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OTHER ARTICLES PUBLISHED IN THIS MINI-REVIEW SERIES ON Th17 CELLS Function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04037.x Are T helper 17 cells really pathogenic in autoimmunity? Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04039.x CD4+ T helper cells: functional plasticity and differential sensitivity to regulatory T cell-mediated regulation. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04040.x Development of mouse and human T helper 17 cells. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04041.x Uncommitted (naive) CD4+ T helper cells (Thp) can be induced to differentiate to specific lineages according to the local cytokine milieu, towards T helper type 1 (Th1), Th2, Th17 and regulatory T cell (Treg) phenotypes in a mutually exclusive manner. Each phenotype is characterized by unique signalling pathways and expression of specific transcription factors, notably T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for Tregs and receptor-related orphan receptor (ROR)α and RORγt for Th17 cells. Tregs and Th17 cells have been demonstrated to arise from common precursors in a reciprocal manner based on exposure to transforming growth factor (TGF)-β or TGF-β plus interleukin (IL)-6 and carry out diametrically opposing functions, namely suppression or propagation of inflammation, respectively. However, while epigenetic modifications in Th1 and Th2 differentiated cells prevents their conversion to other phenotypes, Th17 cells generated in vitro using TGF-β and IL-6 are unstable and can convert to other phenotypes, especially Th1, both in vitro and in vivo. Tregs are generated from naive precursors both in the thymus (natural, nTregs) and in the periphery (induced, iTregs). The highly suppressive function of Tregs enables them to control many inflammatory diseases in animals and makes them particularly attractive candidates for immunotherapy in humans. The stability of the Treg phenotype is therefore of paramount importance in this context. Recent descriptions of Treg biology have suggested that components of pathogens or inflammatory mediators may subvert the suppressive function of Tregs in order to allow propagation of adequate immune responses. Unexpectedly, however, a number of groups have now described conversion of Tregs to the Th17 phenotype induced by appropriate inflammatory stimuli. These observations are particularly relevant in the context of cell therapy but may also explain some of the dysregulation seen in autoimmune diseases. In this paper, we review Treg to Th17 conversion and propose some potential mechanisms for this phenomenon. [ABSTRACT FROM AUTHOR]

OTHER ARTICLES PUBLISHED IN THIS MINI-REVIEW SERIES ON Th17 CELLS Function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04037.x Induction of interleukin-17 production by regulatory T cells. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04038.x Are T helper 17 cells really pathogenic in autoimmunity? Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04039.x CD4+ T helper cells: functional plasticity and differential sensitivity to regulatory T cell-mediated regulation. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04040.x There has been a considerable amount of interest in the immunological community about new phenotypic subsets of CD4+ T cells, particularly cells that produce the cytokine interleukin (IL)-17 [named T helper type 17 (Th17) cells]. While the initial discovery of Th17 cells and the pathways that controlled their development was in the mouse, recent attention has shifted to the existence of these cells and the relevant upstream cytokine signals in humans. While it is clear that CD4+ T cells producing IL-17 exist in vivo, their relevance to disease pathogenesis is only just being understood. In this paper, we review the data regarding the generation of human Th17 cells in vitro and the evidence that this effector population is important in human disease states. [ABSTRACT FROM AUTHOR]

