Immunopathological Diseases Research Articles

Inhibitory effects of leaf extracts of Stachytarpheta jamaicensis (Verbenaceae) on the respiratory burst of rat macrophages.

The anti-oxidant effects of ethyl acetate (EAcE) and n-hexane extracts (nHE) of dried leaves of Stachytarpheta jamaicensis Vahl. (Verbenaceae) on the reactive oxygen species (ROS) generating during the respiratory burst of rat peritoneal macrophages were investigated. Only EAcE, at concentrations between 0.4 and 40 microg/ml, inhibited the extracellular release of oxygen radicals by resident peritoneal macrophages stimulated with phorbol-12-myristate 13-acetate (PMA). At concentrations above 40 microg/ml, EAcE inhibited the production of nitric oxide (NO) in macrophages stimulated in vivo with sodium thioglycollate then in vitro with lipopolysaccharide (LPS) and gamma-interferon (IFN-gamma). nHE extracts at concentrations between 0.4 and 40 microg/ml did not scavenge (O-)2 generated enzymatically by hypoxanthine/xanthine oxidase (HX/XO) system, but EAcE at the same concentrations showed potent (O-)2-scavenging activity. At 40 microg/ml, EAcE also inhibited XO activity. These results suggest that the EAcE extract of S. jamaicensis may be a potential pharmaceutical value in treatment of immunopathological diseases related to oxidative stress.

Autoimmune Diabetes mellitus, Hodgkin’s Disease and Graves’ Ophthalmopathy in a Patient with 8.1 Ancestral Haplotype

In this report, we describe the case of a 43-year-old woman affected by type 1 diabetes mellitus diagnosed 8 years before, who developed Graves' disease 2 years after chemotherapy and mantle radiotherapy treatment for Hodgkin's disease. Bilateral Graves' ophthalmopathy appeared four months before our observations. Intravenous methyl-prednisolone therapy was started, but was interrupted due to severe metabolic failure. Autoantibodies (anti-islet cells, anti-thyroid, thyroid-stimulating, non-organ-specific) were positive. Since the clinical picture suggested a genetic immunological ground predisposing to autoimmunity, we evaluated her HLA haplotype. Genomic typing of the patient permitted identification of the 8.1 ancestral haplotype, a Caucasoid haplotype unique in its association with many immunopathological diseases. Moreover, we also observed a haplotype unusual in Caucasians, trans DRB1*1101, DQA1*0103, DQB1*0603. To our knowledge, HLA-related genetic risk of developing thyroid autoimmunity after neck irradiation has never been studied. Although we cannot confirm a direct association between the 8.1 ancestral haplotype or DRB1*1101, DQA1*0103, DQB1*0603 and the diseases described, we suggest considering immunological parameters and HLA typing in candidate patients for mantle radiation therapy for Hodgkin's disease or other tumors. HLA haplotype determination could be useful in identifying the patients at raised risk of developing autoimmune diseases after irradiation, thus permitting a more appropriate follow-up schedule.

High-Density SNP genotyping defines 17 distinct haplotypes of the TNF block in the Caucasian population: Implications for haplotype tagging

The region spanning the tumor necrosis factor (TNF) cluster in the human major histocompatibility complex (MHC) has been implicated in susceptibility to numerous immunopathological diseases, including type 1 diabetes mellitus and rheumatoid arthritis. However, strong linkage disequilibrium across the MHC has hampered the identification of the precise genes involved. In addition, the observation of "blocks" of DNA in the MHC within which recombination is very rare, limits the resolution that may be obtained by genotyping individual SNPs. Hence a greater understanding of the haplotypes of the block spanning the TNF cluster is necessary. To this end, we genotyped 32 human leukocyte antigen (HLA)-homozygous workshop cell lines and 300 healthy control samples for 19 coding and promoter region SNPs spanning 45 kb in the central MHC near the TNF genes. The workshop cell lines defined 11 SNP haplotypes that account for approximately 80% of the haplotypes observed in the 300 control individuals. Using the control individuals, we defined a further six haplotypes that account for an additional 10% of donors. We show that the 17 haplotypes of the "TNF block" can be identified using 15 SNPs.

