for the many other scientists—in the U.S. and abroad—who have further advanced the therapeutic promise of DCs.

Langerhans cells (LC) are a subtype of dendritic cells, which reside in the epidermis. LCs are antigen-presenting cells that originate in bone marrow and enter the epidermis through blood vessels. LCs exhibit a variety of antigen receptors that are able to respond to a wide range of antigens. Within the last two decades, these receptors have been the subject of considerable research. This article focuses on the rapidly growing body of knowledge with respect to the functions of LC receptors.

The development of the synovial membrane was analyzed in serial sections of 21 temporomandibular joints of human fetuses at 9 to 13 weeks of gestation. Sections of two fetuses at 12 weeks of development were used to perform immunohistochemical expression of the markers CD68 and Hsp27 on the synovial lining. Macrophage-like type A and fibroblast-like type B cells, which express CD68 and Hsp27, respectively, were observed at the twelfth week of development. Our results suggest that the development of the synovial membrane is related to the vascularization of the joint and the formation of the articular cavities.

The aetiology of angio-oedema (AE) is difficult to determine; however, it is essential in emergency situations when two major contexts may be present: mast cell-mediated AE and bradykinin-mediated AE. Different forms of AE are currently distinguished based on clinical criteria (spontaneous duration of the attack, presence of concomitant or late-appearing superficial urticaria, history of atopy, and others), but specific biomarkers could improve patient management.In this prospective study, potential biomarkers have been identified, and their statistical characteristics were examined.Samples were taken on day 0 (D0) and D7 for 3 patient groups (n = 11 each): bradykinin-mediated AE [peripheral site of attack, ear, nose, throat (ENT), and abdominal involvement], mast cell-mediated AE, and non-bradykinin-mediated abdominal pain.Assay of the potential biomarkers revealed no significant differences in C1 inhibitor and C4 levels. In contrast, D-dimer levels peaked during bradykinin-mediated AE attacks (median 2.2 mg/l at D0 vs. 0.52 mg/l at D7; p10-3) as well as during mast cell-mediated AE attacks (1.97 vs. 0.65 mg/l; p = 0.04) and were high in bradykinin-mediated AE compared to the control group (0.69 mg/l; p = 0.01). A threshold value of 0.62 mg/l was found to have a negative predictive value of 100% for bradykinin-mediated AE compared to other causes of abdominal pain (group 3). Circulating VE-cadherin levels were also increased during an attack (1,990 at D0 vs. 1,566 ng/ml at D7; p = 0.01), but could not distinguish between bradykinin-mediated and mast cell-mediated AE, like D-dimers.Exploration of changes in fibrinolysis-related markers (particularly D-dimers) is thus promising for the diagnosis of AE attacks in difficult-to-diagnose abdominal forms, although it was not able to differentiate between bradykinin and mast cell-mediated AE.

Background: Sauna bathing is claimed to provide benefits for patients suffering from cardiovascular diseases. The current study aims at analyzing the induction of potential regenerative processes by quantifying the mobilization of bone marrow-derived stem cells into the peripheral blood of healthy adults following Finnish sauna. Materials and Methods: Twenty healthy unbiased male volunteers (20-30 years old) were exposed to a Finnish sauna bath (3 × 10 min, 90°C). Venous blood samples were drawn before (baseline), immediately, and 6 h as well as 24 h after the sauna bath. Blood analysis included isolation of mononuclear cells, cell staining with mononuclear antibodies, and fluorescence-activated cell sorting (FACS). For baseline and 24 h post-sauna samples colony-forming unit-Hill assays were applied to quantify endothelial progenitor cells (EPC). Results: Flow cytometry revealed an upregulation of circulating CD45+/CD309+ progenitor cells immediately after the sauna bath, however without reaching statistical significance. Circulating cell numbers of the CD45+CD34+, CD45+CD34+CD133+, and CD45+CD34+CD117+ populations did not show clear enhancements following sauna. EPC colony formation tended to be enhanced after sauna as compared to baseline values. Conclusion: Peripheral EPC numbers exhibited a moderate increase following Finnish sauna in a cohort of healthy young men. Furthermore, sauna bathing tended to increase EPC colony-forming capacity. These rather weak responses to thermotherapy might indicate a ceiling effect. In individuals exhibiting cardiovascular risk factors the effects may be more pronounced.

