Immunoblastic lymphadenopathy-like T-cell lymphoma with multiple cutaneous and visceral involvements

Morphologic and immunological findings found in a patient with immunoblastic lymphadenopathy (IBL)-like T-cell lymphoma (IBL-T) are presented. Though the initial clinical features were suggestive of IBL, multiple cutaneous and visceral tumors appeared later in his course. The cutaneous lesion is considered to be unique, because the neoplastic T cells with suppressor/cytotoxic (S/C) phenotype showed focal epidermotropism, resulting in necrosis and ulceration of the overlying epidermis. An interesting feature in IBL-T is the frequent association of polyclonal hypergammaglobulinemia, yet the neoplastic T cells show S/C phenotype. Since Ia-like antigen was expressed on the neoplastic T cells, it is stressed that antigen-presenting and contrasuppressor cells should also be included in the cell populations which have a possibility to be a normal counterpart of IBL-T.     

高原红细胞增多症患者血清IL-2、IL-6及睾酮、雌二醇的水平及其意义

目的:探讨IL-2,IL-6及果酮、雌二醇在高原红细胞增多症的发病机制中的作用。方法:采用放射免疫法检测了20例高红症患者及20名正常人外周血上清中的IL-2,II,-6,皋酮、雌二醇水平。结果:高红症患者血清IL-6水平显著高于正常对照组(P<0.01);而高红症患者血清IL-2,翠酮及雌二醇水平同对照组相比无显著差异。结论:IL-6在高原红细胞增多症的发病过程中可能起一定的作用,而IL-2及性激素在高红症发病中作用不大。     

1,25-dihydroxyvitamin D3 stimulates interleukin-2 production by a T cell lymphoma line (MLA-144) cultured in vitamin D-deficient rat serum

A lymphocyte T cell line (MLA-144), which constitutively secretes interleukin-2 (IL-2), was shown to express receptors for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The proliferation of an IL-2-dependent cell line (HT-2) in response to supernatants from MLA-144 cells was employed as an index of IL-2 production by MLA-144 cells. IL-2 production was two fold higher from MLA-144 cells cultured in 2% vitamin D-deficient rat serum compared to 10% fetal calf serum (FCS). The addition of 1,25(OH)2D3 at 10(-15) M or 10(-11) M augmented IL-2 production by MLA-144 cells in vitamin D-deficient rat serum, but not in fetal calf serum. At 10(-7) M 1,25(OH)2D3 there was inhibition of IL-2 production by MLA-144 cells in either vitamin D-deficient serum or FCS. There was no effect of 1,25(OH)2D3 added directly to HT-2 cells. Monoclonal antibody to the IL-2 receptor competitively inhibited the proliferation of HT-2 cells in response to MLA-144 supernatants, suggesting that it was IL-2 from the MLA-144 supernatants which influenced HT-2 proliferation. Our findings demonstrate biphasic dose effects of 1,25(OH)2D3 on lymphokine secretion. The use of vitamin D-deficient rat serum allowed us to demonstrate the effects of 1,25(OH)2D3 in the physiologic and subphysiologic range.     

Mast cell interleukin-2 production contributes to suppression of chronic allergic dermatitis

The incidence of chronic allergic dermatitis is rapidly increasing. Regulatory control of this disease has not been adequately explored. Here we report that mast cell-derived interleukin-2 (IL-2) contributes to the suppression of chronic allergic dermatitis. Mice deficient in IL-2 production, or deficient in mast cells (Kit(W-sh/W-sh)), showed exacerbated dermatitis upon repeated oxazolone challenge when compared to their wild-type counterparts. Adoptive transfer of wild-type, but not Il2(-/-), mast cells into Kit(W-sh/W-sh) mice dampened the inflammatory response. During the course of disease, mast cell expansion occurred at the site of inflammation and also in the spleen, where production of IL-2 by mast cells was markedly enhanced. In the absence of mast cell IL-2 production, the ratio of activated to regulatory T?cells at the site of inflammation was increased. Thus, MC-derived IL-2 contributes to the maintenance of suppression in chronic allergic skin inflammation.     