High-dose intravenous immunoglobulin (IVIg) preparations are used currently for the treatment of autoimmune or inflammatory diseases. Despite numerous studies demonstrating efficacy, the precise mode of action of IVIg remains unclear. Paradoxically, IgG can exert both pro- and anti-inflammatory activities, depending on its concentration. The proinflammatory activity of low-dose IVIg requires complement activation or binding of the Fc fragment of IgG to IgG-specific receptors (FcγR) on innate immune effector cells. In contrast, when administered in high concentrations, IVIg has anti-inflammatory properties. How this anti-inflammatory effect is mediated has not yet been elucidated fully, and several mutually non-exclusive mechanisms have been proposed. This paper represents the proceedings of a session entitled ‘IVIg – Understanding properties and mechanisms’ at the 6th International Immunoglobulin Symposium that was held in Interlaken on 26–28 March 2009. The presentations addressed how IgG may affect the cellular compartment, evidence for IVIg-mediated scavenging of complement fragments, the role of the dimeric fraction of IVIg, the anti-inflammatory properties of the minor fraction of sialylated IgG molecules, and the genetic organization and variation in FcγRs. These findings demonstrate the considerable progress that has been made in understanding the mechanisms of action of IVIgs, and may influence future perspectives in the field of Ig therapy. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCS) are capable of stimulating the secretion of interleukin (IL)-10 by leucocytes; however, the potential of GCS to modulate leucocyte susceptibility to IL-10-mediated actions has not yet been studied. In the current paper, we performed a detailed cross-sectional analysis of IL-10 receptor (IL-10R) expression by CD4+ and CD8+ T cells, natural killer (NK) cells, monocytes and neutrophils. Next, we analysed the effects of short-term oral GCS treatment on surface IL-10R expression by various leucocyte subpopulations in asthmatic patients. All leucocyte subsets studied presented with substantial levels of surface IL-10R. The highest levels of IL-10R were found on monocytes, predominantly with CD142+CD16+ and CD14+CD16+ phenotypes, and on CD4+CD25high T cells. In contrast, levels of IL-10R on CD8+ T cells, NK cells and neutrophils were significantly lower and similar to each other in intensity. GCS treatment resulted in a significant decrease of IL-10R expression on all analysed peripheral blood leucocyte subsets. Our data suggest that down-regulation of IL-10R could counterbalance the otherwise suppressive action of GCS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system with a poorly defined and complex immunopathogenesis. Although initiated by reactive T cells, persistent inflammation is evident throughout the disease course. A contribution from complement has long been suspected, based on the results of pathological and functional studies which have demonstrated complement activation products in MS brain and biological fluids. However, the extent and nature of complement activation and its contribution to disease phenotype and long-term outcome remain unclear. Furthermore, functional polymorphisms in components and regulators of the complement system which cause dysregulation, and are known to contribute to other autoimmune inflammatory disorders, have not been investigated to date in MS in any detail. In this paper we review evidence from pathological, animal model and human functional and genetic studies, implicating activation of complement in MS. We also evaluate the potential of complement components and regulators and their polymorphic variants as biomarkers of disease, and suggest appropriate directions for future research. [ABSTRACT FROM AUTHOR]

(NZW × BXSB)F1 mice (W/BF1 mice) have been reported to be a type of autoimmune-prone mice, showing symptoms of proteinuria, anti-DNA antibodies and anti-platelet antibodies. In this paper, we report that W/BF1 mice show hyperproduction of tumour necrosis factor (TNF)-α, responding to lipopolysaccharide (LPS) in comparison with normal mice, resulting in induction of death. In normal mice, monocytes/macrophages (Mo/MØ) are the main producer of TNF-α, while both Mo/MØ and dendritic cells (DCs) produce TNF-α in W/BF1 mice. Because the number of DCs is higher in W/BF1 mice, the main producers of TNF-α in W/BF1 mice are thought to be DCs. Moreover, administration of anti-TNF-α antibodies rescued the W/BF1 mice from death induced by LPS, suggesting that TNF-α is crucial for the effect of LPS. Although there is no significant difference in the expression of Toll-like receptor-4 (TLR-4) on DCs between B6 and W/BF1 mice, nuclear factor kappa b activity of DCs from W/BF1 mice is augmented under stimulation of LPS in comparison with that of normal mice. These results suggest that the signal transduction from TLR-4 is augmented in W/BF1 mice in comparison with normal mice, resulting in the hyperproduction of TNF-α and reduced survival rate. The results also suggest that not only the quantity of endotoxin, but also the host conditions, the facility to translate signal from TLR, and so on, could reflect the degree of bacterial infections and prognosis. [ABSTRACT FROM AUTHOR]

Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 infections are considered a public health problem in both developed and developing countries because of their increasing incidence and the severity of clinical presentation. Approximately 10% of infected patients develop complications such as haemolytic uraemic syndrome (HUS) characterized by acute renal failure, thrombocytopenia and haemolytic anaemia. The precise sequence of events leading to HUS is still understood incompletely. Because of the lack of a reproducible small animal model for EHEC infections, in vivo studies examining EHEC–host early interactions are limited and insufficient. The aim of this study was to characterize the weaned BALB/c mouse as a model of E. coli O157:H7 infection. In this paper we report that human Shiga toxin 2 (Stx2)-producing EHEC strains can adhere to the intestinal epithelium of weaned BALB/c mice, and produce local damage which leads to systemic disease and death in a percentage of infected mice. The lethality of the EHEC strain is closely age-dependent, and is related to the bacterial ability to colonize intestine and to produce Stx2. It can be concluded that the weaned BALB/c mouse can be used as a small animal model to study host early responses, and the role of bacterial pathogenic factors in the induction of systemic disease, thus providing a useful tool for the evaluation of therapeutic or vaccine approaches. [ABSTRACT FROM AUTHOR]

