Interactions between the enteric nervous system and the immune system: role of neuropeptides and nutrition

Neuropeptidergic synthesis occurs in enteric nerves and immune cells of the gut-associated lymphoid tissue. Lymphocytes, macrophages, mast cells, and intestinal epithelial cells are capable of responding to these neuropeptides. Neuropeptides generate proliferative or antiproliferative responses of mucosal lymphocytes and intestinal epithelial cells, affect cytokine production and immunoglobulin synthesis by immune cells, and control secretion of water and electrolytes. Some neuropeptides, particularly cholecystokinin, gastrin-releasing peptide, and neurotensin, appear promising to maintain mucosal immunity in patients who cannot receive enteral feeding during critical illness or after GI tract loss. Exogenous administration of neuropeptides to preserve normal immune defenses represents a potential new field of pharmacotherapeutics against bacterial invasion.     

The N314D polymorphism of the GALT gene is not associated with congenital absence of the uterus and vagina

The aetiology of anomalous embryonic and fetal development of the female reproductive tract, ranging from common uterine abnormalities to the somewhat rare congenital absence of the uterus and vagina (CAUV), is unknown. Some have proposed that abnormal galactose metabolism might cause CAUV. An association between CAUV and the N314D allele of the galactose-1-phosphate uridyl transferase (GALT) gene has been proposed as aetiological. We tested this hypothesis further by performing a case-control molecular study analysing 32 patients with CAUV for the presence of the N314D allele. These patients were compared with 138 normal controls. No association between CAUV and the N314D polymorphism was found (P = 0.32). It is unlikely that either maternal or fetal GALT enzyme activity could affect paramesonephric duct development, because neither galactosaemic subjects nor their children have an increased incidence of uterine anomalies.     

The evolution of a Web resource: The Galactosemia Proteins Database 2.0

Galactosemia Proteins Database 2.0 is a Web‐accessible resource collecting information about the structural and functional effects of the known variations associated to the three different enzymes of the Leloir pathway encoded by the genes GALT, GALE, and GALK1 and involved in the different forms of the genetic disease globally called “galactosemia.” It represents an evolution of two available online resources we previously developed, with new data deriving from new structures, new analysis tools, and new interfaces and filters in order to improve the quality and quantity of information available for different categories of users. We propose this new resource both as a landmark for the entire world community of galactosemia and as a model for the development of similar tools for other proteins object of variations and involved in human diseases.     

Pyloric tonsil as a novel gut-associated lymphoepithelial organ of the chicken

The pyloric tonsil is a novel peripheral lymphoepithelial organ of the gastrointestinal tract in the chicken. It forms a complete lymphoid ring at the beginning of the duodenum, where crypts of Lieberkühn are transformed to tonsillar crypts with lymphoepithelial lining. The oesophageal (described previously) and pyloric tonsils are characteristic of the chicken, while they are absent in mammals. The lymphoid system develops from the middle germ layer, the mesoderm, and forms connections with the ecto- and endoderm, namely the skin and gut, respectively. These connections are based on the lymphoepithelial lining of the crypts, and provide gates for environmental antigens. Recent findings, taken together with the literature, suggest that in birds the lymphoid system forms connections with the endoderm-derived organs that are anatomically and histologically more extensive than the ectoderm-derived ones, which may be explained by the absence of regional lymph nodes, and the less developed lymphoid circulation of the skin.     

Genetics of immunoglobulin-A vasculitis (Henoch-Schönlein purpura): An updated review

Immunoglobulin-A vasculitis (IgAV) is classically a childhood small-sized blood vessel vasculitis with predominant involvement of the skin. Gastrointestinal and joint manifestations are common in patients diagnosed with this condition. Nephritis, which is more severe in adults, constitutes the most feared complication of this vasculitis. The molecular bases underlying the origin of IgAV have not been completely elucidated. Nevertheless, several pieces of evidence support the claim that genes play a crucial role in the pathogenesis of this disease. The human leukocyte antigen (HLA) region is, until now, the main genetic factor associated with IgAV pathogenesis. Besides a strong association with HLA class II alleles, specifically HLA-DRB1 alleles, HLA class I alleles also seem to influence on the predisposition of this disease. Other gene polymorphisms located outside the HLA region, including those coding cytokines, chemokines, adhesion molecules as well as those related to T-cells, aberrant glycosylation of IgA1, nitric oxide production, neoangiogenesis, renin-angiotensin system and lipid, Pyrin and homocysteine metabolism, may be implicated not only in the predisposition to IgAV but also in its severity. An update of the current knowledge of the genetic component associated with the pathogenesis of IgAV is detailed in this review.     

Classical galactosemia and mutations at the galactose‐1‐phosphate uridyl transferase (GALT) gene

