多糖特异性免疫识别的分子机制及其免疫生物学意义

多糖是自然界含量最丰富的生物聚合物,广泛表达于微生物、植物和动物中,并以糖基化的方式参与几乎所有蛋白质分子的结构稳态和功能调节.多糖类物质是免疫系统的主要识别对象之一.作为重要的病原体相关分子模式(P'AMP),病原体表面的多糖分子能够通过固有免疫系统的模式识别分子(PRR)启动抗感染免疫应答.此外,多糖能够被MHCⅡ分子呈递并被αβ-TCR直接或者间接识别,从而激活适应性细胞免疫应答.多糖类物质亦能够有效地激活B淋巴细胞,诱导特异性抗体的产生.健康人血清中含有大量的针对不同种类多糖的特异性抗体(如移植抗体和血型抗体),多是抗感染免疫应答的产物.人血清中的多糖特异性抗体也可能源于针对宿主组织或者细胞的糖表位特异性自身免疫应答.自身免疫病患者体内多糖抗体的种类及水平显著高于健康人.免疫系统对衰亡细胞的识别与清除在很大程度上以细胞表面糖表位的变化为基础.肿瘤细胞表面的糖基发生改变亦可引起抗肿瘤特异性免疫应答.总之,免疫识别在很大程度上是以多糖或者糖基为靶向的识别,糖表位特异性免疫应答在抗感染免疫、自身免疫、肿瘤免疫和免疫自稳等方面均具有重要作用.多糖特异性免疫识别的分子机制和生物学意义研究必将成为今后免疫学科新的生长点与热点.     

The anti-Sm immune response in autoimmunity and cell biology

Anti-Sm antibodies are found in greater than 30% of the patients with systemic lupus erythematosus (SLE) and are diagnostic of SLE. The Sm autoantigens are the small nuclear ribonucleoprotein (snRNP) common core proteins. The seven core proteins, B, D1, D2, D3, E, F and G, shared by a majority of the snRNP particles, form a heptamer ring approximately 20 nm in diameter, with the snRNA passing through the center. The Sm epitopes are distributed on the outside surface of the ring. A repeated proline rich motif with homology to an Epstein bar nuclear antigen in the B protein and a gly-arg-gly motif including a symmetrical dimethylarginine post translational modification in the B, D1 and D3 proteins are major Sm epitopes. The anti-Sm response has features typical of an antigen driven immune response. SnRNP proteins share several characteristics with other autoantigens including their assembly into ribonucleoprotein particles, homologies to known viral proteins, presence of post translational modifications, a high abundance and great stability and the presence of repeated motifs. Current work on the snRNP particles is attempting to identify the features that predispose the common core proteins to become autoantigens in vulnerable individuals.     

Australia antigen and the immune response in human diseases

This study discusses immune response to the Au antigen and the role of this antigen in acute hepatitis. The population predisposed to Au antigen is discussed, together with subtyping as a method for explaining family clustering of persistent Au.     

Molecular biology for formyl peptide receptors in human diseases

Leukocytes accumulate at sites of inflammation and immunological reaction in response to locally existing chemotactic mediators. The first chemotactic factors structurally defined were N-formyl peptides. Subsequently, numerous ligands were identified to activate formyl peptide receptors (FPRs) that belong to the seven-transmembrane G protein-coupled receptor superfamily. FPRs interact with this menagerie of structurally diverse pro- and anti-inflammatory ligands to possess important regulatory effects in multiple diseases, including inflammation, amyloidosis, Alzheimer’s disease, prion disease, acquired immunodeficiency syndrome, obesity, diabetes, and cancer. How these receptors recognize diverse ligands and how they contribute to disease pathogenesis and host defense are basic questions currently under investigation that would open up new avenues for the future management of inflammation-related diseases.     

