摘要:

Purpose of reviewV(D)J recombination not only represents the main mechanism for the diversification of the immune system, it also constitutes a critical checkpoint in the development of both B and T lymphocytes. While a defect in V(D)J recombination leads to severe combined immune deficiency, a deregulation of this process can participate in the onset of lymphoid malignancies.Recent findingsThe careful analysis of human severe combined immune deficiency patients as well as engineered murine models provided several new interesting insights into the physiopathology of the V(D)J recombination process. A new factor of the V(D)J recombination/DNA repair machinery, Artemis, was identified based on its deficiency in human severe combined immune deficiency patients. It also became evident from knockout mouse studies that DNA repair factors that participate in V(D)J recombination can be considered as genomic caretakers.SummaryWhile V(D)J recombination was first recognized as a critical checkpoint in the development of the immune system, the discovery of several DNA repair factors that participate in this reaction shed light on more general aspects of genomic stability and cancer predisposition.

ISSN:1528-4050    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewImmune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome is a fatal syndrome of overwhelming autoimmunity. Recent identification ofFOXP3as the causative gene and realization that this same gene defect occurs in the mutant mouse Scurfy has yielded new insights and hopes of unraveling the mechanism of autoimmunity in this and possibly other diseases. In this review, we describe the clinical features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome/Scurfy and compare this phenotype with similar syndromes caused by other single gene mutations. We examine therapeutic options to treat the syndrome, study its immunologic basis, and investigate the structure and function of the FOXP3 protein.Recent findingsThe Scurfy mutant mouse has a characteristic phenotype that causes death by approximately 3 weeks of age. It is known that the effector cells in the Scurfy mouse are CD4+T cells and that a population of normal T cells can control the overwhelming autoimmunity that they induce. Recent data have demonstrated that this process requires antigenic stimulation and that the degree to which the immune system responds is inversely proportional to the level of FOXP3 protein (Forkhead box P3) expression in peripheral T cells. Suppression of immune activation by FOXP3 may occur due to its ability to bind to DNA through a putative forkhead DNA-binding motif and to repress transcriptional activation from certain promoters in T cells.SummaryBecause of the dramatic phenotype and rapidity of onset, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and Scurfy provide a powerful model in which to study mechanisms of T cell regulation. A more complete understanding of this syndrome will provide important insights into mechanisms of immune suppression, tolerance, and autoimmunity.

ISSN:1528-4050    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewThe purpose of this review is to provide an update of the molecular bases of CD40-mediated signalling and of the human immune defects associated with abnormalities of this activation pathway.Recent findingsOver the last years considerable progress in the identification of intracellular molecules mediating CD40 signalling has been achieved. This review focuses on the recent work on the molecular mechanisms of CD40 signalling mediated by tumor necrosis factor receptor-associated factors, by transcription of the activation-induced cytidine deaminase gene and by activation of nuclear factor κB. Furthermore, the importance of CD40/CD40L interaction for the induction of adaptive immunity will be outlined in the context of primary immunodeficiencies due to defects of the genes involved in the CD40 signalling pathway, which are characterized by an immunological phenotype of hyper-IgM syndrome.SummaryThe critical role of CD40/CD40L interactions in the development of various disease states has been fully appreciated, and further understanding of the molecular events involved in CD40 signalling may allow the identifications of candidate genes for other hyper-IgM syndromes. Molecular diagnosis will help to provide the most appropriate treatment and prognosis.

ISSN:1528-4050    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewThe development of lymphoid tissues as well as the ultimate differentiation of naïve and memory T cells are dependent on cytokines. In this review, we will focus on recent advances in the understanding of molecular mechanisms that regulate lymphoid development, homeostasis and tolerance.Recent findingsCytokines play a critical role in the development and differentiation of lymphoid cells. In addition, newer data indicate important roles of interleukin-7 and interleukin-15 in lymphoid homeostasis and memory. Furthermore, a new family of heterodimeric cytokines comprising interleukin-12, interleukin-23 and -27 is important for differentiation of helper T cells and cell-mediated immunity. Finally the importance of tumor necrosis factor superfamily members in the development of lymphoid organs has recently been elucidated and will be discussed in detail.SummaryNew cytokines and receptors continue to be identified. The discovery and characterization of cytokines, their receptors and signaling molecules will provide a more complete understanding of normal lymphoid development, differentiation and function. In addition, this knowledge should improve our understanding of the pathogenesis of immunological diseases and hopefully will provide new treatment strategies.

ISSN:1528-4050    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

This review adresses several questions in the light of the results recently obtained by a gene therapy trial for the treatment of X-linked severe combined immunodeficiency. This primary immunodeficiency, characterized by a complete absence of T and natural killer lymphocytes, appeared as a good model for the application of gene therapy, combining an expected selective advantage for transduced cells, an absence of immunological response to the vector and/or the therapeutic transgene together with accessibility to hematopoietic stem cells. After a brief description of the disease and its physiopathology we summarize the clinical results of the gene therapy trial putting them in perspective with those obtained following allogeneic hematopoietic stem cell transplantation. Definitive conclusions cannot be thrown due to the limited number of gene therapy-treated patients and their relatively short follow-up.

