New insights into innate immune mechanisms underlying allergenicity

Allergic diseases, which have reached epidemic proportions, are caused by inappropriate immune responses to a relatively small number of environmental proteins. The molecular basis for the propensity of specific proteins to promote maladaptive, allergic responses has been difficult to define. Recent data suggest that the ability of such proteins to promote allergic responses in susceptible hosts is a function of their ability to interact with diverse pathways of innate immune recognition and activation at mucosal surfaces. This review highlights recent insights into innate immune activation by allergens—through proteolytic activity, engagement of pattern recognition receptors, molecular mimicry of TLR signaling complex molecules, lipid-binding activity, and oxidant potential—and the role of such activation in inducing allergic disease. A greater understanding of the fundamental origins of allergenicity should help define new preventive and therapeutic targets in allergic disease.     

New insights into the molecular and genetic mechanisms underlying idiopathic epilepsies

Steinlein OK. New insights into the molecular and genetic mechanisms underlying idiopathic epilepsies.
For many years, idiopathic epilepsies have been known to have a strong genetic background. In most subtypes, the mode of inheritance appears to be complex, with only some rare idiopathic epilepsies being monogenic disorders. Thus far, several gene loci have been reported for the common subtypes, such as juvenile myoclonic epilepsy, but the results of linkage studies in independent samples have often been conflicting. Recently, the gene defects underlying two monogenic epilepsies, autosomal dominant nocturnal frontal lobe epilepsy and benign familial neonatal convulsions. have been identified. Both diseases are caused by ion channel mutations, a similarity which may shed light on the understanding of the basic mechanisms of epileptogenesk.     

自身免疫性疾病发病机制新进展

自身免疫性疾病(AD)是一种免疫紊乱状态,机体正常的保护性免疫应答不能区分自身抗原和外源性抗原转而攻击人体正常的组织和细胞,因而会出现一系列的异常症状.目前国际上对AD有了很多新的认识,基因和环境的共同作用增加了发病倾向人群的患病风险,而环境因素是多方面的,有学者针对人体内外的环境暴露提出了暴露组学的概念,暴露组学涵盖了除人体外的各种外界因素.根据目前的研究进展,拟从暴露组学、微生物组学及感染组学等多个方面详细阐述AD发病机理提出了致病假说,为进一步研究提供理论依据.     

Newer insights into the pathogenesis of experimental autoimmune thyroiditis

Experimental autoimmune thyroiditis (EAT), produced in the mouse by immunization with murine thyroglobulin plus complete Freund's adjuvant, represents a valuable model for studying the pathogenesis of human chronic (Hashimoto's) thyroiditis. A major issue requiring clarification is the difference between benign autoimmunity, characterized solely by production of autoantibodies to thyroglobulin, and pathogenic autoimmunity where injury occurs to the thyroid cells. In this article, we describe the role of two key cytokines, IL12 and IFNgamma, in modifying the pathogenic immune response. EAT, defined by cellular infiltration of the thyroid and the development of thyroglobulin-specific autoantibodies, is a dynamic process. Consequently, a cytokine may exert a different effect at different times during the disease process. For purposes of discussion, we propose that there are three stages in the development of EAT: priming; initiation; and progression. Administration of anti-IL12 during the priming stage and initiation dramatically decreases disease and lowers autoantibody levels. In contrast, injection of recombinant IL12 after disease was established significantly decreases the severity of disease and reduces autoantibody levels. Unlike IL-12, IFNgamma was not essential for the priming of EAT. However, the severity of disease in the anti-IFNgamma-treated initiation- and progression-treated animals was higher than in controls, implying a regulatory role for IFNgamma. These findings emphasize that EAT involves a complex array of pathogenic mechanisms. The balance of cytokines produced during the early phase of the autoimmune reaction probably determines the progression from a harmless autoimmune response to autoimmune disease.     

New insights into asthma pathogenesis and treatment

Although national asthma guidelines help organize standards for asthma care, current asthma management is still primarily symptom based. Recent reports provide insights on how to improve asthma management through steps to better understand the natural history of asthma, individualize asthma care, reduce asthma exacerbations, manage inner city asthma, and some potential new ways to use available medications to improve asthma control. Despite many significant gains in managing asthma, we must now find improved strategies to prevent asthma exacerbations, alter the natural history of the disease, and to reduce health disparities in asthma care. Perhaps new directions in personalized medicine including a systems biology approach, along with improved health care access and communication will lead to better methods to alleviate the burden of asthma. This review will discuss the benefits and limitations of the current approach to asthma management, new studies that could impact new directions in asthma management, and new insights related to mechanisms of asthma and allergic airways inflammation that could eventually lead to improved asthma control.     

