Dependence of self-tolerance on TRAF6-directed development of thymic stroma

The microenvironments of the thymus are generated by thymic epithelial cells (TECs) and are essential for inducing immune self-tolerance or developing T cells. However, the molecular mechanisms that underlie the differentiation of TECs and thymic compartmentalization are not fully understood. Here we show that deficiency in the tumor necrosis factor receptor-associated factor (TRAF) 6 results in disorganized distribution of medullary TECs (mTECs) and the absence of mature mTECs. Engraftment of thymic stroma of TRAF6(-/-) embryos into athymic nude mice induced autoimmunity. Thus, TRAF6 directs the development of thymic stroma and represents a critical point of regulation for self-tolerance and autoimmunity.     

Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance

During development in the thymus, T cells are rendered tolerant to self antigens. It is now apparent that thymocytes bearing self-reactive T cell receptors can be tolerized by processes that result in physical elimination (clonal deletion) or functional inactivation (clonal anergy). As these mechanisms have important clinical implications for transplantation and autoimmunity, current investigations are focused on understanding the cellular and molecular interactions that generate these forms of tolerance.     

Autoimmune diseases: the failure of self tolerance

The ability to discriminate between self and nonself antigens is vital to the functioning of the immune system as a specific defense against invading microorganisms. Failure of the immune system to "tolerate" self tissues can result in pathological autoimmune states leading to debilitating illness and sometimes death. The induction of autoimmunity involves genetic and environmental factors that have focused the attention of researchers on the trimolecular complex formed by major histocompatibility complex molecules, antigen, and T cell receptors. Detailed molecular characterization of these components points to potential strategies for disease intervention.     

Human T-cell clones from autoimmune thyroid glands: specific recognition of autologous thyroid cells

The thyroid glands of patients with autoimmune diseases such as Graves' disease and certain forms of goiter contain infiltrating activated T lymphocytes and, unlike cells of normal glands, the epithelial follicular cells strongly express histocompatibility antigens of the HLA-DR type. In a study of such autoimmune disorders, the infiltrating T cells from the thyroid glands of two patients with Graves' disease were cloned in mitogen-free interleukin-2 (T-cell growth factor). The clones were expanded and their specificity was tested. Three types of clones were found. One group, of T4 phenotype, specifically recognized autologous thyroid cells. Another, also of T4 phenotype, recognized autologous thyroid or blood cells and thus responded positively in the autologous mixed lymphocyte reaction. Other clones derived from cells that were activated in vivo were of no known specificity. These clones provide a model of a human autoimmune disease and their analysis should clarify mechanisms of pathogenesis and provide clues to abrogating these undesirable immune responses.     

Deletional tolerance mediated by extrathymic Aire-expressing cells

The prevention of autoimmunity requires the elimination of self-reactive T cells during their development and maturation. The expression of diverse self-antigens by stromal cells in the thymus is essential to this process and depends, in part, on the activity of the autoimmune regulator (Aire) gene. Here we report the identification of extrathymic Aire-expressing cells (eTACs) resident within the secondary lymphoid organs. These stromally derived eTACs express a diverse array of distinct self-antigens and are capable of interacting with and deleting na?ve autoreactive T cells. Using two-photon microscopy, we observed stable antigen-specific interactions between eTACs and autoreactive T cells. We propose that such a secondary network of self-antigen-expressing stromal cells may help reinforce immune tolerance by preventing the maturation of autoreactive T cells that escape thymic negative selection.     

Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication

Antibodies against nuclear self-antigens are characteristic of systemic autoimmunity, although mechanisms promoting their generation and selection are unclear. Here, we report that B cells containing the Y-linked autoimmune accelerator (Yaa) locus are intrinsically biased toward nucleolar antigens because of increased expression of TLR7, a single-stranded RNA-binding innate immune receptor. The TLR7 gene is duplicated in Yaa mice because of a 4-Megabase expansion of the pseudoautosomal region. These results reveal high divergence in mouse Y chromosomes and represent a good example of gene copy number qualitatively altering a polygenic disease manifestation.     