A promoter polymorphism in the central MHC gene, IKBL, influences the binding of transcription factors USF1 and E47 on disease-associated haplotypes.

The human major histocompatibility complex (MHC) contains genes that affect susceptibility to numerous immunopathological diseases. We propose that genes in the central MHC between TNFA and HLA-B explain associations between the 8.1 haplotype (HLA-A1, B8, DR3) and disease. IKBL encodes a protein resembling members of the IkappaB protein family that regulate bioavailability of NFkappaB. We have identified two polymorphisms in the 500 bp upstream of the transcription start site of IKBL that distinguish the 8.1 haplotype from the resistant 7.1 haplotype (HLA-A3, B7, DR15). A single nucleotide polymorphism at -62 disrupts a putative E-box binding sequence. To investigate binding of transcription factors in vitro, we exposed 32P-labeled DNA fragments carrying both alleles to nuclear extracts, showing allele-specific binding of nuclear proteins from Jurkat cells but not from other lineages. Supershift studies using Jurkat nuclear extract showed that the E-box protein, E47, and ubiquitously expressed transcription factor USF1 bind to the E-box element of the 7.1 haplotype. Transient transfections of luciferase reporter constructs carrying promoter alleles of IKBL into Jurkat cells showed an effect of IKBL-62 alleles. In contrast, alleles at -421 did not affect transcription factor binding or transcription. IKBL was expressed at low levels in Jurkat cells but not in blood mononuclear cells, and expression declined following mitogenic stimulation. The restriction of IKBL expression to Jurkat cells is consistent with evidence that E47 is expressed in thymocytes and suggests IKBL may affect autoimmunity through an effect on T-cell selection.

Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: a genetically determined defect of C4 influences immunological parameters of healthy carriers of the haplotype

Subjects with certain HLA alleles have a higher risk of specific autoimmune diseases than those without these alleles. The 8.1 ancestral haplotype (AH) is a common Caucasoid haplotype carried by most people who type for HLA-B8,DR3. It is unique in its association with a wide range of immunopathological diseases. To gain insight into the identification of the mechanism(s) of disease susceptibility of 8.1 AH carriers, we have investigated the prevalence of circulating immune complexes and non-organ-specific autoantibodies in healthy carriers of the haplotype. The results show that carriers of 8.1 AH display both a significant increased prevalence of immune complexes and higher titers of anti-nuclear autoantibodies. This AH carries a single segment characterized by no C4A gene. This null allele does not code for a functional C4A protein that likely plays an anti-inflammatory role being specialized in the opsonization and immunoclearance processes. So, this genetic defect has been claimed to allow that an increased production of autoantibodies directed vs. cells that have undergone apoptosis and are not efficiently disposed because a reduced antigenic clearance. The results obtained in the present study fit very well with this hypothesis. In the AH carriers the simultaneous high setting of tumor necrosis factor (TNF)-α may supply the autoantigens (providing an excess of apoptotic cells) that drive the autoimmune response. In conclusion, the C4 defect associated to the increased spontaneous release of TNF-α, modifying a certain number of immunological parameter may be the most characterizing feature of the 8.1 AH. In the majority of individuals, an autoimmune response clinically relevant will develop only in the presence of other immunological abnormalities.

When T-helper cells don't help: immunopathology during concomitant infection.