Changes of soluble interleukin-2, interleukin-2 receptor, T8 antigen, and interleukin-1 in the serum of autistic children

Immune abnormalities in autistic children led us to study for indirect evidence of immune activation as measured by the serum analysis of soluble interleukin-2 (sIL-2), interleukin-2 receptor (sIL-2R), T8 antigen (sT8), and interleukin-1 (sIL-1). The serum concentration of these soluble antigens was quantitated by enzyme-linked immunosorbent assays. The concentration of sIL-2 and sT8, but not of sIL-2R and sIL-1, antigens was significantly (P less than 0.05) increased in the sera of autistic children over that in the control healthy children or children with mental retardation (non-Down's syndrome). This finding indirectly indicates that the activation of a subpopulation of T cells occurs in some children with autism.     

Interleukin-2-inducible T cell kinase regulates mast cell degranulation and acute allergic responses

Bruton's tyrosine kinase (Btk) is thought to positively regulate mast cell activation, implying a role in allergic responses. We have compared acute and late phase allergic airway reactions in mice lacking either Btk or interleukin-2-inducible T cell kinase (Itk), another Tec kinase expressed in mast cells. Btk(-/-) mice showed minor protection against allergic symptoms when challenged with allergen via the airways. In sharp contrast, both acute and late phase inflammatory allergic responses were markedly reduced in Itk(-/-) mice. Notably, airway mast cell degranulation in Itk(-/-) mice was severely impaired, despite wild-type levels of allergen-specific IgE and IgG1. The degranulation defect was confirmed in DNP-conjugated human serum albumin-challenged mice passively sensitized with anti-DNP IgE antibodies, and was also observed after direct G-protein stimulation with the mast cell secretagogue c48/80. Moreover, late phase inflammatory changes, including eosinophilia, lymphocyte infiltration, and Th2 cytokine production in the lungs, was eliminated in Itk(-/-) mice. Collectively, our data suggest a critical role of Itk in airway mast cell degranulation in vivo that together with an impaired T cell response prevents the development of both acute and late phase inflammatory allergic reactions.     

Human dendritic cell 1 and dendritic cell 2 subsets express FcepsilonRI: correlation with serum IgE and allergic asthma

BACKGROUND: Type 1 dendritic cells (DC1) express the high-affinity IgE receptor (FcepsilonRI); however, the regulation of FcepsilonRI expression by DCs is not well understood. Type 2 DC (DC2) expression of FcepsilonRI has not been demonstrated. OBJECTIVE: We hypothesized that DC2 cellsalso express FcepsilonRI and that expression of FcepsilonRI by the DC1 and DC2 subsets correlates with serum IgE and allergic asthma disease status. METHODS: To test these hypotheses, we quantitated FcepsilonRI alpha chain expression by the peripheral blood precursor DC1 (pDC1) and pDC2 subsets by using flow cytometry. RESULTS: FcepsilonRI was expressed by the pDC1 and pDC2 subsets, as well as tissue DCs from tonsils. Relative FcepsilonRI expression by basophil, pDC1, and pDC2 subsets was 12:6.5:1, respectively. In both pDC subsets, FcepsilonRI expression was significantly greater in allergic asthmatic subjects than in nonatopic control subjects. pDC1 and pDC2 expression of FcepsilonRI was highly correlated to serum IgE concentration. The pDC1, pDC2, and basophil subsets demonstrated a similar magnitude of increase in FcepsilonRI expression relative to changes in serum IgE. CONCLUSIONS: FcepsilonRI expression is characteristic of both the DC1 and DC2 subsets. Furthermore, FcepsilonRI expression by these cells is highly correlated to serum IgE and to basophil FcepsilonRI expression and is greater in subjects with allergic asthma. These data support the concept that novel therapeutic approaches directly targeted at FcepsilonRI expression would affect both the sensitization and the effector phases of the allergen-specific immune response.     