Peripheral selection of the T cell repertoire

T lymphocytes undergo selection events not only in the thymus, but also after they leave the thymus and reside in the periphery. Peripheral selection was found to be dependent on T cell receptor (TCR)-ligand interactions but to differ from thymic selection with regard to specificity and mechanism. Unlike thymic selection, peripheral selection required binding of antigen to the TCR, and it induced expansion of T cell clones. Tolerance to self antigens that are restricted to the periphery occurred through the elimination of self-reactive T cells and by the clonal anergy, which was associated with down-regulation of the alpha beta TCR and CD8.     

Recognition by human V gamma 9/V delta 2 T cells of a GroEL homolog on Daudi Burkitt's lymphoma cells

All human gamma delta T cells coexpressing the products of the variable (V) region T cell receptor (TCR) gene segments V gamma 9 and V delta 2 recognize antigens from mycobacterial extracts and Daudi cells. Exogenous and endogenous ligands on the cell surface, homologous to the groEL heat shock family, induced reactivities that resembled superantigen responses in this major subset of human peripheral blood gamma delta T cells. Stimulation of human V gamma 9/V delta 2 T cells is not restricted by human leukocyte antigens (HLA), including nonpolymorphic beta 2-microglobulin (beta 2M)-associated class Ib molecules. These data may be important for understanding the role of gamma delta T cells in autoimmunity and in responses to microorganisms and tumors.     

Production of immunoglobulin isotypes by Ly-1+ B cells in viable motheaten and normal mice

Almost all B cells in autoimmune mice with the viable motheaten (mev) mutation express the Ly-1 cell surface antigen, which marks a minor population of B cells constituting a separate lineage in normal mice. Immunoglobulins primarily of the M and G3 classes, which in both normal and mev mice contain high levels of lambda light chain, are produced in excess in mev mice. These and other observations suggest that the development of B cells that express Ly-1 is regulated independently from the development of B cells that do not express Ly-1. B cells bearing the Ly-1 surface antigen may play specialized roles in the normal immune system and in autoimmunity by regulating other B cells via lymphokines, by producing antibodies to self and certain foreign antigens, and by preferentially secreting immunoglobulin M and immunoglobulin G3.     

Restoration of tolerance in lupus by targeted inhibitory receptor expression

Lupus, a multigenic autoimmune condition in which a breakdown of tolerance results in the development of autoantibodies, leads to a variety of pathologic outcomes. Despite the heterogeneity of factors influencing disease susceptibility, we demonstrate that the partial restoration of inhibitory Fc receptor (FcgRIIB) levels on B cells in lupus-prone mouse strains is sufficient to restore tolerance and prevent autoimmunity. FcgRIIB regulates a common B cell checkpoint in genetically diverse lupus-prone mouse strains, and modest changes in its expression can result in either tolerance or autoimmunity. Therefore, increasing FcgammaRIIB levels on B cells may be an effective way to treat autoimmune diseases.     

齐口裂腹鱼胸腺组织学研究

通过大体解剖及光学显微镜和透射电子显微镜技术对齐口裂腹鱼胸腺进行观察 ,发现齐口裂腹鱼的胸腺位于鳃腔背侧上角深处 ,第四鳃弓背侧 ,紧贴鳃腔膜下 ,左右各 1个 ,对称分布。胸腺实质分叶不明显 ,可分为 3个区 ,即外区、中区和内区 ,中区和内区分界不明显。中区染色深 ,细胞排列紧密 ,内区细胞排列疏松 ,两区主要由淋巴细胞和网状上皮细胞构成 ,有类似于高等脊椎动物胸腺的皮质和髓质区域。在齐口裂腹鱼胸腺中还发现有少量的浆细胞和肥大细胞     

Neonatal thymectomy results in a repertoire enriched in T cells deleted in adult thymus