Disease directly caused by immune system action is known as immunopathology. Many factors may lead the immune system to cause rather than cure disease, and autoimmune, allergic, and infection-related immunopathological diseases affect millions of people worldwide. This review presents an analysis of T-helper cell mediated, infection-related immunopathology within the framework of evolutionary ecology. A proximate cause of infection-related immunopathology is an error in the type of T-helper response induced. Distinct subsets of T-helper cells enable different effector mechanisms and therefore work optimally against different types of parasites (e.g., extracellular versus intracellular parasites). Immune responses that cure rather than cause disease require that the T-helper subset be tailored to the parasite. It is thus critical for the immunophenotype to match the "environment" of the parasitic infection. As in other cases of adaptive plasticity, a mismatch between an organism's phenotype and the selective environment can decrease fitness. T-helper response induction may be confounded by coinfection of a single host by multiple parasite species. Because of normally adaptive feedback loops that lend to polarize T-helper responses, it can become impossible for the immune system to mount effective, conflicting responses concurrently. Immunophenotype-environment mismatches may thus be inevitable when simultaneous, conflicting immune responses are required. An ultimate cause of infection-related immunopathology in a multiparasite selection regime is the T-helper response polarization that can propagate response errors and constrain the ability of the immune system to resolve conflicting response requirements. A case study is used to illustrate how coinfection can exacerbate immunopathology and to frame testable predictions about optimal responses to coinfection (e.g., is the observed joint response to coinfection accurately predicted by the average of the component single-infection optimal responses, where the single-infection optima are weighted by the contribution of each to fitness). The case study includes immunological and pathological data from mice infected by Schistosoma mansoni alone and by S. mansoni in combination with Toxoplasma gondii. Such data can inform hypothesis tests of evolutionary ecological principles, and ecological analysis can in turn clarify assumptions about responses to coinfection for a greater understanding of the immune system. The synthesis of evolutionary ecology and immunology could therefore be of mutual benefit to the two disciplines.

Lymphocytic choriomeningitis virus and immunology.

I. Neonatal tolerance, absence of immunity after intra-uterine or neonatal infection (TRAUB 1936, 1938). The comprehensive view and interpretation was made by BURNET (1949). 2. Immunity can cause disease (RowE 1954; HOTCHIN 1962). 3. Different LCMV isolates and mutants exhibit distinct tropism and distinct immunopathological diseases (HOTCHIN 1962; JACOBSON 1980; AHMED et al. 1984). 4. Immunity controls virus only partially, since virus survives at low levels (infection-immunity) (RowE 1954; VOLKERT and LUNDSTEDT 1968; CIUREA et al. 1999), but adoptive cytotherapy of virus-carriers (OLDSTONE et al. 1986) is possible by CD8 + T cells and/or CD4 + T cells plus neutralizing antibodyproducing B cells (VOLKERT 1963; PLANZ et al. 1997). 5. Immune complexes in neonatal virus-carriers question B cell tolerance (OLDSTONE and DIXON 1967). 6. Cytotoxic T cells (CTLs) against virus-infected cells act comparably to alloreactive CTLs (OLDSTONE and DIXON 1970; MARKER and VOLKERT 1973). 7. CTLs cause lethal pathology in the form of T cell-mediated choriomeningitis (COLE et al. 1972). 8. T cells (MIMS and BLANDEN 1972), (in particular CTLs, DOHERTY et al. 1976; ZINKERNAGEL and WELSH 1976) also mediate anti-viral protection against LCMV, as had first been shown for ectromelia virus by R.V. Blanden. 9. MHC disease association of choriomeningitis (OLDSTONE et al. 1973; ZINKERNAGEL et al. 1985) and of aggressive hepatitis (LEIST et al. 1989). 10. CTLs recognize a combination of MHC plus viral antigen (MHC restriction) (ZINKERNAGEL and DOHERTY 1974). Heterozygous MHC expands T cell repertoire and response (hybrid vigor) (DOHERTY and ZINKERNAGEL 1975). MHC class I regulates cytotoxic T cell immune response (DOHERTY et al. 1978; ZINKERNAGEL et al. 1978).

On natural and artificial vaccinations.

