Uncertainties − discrepancies in immunology

Summary: The many immunological observations and results from in-vitro or in-vivo experiments vary, and their interpretations differ enormously. A major problem is that within a normal distribution of biological phenomena, which are measurable with many methods, virtually anything is possible. Within a coevolutionary context, the definition of biologically relevant thresholds is an important key to improve our understanding of weaknesses and strengths of the immune system. This review is a personal view, comparing textbook rules and experiments using model antigens with observations on immunity against infections or tumors to critically evaluate our perception and understanding of specificity, affinity maturation, antigen presentation, selection of the class of the immune response, immunological memory and protective immunity, positive selection of T cells and self/nonself discrimination.     

Pituitary corticotroph adenoma with crooke’s hyalinization

The diagnosis of pituitary corticotroph adenoma relies on the demonstration of a loss of the normal feedback control of adrenocorticotropic hormone (ACTH) biosynthesis by cortisol. The marked variability in the degree of ACTH suppression by glucocorticoids in these tumors, however, greatly enhances the difficulty in distinguishing Cushing’s disease from other syndromes of glucocorticoid excess. To illustrate this variability, we describe the clinical, biochemical, and morphological characteristics of a pituitary corticotroph adenoma in a 63-year-old woman, who presented with symptoms of a sellar mass but did not initially have florid Cushing’s disease. Light and electron microscopy of the pituitary tumor showed a corticotroph adenoma with Crooke’s hyalinization of the tumor cells, characterized by the accumulation of keratin immunoreactive microfilaments similar to those observed in normal corticotrophs in the presence of excess glucocorticoids. This case illustrates an unusual clinical presentation that may be associated with pituitary corticotroph adenoma showing Crooke’s hyalinization.     

Numerical chromosomal aberrations in prostate cancer: correlation with morphology and cell kinetics

Eleven routinely processed radical prostatectomy specimens were studied for the presence of numerical chromosomal aberrations by means of in situ hybridization with nucleic acid probes specific for chromosomes 7, 10, 17, X, and Y. Cytogenetic information was correlated with morphology, tumour stage and volume as well as with cell kinetics, the latter being assessed by immunohistochemistry with antibodies raised against the proliferative cell nuclear antigen (PCNA) and against a formalin-resistant epitope of the Ki-67 antigen, MIB 1. In 5 of 11 cases, numerical aberrations of at least one chromosome were found. The cases with normal chromosome numbers were those with the smallest volumes of Gleason grade 4 and/or 5 tumour (mean 0.5 cm³) and represented tumours restricted to the prostate. Tumours with aberrations in the number of detected chromosomes showed advanced stages and large volumes of high-grade tumour (mean 12.5 cm³). All 4 tumours with positive surgical margins were recruited from a group with marked local heterogeneity in chromosome numbers. Immunostaining with MIB 1 and PCNA was most intense in areas of high-grade tumour and was positively correlated with the emergence of chromosomal aberrations. The data suggest that the appearance of numerical chromosomal aberrations in prostate cancer coincides with aggressive tumour behaviour and could be used as an additional prognostic marker.This work is part of E.K.'s doctoral thesis     

Gene profiling reveals increased expression of uteroglobin and other anti-inflammatory genes in glucocorticoid-treated nasal polyps

BACKGROUND: Treatment with local glucocorticoids (GCs) decreases symptoms and the size of nasal polyps. This might depend on the downregulation of proinflammatory genes, as well as the upregulation of anti-inflammatory genes. OBJECTIVE: We sought to identify GC-regulated anti-inflammatory genes in nasal polyps. METHODS: Affymetrix DNA microarrays were used to analyze the expression of 22,283 genes in 4 nasal polyps before and after local treatment with fluticasone (400 microg/d). Expression of uteroglobin and mammaglobin B was analyzed with real-time PCR in 6 nasal polyps and in nasal biopsy specimens from 6 healthy control subjects. RESULTS: Two hundred three genes had changed in expression in treated polyps, and 139 had known functions: 54 genes were downregulated, and 85 were upregulated. Genes associated with inflammation constituted the largest single functional group. These genes affected key steps in inflammation (eg, immunoglobulin production; antigen processing and presentation; and the chemoattraction and activation of granulocytes, T cells, and B cells). Several proinflammatory genes were downregulated. In contrast, some anti-inflammatory genes were upregulated. The gene that increased most in terms of expression was uteroglobin. This was confirmed with real-time PCR. By contrast, expression of uteroglobin was lower in untreated polyps than in healthy nasal mucosa. Immunohistochemical investigation showed staining of uteroglobin in the epithelium and in seromucous glands in control subjects and in nasal polyps. CONCLUSION: Upregulation of anti-inflammatory genes, such as uteroglobin, might contribute to the effects of local treatment with GCs in nasal polyps.     