The intracellular chaperone heat‐shock protein 70 (Hsp70) can be secreted from cells, but its extracellular role is unclear, as the protein has been reported to both activate and suppress the innate immune response. Potential immunomodulatory receptors on myelomonocytic lineage cells that bind extracellular Hsp70 are not well defined. Siglecs are Ig‐superfamily lectins on mammalian leukocytes that recognize sialic acid‐bearing glycans and thereby modulate immune responses. Siglec‐5 and Siglec‐14, expressed on monocytes and neutrophils, share identical ligand‐binding domains but have opposing signaling functions. Based on phylogenetic analyses of these receptors, we predicted that endogenous sialic acid‐independent ligands should exist. An unbiased screen revealed Hsp70 as a ligand for Siglec‐5 and Siglec‐14. Hsp70 stimulation through Siglec‐5 delivers an anti‐inflammatory signal, while stimulation through Siglec‐14 is pro‐inflammatory. The functional consequences of this interaction are also addressed in relation to a SIGLEC14 polymorphism found in humans. Our results demonstrate that an endogenous non‐sialic acid‐bearing molecule can be either a danger‐associated or self‐associated signal through paired Siglecs, and may explain seemingly contradictory prior reports on extracellular Hsp70 action.

Previous studies have shown that a major block to HIV-1 replication in common marmosets operates at the level of viral entry and that this block can be overcome by adaptation of the virus in tissue-cultured cells. However, our current studies indicate that HIV-1 encounters additional postentry blocks in common marmoset peripheral blood mononuclear cells. Here, we show that the common marmoset APOBEC3G (A3G) and BST2 proteins block HIV-1 in cell cultures. Using a directed-evolution method that takes advantage of the natural ability of HIV-1 to mutate during replication, we have been able to overcome these blocks in tissue-cultured cells. In the adapted viruses, specific changes were observed in gag, vif, env, and nef. The contribution of these changes to virus replication in the presence of the A3G and BST2 restriction factors was studied. We found that certain amino acid changes in Vif and Env that arise during adaptation to marmoset A3G and BST2 allow the virus to replicate in the presence of these restriction factors. The changes in Vif reduce expression levels and encapsidation of marmoset APOBEC3G, while the changes in Env increase viral fitness and discretely favor cell-to-cell transmission of the virus, allowing viral escape from these restriction factors, Spanish Ministry of Economy and Competitiveness grant (BIO2013-48788-C2-1-R) to L.M.-A.; and by an institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa

There are few reports on the migration of CLA+ T cells through E-selectin in cutaneous lichen planus, with only one study on oral lichen planus (OLP). This study aimed to analyze CLA expression and assess whether there is a correlation with E-selectin (CD62E) in OLP lesions.Biopsies were performed on 11 patients including two areas: one without clinical and histopathological features of OLP [perilesional group (PLG)] and the other with clinical and histopathological features of OLP [OLP group (OLPG)]. The specimens obtained were divided into two: One was fixed in formalin for routine analysis (HE), and the other was frozen for CD3, CD4, CD8, CLA, and CD62E immunofluorescence markers.More CD4+ (median 1409, range 860-2519), CD8+ (median 1568, range 654-3258), and CLA+ T cells (median 958, range 453-2198) and higher CD62E expression (median 37, range 27-85) were identified in OLPG (P = 0.003; P = 0.003; P = 0.004; P = 0.003, respectively) than those in PLG. The median prevalence analysis was also significantly higher for CLA+CD8+ T cells in OLPG (OLPG = 39.4%, range 18.4-64.2; PLG = 29.4%, range 12.1-47.1) (P = 0.026). None of the correlations between CD3+ or CLA+ T cells and CD62E in OLPG and in PLG were significant.The significant presence of CLA+ T cells and E-selectin expressions in the OLPG suggests their involvement in the etiopathogenesis of OLP; however, only a weak correlation between CLA+ T cells and E-selectin was observed.

Beneficial microbes hold great promise for the treatment of a wide range of immune and inflammatory disorders. In this issue of The EMBO Journal, Lightfoot and colleagues report how the food-grade bacterium Lactobacillus acidophilus helps the immune system to limit experimental colitis in mice through interaction between SIGNR3 and surface layer protein A (SlpA) in L. acidophilus. These results pave the way for future development of novel therapies for inflammatory diseases, including inflammatory bowel disease.