This review summarizes the general parameters of cell- and antibody-mediated immune protection and the basic mechanisms responsible for what we call immunological memory. From this basis, the various successes and difficulties of vaccines are evaluated with respect to the role of antigen in maintaining protective immunity. Based on the fact that in humans during the first 12-48 months maternal antibodies from milk and serum protect against classical acute childhood and other infections, the concept is developed that maternal antibodies attenuate most infections of babies and infants and turn them into effective vaccines. If this "natural vaccination" under passive protective conditions does not occur, acute childhood diseases may be severe, unless infants are actively vaccinated with conventional vaccines early enough, i.e., in synchronization with the immune system's maturation. Although vaccines are available against the classical childhood diseases, they are not available for many seemingly milder childhood infections such as gastrointestinal and respiratory infections; these may eventually trigger immunopathological diseases. These changing balances between humans and infections caused by changes in nursing habits but also in hygiene levels may well be involved in changing disease patterns including increased frequencies of certain autoimmune and degenerative diseases.

Diagnostic value of the detection of t(14;18) chromosome translocation in malignant hematological and immunopathological diseases using polymerase chain reaction.

The majority of the t(14;18) chromosome translocations that occur in non-Hodgkin centroblastic-centrocytic follicular lymphoma can be detected by various methods. During the translocation process the bcl-2 gene located on chromosome 18 (18q21) is translocated to the JH region of the immunoglobulin gene of chromosome 14 (14q32). The most frequent type of bcl-2 translocations is the mbr type, whereas the immunoglobulin gene breaks mainly at the JH1-6 exons. About one of the 10(5) cells bearing the translocation can already be detected by using nested polymerase chain reaction (PCR). Eight patients suffering from follicular lymphoma were included in this study, which considered the usefulness of the PCR method. The results are in good agreement with those obtained by conventional diagnostic methods. Translocation can be detected, however, in patients with non-malignant diseases such as Sjögren's syndrome (about 5% of the patients) and in a patient with Whipple disease. In addition, translocation was detected in lymphocytes of peripheral blood of a healthy donor. Since lymphomas are detected in patients with Sjögren's syndrome with a relative high frequency, an early diagnosis of the translocation could improve the treatment of the disease. Nevertheless, a diagnosis of lymphoma is valid only in cases of bone marrow translocation-positivity.

Tumor Necrosis Factor-α Production Is Differently Regulated in γδ and αβ Human T Lymphocytes

Tumor necrosis factor-alpha (TNF-alpha) plays a crucial role in the early defense against pathogens. This cytokine is produced by several cell types including T lymphocytes expressing the alphabeta as well as the gammadelta T cell receptor (TcR). In human, the circulating gammadelta T cells, which mostly express Vgamma9Vdelta2 TcR, have been strongly suggested to play an important protective role against infectious agents. These activated cells early produce high amounts of TNF-alpha, which induce a determinant beneficial effect against development of intracellular pathogens; however, sustained production of this cytokine can result in immunopathological diseases. The signals that regulate TNF-alpha production in Vgamma9Vdelta2 T cells are totally unknown. In primary alphabeta T cells, TNF-alpha production was shown to necessitate engagement of the TcR and CD28, and to be independent of the p38 mitogen activated protein kinase pathway. We demonstrate herein that, in contrast to alphabeta T cells, TNF-alpha production in Vgamma9Vdelta2 T lymphocytes is independent of CD28 costimulation and highly dependent on TcR-induced p38 kinase and extracellular signal-regulated kinase 2 pathway activation for optimal cytokine release. Moreover, we bring elements supporting the idea that the "activation threshold" of gammadelta T cells leading to cytokine production is lower than that of alphabeta T cells.

