Recombinant allergens: what does the future hold?

This year we are celebrating not only the centenary of allergen-specific immunotherapy but also the 10-year anniversary of the first administration of recombinant allergen-based vaccines to allergic patients. By using recombinant DNA technology, defined and safe allergy vaccines can be produced that allow us to overcome many, if not all, of the problems associated with the use of natural allergen extracts, such as insufficient quality, allergenic activity, and poor immunogenicity. Here we provide an update of clinical studies with recombinant allergen-based vaccines, showing that some of these vaccines have undergone successful clinical evaluation up to phase III studies. Furthermore, we introduce a strategy for allergen-specific immunotherapy based on recombinant fusion proteins consisting of viral carrier proteins and allergen-derived peptides without allergenic activity, which holds the promise of being free of side effects and eventually being useful for prophylactic vaccination.     

Partner aggression and problem drinking across the lifespan: how much do they decline?

Cross-sectional analyses from nationally-representative samples demonstrate significant age-related trends in partner aggression and problem drinking. Both behaviors are most prevalent in the early to mid-twenties and increasingly less common thereafter. Aggregate associations based on percentage of individuals displaying the behavior in each age range are dramatically stronger than those found when correlating individuals' ages and behavior. Multilevel modeling demonstrates that group-level effects do not mask associations found at the level of the individual for either problem drinking or partner aggression. An analysis of recent abstracts from psychology journals showed that issues of aggregate and individual data are rarely if ever discussed, and even well-known statistics books in psychology rarely discuss such issues. The interpretation of aggregate data will become increasing important as psychologists themselves, and in collaboration with epidemiologists and sociologists, have access to large data sets that allow for data aggregation. Both aggregate and individual analyses are valid, although they provide answers to different questions. Individual analyses are necessary for predicting individual behavior; aggregate analyses are useful in policy planning for large scale prevention and intervention. Strengths and limitations of cross-sectional community samples and aggregate data are also discussed.     

Pediatric renal cell carcinomas: where do they fit in the new histologic classification of renal cell carcinoma?

Genetic, immunohistochemical, and histologic data has led to the reclassification of renal cell carcinoma in the last decade. Recent studies suggest that renal cell carcinomas in children and young adults may represent a distinct group of tumors. These tumors have unique genetic findings (most commonly t(x;1)(p11:q21)), a predominantly papillary architecture, numerous calcifications, granular cytoplasm, and a possible relationship with neuroblastoma.     

Host immune responses to the intracellular bacteria Brucella: does the bacteria instruct the host to facilitate chronic infection?

Brucella spp. are intracellular gram-negative bacteria that include a number of virulent species that cause chronic infections in a variety of mammalian hosts. Human infections are proportional to the level of disease in domestic animals because humans are infected zoonotically after contact with infected animals or their products. The chronicity of infection results from the ability of some brucellae to survive reactive oxygen intermediate and nitric oxide killing in host phagocytes, following which they activate bacterial genes in response to the acidic phagosome environment, prevent phagolysosomal fusion by remodeling the intracellular compartment, and subsequently replicate intracellularly. The crucial component of immunity that results in survival of the host and thus maintenance of this chronic infective state is interferon-gamma (IFN-gamma). Production of IFN-gamma results from the ability of brucella components, including lipid A, to interact with Toll-like receptors for the production of IL-12 and TNF-alpha, although the regulatory cytokine IL-10 is also produced and decreases control of the infection. Although CD4 and CD8 T cells are clearly involved in the production of IFN-gamma, and CD8 T cells may be cytotoxic, a role for NK cells and cytotoxicity in protective immunity to brucellosis has not been substantiated experimentally. Moreover, antibodies have been shown to have a limited role in passive transfer studies.     

Presymptomatic autoantibodies in Sjögren’s syndrome: what significance do they hold for the clinic?

In a number of autoimmune diseases, for example, rheumatoid arthritis and systemic lupus erythematosus, it is known that autoantibodies are present before the clinical onset. Recently we have shown that autoantibodies can be found many years before symptom onset in primary Sjögren’s syndrome. This implies that screening for autoantibodies may be used to identify individuals at risk of developing systemic autoimmune disease. Possibly, autoantibody screening may also contribute to detection of incipient malignancy. This concept stems from a novel finding, on scleroderma patients, suggesting that an anti-tumor immune response elicited by a mutated self-antigen will cross-react with the unmodified version of the self-antigen, and thus come to trigger the formation of autoantibodies.     

Improving quality of life in ageing populations: what can volunteering do?