Classical galactosemia is caused by a deficiency in activity of the enzyme galactose‐1‐phosphate uridyl transferase (GALT), which, in turn, is caused by mutations at the GALT gene. The disorder exhibits considerable allelic heterogeneity and, at the end of 1998, more than 150 different base changes were recorded in 24 different populations and ethnic groups in 15 countries worldwide. The mutations most frequently cited are Q188R, K285N, S135L, and N314D. Q188R is the most common mutation in European populations or in those predominantly of European descent. Overall, it accounts for 60–70% of mutant chromosomes, but there are significant differences in its relative frequency in individual populations. Individuals homoallelic for Q188R tend to have a severe phenotype and this is in keeping with the virtually complete loss of enzyme activity observed in in vitro expression systems. Globally, K285N is rarer, but in many European populations it can be found on 25–40% of mutant chromosomes. It is invariably associated with a severe phenotype. S135L is found almost exclusively in African Americans. In vitro expression results are discrepant, but some individuals carrying S135L appear to exhibit GALT activity in some tissues. Duarte 1 (or Los Angeles) and Duarte 2 (or Duarte) variants carry the same amino acid substitution, N314D, even though D1 is associated with increased erythrocyte GALT activity and D2 with reduced activity. N314D is in linkage disequilibrium with other base changes that differ on the D1 and D2 alleles. N314D does not impair GALT activity in in vitro expression systems. However, there are differences in the abundance of GALT protein in lymphoblastoid cells lines from D2 and D1 individuals. It is unclear whether the specific molecular changes that distinguish the D1 and D2 alleles account for the different activities. The considerable genetic heterogeneity documented to date undoubtedly contributes to the phenotypic heterogeneity that is observed in galactosemia. The additional effects of nonallelic variation and other constitutional factors on phenotypic variability remain to be elucidated. Hum Mutat 13:417–430, 1999. © 1999 Wiley‐Liss, Inc.     

IgA/IgM and Secretory Immunity

The mucosal wall is equipped with a highly developed defence system. The concept of local or mucosal immunity has expanded dramatically during the past decades. The bronchus-associated lymphoid tissue (BALT) and the gut-associated lymphoid tissue (GALT) belong to the common mucosal immune system (CMIS), which also includes mucosal sites in the genital tract, the salivary glands, ocular tissues and the mammary glands. These systems not only communicate with each other, they also communicate with the external environment. The intestinal mucosa contains more than 80% of all immunoglobulin producing cells in the human body. GALT and BALT are primary inductive sites for secretory immunoglobulin isotypes of which sIgA are the dominant molecules. Responses are directed against ingested and inhaled antigens. Therapeutic IgM- and IgA-containing immunoglobulin concentrates can modify mucosal immunity. The progress in the field of molecular biology and genetics offers new strategies and tools for the improvement and further development of conventional vaccines for mucosal immunization.     

两株双价痢疾菌苗免疫小鼠后GALT中CD4+、CD8+ T细胞亚群的反应

目的 FSM-2117和FS-5416是两株具有不同生物表型的福氏、宋内氏双价痢疾菌苗株,FSM-2117无侵袭表型,无溶血活性,不表达侵袭蛋白抗原(Ipa-),FS-5416则为Ipa+,本实验是为了观测两株菌苗(Ipa-,Ipa+)免疫后引起的肠粘膜相关淋巴组织(GALT)中的细胞免疫反应,以探明痢疾菌苗在肠粘膜的免疫保护机制.方法 以BALB/c小鼠随机分成两组,每组25只,灌胃免疫FSM-2117及FS-5416,8×108CFU/只,分别在1,4,7,10,13天随机取各组小鼠5只分离GALT淋巴细胞;同时设一组PBS对照组,以间接免疫荧光法检测GALT中诱导部位[派伊尔小结(PP)、肠系膜淋巴结(MLN)]及效应部位[上皮间淋巴细胞(IEL)、粘膜固有层(LPL)]T细胞亚群的变化,荧光显微镜计数200个细胞计算阳性率.结果 用SAS软件,单因素方差分析,表明两株双价菌苗株均可引起肠粘膜GALT中CD4+、CD8+淋巴细胞亚群改变,不同粘膜部位免疫反应不同.诱导部位(派氏小结、肠系膜淋巴结)CD4+细胞亚群明显升高,末次免疫后第7天达峰值,而后迅速下降;在效应部位,粘膜固有层表现为CD4+细胞亚群明显升高,而IEL主要表现为CD8+细胞亚群的升高,均于第7天达峰值.两株菌苗与对照组相比,差异都具有显著性(FSM-2117 P≤0.01,FS-5416 P＜0.01),但两菌苗株之间差别无统计学意义(P＞0.05).结论 两株双价痢疾菌苗均可在小鼠GALT引起免疫反应,说明其均有较好的免疫原性.     

C1GALT1/Cosmc在免疫相关性疾病中的作用机制

C1GALT1,即β1,3-半乳糖基转移酶,又称为T-合酶,是O-糖基化过程中的关键酶.在C1 GALT1催化作用下,半乳糖(Gal)连接到Tn抗原(GalNAc-α-O-Ser/Thr-)上,从而形成T抗原或TF抗原(Galβ1,3 GalNAc-α-O-Ser/Thr的核心-1-结构).Cosmc作为C1 GALT1特异性的分子伴侣,对其正确折叠及功能的发挥起着至关重要的作用.C1GALT1或Cosmc的异常均会导致C1 GALT1活性的改变,从而影响O-糖基化过程,最终导致相关疾病的发生.越来越多的研究表明O-糖基化与一些自身免疫性疾病的发生有关,但其确切的发病机制仍不清楚.因此,该文针对C1 GALT1/Cosmc在儿童自身免疫性疾病以及肿瘤中的作用机制予以综述.     

Regulation of macrophage and dendritic cell function by pathogens and through immunomodulation in the avian mucosa

Macrophages (MPh) and dendritic cells (DC) are members of the mononuclear phagocyte system. In chickens, markers to distinguish MPh from DC are lacking, but whether MPh and DC can be distinguished in humans and mice is under debate, despite the availability of numerous markers. Mucosal MPh and DC are strategically located to ingest foreign antigens, suggesting they can rapidly respond to invading pathogens.