Characterisation of the Human Central MHC Gene, BAT1: Genomic Structure and Expression

The BAT1 gene (D6S81E) encodes a member of the DEAD-box family of RNA-binding proteins, and lies in the central MHC. This region contains genes which affect susceptibility to immunopathological diseases. A 14-kb section of the human MHC containing the BAT1 gene and a further 5-kb telomeric of BAT1 was sequenced using DNA from individuals homozygous for HLA-A1, B8, DR3 and HLA- A1, B57, DR7. Analysis of our sequences and the previously reported human cDNA sequence showed that the expressed sequence of the 8.1 and 57.1 haplotypes is identical with only minor substitutions in the introns. Phylogenetic analysis suggests BAT1 may be a translation initiation factor. Screening of cells and tissues for BAT1 mRNA suggests an abundant member of a family of proteins expressed in multiple cell types, notably macrophages and hepatocytes. Expression was independent of MHC haplotype, consistent with the lack of sequence polymorphism.

The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases.

An individual's major histocompatibility complex (MHC) ancestral haplotype (AH) is the clearest single determinant of susceptibility to MHC associated immunopathological disease, as it defines the alleles carried at all loci in the MHC. However, the direct effects of any of the 150-200 genes that constitute the MHC are difficult to determine since recombination only occurs at defined hotspots. This review concerns the 8.1 AH (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2), which is carried by most Caucasians with HLA-B8. It is associated with accelerated human immunodeficiency virus (HIV) disease, and susceptibility to insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus, dermatitis herpetiformis, common variable immunodeficiency and IgA deficiency, myasthenia gravis and several other conditions. We have mapped susceptibility genes for HIV, IDDM and myasthenia gravis to the central MHC between HLA-B and the tumour necrosis factor or complement genes. Here we consider which of the remaining 8.1-associated diseases are more closely associated with HLA-DR3 and/or DQ2. Several candidate genes in the central MHC have the potential to modulate immune or inflammatory responses in an antigen-independent manner, as is seen in studies of cultured cells from healthy carriers of the 8.1 AH. Hence these genes may act as a common co-factor in the diverse immunopathological conditions associated with the 8.1 AH.

Structure and polymorphism of two stress-activated protein kinase genes centromeric of the MHC: SAPK2a and SAPK4.

As MHC genes are potent determinants of susceptibility to immunopathological diseases, the mapping of SAPK2a (CSBP) and SAPK4 to chromosome 6p 21.2-21.3 suggested that these genes may mediate the effects of the MHC on disease. Here we describe the genomic structure and localisation of both genes approximately 2.3Mb centromeric of HLA-DP. Examination of the complete coding region and selected intronic regions of SAPK2a and SAPK4 from 22 human EBV-transformed B-cell lines of different MHC haplotypes and racial background revealed complete sequence conservation. There were no notable differences in levels of expression of SAPK2a and SAPK4 mRNA in cell lines of different MHC haplotypes or racial origin. Examination of the SAPK2a and SAPK4 sequences from two chimpanzees revealed 3 nucleotide differences between human and chimpanzee in each gene resulting in only one amino acid change in SAPK4, and 6 nucleotide substitutions plus 2 deletions in 600bp of intronic sequence from SAPK4. This highlights the selective pressure placed on these genes to maintain their protein sequence, but does not favour a role in genetic regulation of disease or provide evidence of linkage disequilibrium with the MHC.

Induction of IgG Rheumatoid Factor (RF) Production by Antibody–antibody (RF-like) Immune Complexes: the Role of T cells, Complement and Fcγ Receptors

Rheumatoid factors (RF) are autoantibodies with specificity for the constant regions of IgG molecules. They are found in several immunopathological diseases. The mechanism(s) by which these autoantibodies are produced is largely unknown. We have previously shown that a single injection of RF-like immune complexes (ICs) into mice selectively induced an intense IgG1-antibody production with RF activity. This response was sustained for several months and did not resemble a conventional immune response to an antigen or other immune complexes. In the present study, we sought to elucidate the mechanism for the IgG1 RF response to RF-like ICs. Therefore, the roles of CD4+T cells, complement and Fcγ receptors were analysed. In order to characterize the role of CD4+T cells, RF-like induced IgG1-RF production was analysed in NZB mice treated with a monoclonal antibody (mAb) against the CD4 molecule, which resulted in complete abrogation of IgG1 RF production. To evaluate the importance of FcγRs, the effect of RF-like ICs was tested in mice deficient for RFγRI/III. A significant decrease in the numbers of IgG1 antibody secreting cells, as well as in serum IgG1 RF levels, was found in the deficient mice, as compared with their normal outbred littermates. The role of complement in RF-like ICs mediated IgG1 RF was tested in complement depleted NZB mice, using Cobra venom factor. The IgG1 RF response in complement depleted and intact mice was comparable. Thus, our results demonstrate that RF-like immune complexes selectively induce an FcγR-dependent, complement independent antibody response in mice.

