Noroviruses (NVs) are a major cause of acute gastroenteritis epidemics in both developing and developed countries and affect people of all ages. Three main human histo-blood group antigens (HBGAs) – the ABO, Lewis and secretor families – are involved in NV recognition and eight strain-specific receptor-binding patterns in two major binding groups have been described. The receptor-binding interface is located at the outermost surface of the P domain of the viral capsid. Each interface contains two major binding sites and each site interacts with a carbohydrate side-chain of the HBGAs via multiple hydrogen bonds. Soluble HBGAs in human milk are able to block binding of NV to HBGA receptors, suggesting a potential decoy receptor for the protection of infants from NV infection. Phylogenetic analysis has revealed limited genetic relatedness among NVs with similar receptor-binding patterns. This review summarises and discusses recent advances and highlights implications for future studies in the control and prevention of NV gastroenteritis.

Antiphospholipid (aPL) antibodies (Abs) are associated with thrombosis and pregnancy loss in antiphospholipid syndrome (APS), a disorder initially characterised in patients with systemic lupus erythematosus (SLE) but now known to occur in the absence of other autoimmune disease. There is strong evidence that aPL Abs are pathogenic in vivo, from studies of animal models of thrombosis, endothelial cell activation and pregnancy loss. In recent years, progress has been made in characterising the molecular basis of this pathogenicity, which includes direct effects on platelets, endothelial cells and monocytes as well as activation of complement. This review summarises the clinical manifestations of APS and current modalities of treatment, and explains recent advances in understanding the molecular events triggered by aPL Abs on target cells in coagulation pathways as well as effects of aPL Abs on complement activation. Based on this information and on additional scientific evidence using in vitro and in vivo models, new potential targeted therapies for treatment and/or prevention of thrombosis in APS are proposed and discussed.

Epithelial ovarian cancer comprises several subtypes of tumours that exhibit diverse histopathological features. The intriguing assumption by many epithelial ovarian cancers of specialised features of nonovarian tissue lineages has promoted considerable debate as to whether these tumours arise from the deceptively simple surface epithelium of the ovary. This review focuses on recent molecular and pathological studies of epithelial ovarian cancers that support and challenge their surface-epithelial derivation, and discusses the findings in the context of current views of the ‘cell-of-origin’ of solid tumours.

Immune responses influence the development and progression of a malignancy. The tumour can also manipulate the immune system to its own ends, often resulting in an ineffective or transient antitumour response. An appreciation of the complexity of these host–tumour interactions is therefore important for the development of more-effective cancer therapies. This article highlights some prominent mechanisms whereby tumours escape recognition and destruction by the host immune system, thus facilitating disease progression. One important consequence of tumour escape is that an antitumour immune response may unintentionally lead to the outgrowth of less immunogenic or more apoptosis-resistant tumour escape variants, which possess enhanced tumourigenic potential. Insights into the molecular mechanisms of cancer evasion and the complexity of the ever-changing interactions between host and tumour will enable a more rational design of antitumour therapies and may help not only explain disease recurrence, but also identify potential targets for therapeutic interventions. This article also offers a brief review of preclinical animal models, which are essential tools in the study of tumour immunology and cancer biology, particularly those that recapitulate the chronic nature of host–tumour interactions and help guide the development and testing of new therapies.

Pregnancy success remains a fascinating phenomenon to immunologists as it defies the immunological rules of rejection. Although it was previously thought that the maternal immune system does not see the fetus, it is now well documented that fetal cells reach the maternal body and encounter host immune cells. Natural tolerance mechanisms following this interaction remain to be fully elucidated. This article reviews the current literature on mechanisms of adaptive immunity, with emphasis on regulatory T cells and heme oxygenase 1 (HO-1). We propose a scenario in which regulatory T cells create a tolerant microenvironment at the fetal–maternal interface characterised by the presence of tolerance-associated molecules such as HO-1, which has been shown to be of vital importance for fetal survival.