Recurrent or persistent infection is the major manifestation of primary immunodeficiency, which also results in atypical infection with opportunistic organisms. Young children are also vulnerable to infection and recurrent infection is common. While most children with recurrent infection have a normal immunity, it is important to recognize the child with an underlying primary immunodeficiency and investigate and treat appropriately and yet not over investigate normal children. Prompt, accurate diagnosis directs the most appropriate treatment, and early and judicious use of prophylactic antibiotics and replacement immunoglobulin can prevent significant end organ damage and improve long-term outlook and quality of life. This paper describes important presenting features of primary immunodeficiency and indicates when further investigation is warranted. [ABSTRACT FROM AUTHOR]

Genetic and acquired abnormalities in complement factor H (CFH) have been associated with two different human renal diseases: haemolytic uraemic syndrome and membrano proliferative glomerulonephritis. The new genetic and pathogenetic findings in these diseases and their clinical implications for the management and cure of patients are reviewed in this paper. [ABSTRACT FROM AUTHOR]

Factor H is the major regulatory protein of the alternative pathway of complement activation. Abnormalities in factor H have been associated with renal disease, namely glomerulonephritis with C3 deposition including membranoproliferative glomerulonephritis (MPGN) and the atypical haemolytic uraemic syndrome (aHUS). Furthermore, a common factor H polymorphism has been identified as a risk factor for the development of age-related macular degeneration. These associations suggest that alternative pathway dysregulation is a common feature in the pathogenesis of these conditions. However, with respect to factor H-associated renal disease, it is now clear that distinct molecular defects in the protein underlie the pathogenesis of glomerulonephritis and HUS. In this paper we review the associations between human factor H dysfunction and renal disease and explore how observations in both spontaneous and engineered animal models of factor H dysfunction have contributed to our understanding of the pathogenesis of factor H-related renal disease. [ABSTRACT FROM AUTHOR]

Previous studies have shown the down-regulating in vitro effect of cocoa flavonoids on lymphocyte and macrophage activation. In the present paper, we report the capacity of a long-term rich cocoa diet to modulate macrophage cytokine secretion and lymphocyte function in young rats. Weaned rats received natural cocoa (4% or 10% food intake), containing 32 mg flavonoids/g, for 3 weeks. Spleen immune function was then evaluated through the analysis of lymphocyte composition, their proliferative response and their ability to secrete cytokines and Ig. In addition, the status of activated peritoneal macrophages was established through tumour necrosis factor (TNF)-α secretion. The richest cocoa diet (10%) caused a reduction of TNF-α secretion by peritoneal macrophages showing anti-inflammatory activity. Similarly, although a 10% cocoa diet increased lymphocyte proliferation rate, it down-regulated T helper 2 (Th2)-related cytokines and decreased Ig secretion. These changes were accompanied by an increase in spleen B cell proportion and a decrease in Th cell percentage. In summary, these results demonstrate the functional activity of a cocoa-high dosage in down-regulating the immune response that might be beneficial in hypersensitivity and autoimmunity. [ABSTRACT FROM AUTHOR]