Some recent advances in biology and diseases manifested by abnormal immune regulation

Diseases manifested by abnormal immune regulation represent perturbations of a system of heterologous genetic recombination. This heterologous recombination is mediated by plasmids and viruses, facilitated by immune multigene families, and may be affected by physical factors. Heterologous recombination facilitates individual adaptation to new environmental challenges, thereby promoting survival and evolution. Present evidence which supports this hypothesis and a means to test it are outlined. The medical implications of the hypothesis are briefly discussed.     

Accelerated atherosclerosis, immune response and autoimmune rheumatic diseases

Atherosclerosis (AT) is a chronic autoimmune inflammatory disease, characterized by lipoproteins metabolism alteration leading to formation of pro-inflammatory and pro-oxidative lipids and immune response. Identification of macrophages, T cells, pro-inflammatory cytokines, adhesion cell molecules in atherosclerotic lesions support the hypothesis that innate and adaptive immune response participate in the atherogenesis mechanism. Multiple factors such as inflammatory, infectious and immune system, among others participate in this process. The principal antigens identified in atherogenesis are: oxidized LDL (oxLDL), HSPs and beta2GPI. During LDL oxidation, multiple neoantigens are formed (anti-EO). These antibodies seem to be protective. Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) have accelerated AT. The association of both diseases with AT suggests a common pathogenic mechanism. SLE and atherosclerosis are immune-complex mediated diseases. Participation of complement activation, and CD40, CD40 ligand interactions have been demonstrated in AT and SLE. AT may be the initial presentation or the consequence of primary antiphospholipid syndrome. The similarities between AT, SLE, and APS and the identification of protective antibodies offer opportunities for new immunomodulation treatment strategies.     

免疫应答异常与中枢神经系统退变性疾病

免疫功能异常参与了中枢神经系统退变性疾病的发生。中枢免疫功能异常主要为小胶质细胞异常激活。激活的小胶质细胞可形成活性中间代谢产物、一氧化氮、促炎因子等细胞毒性物质。发病率最高的两种中枢神经系统退变性疾病阿尔茨海默病（Alzheimer′s disease,AD)和帕鑫森病（Parkinson′s disease,PD)的发生都与免疫功能异常密切相关。由于免疫功能异常特别是小胶质细胞激活普遍存在于中枢神经系统退变性疾病过程中，调节小胶质细胞功能的药物可能会具有神经保护作用，延迟甚至阻止神经元变性。     

The immune response to citrullinated antigens in autoimmune diseases

Post-translational modifications of proteins occur very frequently. One of these modifications, citrullination, is the result of arginine deimination operated by an enzyme, peptidylarginine deiminase (PAD), whose activity is under strict genetic control. Serum antibodies reactive with citrullinated proteins/peptides are a very sensitive and specific marker for rheumatoid arthritis. Genes encoding for PAD enzymes have been investigated in RA: the PADI4 gene confers susceptibility to RA in Japanese patients, but not in Caucasians.     

Pericyte biology and diseases

Microvessels are composed of two types of cells: endothelial cells and pericytes. Pericytes are elongated cells of mesodermal origin that partially surround the endothelial cells of small vessels. As pericytes contain contractile muscle filaments on their endothelial cell side, they have long been regarded as just microvascular counterparts of smooth muscle cells, thus being implicated in the regulation of capillary tone. However recent understanding of pericyte biology suggests that pericytes play an important role in the maintenance of microvascular homeostasis. Indeed, loss or dysfunction of pericytes has been considered to play an active part in the pathogenesis of various types of disorders. In this study, we review the biology of pericytes and the pathological role of pericyte loss or dysfunction in various devastating disorders such as diabetic retinopathy, atherosclerosis and tumor angiogenesis     

Combinations of common chronic paediatric diseases deviate the immune response in diverging directions