Immunoblastic lymphoma with abundant clear cytoplasm. A comparative study of B- and T-cell types

The morphologic, phenotypic, molecular genetic, and clinical features of 34 cases of clear-cell immunoblastic lymphoma (IBLC) are described. Sixteen cases were of B-cell type (IBLC-B) and 18 cases were of T-cell type (IBLC-T). There were no significant differences in the morphologic characteristics of the neoplastic cells in the two types, although IBLC-B was less likely to be polymorphic than IBLC-T. Interfollicular proliferation, a higher mitotic rate, infiltration by eosinophils, and an increase in capillary-sized blood vessels were also features of IBLC-T, whereas necrosis and fibrosis were more extensive in IBLC-B. Patients with IBLC-B were predominantly female, whereas those with IBLC-T were predominantly male. The mean age was 62 years for those with IBLC-B and 46 years for those with IBLC-T. Patients with IBLC-B usually had lower-stage disease, but there was no significant difference in survival rate between those with IBLC-B and those with IBLC-T. Although most cases of IBLC have been considered to be of peripheral T-cell origin, the authors conclude that IBLC-B is more common than previously considered and that clear-cell morphologic characteristics are not a reliable indicator of T-cell type.     

T cell sensitivity to HLA class I-mediated apoptosis is dependent on interleukin-2 and interleukin-4

Antibody interaction with a specific epitope of the HLA class I α1 domain triggers apoptosis of activated but not resting T and B cells by a pathway which involves neither Fas ligand nor tumor necrosis factor-α. We have investigated at which stage of activation and proliferation T cells become sensitive to HLA class I-mediated apoptosis, using two monoclonal antibodies (mAb) which recognize the same monomorphic epitope of the HLA class I α1 domain (mAb90, mouse IgG1, and YTH862, rat IgG2b) and can induce apoptosis of phytohemagglutinin (PHA)-activated peripheral blood lymphocytes. Sensitivity to apoptosis develops after the expression of G1 markers (CD69 expression) but it is accelerated by addition of recombinant interleukin-2 (rIL-2). Blocking the IL-2 pathway by cyclosporin A, FK506, rapamycin, anti-IL-2 or CD25 antibodies, prevented the development of sensitivity to apoptosis. Addition of IL-2 and, to a lesser extent, IL-4, reversed the inhibitory effect of cyclosporin A. Conversely, rIL-7 and recombinant interferon-γ restored proliferation of peripheral blood lymphocytes stimulated by PHA in the presence of cyclosporin A but did not restore sensitivity to class I-mediated apoptosis. Finally cells stimulated in the presence of the DNA polymerase inhibitor aphidicolin did not enter into S phase of the cell cycle but secreted IL-2 and underwent apoptosis when exposed to mAb90 or YTH862. Together, the data indicate that sensitivity of peripheral T cells to HLA class I-mediated apoptosis depends on both activation signals and IL-2 or IL-4, but does not require cell proliferation. These data suggest that YTH862 and mAb90 might be used for achieving clonal deletion of antigen-activated peripheral T cells in vivo, provided that the IL-2 pathway is not blocked by other immunosuppressive agents.     

Correlation of T cell receptor gene rearrangements to T cell surface antigen expression and to serum immunoglobulin level in scid mice

The severe combined immunodeficient (scid) mouse which has undetectable serum immunoglobulin (Ig) contains a small number of thymic lymphocytes which express Thy-1 and IL 2 receptors (IL 2R) but not Lyt-2 or L3T4 molecules. These thymocytes did not show any rearrangement of T cell receptor (TCR) β-chain genes. Such thymocyte characteristics in the scid mouse were similar to the 15-day embryonic thymocytes in ordinary mice, indicating that the scid mouse thymocytes are arrested in the early stage of intrathymic differentiation. However, low or medium level serum Ig was occasionally found in the littermates of the scid mouse. The thymocytes of these mice showed some evidence of TCR β-chain gene rearrangement and the presence of Lyt-2⁺/L3T4⁺ cells in correlation with the serum Ig level. In the mice with some serum Ig the thymocyte cell number was increased and the proportion of IL 2R⁺ cells was decreased. Collectively, these results suggest that the rearrangement of TCR β-chain genes is associated with the expression of Lyt-2 and L3T4 molecules in intrathymic differentiation and probably with cell proliferation of the migrated lymphoid cells in the scid mouse.     