Recently we demonstrated that in inflammatory bowel disease (IBD) macrophage-oxidative burst activity is increased and NADPH oxidase mRNA is induced. The herbal phenylethanoid acteoside isolated from Plantago lanceolata L. was shown to exhibit anti-oxidative potential. Using the dextran sulphate sodium (DSS)-induced colitis model, in this study we have assessed whether systemic application of acteoside affects colitis. Colitis was induced by DSS in Balb/c mice. Treatment with acteoside (120, 600 µg/mouse/day) was performed intraperitoneally. The colon lengths were determined. Colonic tissue was scored histologically (max. score 8) by a blinded investigator. T cells isolated from mesenteric lymph nodes (MLN) were stimulated with anti-CD3 antibody in the presence of interleukin (IL)-2 (final concentration 10 U/ml). After incubation for 24 h, IL-1β, IL-6, IL-12 tumour necrosis factor (TNF)-α and interferon (IFN)-γ levels in supernatants were analysed by the beadlyte® cytokine detection system. Histological scoring of colonic tissue revealed that application of acteoside was followed by a significantly improved histological score. In acute colitis the histological score was 3·2 with acteoside versus 5·2 with phosphate-buffered saline (PBS) ( P < 0·02). In chronic colitis both 120 µg (3·3 versus 5·2) or 600 µg acteoside (3·0 versus 5·2) significantly ameliorated colitis (both P < 0·02). Stimulated MLN from mice with chronic DSS-induced colitis treated with acteoside showed a significant down-regulation of IFN-γ secretion (195 pg/ml with 600 µg acteoside versus 612 pg/ml with PBS, P < 0·02). Inhibition of oxidative burst activity with acteoside reduced mucosal tissue damage in DSS colitis and could be a therapeutic alternative for IBD treatment. Further studies of this agent are warranted. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is often considered the prototype organ-specific autoimmune disease in clinical immunology circles. The key disease features − precise destruction of a single endocrine cell type occurring on a distinct genetic and autoimmune background − have been unravelled in recent years to such an extent that there is a growing expectation that the disease should be curable. T1D is something of an orphan disease, currently managed by endocrinologists yet dependent upon the wit of immunologists, both basic and clinical, to find the best approaches to prevention and cure. Type 1 diabetes thus represents one of the most active arenas for translational research, as novel immune-based interventions find their way to the clinic. The first serious attempt at immune-based treatment for T1D was in 1984, the first at prevention in 1993; current and planned trials will take us into the next decade before reporting their results. This paper represents the first attempt at a comprehensive review of this quarter century of endeavour, documenting all the strategies that have emerged into clinical studies. Importantly, the intense clinical activity has established robust infrastructures for future T1D trials and frameworks for their design. The evident success of the monoclonal anti-CD3 antibody trials in established T1D demonstrate that modulation of islet autoimmunity in humans after the onset of overt disease can be achieved, and give some reason to be cautiously optimistic for the ability of these and other agents, alone and in combination, to provide an effective immunotherapy for the disease. [ABSTRACT FROM AUTHOR]

Uncommitted (naive) murine CD4+ T helper cells (Thp) can be induced to differentiate towards T helper 1 (Th1), Th2, Th17 and regulatory (Treg) phenotypes according to the local cytokine milieu. This can be demonstrated most readily both in vitro and in vivo in murine CD4+ T cells. The presence of interleukin (IL)-12 [signalling through signal transduction and activator of transcription (STAT)-4] skews towards Th1, IL-4 (signalling through STAT-6) towards Th2, transforming growth factor (TGF)-β towards Treg and IL-6 and TGF-β towards Th17. The committed cells are characterized by expression of specific transcription factors, T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for Tregs and RORγt for Th17 cells. Recently, it has been demonstrated that the skewing of murine Thp towards Th17 and Treg is mutually exclusive. Although human Thp can also be skewed towards Th1 and Th2 phenotypes there is as yet no direct evidence for the existence of discrete Th17 cells in humans nor of mutually antagonistic development of Th17 cells and Tregs. There is considerable evidence, however, both in humans and in mice for the importance of interferon (IFN)-γ and IL-17 in the development and progression of inflammatory and autoimmune diseases (AD). Unexpectedly, some models of autoimmunity thought traditionally to be solely Th1-dependent have been demonstrated subsequently to have a non-redundant requirement for Th17 cells, notably experimental allergic encephalomyelitis and collagen-induced arthritis. In contrast, Tregs have anti-inflammatory properties and can cause quiescence of autoimmune diseases and prolongation of transplant function. As a result, it can be proposed that skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD or acute transplant rejection in humans. Blocking critical cytokines in vivo, notably IL-6, may result in a shift from a Th17 towards a regulatory phenotype and induce quiescence of AD or prevent transplant rejection. In this paper we review Th17/IL-17 and Treg biology and expand on this hypothesis. [ABSTRACT FROM AUTHOR]