The cytokine pattern of T lymphocytes has not been characterized in children with combinations of paediatric immunological disorders. We describe cytokine secretion in children with type 1 diabetes, coeliac disease and allergy and combinations of two of these diseases after stimulation with 'disease-specific' antigens. Peripheral blood mononuclear cells (PBMC) were collected from 68 children with type 1 diabetes, allergy or coeliac disease, two of these diseases in combination or none of these diseases. Using the enzyme-linked immunospot (ELISPOT) technique, interferon (IFN)-gamma and interleukin (IL)-4 were analysed from fresh PBMC spontaneously and after in vitro stimulation with antigens associated with one or more of these diseases (insulin, gluten, birch and cat extract, beta-lactoglobulin, ovalbumin and phytohaemagglutinin) in order to divide T helper (Th)1- from Th2-like lymphocytes. Stimulation with birch and cat extract caused increased IL-4 secretion in allergic children. A low IFN-gamma response to insulin was found in type 1 diabetic children, whereas allergic children responded to insulin by increased IL-4 secretion. Children suffering from both type 1 diabetes (Th1-prone) and allergy (Th2-prone) reacted distinctly to general mitogen stimulation. Children suffering from two Th1-dominated diseases (type 1 diabetes and coeliac disease) showed hardly any response to either food or inhalation allergens. Our results indicate an important interplay between common immunological diseases in children. The combination of two Th1-deviated diseases is associated with a suppressed immune response, whereas a combination of Th1- and Th2-dominated diseases appears to increase the general immune response.     

Quantified deficiency of lymphocyte response to phytohaemagglutinin in immune deficiency diseases

Using a quantitative assay of lymphocyte responsiveness to different concentrations of phytohaemagglutinin (PHA), it has been possible to demonstrate that the lymphocytes of children with ataxia telangiectasia do not respond normally. The response to PHA is nearer normal at higher concentrations of PHA.

In the same system, it has been shown that although the lymphocytes of children with probable infantile sex-linked agammaglobulinaemia (Bruton's disease) may respond normally at higher concentrations of PHA, at lower concentrations their response is subnormal.

The results reported indicate that if lymphocyte response to PHA is defective in an immune deficiency disease, then the response at lower concentrations of PHA provides the most sensitive discriminatory information.

     

Molecular biology of the Wiskott-Aldrich syndrome

The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency associated with thrombocytopenia, bloody diarrhea, eczema, recurrent infections, and a high incidence of malignancies. X-linked thrombocytopenia (XLT) is a milder form with predominant platelet abnormalities. Both are caused by mutations of the cytoplasmic WAS protein (WASP). To date, mutations of WASP have been identified in over 340 families and consist of missense and nonsense mutations, deletions and insertions, and splice site mutations. There is a striking correlation between phenotype and genotype. The complex gene product of WASP has multiple functional domains that contribute to actin polymerization, cell motility, intracellular signaling, and apoptosis. Understanding the molecular basis of WAS/XLT not only explains the highly variable clinical phenotype, but also affects the medical management of this serious congenital disorder.     

The role of elastin peptides in modulating the immune response in aging and age-related diseases

It is now well accepted that aging is associated with the occurrence of a low-grade inflammation called Inflamm-aging. This leads to the imbalance between the various mediators of the inflammatory response in favour of the pro-inflammatory response represented by pro-inflammatory cytokines and oxidative stress. The question that arises, and is still under investigation, what is the origin of the driving force leading to these changes. One of the current hypotheses is that chronic stimulation of the immune system contributes to the pro-inflammatory shift. The chronic stimulation can be of viral origin such as cytomegalovirus, from tumor antigens or from other sources such as the extracellular matrix, especially from elastin fibres and collagens. Aging and various inflammatory diseases such as atherosclerosis, abdominal aortic aneurysms, chronic obstructive pulmonary diseases (COPD), cancer and type 2 diabetes are characterized by the destruction of elastin fibers and the consequent generation of elastin peptides which are biologically active. This review will describe the putative contribution of elastin peptides to inflamm-aging and extend on their role on immunosenescence, as well as on age-associated chronic inflammatory diseases.     

Molecular biology of retroelements

Conclusions The observations presented on the molecular biology primarily of viral retroelements illustrate the complexity of the replication and expression of these molecules. They are revealing the subtle and intricate mechanisms by which these molecules bypass the constraints of the normal cellular machinery. Whether the majority of nonviral retroelements use similar mechanisms remains to be seen