Tolerance and immune regulation

Understanding of both the phenomenon of immunological tolerance and the mechanisms by which it is achieved is rapidly advancing, as was evident from a recent meeting. This report summarizes key developments in both T- and B-cell biology.     

PD-L1分子与疾病免疫调节

PD-LI(曾命名为B7-H1)是迄今发现的B7家族中较新的共刺激分子,与T细胞上的配体(PD-1)结合后可调节T细胞的活化及分化.它通过激活初始T细胞、抑制活化的效应T细胞及调节细胞因子的分泌等而参与多种免疫过程.以PD-L1为靶点的免疫调节与动物器官移植排斥反应、自身免疫性疾病、慢性病毒感染、肿瘤免疫逃逸等疾病的发生、发展密切相关.本文就PD-LI在上述疾病中发生、发展及治疗中的作用做一综述.     

Lymphocyte activation and immune regulation

Occupation of cell surface receptors on lymphocytes by appropriate antigens and/or growth and differentiation factors initiate activation steps essential for acquisition of differentiated functions and clonal expansion. The diversity of lymphocyte antigen-specific receptors and selective expression of binding sites for distinct growth and differentiation factors form the basis for the specificity of the immune response. In contrast to the diversity of receptor-associated recognition systems, transduction of signals to lymphocyte nuclei seems to occur via a limited number of biochemical pathways. One ubiquitous mechanism of signal transduction involves the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂) and formation of two second messengers, diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP₃), which trigger numerous physiological responses in T and B lymphocytes. Lymphocytes which are triggered by different or even identical ligands can use a single signal transduction pathway but respond with any of several genetically predetermined effector functions. Ligands and cell surface receptors that participate in lymphocyte activation, and the intracellular events accompanying this activation step were the topic of a recent meeting.     

Stress and immune modulation in fish

Stress is an event that most animals experience and that induces a number of responses involving all three regulatory systems, neural, endocrine and immune. When the stressor is acute and short-term, the response pattern is stimulatory and the fish immune response shows an activating phase that specially enhances innate responses. If the stressor is chronic the immune response shows suppressive effects and therefore the chances of an infection may be enhanced. In addition, coping with the stressor imposes an allostatic cost that may interfere with the needs of the immune response. In this paper the mechanisms behind these immunoregulatory changes are reviewed and the role of the main neuroendocrine mechanisms directly affecting the building of the immune response and their consequences are considered.     

Stress and immune modulation in fish

Stress is an event that most animals experience and that induces a number of responses involving all three regulatory systems, neural, endocrine and immune. When the stressor is acute and short-term, the response pattern is stimulatory and the fish immune response shows an activating phase that specially enhances innate responses. If the stressor is chronic the immune response shows suppressive effects and therefore the chances of an infection may be enhanced. In addition, coping with the stressor imposes an allostatic cost that may interfere with the needs of the immune response. In this paper the mechanisms behind these immunoregulatory changes are reviewed and the role of the main neuroendocrine mechanisms directly affecting the building of the immune response and their consequences are considered.     

Histamine and gut mucosal immune regulation

Histamine is a biogenic amine with extensive effects on many cell types, mediated by the activation of its four receptors (H1R–H4R). Distinct effects are dependent on receptor subtypes and their differential expression. Within the gastrointestinal tract, histamine is present at relatively high concentrations, particularly during inflammatory responses. In this review, we discuss the immunoregulatory influence of histamine on a number of gastrointestinal disorders, including food allergy, scombroid food poisoning, histamine intolerance, irritable bowel syndrome, and inflammatory bowel disease. It is clear that the effects of histamine on mucosal immune homeostasis are dependent on expression and activity of the four currently known histamine receptors; however, the relative protective or pathogenic effects of histamine on inflammatory processes within the gut are still poorly defined and require further investigation.     

The proteasome and its inhibitors in immune regulation and immune disorders

The ubiquitin-proteasome pathway is a well-characterized mechanism deputed to the degradation of intracellular proteins. Proteasomal degradation intervenes in the regulation of numerous cellular functions including signal transduction, apoptosis, cell cycle, and antigen presentation. In vitro and in vivo studies have shown that both normal and malignant cells of the immune system are exquisitely affected by inhibition of proteasome activity. This property is currently exploited in the treatment of multiple myeloma and mantle cell lymphoma, two B-cell malignancies that respond to treatment with the proteasome inhibitor bortezomib. Pharmacological inhibitors of the proteasome also affect function and survival of B and T lymphocytes and of dendritic cells and were shown to reduce autoimmune and inflammatory manifestations in several models of immune-mediated disorders. The present review offers an overview of the mechanisms implicated in the immunomodulatory effects of proteasome inhibitors and discusses prospective future applications for these small molecules in immune and inflammatory diseases.     