Economic and political factors have led to the increased use of home therapy programmes for patients who have traditionally been treated in hospital. Many patients with hereditary angioedema (HAE) experience intermittent severe attacks that affect their quality of life and may be life-threatening. These attacks are treated with C1-inhibitor concentrate which, for most patients, is infused at the local hospital. Home therapy programmes for HAE are currently being established. This paper reviews the extent of use of these programmes and summarizes the advantages and potential disadvantages of the concept so far. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is characterized by an excessive inflammatory response to inhaled particles, mainly tobacco smoking. T lymphocytes are important regulatory cells that secrete several cytokines and participate actively in this inflammatory response. According to the pattern of cytokines secreted, the immune response is classified as cytotoxic or type 1 [interferon (IFN)-γ-, interleukin (IL)-2-dependent] and humoral or type 2 (IL-4-, IL-5-, IL-10- and IL-13-dependent). This paper sought to compare the intracellular profile of cytokine expression determined by flow cytometry in T lymphocytes harvested from bronchoalveolar lavage (BAL) and peripheral blood in patients with COPD, smokers with normal lung function and never smokers. We found that BAL T lymphocytes from COPD patients had a higher percentage of positive stained cells for most of the cytokines analysed when compared to never smokers or smokers with normal lung function. Differences reached statistical significance for IL-4, IL-10 and IL-13, particularly in CD8+ T cells. Furthermore, the expression of most of these cytokines was related inversely to the degree of airflow obstruction present suggesting local activation and/or selective homing of T lymphocytes to the lungs in COPD patients. These observations were not reproduced in circulating T lymphocytes. These results suggest that BAL T lymphocytes in patients with COPD produce more cytokines than in controls and tend to show a type 2 pattern of intracellular cytokine expression, particularly a Tc-2 profile. This is related inversely to the degree of airflow obstruction present. [ABSTRACT FROM AUTHOR]

An increasing number of cell types, including peripheral blood mononuclear cells (PBMCs), have been demonstrated to release heat shock proteins (Hsps). In this paper we investigate further the hypothesis that Hsps are danger signals. PBMCs and Jurkat cells released Hsp70 (0·22 and 0·7 ng/106 cells, respectively) into medium over 24 h at 37°C. Release of Hsp70 was stimulated 10-fold by GroEL ( P < 0·001) and more than threefold by lipopolysaccharide (LPS) ( P < 0·001). Although Hsp60 could be detected in the medium of cells cultured at 37°C for 24 h, the low rates of release were due probably to cell damage. Significant release of Hsp60 was observed when Jurkat cells were exposed to GroEL (2·88 ng/106 cells) or LPS (1·40 ng/106 cells). The data are consistent with the hypothesis that Hsp70 and Hsp60 are part of a danger signalling cascade in response to bacterial infection. [ABSTRACT FROM AUTHOR]

Cannabinoids have been suggested as possessing immunomodulatory properties, and cannabinoid receptors are present on leucocytes. Clinically, there is some evidence that cannabinoids may be therapeutically useful in treating multiple sclerosis, which is generally believed to be an autoimmune condition. This paper reports data derived from the Cannabinoids in MS (CAMS) study, which was the largest randomized controlled trial yet conducted to evaluate the therapeutic efficacy of cannabinoids. We found no evidence for cannabinoid influence on serum levels of interferon (IFN)-γ, interleukin (IL)-10, IL-12 or C-reactive protein as measured using enzyme-linked immunosorbent assay (ELISA), in comparison to control values. Mitogenic stimulation experiments also failed to demonstrate any significant reduction in percentage of CD3+, IFN-γ producing cells after exposure to cannabinoidsin vivo, although numbers were small. Further work is needed to establish the functional significance of cannabinoid receptors on immune cells. [ABSTRACT FROM AUTHOR]

Neutrophils can be primed by bacterial lipopolysaccharide (LPS) for an enhanced oxidative burst, which is a key element in the pathogenesis of Gram-negative sepsis. Some serum proteins (e.g. lipopolysaccharide-binding protein) avidly bind LPS and markedly enhance receptor binding and cellular activation while other serum factors (lipoproteins, bactericidal/permeability-increasing protein) neutralize LPS and prevent neutrophil activation. In this paper we examined the kinetics of this priming reaction in whole blood. To study the balance between neutrophil activation and LPS neutralization a sensitive chemiluminescence assay was used in a whole blood system. LPS was able to prime neutrophils for enhanced oxidative burst in whole blood with an optimum incubation time of 25 min. However, LPS was neutralized very rapidly with at1/2 of 10 min. After 20 min a second priming factor was already generated, which was shown to be monocyte-derived tumour necrosis factor (TNF). [ABSTRACT FROM AUTHOR]