Role of repetitive antigen patterns for induction of antibodies against antibodies.

Antibody responses against antibodies, such as rheumatoid factors, are found in several immunopathological diseases and may play a role in disease pathogenesis. Experience shows that they are usually difficult to induce experimentally. Antibodies specific for immunoglobulin constant regions (anti-allotypic) or for variable regions (anti-idiotypic) have been investigated in animal models; the latter have even been postulated to regulate antibody and T cell responses via network-like interactions. Why and how such anti-antibodies are induced during autoimmune diseases, has remained largely unclear. Because repetitively arranged epitopes in a paracrystalline structure of a viral envelope cross-link B cell receptors efficiently to induce a prompt T-independent IgM response, this study used immune complexes containing viruses or bacteria to evaluate the role of antigen pattern for induction of anti-antibody responses. We present evidence that antibodies bound to strictly ordered, but not to irregularly arranged, antigens dramatically enhance induction of anti-antibodies, already after a single immunization and without using adjuvants. The results indicate a novel link between anti-antibody responses and infectious agents, and suggest a similar role for repetitive self-antigens such as DNA or collagen involved in chronic immunopathological diseases.

Nitric oxide in cardiovascular diseases.

Nitric oxide (NO), synthesized from L-arginine by a family of NO synthases (NOS), is a widespread biological mediator implicated in many physiological and pathophysiological processes, including a variety of cardiovascular diseases. Endothelium-derived NO, synthesized by a constitutive NOS, is involved in hypertension, atherosclerosis and certain heart diseases. In hypertension and atherosclerosis the role of NO is still controversial and seems to vary depending on the stage of the disease and model studied. In spontaneous hypertension, the production of NO is increased, but inefficacious, probably because of increased inactivation. In salt-induced hypertension NO production may be impaired. In atherosclerosis, an enhanced degradation of NO by superoxide radicals may explain the reduced endothelium-dependent relaxations. In pulmonary hypertension, the use of NO gas inhalation has been proposed as a future therapy for this condition. In the heart, NO regulates coronary flow and myocardial function; both functions are altered in coronary artery disease and cardiomyopathy. Nitric oxide synthesized by the inducible NOS takes part in several immunopathological diseases, such as endotoxin shock, which can particularly affect the heart. In endotoxaemia inducible NOS is overexpressed and the excess in NO production may account for the impaired cardiac performance of this condition. The overproduction of NO occurring in endotoxin shock is also responsible for the hypotension, catecholamine resistance and tissue damage characteristic of this disease. Treatment with inhibitors of NO synthesis is a promise for the future.