Rational approaches to immune regulation

Our laboratory is interested in the properties of proteins that render them immunogenic, and how such immunogenicity may be modulated in vivo. We are attempting to enhance the immune response in the design of more effective vaccines against viral diseases, such as HIV, and against tumor antigens expressed on breast, ovarian, and cervical cancer and B cell lymphomas. Our main approach is to use a facultative intracellular bacterium, Listeria monocytogenes, which has the unusual ability to live and grow in the cytoplasm of the cell and is thus an excellent vector for targeting passenger antigens to the major histocompatibility complex (MHC) class I pathway of antigen processing with the generation of authentic cytotoxic T lymphocytes (CTL) epitopes. In the field of tumor immunotherapy, we are also developing nonliving vaccine vectors for tumor antigens.     

Rational approaches to immune regulation

Our studies are mainly focused on developing strategies of immune regulation. In the case of infectious and neoplastic disease, our approach is to upregulate cell-mediated immunity to viral of tumor antigens using an intracellular bacterium as a vector for targeting these antigens to the major histocompatibility complex (MHC) class I and class II pathways of antigen processing, in addition to exploiting the adjuvant properties of the vector to stimulate innate immunity. In the area of autoimmunity, we are attempting to downregulate the immune response by specific immune intervention directed against autoreactive T cells. In these studies we use murine models for multiple sclerosis. Our approach is to use both rationally designed T cell receptor (TCR) peptide analogs and recombinant viral vectors that express TCR components to regulate the disease.     

Stress and immune mediators in miscarriage.

BACKGROUND: Stress is thought to be abortogenic and psycho-neuro-immunological pathways have been suggested to be involved in triggering miscarriages. From experiments in pregnant mice exposed to stress some insights into the underlying mechanisms have been gained, delineating immunological imbalances as a cause of pregnancy failure. In order to test the validity of the conclusions drawn from murine experiments and the role of stress in human pregnancy loss, the following study was performed. METHODS: We used an established perceived stress questionnaire and measured the stress score of women with a confirmed diagnosis of first trimester spontaneous abortion (n = 94). Decidual tissue was investigated by immunohistochemistry and in-situ hybridization to detect the presence and distribution of immunocompetent decidual cells [CD56(+) natural killer (NK) cells, CD8(+)and CD3(+) T cells, tryptase(+) mast cells (MCT(+)) and tumour necrosis factor (TNF)-alpha(+) cells]. The patient cohort was divided into women experiencing low or high levels of stress. RESULTS: In the decidua of women with high stress scores we observed significantly higher numbers of MCT(+), CD8(+) T cells and TNF-alpha(+) cells per mm(2) tissue (P < or = 0.05). No significant differences between individuals with lower or higher stress scores could be observed with respect to decidual CD56(+) NK and CD3(+) T cells. CONCLUSIONS: Using a questionnaire to score perceived stress in humans may be a valid approach to assess non-biased stress scores. Stress-triggered abortion in humans, identified by a questionnaire, can be linked to immunological imbalances.     

GITR及其在免疫调节中的作用

糖皮质激素诱导的TNFR家族相关受体（GITR），也被称为TNFRSF18、AITR（人类）。静止T细胞低水平表达GITR，而CD4^＋CD25^＋调节性T细胞则呈高水平表达。GITR与其配体（GITRL）结合后会增强T细胞激活、增殖、分泌细胞因子、MAPKs和NF-κB激活效应、抑制CD4^＋CD25^＋Treg细胞的功能，从而加强效应性T细胞的活性，有利于增强抗肿瘤免疫和抗病毒免疫。随着生物学环境的变化，GITR激活Siva或者TRAF，起着促进或诱导凋亡的作用。     

Phagocytosis of apoptotic cells and immune regulation

The termination of the apoptotic programme occurs in most cases via recognition and clearance by phagocytes, especially the professional phagocytes, such as macrophages and immature dendritic cells. Engulfed cells do not simply disappear from the midst of living tissues. The fine-defined presentation of yielded self-antigens to T cells is a central event in the induction or the maintenance of the peripheral immune tolerance to self. Conversely, abnormality in this pathway may contribute to the pathogenesis of systemic and organ-specific autoimmune diseases. We herein reviewed the relationship between phagocytosis of apoptotic cells and immune regulation, especially the effects of engulfed apoptotic cells on immune tolerance and autoimmune diseases.     

Ontogeny and regulation of the immune system

Classic studies in embryology and contemporary research in immunology and molecular biology have disclosed the carefully orchestrated events leading to development of the immune system and immunoregulation that ultimately provide immunohomeostasis. During ontogeny, the pluripotential stem cell emerges and differentiates into all hematopoietic lineages, including three major immunologically relevant components: T-cell differentiation occurs within the thymus; B cells appear within fetal liver, adult bone marrow, and possibly other abdominal sites; and concurrently, the monocyte-macrophage system develops. Under the influence of an array of cytokines and cellular interactions, immune regulation is established. T and B lymphocytes elaborate genetically encoded messages that acquire specificity via transposable genetic elements. Receptors and cytokines provide immune recognition, communication, regulation, and memory for antigens. Inherited and acquired defects in ontogeny and immune regulation are the basis for immunodeficiency disorders.