Peripheral neuropathy is a common medical problem with numerous aetiologies. Unfortunately, for the majority of cases there is no available medical solution for the underlying cause, and the only option is to try to treat the resulting symptoms. Treatment options exist when neuropathy results in positive symptoms such as pain, but there is a significant lack of treatments for negative symptoms such as numbness and weakness. Systemic application of growth factor peptides has shown promise in protecting nerves from neuropathic insults in preclinical animal studies, but translation into human trials has been problematic and disappointing. Significant advancements have been made in the past few years in utilising gene therapy approaches to treat peripheral neuropathy by expressing neuroprotective gene products either systemically or in specific nervous tissues. For example, plasmids expressing vascular endothelial growth factor injected into muscle, or herpes-simplex-virus-based vectors expressing neurotrophin gene products delivered to dorsal root ganglion neurons, have been used to protect peripheral nerve function in animal models of diabetes-associated peripheral neuropathy. Many published studies support the feasibility of this approach, although several questions still need to be addressed as gene therapy to treat peripheral neuropathy moves out of the laboratory and into the clinic.

Endometriosis is considered to be a polygenic disease with a complex, multifactorial aetiology that affects about 10% of women in the reproductive age. Women with endometriosis have symptoms that include chronic pelvic pain, dysmenorrhoea and dyspareunia, significantly reducing their quality of life. Endometriosis is also the primary cause of infertility in women, with the prevalence rate ranging from 20% to 50%. The high prevalence and severe outcomes of this disease have made it a major public health concern in modern society. Currently, the mechanism(s) responsible for the initiation and promotion of this disease remains obscure. In this review, we focus on the expression, regulation and action of prostaglandins in the cellular and molecular mechanisms that contribute to the development and/or maintenance of endometriosis.

Average life expectancy is continuously rising in all developed countries, leading to an ever-increasing elderly population. Of the many functions of the body affected by the complex process of ageing, the immune system in particular undergoes various changes, collectively termed immunosenescence. As a result, elderly people are more susceptible to infections and are frequently less protected by vaccines. This review summarises the effect of ageing on immunity, emphasising the age-associated changes within T and B cells at a molecular and cellular level. Furthermore, it discusses strategies, such as the addition of immunostimulatory adjuvants and the use of potent antigen-delivery systems, that may counteract age-related defects in immune responses to vaccination. A proper understanding of how immunological memory is affected by ageing, and the introduction of strategies to ameliorate vaccine efficacy in the elderly, might reduce the incidence and the severity of infectious disease within this fragile age group and have a strong impact on the quality of life of elderly individuals.

Paget disease of bone (PDB) is a condition characterised by increased bone remodelling at discrete lesions throughout the skeleton. The primary cellular abnormality in PDB involves a net increase in the activity of bone-resorbing osteoclasts, with a secondary increase in bone-forming osteoblast activity. Genetic factors are known to play an important role, with mutations affecting different components of the RANK–NF-κB signalling pathway having been identified in patients with PDB and related disorders. Whilst the disease mechanism in these cases is likely to involve aberrant RANK-mediated osteoclast NF-κB signalling, the precise relationship between other potential contributors, such as viruses and environmental factors, and the molecular pathogenesis of PDB is less clear. This review considers the roles of these different factors in PDB, and concludes that a fuller understanding of their contributions to disease aetiology is likely to be central to future advances in the clinical management of this debilitating skeletal disorder.

Although great advances have been made in the treatment of low- and intermediate-risk neuroblastoma in recent years, the prognosis for advanced disease remains poor. Therapies based on monoclonal antibodies that specifically target tumour cells have shown promise for treatment of high-risk neuroblastoma. This article reviews the use of monoclonal antibodies either as monotherapy or as part of a multifaceted treatment approach for advanced neuroblastoma, and explains how toxins, cytokines, radioactive isotopes or chemotherapeutic drugs can be conjugated to antibodies to enhance their effects. Tumour resistance, the development of blocking antibodies, and other problems hindering the effectiveness of monoclonal antibodies are also discussed. Future therapies under investigation in the area of immunotherapy for neuroblastoma are considered.

Charcot–Marie–Tooth type 4B (CMT4B) is a severe autosomal recessive neuropathy with demyelination and myelin outfoldings of the nerve. This disorder is genetically heterogeneous, but thus far, mutations in myotubularin-related 2 (MTMR2) and MTMR13 genes have been shown to underlie CMT4B1 and CMT4B2, respectively. MTMR2 and MTMR13 belong to a family of ubiquitously expressed proteins sharing homology with protein tyrosine phosphatases (PTPs). The MTMR family, which has 14 members in humans, comprises catalytically active proteins, such as MTMR2, and catalytically inactive proteins, such as MTMR13. Despite their homology with PTPs, catalytically active MTMR phosphatases dephosphorylate both PtdIns3P and PtdIns(3,5)P2 phosphoinositides. Thus, MTMR2 and MTMR13 may regulate vesicular trafficking in Schwann cells. Loss of these proteins could lead to uncontrolled folding of myelin and, ultimately, to CMT4B. In this review, we discuss recent findings on this interesting protein family with the main focus on MTMR2 and MTMR13 and their involvement in the biology of Schwann cell and CMT4B neuropathies.