Effects of systemic complement activation on renal circulation of rats

In a variety of immunopathological diseases activation of the complement cascade occurs either systemically or localized in the kidney. To elucidate the functional impact of complement activation upon the renal microcirculation, we administered cobra venom factor of Naja naja kaouthia (CVF) i.v. into thiobarbital anaesthetized female rats. CVF is a potent activator of the alternative pathway of complement by forming the C3-convertase CVF, Bb which cannot be downregulated by the natural inhibitor factors H and I and thereby leads to generation of the anaphylatoxins C3a and C5a and formation of the membrane attack complex (MAC). We utilized creatinine clearance and flowmeter measurements in the normal kidney and intravital microscopy of the split hydronephrotic rat kidney model to observe the microvascular changes. Bolus injection of CVF (100 U kg-1) resulted in an immediate reduction of RBF (-68% after 10 min), which remained decreased during the entire experiment (90 min). Systemic blood pressure was significantly reduced only in the early period (-23% of control: 126 mmHg after 10 min). After an initial anuric phase of 30 min duration, the glomerular filtration rate was significantly diminished by 47%. White cell count was decreased by about 50% after the experiments. Application of the competitive thromboxane A2-antagonist, BM 13505, reversed all renal and systemic CVF-effects. Continuous infusion of the competitive leukotriene D4-antagonist, ICI 198615, attenuated the late renal CVF-effects (i.e. 30 min after injection of CVF). Depletion of polymorphonuclear cells (PMN) attenuated the CVF-effects similar to BM 13505. Intravenous administration of CVF in the hydronephrotic kidney model resulted in a massive constriction of the interlobar and arcuate artery, with a fall in glomerular blood flow comparable to the reduction of RBF in the normal kidney. Diameters of the afferent arterioles--most sensitive to many vasoconstricting agents--were not significantly altered. Our results suggest that injection of CVF and the liberation of high amounts of the anaphylatoxins, C3a and C5a, induces the release of TXA2, which contributes to the early renal effects and the formation of cysteinyl-leukotrienes which play an important role in the late phase of systemic complement activation. Utilizing the split hydronephrotic kidney model we demonstrated the predominant action of complement activation on the large preglomerular vessels for the first time. PMN are seemingly involved in the liberation of secondary mediators which appear to reduce renal blood flow and glomerular filtration.

Vaccination or tolerance to prevent diabetes.

Experiments with transgenic mice expressing the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) under the control of the rat insulin promoter (RIP) have demonstrated that potentially self-reactive T cells that normally ignore self peptides may nevertheless be induced by self peptides or "cross-reactive" foreign (e.g. viral) peptides that arise in the host in an immunogenic form; once activated these potentially self-reactive T cells may cause autoaggressive diseases (e.g. diabetes). The possibility of vaccinating against such T cell-mediated immunopathological diseases was evaluated in the RIP-GP transgenic mouse line Bln. Any attempt to vaccinate with the self antigen itself (e.g. recombinant vaccinia virus expressing LCMV-GP) failed to protect mice from disease. However, immunization with a recombinant vaccinia virus expressing LCMV-nucleoprotein (vacc-NP) as a non-GP LCMV vaccine was able to modulate the immune response and prevented autoaggressive disease in a MHC-dependent fashion. In contrast, tolerance induction neonatally or, more generally applicable, by lethal irradiation and reconstitution with neo-self antigen-expressing bone marrow cells always resulted in prevention of virally induced diabetes in this model situation.

The adrenoblockers influence on bone marrow cytokines production after stress

A major function of NKG2D linking innate and adaptive immunity is to upregulate antigen-specific CTL-mediated cytotoxicity in tissues expressing stress-induced NKG2D ligands, such as MIC, by coactivating TCR signaling. Here, we show that, under conditions of dysregulated IL15 expression in vivo in patients with celiac disease and in vitro in healthy individuals, multiple steps of the NKG2D/DAP10 signaling pathway leading to ERK and JNK activation are coordinately primed to activate direct cytolytic function independent of TCR specificity in effector CD8 T cells. These findings may not only explain previous reports of transformation of CTL into NK-like “lymphokine-activated killers” (LAK cells) under high doses of IL2 (a substitute for IL15) but may also have significant implications for understanding and treating immunopathological diseases.

The positive aspects of medical ethics today.

The author of this comment suggests that some of the important points made by Dr Adrian Rogers are vitiated by a tendency to contrast the worst of modern medical practice with an over-idealised view of the past. The state of medical ethics today, the author suggests, is more hopeful than Dr Rogers allows.