Arrhythmogenic right ventricular cardiomyopathy: new insights into mechanisms of disease

Arrhythmogenic right ventricular cardiomyopathy is a primary heart muscle disorder characterized by the early occurrence of arrhythmias often out of proportion to the extent of structural remodeling and contractile derangement. Approximately 40% of patients with arrhythmogenic right ventricular cardiomyopathy have one or more mutations in genes encoding proteins in desmosomes, intercellular adhesion junctions which, in cardiac myocytes, reside within intercalated disks. Some desmosomal proteins fulfill roles both as structural proteins in cell–cell adhesion junctions and as signaling molecules in pathways mediated by Wnt ligands. Evidence is increasing that mutations in desmosomal proteins can perturb the normal balance of critical proteins in junctions and the cytosol which, in turn, could alter gene expression by circumventing normal Wnt signaling pathways. This review highlights recent advances in understanding the pathogenesis of arrhythmogenic right ventricular cardiomyopathy and presents evidence suggesting that the disease is caused by a combination of altered cellular biomechanical behavior and altered signaling.     

New insights into the pathogenesis of IgA nephropathy

IgA nephropathy (IgAN) is the most common diagnosis amongst primary glomerular diseases in most countries where renal biopsies are regularly performed. Only a fraction of these patients is at high risk of losing glomerular filtration rate (GFR) in particular those with high grade proteinuria, uncontrolled hypertension or already impaired GFR at diagnosis, and those with renal scars in the renal biopsy. Genetic modifiers of IgAN onset and/or course are emerging. Spontaneous animal models of IgAN are problematic given considerable species differences between the rodent and human IgA system. However, new transgenic models help to better understand the pathogenesis. A key pathogenetic role appears to be played by underglycated IgA1 as well as autoantibodies to these IgA glycoforms and IgA receptors such as CD89 and transferrin receptor 1. Once IgA and/or IgA-containing immune complexes are deposited or formed in the mesangium, secondary effector mechanisms become important including complement activation, release of mesangial growth factors (in particular platelet-derived growth factor), and finally non-IgAN-specific events that culminate in glomerular and subsequently renal tubulointerstitial scaring. Here, we review these processes and describe potential novel therapeutic targets in IgAN.     

New insights into the pathogenesis of systemic sclerosis

Systemic sclerosis (SSc) is a connective tissue disorder characterized by vascular abnormalities and excessive collagen synthesis. Extracellular matrix overproduction by fibroblasts results from abnormal interactions among endothelial cells, mononuclear cells (lymphocytes and monocytes) and fibroblasts, in a setting of vascular hyperreactivity and tissue hypoxia. Many autoantibodies have been identified in the sera of SSc patients; some of them are specific to the disease, such as anti-centromere antibodies in limited SSc, anti-topoisomerase 1 and anti-RNA polymerase I/III antibodies in diffuse SSc. Their pathogenetic role(s) remains uncertain. However, genetic, environmental and possibly alloreactive factors might also contribute to disease susceptibility.     

New insights into the mechanisms underlying hydrosalpinx fluid formation and its adverse effect on IVF outcome

The adverse effects of hydrosalpinx on the outcome of IVF have been well documented; however, the causes for impaired implantation in patients with hydrosalpinx are poorly understood. Hydrosalpinx fluid has been shown to be toxic to mouse embryos but not human embryos, and this has become a topic of intense debate. An understanding of the mechanisms underlying hydrosalpinx formation following pelvic inflammatory disease appears to be essential in elucidating the causes for reduced implantation in hydrosalpinx patients and providing more rational treatments. This review discusses the mechanisms underlying hydrosalpinx formation and its adverse effect on IVF outcome, with new insights into possible involvement of Fallopian tube epithelial transporters and ion channels, particularly the cystic fibrosis transmembrane conductance regulator (CFTR). Possible links between Chlamydia trachomatis in pelvic inflammatory disease and the subsequent CFTR-mediated events in hydrosalpinx formation leading to infertility in hydrosalpinx are proposed. The causes of reduced implantation, particularly in patients with visible hydrosalpinges shown on ultrasound scanning, are re-examined in light of these possible mechanisms.     