The mechanisms causing non-responsiveness to hepatitis B surface antigen (HBsAg) vaccines in man remain elusive. The increased incidence of non-responsiveness in subjects with HLA-DR3+ or -DR7+ haplotypes suggests that immune response mechanisms governed by genes of the MHC are involved. Homozygotes for these two haplotypes are found almost exclusively in the non-responder (NR) population. It is conceivable that antigen-presenting cells (APC) of NR are defective in the uptake of HBsAg and that they are unable to present this Ag adequately. Previously, we demonstrated thatDR2+,DR7+ andDP4+ NR were able to present HBsAg. In the present paper we demonstrate that six DR0301+ NR, five of which are homozygous for this marker, were able to take up, process and present HBsAg to HBsAg-specific, DR0301-restricted T cell lines. Non-fractionated peripheral blood mononuclear cells (PBMC) from the DR0301+ NR did not proliferate to HBsAgin vitro, whereas they proliferated vigorously upon stimulation with tetanus toxoid, thus ruling out the presence of a generalized immunodeficiency. We therefore conclude that HLA-DR0301+ NR vaccinees are not deficient in their HBsAg-presentation. Because it was demonstrated that recently activated T cells can apparently bypass the requirement for B7, we may have overlooked the role of the B7-co-stimulation in our set-up that used HBsAg-specific T cell lines. Therefore we examined the expression of B7 co-stimulatory molecules on NR-APC. CD86 was normally present on these cells and was not down-regulated after culturing the PBMC in the presence of HBsAg. We conclude that CD86 expression on CD14+ monocytes of DR0301- and DR07-homozygous poor responders is not deficient and cannot be the mechanism underlying the non-responsiveness of these subjects. [ABSTRACT FROM AUTHOR]

Intranasal vaccination may offer practical benefits and better protection against respiratory infections, including tuberculosis. In this paper, we investigated the persistence of the Mycobacterium bovis-strain bacille Calmette-Guérin (BCG) Pasteur, lung granuloma formation and protection against pathogenic tuberculous challenge in mice. A pronounced BCG dose-dependent granulomatous infiltration of the lungs was observed following intranasal, but not after subcutaneous, vaccination. Corresponding doses of BCG, over a 100-fold range, imparted similar protection against H37Rv challenge when comparing the intranasal and subcutaneous vaccination routes. Interestingly, a BCG dose-dependent reduction of the H37Rv challenge infection was observed in the lungs, but not in the spleens, following both intra- nasal and subcutaneous vaccination. In the light of the observed concurrence between the extent of granuloma formation and the level of protection of the lungs, we conclude that intranasal vaccination leading to best protective efficacy needs to be balanced with an acceptable safety margin avoiding undue pathology in the lungs. [ABSTRACT FROM AUTHOR]

Protection against tuberculosis depends upon the generation of CD4+ T cell effectors capable of producing IFN-γ and stimulating macrophage antimycobacterial function. Effector CD4+ T cells are known to express CD44hiCD62Llo surface phenotype. In this paper we demonstrate that a population of CD44hiCD62Llo CD4+ effectors generated in response toMycobacterium bovisBCG orM. tuberculosisinfection in C57BL/6 mice is heterogeneous and consists of CD27hi and CD27lo T cell subsets. These subsets exhibit a similar degree ofin vivoproliferation, but differ by the capacity for IFN-γ production.Ex vivoisolated CD27lo T cells express higher amounts of IFN-γ RNA and contain higher frequencies of IFN-γ producers compared to CD27hi subset, as shown by real-time PCR, intracellular staining for IFN-γ and ELISPOT assays. In addition, CD27lo CD4+ T cells uniformly express CD44hiCD62Llo phenotype. We propose that CD27lo CD44hiCD62Llo CD4+ T cells represent highly differentiated effector cells with a high capacity for IFN-γ secretion and antimycobacterial protection at the site of infection. [ABSTRACT FROM AUTHOR]

Activation of T cells requires both TCR-specific ligation and costimulation through accessory molecules during T cell priming. IFNγ is a key cytokine responsible for macrophage activation duringMycobacterium tuberculosis(Mtb) infection while IL-10 is associated with suppression of cell mediated immunity in intracellular infection. In this paper we evaluated the role of IFNγ and IL-10 on the function of cytotoxic T cells (CTL) and on the modulation of costimulatory molecules in healthy controls and patients with active tuberculosis (TB).γ-irradiated-Mtb(i-Mtb) induced IL-10 production from CD14+ cells from TB patients. Moreover, CD3+ T cells of patients with advanced disease also produced IL-10 after i-Mtbstimulation. In healthy donors, IL-10 decreased the lytic activity of CD4+ and CD8+ T cells whereas it increasedγδ-mediated cytotoxicity. Furthermore, we found that the presence of IL-10 induced a loss of the alternative processing pathways of antigen presentation along with a down-regulation of the expression of costimulatory molecule expression on monocytes and macrophages from healthy individuals. Conversely, neutralization of endogenous IL-10 or addition of IFNγ to either effector or target cells from TB patients induced a strong lytic activity mediated by CD8+ CTL together with an up-regulation of CD54 and CD86 expression on target cells. Moreover, we observed that macrophages from TB patients could use alternative pathways for i-Mtbpresentation. Taken together, our results demonstrate that the presence of IL-10 duringMtbinfection might contribute to mycobacteria persistence inside host macrophages through a mechanism that involved inhibition of MHC-restricted cytotoxicity against infected macrophages. [ABSTRACT FROM AUTHOR]