Autoimmune diseases of the central nervous system (CNS) involve the migration of abnormal numbers of self-directed leukocytes across the blood–brain barrier that normally separates the CNS from the immune system. The cardinal lesion associated with neuroinflammatory diseases is the perivascular infiltrate, which comprises leukocytes that have traversed the endothelium and have congregated in a subendothelial space between the endothelial-cell basement membrane and the glial limitans. The exit of mononuclear cells from this space can be beneficial, as when virus-specific lymphocytes enter the CNS for pathogen clearance, or might induce CNS damage, such as in the autoimmune disease multiple sclerosis when myelin-specific lymphocytes invade and induce demyelinating lesions. The molecular mechanisms involved in the movement of lymphocytes through these compartments involve multiple signalling pathways between these cells and the microvasculature. In this review, we discuss adhesion, costimulatory, cytokine, chemokine and signalling molecules involved in the dialogue between lymphocytes and endothelial cells that leads to inflammatory infiltrates within the CNS, and the targeting of these molecules as therapies for the treatment of multiple sclerosis.

Infantile haemangioma is the most common tumour of infancy, yet the origin of these lesions remains controversial and the predictable life cycle is poorly understood. Much new information on infantile haemangiomas has emerged over the past decade, but experts continue to debate fundamental features, including cell of origin, nonrandom distribution, and mechanisms regulating the sometimes explosive growth and slow involution. The development of useful laboratory models has been difficult, in turn restricting the development of treatment options available to the clinician. Despite this, new research and creative thinking has spawned several hypotheses on the origin of these tumours and their interesting clinical behaviour, including suggestions of an intrinsic defect in local endothelial cells, a contribution of circulating endothelial progenitors or haemangioblasts, embolisation of shed placental cells and developmental field defects. While no single hypothesis seems to describe all features of infantile haemangioma, continued research seeks to integrate these ideas, create a better understanding of these important tumours and bring new treatments to the clinic.

Haematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for many patients with malignant and non-malignant haematological diseases. The success of HSCT is greatly reduced by the development of complications, which include graft-versus-host disease (GVHD), relapse and infection. Human leukocyte antigen (HLA) matching of patients and donors is essential, but does not completely prevent these complications; non-HLA genes may also have an impact upon transplant outcome. Polymorphisms within genes that are associated with an individual's capability to mount an immune response to alloantigen and infectious pathogens and/or response to drugs (pharmacogenomics) are all currently being studied for their association with HSCT outcome. This review summarises the potential role of non-HLA polymorphisms in predicting HSCT outcome, from studies on retrospective transplant cohorts of HLA-identical siblings and matched unrelated donors. The clinical relevance and interpretation of non-HLA genetics, and how these could be used alongside clinical risk factors in HSCT, are also discussed.

ATP-sensitive potassium (KATP) channels play a key role in the regulation of insulin secretion by coupling glucose metabolism to the electrical activity of pancreatic β-cells. To generate an electric signal of suitable magnitude, the plasma membrane of the β-cell must contain an appropriate number of channels. An inadequate number of channels can lead to congenital hyperinsulinism, whereas an excess of channels can result in the opposite condition, neonatal diabetes. KATP channels are made up of four subunits each of Kir6.2 and the sulphonylurea receptor (SUR1), encoded by the genes KCNJ11 and ABCC8, respectively. Following synthesis, the subunits must assemble into an octameric complex to be able to exit the endoplasmic reticulum and reach the plasma membrane. While this biosynthetic pathway ensures supply of channels to the cell surface, an opposite pathway, involving clathrin-mediated endocytosis, removes channels back into the cell. The balance between these two processes, perhaps in conjunction with endocytic recycling, would dictate the channel density at the cell membrane. In this review, we discuss the molecular signals that contribute to this balance, and how an imbalance could lead to a disease state such as neonatal diabetes.