混合性经典型霍奇金淋巴瘤合并T细胞淋巴瘤一例

混合性淋巴瘤是指两种不同类型的淋巴瘤同时发生。该例患者男性,44岁,因无意中发现左颈部肿物入院,彩超提示左颈部4 cm大小肿物。镜下见弥漫小淋巴细胞间散在核大异型细胞。免疫组织化学显示散在核大细胞CD15、CD30、MUM1、PAX5等标记阳性,EB病毒编码的小RNA(EBER)显色原位杂交(CISH)检测显示核大细胞阳性,符合经典型霍奇金淋巴瘤。免疫组织化学显示背景小淋巴细胞CD3、CD2、CD7等标志物阳性,EBER CISH检测显示部分细胞阳性,T细胞受体基因检测提示2个位点单克隆重排,符合T细胞淋巴瘤。混合性淋巴瘤治疗不同于普通的淋巴瘤,需要综合制定化疗方案。     

Characterization of bovine serum albumin epitopes and their role in allergic reactions

Objective:  This review provides updated information on conformational and sequential epitopes identified in bovine serum albumin (BSA) and summarizes available data about the role of structural modifications on BSA antigenicity/allergenicity.
Data sources:  Data on beef allergy and BSA antigenicity are reported, with reference both to the basic literature and to clinical results obtained by our group.
Results and discussion:  BSA is an important allergen involved in milk and beef allergy. The presence of conformational epitopes has been suggested by indirect evidence, while at least one sequential epitope has been experimentally identified. The role of structural modifications on BSA antigenicity is discussed as well as the increased tolerance observed in allergic subjects consuming beef as strained (homogenized) and freeze-dried derivatives.
Conclusion:  Study of the molecular characteristics of a known major allergen allows the identification of technological processes that may be capable of improving the tolerance of allergic subjects to a specific food. Even though any hoped for reduced allergenicity must be verified under medical supervision, the use of new products could obviate the need to avoid important foods such as meat in childhood.     

Effects of polyunsaturated fatty acids on interleukin-2-dependent T cell growth

Cellular membranes, in addition to serving as structural constituents of cells, also provide precursors for a number of chemical messengers involved in intracellular signal transduction. This includes the eicosanoids (prostaglandins and leukotrienes) and diacylglycerol, and activator of protein kinase C (PKC). Changes induced in the fatty acid profile of lymphocytes can influence vital metabolic processes in cells. Such changes, independent of the function of fatty acids as prostaglandin and leukotriene precursors, can alter the development and regulation of immune responses. In this report we study the effects of the polyunsaturated fatty acids (PUFA) on proliferation and signal transduction in the interleukin-2 (IL-2)-dependent murine T cell line CTL.L-2. Culture of CTL.L-2 cells in the presence of specific PUFA resulted in their incorporation into the cellular phospholipids. IL-2-induced proliferation of CTL.L-2 cells was markedly suppressed in a dose-dependent fashion by incubation in media supplemented with dihomogammalinolenic acid (an n-6 PUFA) slightly inhibited proliferation, while eicosapentaenoic acid (an n-3 PUFA) had no effect. Neither indomethacin (a cyclooxygenase inhibitor) nor nordihydroguaiaretic acid (NDGA, a lipoxygenase inhibitor) reversed the effect of DGLA. In contrast, phorbol 12-myristate 13-acetate (a phorbol ester and activator of PKC), blocked, in a dose-dependent manner, the antiproliferative effect of DGLA. This study presents evidence that PUFA alter signal transduction in cells in a manner which is separate from their function as eicosanoid precursors. The botanical lipid-derived DGLA has a potent suppressive effect on IL-2-driven T cell proliferation and may alter signal transduction by modification of second messenger or PKC activity.     