SUMMARY The identification of immunodominant and universal mycobacterial peptides could be applied to vaccine design and have an employment as diagnostic reagents. In this paper we have investigated the fine specificity, clonal composition and HLA class II restriction of CD4+ T cell clones specific for an immunodominant epitope spanning amino acids 91–110 of the 16-kDa protein of Mycobacterium tuberculosis . Twenty-one of the tested 28 clones had a Th1 profile, while seven clones had a Th0 profile. None of the clones had a Th2 profile. While the TCR AV gene usage of the clones was heterogeneous, a dominant TCR BV2 gene family was used by 18 of the 28 clones. The CDR3 regions of BV2+ T cell clones showed variation in lengths, but a putative common motif R-L/V-G/S-Y/W-E/D was detected in 13 of the 18 clones. Moreover, the last two to three residues of the putative CDR3 loops, encoded by conserved BJ sequences, could also play a role in peptide recognition. Antibody blockade and fine restriction analysis using HLA-DR homozygous antigen-presenting cells established that 16 of 18 BV2+ peptide-specific clones were DR restricted and two clones were DR-DQ and DR-DP restricted. Additionally, five of the 18 TCRBV2+ clones recognized peptide 91–110 in association with both parental and diverse HLA-DR molecules, indicating their promiscuous recognition pattern. The ability of peptide 91–110 to bind a wide range of HLA-DR molecules, and to stimulate a Th1-type interferon (IFN)-γ response more readily, encourage the use of this peptide as a subunit vaccine component. [ABSTRACT FROM AUTHOR]

Summary This paper considers both monocytes and peripheral blood lymphocytes as potential targets for maternal immunological modulation in pregnancy. Peripheral blood mononuclear cells (PBMCs) from non-pregnant and normal pregnant donors were stimulated in vitro , and cytokine production detected intracellularly by flow cytometry. It was found that monocyte production of TNF-α was unaltered in pregnancy, while production of IL-12 was significantly enhanced. In contrast, production of the Th1 type cytokine IFN-γ was suppressed in the lymphocyte subsets: CD4+ T helper cells and CD56+ NK cells. Production of the Th2 type cytokine IL-4 in CD4+ cells was not significantly altered in pregnancy. These data suggest that the concept that pregnancy is a ‘Th2 phenomenon’ cannot be generalized to the function of all aspects of maternal cellular immunity as, paradoxically, circulating monocytes are ‘primed’ to produce the Th1 cytokine IL-12. Furthermore, these data support the hypothesis that components of maternal innate immunity are activated in normal pregnancy. [ABSTRACT FROM AUTHOR]

SUMMARY The addition of a foreign antigen to an inoculum completely inhibits the development of collagen-induced arthritis (CIA). However, the mechanism of this phenomenon, antigen -inhibition, is incompletely understood. Previous studies have demonstrated that the inhibition of arthritis is not mediated through suppression of the antibody response to cartilage antigens. In this paper we investigated cytokine mRNA levels in lymph nodes cells recovered 3, 7 or 16 days from animals immunized with either collagen II in IFA or OVA + collagen II in IFA. At day 7, but not at other time-points, IL-4 mRNA was up-regulated in the lymph nodes of OVA-inhibited non-arthritic animals compared to control animals which all developed arthritis. No significant differences between the two groups could be detected when expression of IFN-γ , IL-2, TNF-α , IL-1β or IL-10 mRNA was analysed. Flow cytometry analysis of draining lymph node cells demonstrated that the T cell marker Ox40 was up-regulated in the OVA-inhibited group. Our results indicate that the complete inhibition of CIA caused by addition of OVA to the collagen II inoculum is due to the presence of a TH2 environment resulting from an increased production of IL-4 mRNA and a parallel increase in Ox40+ T cells. [ABSTRACT FROM AUTHOR]