Rubinstein–Taybi syndrome is characterised by mental retardation, growth retardation and a particular dysmorphology. The syndrome is rare, with a frequency of approximately one affected individual in 100 000 newborns. Mutations in two genes – CREBBP and EP300 – have been identified to cause the syndrome. These two genes show strong homology and encode histone acetyltransferases (HATs), which are transcriptional co-activators involved in many signalling pathways. Loss of HAT activity is sufficient to account for the phenomena seen in Rubinstein–Taybi patients. Although some mutations found in CREBBP are translocations, inversions and large deletions, most are point mutations or small deletions and insertions. Mutations in EP300 are comparatively rare. Extensive screening of patients has revealed mutations in CREBBP and EP300 in around 50% of cases. The cause of the syndrome in the remaining patients remains to be identified, but other genes could also be involved. Here, we describe the clinical presentation of Rubinstein–Taybi syndrome, review the mutation spectrum and discuss the current understanding of causative molecular mechanisms.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by defects in one of several steroidogenic enzymes involved in the synthesis of cortisol from cholesterol in the adrenal glands. More than 90% of cases are caused by 21-hydroxylase deficiency, and the severity of the resulting clinical symptoms varies according to the level of 21-hydroxylase activity. 21-Hydroxylase deficiency is usually caused by mutations in the CYP21A2 gene, which is located on the RCCX module, a chromosomal region highly prone to genetic recombination events that can result in a wide variety of complex rearrangements, such as gene duplications, gross deletions and gene conversions of variable extensions. Molecular genotyping of CYP21A2 and the RCCX module has proved useful for a more accurate diagnosis of the disease, and prenatal diagnosis. This article summarises the clinical features of 21-hydroxylase deficiency, explains current understanding of the disease at the molecular level, and highlights recent developments, particularly in diagnosis.

Holoprosencephaly (HPE) is a common congenital malformation that is characterised by a failure to divide the forebrain into left and right hemispheres and is usually accompanied by defects in patterning of the midline of the face. HPE exists in inherited, autosomal dominant (familial) forms and mutation-associated sporadic forms, but environmental factors are also implicated. There are several features of HPE that are not well understood, including the extremely variable clinical presentation, even among obligate carriers of familial mutations, and the restriction of structural anomalies to the ventral anterior midline, despite association with defects in signal transduction pathways that regulate development of many additional body structures. The new animal models described in this review may help unravel these puzzles. Furthermore, these model systems suggest that human HPE arises from a complex interaction between the timing and strength of developmental signalling pathways, genetic variation and exposure to environmental agents.

Nasopharyngeal carcinoma (NPC) is a prevalent tumour in southern China and southeast Asia, particularly in the Cantonese population, where its incidence has remained high for decades. Recent studies have demonstrated that the aetiology of NPC is complex, involving multiple factors including genetic susceptibility, infection with the Epstein–Barr virus (EBV) and exposure to chemical carcinogens. During development of the disease, viral infection and multiple somatic genetic and epigenetic changes synergistically disrupt normal cell function, thus contributing to NPC pathogenesis. NPC is highly radiosensitive and chemosensitive, but treatment of patients with locoregionally advanced disease remains problematic. New biomarkers for NPC, including EBV DNA copy number or methylation of multiple tumour suppressor genes, which can be detected in serum and nasopharyngeal brushings, have been developed for the molecular diagnosis of this tumour. Meanwhile, new therapeutic strategies such as intensity-modulated radiation therapy and immuno- and epigenetic therapies might lead to more specific and effective treatments.

The neuromuscular junction (NMJ) is a complex structure that efficiently communicates the electrical impulse from the motor neuron to the skeletal muscle to induce muscle contraction. Genetic and autoimmune disorders known to compromise neuromuscular transmission are providing further insights into the complexities of NMJ function. Congenital myasthenic syndromes (CMSs) are a genetically and phenotypically heterogeneous group of rare hereditary disorders affecting neuromuscular transmission. The understanding of the molecular basis of the different types of CMSs has evolved rapidly in recent years. Mutations were first identified in the subunits of the nicotinic acetylcholine receptor (AChR), but now mutations in ten different genes – encoding post-, pre- or synaptic proteins – are known to cause CMSs. Pathogenic mechanisms leading to an impaired neuromuscular transmission modify AChRs or endplate structure or lead to decreased acetylcholine synthesis and release. However, the genetic background of many CMS forms is still unresolved. A precise molecular classification of CMS type is of paramount importance for the diagnosis, counselling and therapy of a patient, as different drugs may be beneficial or deleterious depending on the molecular background of the particular CMS.