ISSN:1528-4050    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewTo review the remarkable recent progress in our understanding of a range of inflammatory conditions in humans that until recently appeared unrelated. The term autoinflammatory disease has been proposed to describe a group of disorders characterized by attacks of seemingly unprovoked inflammation without significant levels of autoantibodies and autoreactive T cells.Recent findingsAs the link between the innate immune response and disease susceptibility has become more apparent, some remarkable associations have emerged. The majority of hereditary periodic fevers are due to mutations in the pyrin and tumour necrosis factor receptor superfamilies of molecules, both of which are intimately involved in innate immunity. Pyrin/marenostrin protein is mutated in familial Mediterranean fever, while mutations in a related protein, cryopyrin, are associated with Muckle-Wells/familial cold urticaria and chronic infantile neurologic cutaneous and articular syndrome. Both of these proteins interact with the apoptotic speck-like protein involved in caspase-1 activation and regulation of nuclear factor kappa B transcription; furthermore cryopyrin contains regions of homology with the nucleotide-binding oligomerization domain 2 protein, which is associated with susceptibility to Crohn's disease. Variants in the leucine-rich repeat domain of nucleotide-binding oligomerization domain are found in approximately 20% of patients with Crohn's disease, depending on ethnic background, while mutations in the NACHT domain are associated with a rare dominant granulomatous disease called Blau syndrome.SummaryThe study of autoinflammatory disease has progressed from genetics to definition of the functional defects in these patients. Although a direct association between defective innate immune responses to bacterial components and these diseases has not been formally established, much ongoing research is aimed towards confirmation of that hypothesis.

ISSN:1528-4050    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewRecent clinical studies in patients with genetically proven X-linked or autosomal recessive agammaglobulinemia provide some guidelines that should influence our management of patients with suspected immunodeficiency.Recent findingsMales who are at a high risk of having X-linked agammaglobulinemia because they have an affected brother or uncle are often not evaluated for immunodeficiency until they are hospitalized for infection. Some of those who are evaluated are not started on gammaglobulin therapy immediately. More than 10% of patients with X-linked agammaglobulinemia are hospitalized for infection at less than 6 months of age, indicating that patients with known X-linked agammaglobulinemia should be started on therapy by 2-3 months of age. In patients with sporadic X-linked agammaglobulinemia, the incidence of chronic lung disease correlates with the age at diagnosis, highlighting the importance of early diagnosis. Although almost all patients who are diagnosed as having the condition at more than 12 months of age have a history of recurrent otitis, 93% are not evaluated for immunodeficiency until they are hospitalized for infection. Because the physical exam provides a clue to the diagnosis of the condition - unusually small or absent cervical lymph nodes and tonsils - it should be possible to make an early diagnosis in a greater percentage of patients. Patients with autosomal recessive agammaglobulinemia have an earlier onset of disease compared with patients with X-linked agammaglobulinemia and they are more likely to have severe complications of the disease.SummaryThere is plenty of room for improvement in the diagnosis and management of patients with defects in early B cell development.

ISSN:1528-4050    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewSublingual immunotherapy has become increasingly popular and in some countries more allergic patients are treated by the sublingual route than the subcutaneous route. Evaluation of the scientific documentation for clinical efficacy is important before a treatment is used unrestrictedly. This review critically analyses every placebo-controlled, double-blind study providing symptom/medication scores for the primary outcome; that is, a significant and clinically relevant reduction in disease severity of actively treated patients.Recent findingsIn total 23 papers fulfill the evaluation criteria; 26% are categorized as unequivocally effective, 35% are possibly effective (significant improvement in either symptom or medication scores), and 39% have no statistically documented efficacy.SummaryThe majority of papers have used an inadequate study design that may be responsible for the large number of inconclusive and negative studies. Before sublingual immunotherapy can be recommended as a routine treatment, more documentation for beneficial efficacy is needed.

ISSN:1528-4050    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewTo describe the potential of a new class of respiratory drugs, respirable antisense oligonucleotides.Recent findingsThe first respirable antisense oligonucleotide, EPI-2010, has now reached clinical trials. It has shown intriguing initial indications of efficacy and the potential to be the first once-per-week asthma preventative. Respirable antisense oligonucleotides are capable of addressing targets that have proven to be intractable to traditional ‘small molecule’ approaches, and against which newer monoclonal antibody strategies may also not be optimal. Respirable antisense oligonucleotides functionally, but not genetically, ablate gene expression by blocking the template function of target respiratory messenger RNAs by as yet incompletely defined mechanisms. They do so with an avidity and specificity which can be several orders of magnitude greater than those shown by small molecule antagonists for their protein targets. The target properties of respiratory messenger RNAs are strikingly different from those of respiratory proteins, enabling respirable antisense oligonucleotides to offer the potential of longer duration of effect, increased specificity of effect, and lack of systemic side effects compared with either traditional small molecule protein antagonists or monoclonal antibodies.SummaryRespirable antisense oligonucleotides represent a new, third class of respiratory drugs with the potential to extend the range of therapeutic responses to otherwise intractable respiratory targets, and to address precedented targets with the possibility of improving on such features as safety and durability of response.

ISSN:1528-4050    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewThe purpose of this review is to summarize the basic principles of effective immunotherapy, and to highlight some of the advances that have been published in the past year.Recent findingsRecent findings show that immunotherapy, when performed appropriately and properly, not only causes a decrease in symptoms, use of medication and an improved quality of life, but also that the shift from allergic rhinitis to asthma is substantially decreased and the development of new allergies is diminished. In addition, laboratory studies continue to demonstrate significant changes in the immune system moving the patient towards a non-allergic immune function T helper type 2 cell to T helper type 1 cell shift.SummaryIn summary, recent research clearly continues to demonstrate the efficacy of immunotherapy not only as a therapeutic agent but as a preventive one as well.

ISSN:1528-4050    

出版商:OVID    

年代:2002

数据来源: OVID