New insights into the mechanisms of allergen-specific immunotherapy

PURPOSE OF REVIEW: Specific immunotherapy represents the only curative treatment of a specific allergy, and is therefore of great interest in terms of immunological mechanisms and therapeutic developments. RECENT FINDINGS: Allergen-specific regulatory T cells are induced after the initiation of specific immunotherapy, and are assumed to suppress effector T cells directly mediating allergic inflammation. Therefore regulatory T cells may play a key role in the re-induction of allergen tolerance. Multiple pathways in many systems are described to promote or enhance regulatory T cells. This review summarizes the current view on immunological mechanisms leading to and coming from regulatory T cells. SUMMARY: The highlighted mechanisms may not only contribute to improved specific immunotherapy, but also give insight into a clinically relevant therapy targeting regulatory T cells. The approach of addressing endogenous regulatory mechanisms specifically controlling inflammation instead of targeting inflammation itself is relevant for future pharmacological developments.     

Toll-like receptors: insights into their possible role in the pathogenesis of lyme neuroborreliosis

Lyme neuroborreliosis is likely caused by inflammatory effects of the tick-borne spirochete Borrelia burgdorferi on the nervous system. Microglia, the resident macrophage cells within the central nervous system (CNS), are important in initiating an immune response to microbial products. In addition, astrocytes, the major CNS glial cell type, also can contribute to brain inflammation. TLRs (Toll-like receptors) are used by glial cells to recognize pathogen-associated molecular patterns (PAMPs), mediate innate responses, and initiate an acquired immune response. Here we hypothesize that because of their PAMP specificities, TLR1, -2, -5, and -9 may be involved in the pathogenesis of Lyme neuroborreliosis. Previous reports have shown that the rhesus monkey is the only animal model to exhibit signs of Lyme neuroborreliosis. Therefore, we used primary cultures of rhesus astrocytes and microglia to determine the role of TLRs in mediating proinflammatory responses to B. burgdorferi. The results indicate that microglia and astrocytes respond to B. burgdorferi through TLR1/2 and TLR5. In addition, we observed that phagocytosis of B. burgdorferi by microglia enhances not only the expression of TLR1, -2, and -5, but also that of TLR4. Taken together, our data provide proof of the concept that astrocyte and microglial TLR1, -2, and -5 are involved in the in vivo response of primate glial cells to B. burgdorferi. The proinflammatory molecules elicited by these TLR-mediated responses could be a significant factor in the pathogenesis of Lyme neuroborreliosis.     

Rethinking mechanisms of autoimmune pathogenesis

Why exactly some individuals develop autoimmune disorders remains unclear. The broadly accepted paradigm is that genetic susceptibility results in some break in immunological tolerance, may enhance the availability of autoantigens, and may enhance inflammatory responses. Some environmental insults that occur on this background of susceptibility may then contribute to autoimmunity. In this review we discuss some aspects related to inhibitory signaling and rare genetic variants, as well as additional factors that might contribute to autoimmunity including the possible role of clonal somatic mutations, the role of epigenetic events and the contribution of the intestinal microbiome. Genetic susceptibility alleles generally contribute to the loss of immunological tolerance, the increased availability of autoantigens, or an increase in inflammation. Apart from common genetic variants, rare loss-of-function genetic variants may also contribute to the pathogenesis of autoimmunity. Studies of an inhibitory signaling pathway in B cells helped identify a negative regulatory enzyme called sialic acid acetyl esterase. The study of rare genetic variants of this enzyme provides an illustrative example showing the importance of detailed functional analyses of variant alleles and the need to exclude functionally normal common or rare genetic variants from analysis. It has also become clear that pathways that are functionally impacted by either common or rare defective variants can also be more significantly compromised by gene expression changes that may result from epigenetic alterations. Another important and evolving area that has been discussed relates to the role of the intestinal microbiome in influencing helper T cell polarization and the development of autoimmunity.     

New insights into possible causes of male infertility

Male subfertility/infertility is acknowledged to contribute significantly to infertility problems experienced by couples. In some instances, morphological and/or physiological defects known to interfere with normal sperm function can be identified. However, in others, no obvious cause of fertilization failure can be identified. The recent introduction of molecular methods has made it possible to diagnose more subtle defects that could affect the function of spermatozoa produced by some males. For others, though, the problems may result from defects in the physiological mechanisms that need to be activated in spermatozoa so that they 'switch on' functionally following their release from the male reproductive tract. Capacitation, the term applied to this 'switching on', encompasses a number of changes that, collectively, confer fertilizing potential on sperm cells. This article focuses on two extrinsic factors, one a protein and one a very small peptide, that become associated with spermatozoa either in the epididymis or following contact with seminal plasma. These factors modulate capacitation in vitro in ways that could be very relevant to fertilization in vivo, possibly helping to maximize the fertilizing potential of the few cells that reach the site of fertilization. In some men, defects in either of the factors and the systems they modulate could result in defective fertilization. However, by understanding the underlying mechanisms, it may prove possible to develop new diagnostic techniques and new therapeutic treatments to alleviate the infertility.