The year 2011 was declared the ‘European Year of Volunteering’ to recognise the contribution volunteers make to society. Such cross-national events reflect the high profile of volunteering and political imperatives to promote it. The purpose of this review is to provide a comprehensive review of current knowledge (articles published between 2005 and 2011) regarding the role of volunteering in improving older people's quality of life (QoL) and to identify areas requiring further research. Volunteering was defined as an activity that is freely chosen, does not involve remuneration and helps or benefits those beyond an individual's immediate family. Our search identified 22 studies and 5 review articles that addressed the benefits of volunteering on older people's quality of life. Most of the research had been conducted in the United States, Canada and Australia using data from longitudinal studies. The majority of the studies concluded that there is a positive association between older people's quality of life and engagement in volunteering. Due to the study designs and the heterogeneity of the research, causality is difficult to demonstrate and the knowledge the studies bring to the subject is variable. This review shows that volunteering may help to maintain and possibly improve some older adults’ quality of life. However, there are still major gaps in our understanding of who actually benefits, the social and cultural context of volunteering and its role in reducing health and social inequalities.     

Accelerating the induction of Fas‐mediated T cell apoptosis: a strategy for transplant tolerance?

Acute allograft rejection is primarily a consequence of clonal expansion of donor-specific T cells with specificity for donor antigen. Immunosuppression current involves the administration of toxic drugs that limit lymphoproliferation, but this treatment is not antigen-specific and allows opportunistic infection. An ideal strategy would be production of donor-specific T cell tolerance in the presence of an otherwise intact and functional T cell repertoire. Methods to enhance normal apoptotic clearance of activated T cells might contribute to development of this state. This study focuses on manipulation in vitro of Fas-mediated T cell apoptosis and compares two methods to enhance the extent and kinetics for clearance of activated T cells. First, the CD4 coreceptor was cross-linked in the presence and absence of Fas-stimulation. It was found that CD4 cross-linking potently induced apoptosis, even in the absence of Fas stimulation. Resting and activated T cells were susceptible to this treatment, precluding the development of antigen-specific tolerance after T cell activation. In a second system, T cells were treated with two staurosporine analogues, Bisindolylmaleimide (Bis) III and VIII and apoptosis was induced by stimulation of Fas. Resting T cells remained resistant to Fas-mediated apoptosis, but treatment of mitogen or alloantigen-activated cells with either Bis III or VIII caused a synergistic increase in apoptosis. These agents also reduced the period of resistance to Fas-mediated apoptosis after T cell activation, possibly by reducing expression of c-FLIP, allowing early activation of caspase 8 in alloreactive T cells. Development of this strategy might provide a route to the induction of specific tolerance after organ transplantation.     

Regional specialization in the mucosal immune system: what happens in the microcompartments?

Mucosal immunity is an important arm of the immune system because it operates in tissues involved in everyday infectious defence as well as in tolerance against innocuous environmental and dietary antigens. Here, Per Brandtzaeg and colleagues discuss compartmentalized regulation of mucosal B cells and mechanisms that might explain the strikingly regionalized effector disparity of the human mucosal immune system.     

Protection from autoimmunity: Immunological indifference versus T‐cell mediated suppression?

A long-held dogma was that immune tolerance could only be achieved through central deletion of potentially reactive cells at their site of origin, a concept supported by the direct demonstration of natural negative selection in bone marrow and thymus; however, it is now extensively documented that although deletion mechanisms ensure the elimination of most autoreactive cells, this purging is far from complete.There are major immune mechanisms that ensure tolerance in the periphery which are clearly non-deletional. A paper in this issue of the European Journal of Immunology demonstrates that T cell-mediated immunoregulation involving in particular the CTLA-4 signaling pathway plays a key role in controlling the pathogenic potential of fully differentiated autoreactive T cells.     

The pathology of essential fatty acid deficiency: is it cell adhesion mediated?

For almost 70 years, essential fatty acid deficiency has been known to be associated with skin disorders, vessel abnormalities, and increased tumorigenesis. However, the underlying molecular and cellular mechanism is largely unknown. Recently, it has been reported that essential fatty acids regulate cell adhesion by modifying the expression of cell adhesion molecules. These findings may provide molecular explanations for those phenomena seen in EFAD and this paper aims to discuss these relationships and raise points for further discussion.     

Insights into mechanisms behind arteriogenesis: what does the future hold?

Arteriogenesis, the enlargement of collateral vessels, seems a promising new target to improve blood flow to ischemic regions in patients suffering from cardiovascular conditions. With the growing knowledge of the mechanisms involved in arteriogenesis and the factors that influence the process, an increasing number of clinical trials are being performed to stimulate arteriogenesis, providing more insight in therapeutic opportunities for arteriogenesis. The expression of growth factors and the cooperation of surrounding and infiltrating cells seem to be essential in orchestrating the complex processes during arteriogenesis. In this review, we will discuss the regulating mechanisms of arteriogenesis, including the role of growth factors and different cell types and their implementation in a clinical setting. Furthermore, individual differences in the arteriogenic response will be considered, in light of the effect this will have on the success of therapeutic strategies to improve blood flow to ischemic tissue.