In B6AF1 mice, T lymphocytes that use the V beta 11-positive (and not V beta 6-positive or V beta 8-positive) segment in their receptor for antigen are greatly reduced in the thymus and peripheral lymphoid tissues, most likely as a result of clonal deletion. The relative number of V beta 11-positive cells in adult lymph nodes was ten times as high in B6AF1 mice thymectomized 1 to 4 days after birth as in normal mice. Moreover, for the first 10 days of life of B6AF1 mice, mature V beta 11-positive T cells were readily detected in the thymus and spleen. Thus neonatal thymectomy results in the maintenance of the receptor repertoire of early postnatal life, and this correlates with the subsequent development of organ-specific autoimmune diseases.     

中华鳖胸腺的显微与亚显微结构研究

中华鳖胸腺表面覆盖有薄层被膜，实质被小梁分成若干小叶，胸腺小叶由周缘的皮质和中央的髓质构成。皮质淋巴细胞密集，着色深；髓质淋巴细胞较稀疏，着色淡，上皮网状细胞轮廓清晰，网状纤维含量多。实质中还分有类肌细胞、嗜派若宁细胞、巨噬细胞和肥大细胞。ＡＮＡＥ阳性细胞主要分布于皮质－髓质交界处和血管周围。     

Autoimmune encephalomyelitis: activation of thymus lymphocytes against syngeneic brain antigens in vitro

Thymus lymphocytes of normal adult rats were autosensitized in vitro against soluble antigens extracted from the brains of syngeneic rats. Injection of the autosensitized lymphocytes into syngeneic rats led to the development of brain lesions suggestive of autoimmune encephalomyelitis. Injection of control lymphocytes or the antigen extract alone did not cause lesions. Since sensitization in vitro requires the presence of lymphocytes programmed with specific receptors, the results indicate that normal rats have lymphocytes capable of recognizing central nervous system self-antigens. Hence, regulatory mechanisms, inoperative in vitro, probably function in vivo to prevent immune activation of self-recognizing lymphocytes and autoimmunity. This concept suggests a new approach to exploring the pathogenesis of autoimmune diseases.     

花鲈胸腺显微结构与超微结构的研究

采用光镜和电镜技术研究花鲈(Lateolabrax japonicus)胸腺的组织结构。花鲈胸腺位于鳃腔背侧上角深处,第4鳃弓背侧,紧贴在鳃腔上皮层之下,为鳃盖粘膜所覆盖,呈一对卵圆形的薄片组织。光镜下,胸腺实质的结构可明显分为外区、中区和内区。外区为鳃腔膜之下,由粘液细胞、胸腺上皮细胞和淋巴细胞构成;中区细胞多且排列紧密,染色深;内区细胞少,排列疏松,染色浅,中区和内区主要由淋巴细胞和胸腺上皮细胞构成,类似于哺乳动物胸腺的皮质和髓质。电镜下观察了花鲈胸腺中的淋巴细胞、胸腺上皮细胞、巨噬细胞、浆细胞、肥大细胞、凋亡的淋巴细胞、血-胸腺屏障。并对花鲈胸腺各分区的结构、各种细胞的形态进行了描述和讨论。     

Dendritic cell apoptosis in the maintenance of immune tolerance

Apoptosis in the immune system is critical for maintaining self-tolerance and preventing autoimmunity. Nevertheless, inhibiting apoptosis in lymphocytes is not alone sufficient to break self-tolerance, suggesting the involvement of other cell types. We investigated whether apoptosis in dendritic cells (DCs) helps regulate self-tolerance by generating transgenic mice expressing the baculoviral caspase inhibitor, p35, in DCs (DC-p35). DC-p35 mice displayed defective DC apoptosis, resulting in their accumulation and, in turn, chronic lymphocyte activation and systemic autoimmune manifestations. The observation that a defect in DC apoptosis can independently lead to autoimmunity is consistent with a central role for these cells in maintaining immune self-tolerance.