Hypergammaglobulinemia and autoantibody induction mechanisms in viral infections

Polyclonal hypergammaglobulinemia is a characteristic of chronic inflammatory conditions, including persisting viral infections and autoimmune diseases. Here we have studied hypergammaglobulinemia in mice infected with lymphocytic choriomeningitis virus (LCMV), which induces nonspecific immunoglobulins as a result of switching natural IgM specificities to IgG. The process is dependent on help from CD4+ T cells that specifically recognize LCMV peptides presented by B cells on major histocompatibility complex class II molecules. Thus, hypergammaglobulinemia may arise when specific helper T cells recognize B cells that have processed viral antigens irrespective of the B cell receptor specificity. This nonspecific B cell activation may contribute to antibody-mediated autoimmunity.     

Immunization with recombinant protein: conditions for cytotoxic T cell and/or antibody induction

Safe vaccines should optimally induce both cell-mediated and humoral immunity. Recently, it has been shown that protective cytotoxic T cells (CTLs) can be induced not only with live vaccines, but also with recombinant viral proteins. This report shows in C57BL/6 (H-2^b) mice that the recombinant nucleoprotein (N) of vesicular stomatitis virus (VSV) induced protective CTLs but no neutralizing antibodies in mice, whereas the recombinant glycoprotein (G) of VSV alone induced neutralizing antibodies but no CTLs. If the N and G of VSV were coinjected, both CTLs and a long-lasting neutralizing IgG response was measurable, demonstrating that mixed vaccines can be used to induce protective CTLs and antibodies with an efficiency comparable to live virus. In an attempt to define optimal conditions for CTL priming, the intravenous, intraperitoneal and subcutanous route of injection were compared. Intravenous injection of recombinant VSV-N induced up to 30 times higher responses than the latter two routes. Finally, we tried to define conditions inducing only CTLs and no antibodies binding to the native protein form, or vice versa, only antibodies and no CTLs. Intravenous injection of boiled VSV-N induced a CTL response but no antibodies specific for the native VSV-N, whereas VSV-N injected subcutanously in incomplete Freund's adjuvant induced high amounts of anti-VSV-N antibodies but virtually no CTLs. The conditions defined here permit vaccines to be designed which would function along selected and defined immunological effector pathways.     

材料参数与镍钛形状记忆合金的本构关系

在Ｔａｎａｋａ模型基础上，我们讨论了形状记忆合金热力学特性的本构关系。特别注意了桓温拉伸过程和强迫回复过程。本构方程的材料参数，即弹性模量Ｄ，变化张量Ω，热力弹性张量均以镍钛合金实验测试值来确定。在不同的应力－应变－温度关系试验中发现Ｄ和Ω与温度之间有很强的相关性。     

Characterization of DEAE-dextran by means of light scattering and combined size-exclusion chromatography/low-angle laser light scattering/viscometry

Ten DEAE (2-(diethylamino)ethyl) dextran samples were investigated by means of static and dynamic light scattering, viscometry and size-exclusion chromatography (SEC) in combination with on-line small-angle laser light scattering (LALLS) and viscometry (VISC). In dilute solution the behavior of DEAE-dextran was compared with that of unsubstituted dextran and the molecular weight M dependences of the radius of gyration R_g, hydrodynamic radius R_h, intrinsic viscosity [η], second virial coefficient A₂ and z-average diffusion coefficient D _z were determined. The relationships for DEAE-dextran dissolved in a 0,8 molar sodium nitrate solution were nearly the same as for dextran dissolved in water with 0,05 wt.-% sodium azide and gave the same exponents. The molecular weight dependence of the intrinsic viscosity cannot be described by a Kuhn-Mark-Houwink relationship with a constant exponent. The slope in the plot of log [η] versus log M decreases with increasing molecular weight which indicates the occurrence of branching. By means of SEC/LALLS/VISC measurements the molecular weight distributions were determined. The distributions were calculated (1) directly from the light scattering signal, (2) from a calibration line obtained by light scattering data of a DEAE-dextran sample with a broad distribution and (3) from the intrinsic viscosity distribution obtained by the on-line viscosity/refractive index detector in combination with the [η]-M relationship. In order to get the correct molecular-weight dependence of the intrinsic viscosity it is necessary to determine the molecular weight distribution directly by LALLS (technique 1) and to combine this with the appropriate intrinsic viscosity data from the viscometer. Only the third technique, which is an extension of technique 1, gave satisfactory results over the whole molecular weight region observed.