Hepatosplenic T cell lymphoma with no expression of cytotoxic molecules

Hepatosplenic T cell lymphoma is defined as an extranodal and systemic neoplasm derived from cytotoxic T cells. This report describes a postmortem case of T cell lymphoma that showed histological features of hepatosplenic T cell lymphoma but did not express cytotoxic molecules. The patient was a 57 year old man who presented with severe icterus and hepatosplenomegaly, followed by an aggressive clinical course. The liver and spleen were enlarged, weighing 2000 g and 360 g, respectively. Histologically, the liver, spleen, and bone marrow were entirely affected by lymphoma, comprising pleomorphic small and large cells, which displayed sinusoidal infiltration in the liver, diffuse infiltration in the splenic cord, and interstitial/diffuse infiltration with fibrosis in the bone marrow. Lymphoma cells showed positivity for CD3 epsilon, CD8, and CD45RO and clonal rearrangement of the TCRgamma gene by the polymerase chain reaction on paraffin wax embedded sections. However, they were negative for TIA-1 and granzyme B, in addition to betaF1, CD4, and CD56. Few neoplastic cells were stained for Epstein-Barr virus encoded mRNA 1. These findings indicate that this case might represent a variant of hepatosplenic T cell lymphoma despite the absence of cytotoxic molecules.     

Study of the immunohistochemistry and T cell clonality of enteropathy-associated T cell lymphoma.

Specimens from 23 patients with enteropathy-associated T cell lymphoma were studied by immunohistochemistry after antigen retrieval. Specimens from 14 of these patients were investigated for the presence of clonal T cell gene rearrangements in both the tumor and the adjacent enteropathic intestine by the polymerase chain reaction. Primers for T cell receptor beta and gamma genes were used in a combination that permits the identification of approximately 90% of T cell receptor rearrangements. Clonal rearrangements of the T cell receptor were found in 13 of the 14 tumors studied. Specimens of enteropathic bowel resected with the tumor, but showing no morphological or immunohistochemical evidence of tumor involvement, showed clonal T cell receptor gene rearrangements in 11 cases. In 10 of these, the amplified DNA was of the same molecular weight in the enteropathic bowel as in the corresponding tumor. In 2 cases, sequencing the polymerase chain reaction product showed identical T cell receptor gene rearrangements in the tumor and in the adjacent intestine. Uniform staining for p53 was seen in 22 of the 23 tumors. In 9 of 19 cases studied, collections of small lymphocytes in the enteropathic bowel expressed p53. In all but one of these specimens, a clonal rearrangement of the T cell receptor genes was identified. We interpret these findings as support for the concept that enteropathy-associated T cell lymphoma arises on a background of gluten-sensitive enteropathy with evolution of neoplastic T cell clones from the reactive T cell population present in the enteropathic bowel.     

轮状病毒肠炎患儿血清和大便IL-2,IL-6,IFN-γ动态变化及与临床指标关系的研究

目的　研究轮状病毒肠炎患儿血清和大便IL 2、IL 6、IFN γ的动态变化 ,及临床指标的关系。方法　采用双抗体夹心ELISA法。结果　 119例腹泻患儿RV阳性率 6 3.0 % ,当年 11月份为高峰月。这些细胞因子在病程中呈不同的高峰时相 ,大便IFN γ达峰值最早 ,血清及大便IL 2达峰值最晚 ,大便IL 2与IL 6差异有非常显著性 (P <0 .0 1) ,大便IL 2与IFN γ、IL 6与IFN γ、血清IL 2与IL 6、腹泻恢复时间与大便IL 2、血、便IL 2及IFN γ与淋巴细胞 +单核细胞均差异有非常显著性或差异有显著性 (P <0 .0 1或P <0 .0 5 )。结论　IL 2、IL 6、IFN γ在婴幼儿轮状病毒肠炎中发挥了重要的免疫调控作用 ,且与临床指标密切相关。