Activated group 3 innate lymphoid cells promote T-cell-mediated immune responses.

Group 3 innate lymphoid cells (ILC3s) have emerged as important cellular players in tissue repair and innate immunity. Whether these cells meaningfully regulate adaptive immune responses upon activation has yet to be explored. Here we show that upon IL-1β stimulation, peripheral ILC3s become activated, secrete cytokines, up-regulate surface MHC class II molecules, and express costimulatory molecules. ILC3s can take up latex beads, process protein antigen, and consequently prime CD4(+) T-cell responses in vitro. The cognate interaction of ILC3s and CD4(+) T cells leads to T-cell proliferation both in vitro and in vivo, whereas its disruption impairs specific T-cell and T-dependent B-cell responses in vivo. In addition, the ILC3-CD4(+) T-cell interaction is bidirectional and leads to the activation of ILC3s. Taken together, our data reveal a novel activation-dependent function of peripheral ILC3s in eliciting cognate CD4(+) T-cell immune responses.

The influence of environmental conditions on immune responses, morphology and recapture probability of nestling house martins (Delichon urbica)

Nestling birds produced later in the season are hypothesized to be of poor quality with a low probability of survival and recruitment. In a Spanish population of house martins (Delichon urbica), we first compared reproductive success, immune responses and morphological traits between the first and the second broods. Second, we investigated the effects of an ectoparasite treatment and breeding date on the recapture rate the following year. Due probably to a reverse situation in weather conditions during the experiment, with more rain during rearing of the first brood, nestlings reared during the second brood were in better condition and had stronger immune responses compared with nestlings from the first brood. Contrary to other findings on house martins, we found a similar recapture rate for chicks reared during the first and the second brood. Furthermore, ectoparasitic house martin bugs had no significant effect on the recapture rate. Recaptured birds had similar morphology but higher immunoglobulin levels when nestlings compared with non-recaptured birds. This result implies that a measure of immune function is a better predictor of survival than body condition per se.

Total shoulder arthroplasty: downward inclination of the glenoid component to balance supraspinatus deficiency.

HYPOTHESIS: Supraspinatus deficiency associated with total shoulder arthroplasty (TSA) provokes eccentric loading and may induce loosening of the glenoid component. A downward inclination of the glenoid component has been proposed to balance supraspinatus deficiency. METHODS: This hypothesis was assessed by a numeric musculoskeletal model of the glenohumeral joint during active abduction. Three cases were compared: TSA with normal muscular function, TSA with supraspinatus deficiency, and TSA with supraspinatus deficiency and downward inclination of the glenoid. RESULTS: Supraspinatus deficiency increased humeral migration and eccentric loading. A downward inclination of the glenoid partly balanced the loss of stability, but this potential advantage was counterbalanced by an important stress increase within the glenoid cement. The additional subchondral bone reaming required to incline the glenoid component indeed reduced the bone support, increasing cement deformation and stress. CONCLUSION: Glenoid inclination should not be obtained at the expense of subchondral bone support.

A single high dose of oral Vitamin D3 is not enough to correct insufficiency and deficiency in a rheumatologic population

Introduction: Vitamin D plays a major role in bone metabolism and neuromuscular function. Supplementation with vitamin D is effective to reduce the risk of fall and of fracture. However adherence to oral daily vitamin D supplementation is low. Screening and correcting vitamin D insufficiency in a general rheumatologic population could improve both morbidity and quality of life in these patients with chronic painful disorders and at high risk of osteoporosis. After determining the prevalence of vitamin D deficiency in this population, we evaluated if supplementation with a single high dose of oral 25-OH vitamin D3 was sufficient to correct this abnormality. Methods: During one month (November 2009), levels of 25-OH vitamin D were systematically determined in our rheumatology outpatient clinic and classified into three groups: vitamin D deficiency (<10 µg/l), vitamin D insufficiency (10 to 30µg/l) or normal vitamin D (>30 µg/l). Patients with insufficiency or deficiency received respectively a single high dose of 300'000 IU or 600'000 IU oral vitamin D3. In addition, all patients with osteoporosis were prescribed daily supplement of calcium (1g) and vitamin D (800 IU). 25-OH vitamin D levels were reevaluated after 3 months. Results: Vitamin D levels were initially determined in 292 patients (mean age 53, 211 women, 87% Caucasian). 77% had inflammatory rheumatologic disease (IRD), 20% osteoporosis (OP) and 12% degenerative disease (DD). Vitamin D deficiency was present in 20 (6.8%), while 225 (77.1%) had insufficiency. Of the 245 patients with levels <30µg/l, a new determination of vitamin D level was available in 173 (71%) at 3 months (table 1). Conclusion: Vitamin D insufficiency is highly prevalent in our rheumatologic population (84%), and is not adequately corrected by a single high dose of oral vitamin D3 in more than half of the patients with IRD and DD. In patients with OP, despite association of a single high dose with daily oral vitamin D supplementation, 40% of patients are still deficient when reevaluated at 3 months.

Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape.

Malignant melanoma accounts for most of the increasing mortality from skin cancer. Melanoma cells were found to express Fas (also called Apo-1 or CD95) ligand (FasL). In metastatic lesions, Fas-expressing T cell infiltrates were proximal to FasL+ tumor cells. In vitro, apoptosis of Fas-sensitive target cells occurred upon incubation with melanoma tumor cells; and in vivo, injection of FasL+ mouse melanoma cells in mice led to rapid tumor formation. In contrast, tumorigenesis was delayed in Fas-deficient lpr mutant mice in which immune effector cells cannot be killed by FasL. Thus, FasL may contribute to the immune privilege of tumors.

Calcifications vasculaires et déficit en vitamine K: un facteur de risque modifiable dans l'insuffisance rénale chronique [Vascular calcifications and vitamin K deficiency: a modifiable risk factor in chronic kidney disease].

The mechanisms of vascular calcifications in chronic renal failure are complex. Apart for clotting factors, vitamin K-dependent proteins include matrix Gla protein. Glutamic acid residues in matrix Gla protein are carboxylated by vitamin K-dependent gamma-carboxylase, which enables it to inhibit calcification. The purpose of this review is to discuss available evidence implicating vitamin K as a modifiable risk factor in the pathogenesis of vascular calcification in renal diseases.

Phenotype and function of protective T cell immune responses in HIV.

PURPOSE OF REVIEW: Definition of T cell immune correlates in HIV infection remains a lofty goal towards our understanding of the HIV-specific immune response. This review will focus upon recent developments and controversies in our understanding of protective T cell responses against HIV. RECENT FINDINGS: It has become clear that multiple functions and phenotypic markers of T cells must be assessed to accurately characterize the complexity of CD4 and CD8 T cell responses. While evidence indicates that a hallmark of protective immune responses in HIV infection is the presence of 'polyfunctional' T cell responses, a disconnect remains between the function and phenotype of effective HIV-specific T cells. Moreover, there may be inherent differences in the ability of specific human leukocyte antigen class I families to promote CD8 T cell effector versus polyfunctional responses. It remains to be determined how polyfunctional responses arise in HIV infection, which functions are important for control, and whether surface phenotype markers provide an indication of protective capacity. SUMMARY: Polyfunctional and phenotypic assessment of T cell responses have clearly advanced our understanding of HIV specific immune responses. Critical questions remain, however, especially whether polyfunctional T cell responses control, or are controlled by, HIV replication.

Immune response to hepatitis B vaccination in HIV-positive adults with isolated antibodies to HBV core antigen.

OBJECTIVE: To investigate the merits of vaccination against hepatitis B virus (HBV) in HIV-positive individuals with isolated antibodies to hepatitis B core antigen (anti-HBc). METHODS: HIV-positive patients with isolated anti-HBc and CD4 counts >200 cells/mm(3) received HBV vaccination. An antibody titre to hepatitis B surface antigen (anti-HBs titres) ≥10 IU/L one month post-vaccination was termed an anamnestic response; a titre <10 IU/L was termed a primary response. Patients with primary responses received a 3-dose vaccine course. Anti-HBs titres in all responders were measured 12 and 24 months post-vaccination. RESULTS: 37 patients were studied: 19 (51%) were co-infected with hepatitis C; median CD4 count was 443 cells/mm(3). 8/37 patients (22%) elicited an anamnestic response. 29/37 patients (78%) elicited a primary response. After a 3-dose vaccine course, 15/25 primary responders (60%) achieved anti-HBs titres ≥10 IU/L. HIV acquisition through injecting drug use was the only independent predictor of an anamnestic response (OR 22.9, CI 1.71-306.74, P=0.018). Median anti-HBs titres for anamnestic and primary responders were 51 IU/L (13-127) and 157 IU/L (25-650) respectively. Of all responders, 12/23 (52%) retained anti-HBs titres ≥10 IU/L at 24 months. Anti-HBs duration was not significantly different between anamnestic and primary responders. CONCLUSIONS: 23/37 HIV-positive patients (62%) with isolated anti-HBc achieved anti-HBs titres ≥10 IU/L after 1-3 vaccine doses. However, duration of this immune response was short-lived (

Mating triggers dynamic immune regulations in wood ant queens.

Mating can affect female immunity in multiple ways. On the one hand, the immune system may be activated by pathogens transmitted during mating, sperm and seminal proteins, or wounds inflicted by males. On the other hand, immune defences may also be down-regulated to reallocate resources to reproduction. Ants are interesting models to study post-mating immune regulation because queens mate early in life, store sperm for many years, and use it until their death many years later, while males typically die after mating. This long-term commitment between queens and their mates limits the opportunity for sexual conflict but raises the new constraint of long-term sperm survival. In this study, we examine experimentally the effect of mating on immunity in wood ant queens. Specifically, we compared the phenoloxidase and antibacterial activities of mated and virgin Formica paralugubris queens. Queens had reduced levels of active phenoloxidase after mating, but elevated antibacterial activity 7 days after mating. These results indicate that the process of mating, dealation and ovary activation triggers dynamic patterns of immune regulation in ant queens that probably reflect functional responses to mating and pathogen exposure that are independent of sexual conflict.