Isolated lymphoid follicles (ILFs) are organized intestinal lymphoid structures whose formation can be induced by luminal stimuli. ILFs have been demonstrated to act as inductive sites for the generation of immune responses directed toward luminal stimuli; however, the phenotype of the immune response initiated within ILFs has largely been uninvestigated. To gain a better understanding of the immune responses initiated within ILFs, we examined phenotypic and functional aspects of the largest cellular component of the murine ILF lymphocyte population, B lymphocytes. We observed that murine ILF B lymphocytes are composed of a relatively homogenous population of follicular B-2 B lymphocytes. Consistent with their proximity to multiple stimuli, ILF B lymphocytes displayed a more activated phenotype compared with their counterparts in the spleen and Peyer's patch (PP). ILF B lymphocytes also expressed higher levels of immunomodulatory B7 and CD28 family members B7X and programmed death-1 compared with their counterparts in the spleen and PP. ILF B lymphocytes preferentially differentiate into IgA-producing plasma cells and produce more IL-4 and IL-10 and less interferon-γ compared with their counterparts in the spleen. Immunoglobulin repertoire analysis from individual ILFs demonstrated that ILFs contain a polyclonal population of B lymphocytes. These findings indicate that murine ILFs contain a polyclonal population of follicular B-2 B lymphocytes with a phenotype similar to PP B lymphocytes and that, in unchallenged animals, ILFs promote immune responses with a homeostatic phenotype.

Around 700 BCE, a new military formation called the phalanx was established in ancient Greece: a tight column of heavy infantry carrying long spears, or pikes, used in a single prong of attack. Later, in the battle of Marathon described by Herodotus, the Greeks learned the advantages of multipronged attacks, a strategy still used in modern warfare. Is the immune system similar in its approach to combating pathogens or tumors?

Individuals with deficiencies of the late components of complement exhibit a susceptibility to the recurrence of meningococcal disease with a usually mild clinical presentation. We report the recurrence of fulminant meningococcal disease in a complement component C7-deficient patient. We found a total deficiency of FcgammaRIIIb on neutrophils, which could partially explain the unusually severe clinical presentation.

La maladie de Rendu-Osler est une maladie rare vasculaire d’origine genetique, de transmission autosomique dominante, qui se manifeste par l’existence de telangiectasies cutaneomuqueuses et de malformations vasculaires pulmonaires, hepatiques et cerebrales [1]. Les telangiectasies nasales sont responsables du symptome principal de la maladie que sont les epistaxis. Cette maladie concerne environ un sujet sur 6000. La prise en charge de ces patients a fait l’objet de recommandations depuis la mise en place du centre de reference maladies rares et de centres de competence. Le diagnostic de cette maladie est clinique et repose sur l’existence d’au moins trois criteres parmi les suivants : epistaxis recurrentes, telangiectasies cutanees multiples, histoire familiale et existence de malformations arterioveineuses viscerales [2]. Deux genes principaux sont responsables d’environ 92 % des cas de maladie de Rendu-Osler : ENG qui code pour l’Endogline (OMIM #131195) et ALK1 qui code pour l’« activinreceptor-like kinase 1 » (OMIM #600376). Des mutations du gene MADH4 qui code pour SMAD4 ont ete identifiees chez des patients qui presentaient des tableaux associant des polyposes juveniles et la maladie de Rendu-Osler [3]. Les genes impliques dans la maladie de Rendu-Osler ont un role important dans la balance angiogenique [1]. Une hypothese physiopathologique pour la maladie de Rendu-Osler est qu’il existe un dereglement de la balance angiogenique associe a une neoactivation de l’angiogenese. L’utilisation d’anticorps anti-VEGF pourrait donc permettre d’inhiber cette activation de l’angiogenese et de retourner a un etat quiescent d’angiogenese. Depuis plusieurs annees, nous nous sommes particulierement interesses aux malformations vasculaires hepatiques presentes dans la maladie de Rendu-Osler. L’hypervascularisation hepatique est frequente dans cette pathologie, puisque selon les techniques utilisees (echographie

Monocytes, like all leukocytes, undergo a series of sequential steps during extravasation from blood into tissues: tethering, rolling, adhesion and diapedesis. We have discovered an essential step, which we call locomotion, in which the monocyte moves from a site of firm adhesion to the nearest junction to begin diapedesis. Blocking CD11a-CD18 and CD11b-CD18 on human monocytes or adhesion molecules ICAM-1 and ICAM-2 on endothelial cells prevented the monocytes from reaching junctions. The blocked monocytes spun in circles as if they were unable to direct their movement despite being able to adhere and polarize normally. This step fills a gap in the paradigm of extravasation as a multistep process.