Overview of primary monogenic dystonia.

Primary monogenic forms of dystonia manifest solely or mainly with dystonia; they have been linked to a number of genes and loci and assigned "DYT" numbers. The pure dystonia syndrome early-onset primary dystonia (DYT1) manifests with dominantly-inherited generalized dystonia, often with focal onset in a limb. DYT1 is caused by a GAG deletion in the TOR1A gene. Mutations in the THAP1 gene cause DYT6, a form of pure dystonia that primarily involves cranio-cervical and upper limb muscles. Patients with the dystonia plus syndrome DYT5 display levodopa-responsive dystonia sometimes associated with tremor or parkinsonism (DYT5a, mutations in GCH1); a more severe phenotype with psychomotor involvement can be seen in recessive forms (DYT5b with TH mutations, SPR-deficiency syndrome). Other forms of dystonia plus syndromes include myoclonic dystonia (DYT11) and rapid-onset dystonia-parkinsonism (DYT12). Finally, paroxysmal exertion-induced dystonia (DYT18, GLUT1 deficiency) is caused by mutations in the SLC2A1 gene (DYT9 and DYT18). It is part of the paroxysmal dystonia group and manifests with paroxystic movements sometimes associated with seizures and psychomotor developmental delay.

Deciphering and reversing tumor immune suppression.

Generating an anti-tumor immune response is a multi-step process that is executed by effector T cells that can recognize and kill tumor targets. However, tumors employ multiple strategies to attenuate the effectiveness of T-cell-mediated attack. They achieve this by interfering with nearly every step required for effective immunity, from deregulation of antigen-presenting cells to establishment of a physical barrier at the vasculature that prevents homing of effector tumor-rejecting cells and the suppression of effector lymphocytes through the recruitment and activation of immunosuppressive cells such as myeloid-derived suppressor cells, tolerogenic monocytes, and T regulatory cells. Here, we review the ways in which tumors exert immune suppression and highlight the new therapies that seek to reverse this phenomenon and promote anti-tumor immunity. Understanding anti-tumor immunity, and how it becomes disabled by tumors, will ultimately lead to improved immune therapies and prolonged survival of patients.

RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses.

The receptor for hyaluronic acid-mediated motility (RHAMM) is an antigen eliciting both humoral and cellular immune responses in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM). We initiated a phase 1 clinical trial vaccinating 10 patients with R3 (ILSLELMKL), a highly immunogenic CD8(+) T-cell epitope peptide derived from RHAMM. In 7 of 10 patients, we detected an increase of CD8(+)/HLA-A2/RHAMM R3 tetramer(+)/CD45RA(+)/CCR7(-)/CD27(-)/CD28(-) effector T cells in accordance with an increase of R3-specific CD8(+) T cells in enzyme linked immunospot (ELISpot) assays. In chromium release assays, a specific lysis of RHAMM-positive leukemic blasts was shown. Three of 6 patients with myeloid disorders (1/3 AML, 2/3 MDS) achieved clinical responses: one patient with AML and one with MDS showed a significant reduction of blasts in the bone marrow after the last vaccination. One patient with MDS no longer needed erythrocyte transfusions after 4 vaccinations. Two of 4 patients with MM showed a reduction of free light chain serum levels. Taken together, RHAMM-R3 peptide vaccination induced both immunologic and clinical responses, and therefore RHAMM constitutes a promising target for further immunotherapeutic approaches. This study is registered at http://ISRCTN.org as ISRCTN32763606 and is registered with EudraCT as 2005-001706-37.

A critical review of the molecular pathophysiology of lenalidomide sensitivity in 5q - myelodysplastic syndromes.

Abstract The 5q deletion is a chromosomal abnormality that is observed in a subset of myelodysplastic syndromes (MDS). When isolated, this abnormality defines a specific clinical syndrome termed MDS associated with isolated deletion 5q, presenting with macrocytic anemia, normal platelet count or slight thrombocytosis, hypolobated megakaryocytes and fewer than 5% blasts in the bone marrow. MDS with the 5q deletion have a particular sensitivity to treatment with lenalidomide, a thalidomide analog. In this article, molecular changes in 5q- MDS derived from haploinsufficiency of genes encoded from the deleted region in 5q are reviewed, and mechanisms that link these molecular lesions with lenalidomide sensitivity are proposed.

Immune response to mouse mammary tumour virus.

Superantigens of mouse mammary tumor virus induce a strong cognate interaction between T cells and B cells. In addition to amplifying the virus-infected B-cell pool, this superantigen-driven interaction leads to the differentiation of virus-specific B cells into plasma cells. Successful interaction between T cells and B cells is required for completion of the viral life cycle.