Summary Child mortality in diarrhoeal disease is increased significantly by vitamin A deficiency in poor countries. The pathological mechanisms are not known in detail. However, in this paper we report that vitamin A-deficient Wistar rats had much reduced IgA+ plasma cells in the ileal lamina propria (eightfold reduction from 470 cells/mm2 , P = 0·009), as well as a prominent reduction of CD4+ cells in the parafollicular regions of ileal Peyer's patches (reduction from 7200 to 105 cells/mm2 , P = 0·009). IL-2Ralpha-chain (CD25) positive lymphocytes in the ileal Peyer's patches were also reduced significantly in vitamin A deficiency (from 1400 to 300 cells/mm2 , P = 0·009). The density of CD8 cells tended to be increased relative to the control animals (from 5100 to 6000 cells/mm2 , not statistically significant). In conclusion, the marked decrease of lamina propria IgA+ plasma cells may be one cause of the high diarrhoeal mortality in vitamin A deficiency. This, in turn, appears to be related to reduced numbers of activated or regulatory CD4+ T cells in Peyer's patches. [ABSTRACT FROM AUTHOR]

SUMMARY In this paper we addressed the expression of the HIV co-receptors CXCR-4 and CCR-5 in human thymocytes by phenotypic, molecular and functional approaches. Cytofluorimetric analysis disclosed that CXCR-4 was constitutively expressed by freshly isolated thymocytes (~10 000 molecules/cell in about 30% of thymocytes); the receptor was endowed with functional activity, as it mediated polarization, migration and intracellular Ca2+ increase in response to its ligand, SDF-1. On the contrary, CCR-5 expression in freshly isolated thymocytes was significantly lower (<4000 molecules/cell in less than 5% of the cells), and no functional response to CCR-5 agonists could be documented. Northern blot analysis of freshly isolated thymocytes showed high CXCR-4 mRNA levels, whereas the message for CCR-5 was barely detectable. On the other hand, a modest increase in the expression of CCR-5 was associated with in vitro thymocyte stimulation, and CCR-5 density at the cell surface attained CXCR-4 figures in most cases. None the less, no functional response to CCR-5 agonists could be documented in in vitro stimulated thymocytes. In vitro infection of thymocytes by CAT-expressing recombinant HIV bearing the envelope glycoproteins from different isolates showed that T-tropic strains, which use CXCR-4 as a co-receptor, were more efficient in infecting thymocytes than M-tropic strains, which preferentially use CCR-5. Altogether, these data indicate that expression of the major co-receptors involved in infection by M-tropic HIV strains is very poor in human thymocytes, and would suggest that thymocyte infection by M-tropic HIV strains may be a rare event in vivo . [ABSTRACT FROM AUTHOR]

In this paper we describe the clinical and molecular features of a new case (GOR) of homozygous human TAP2 deficiency, analysing the phenotype and function of NK cells. The patient presented from infancy with recurrent sinopulmonary infections; a selective IgG2 deficiency, negative antibody response to polysaccharide vaccination and low level of cell surface expression of HLA class I antigens were found. The sequence of TAP2 gene identified a single mutation, a C to T substitution changing the CGA arg codon at amino acid 220 into TGA stop codon in exon 3. By using MoAbs for KIRs, CD94, CD94/NKG2A and ILT2 we observed, in agreement with others, that the latter two receptors were overexpressed on TAP2-deficient NK cells. The inhibitory CD94/NKG2A and triggering CD94/NKG2C NK receptors, specific for HLA-E, appeared to be functional in a limited number of NK clones that could be expanded in vitro. Expression of HLA-E was virtually undetectable in GOR B-LCL and very faint in PBMC, further supporting that interactions of class I leader sequence nonamers with HLA-E in the ER depend on a functional TAP complex. [ABSTRACT FROM AUTHOR]

Investigates the characterization of the antigens identified by the anti-endothelial cell antibodies (AECA) in patients with systemic sclerosis. Prevalence and clinical significance of AECA; Affinity purification of antibody from nitrocellulose paper; Analysis of antinuclear antibodies.

This paper demonstrates that CD40 is expressed on rheumatoid synovial pannus and primary fibroblast cell lines established from rheumatoid and osteoarthritic synovium as well as normal skin. Among various tested cytokines, interferon-gamma (IFN-γ) and lo a lower extent, tumour necrosis factor-alpha (TNE-α) were found to upregulate CD40 expression on fibroblasts. Synovial and skin fibroblasts cultured over CD40 Ligand transfected L cells (L-CD40L) demonstrate a CD40 specific increase of DNA synthesis as measured by tritiated thymidine incorporation. Cell-cycle analysis and enumeration of viable cells further show that CD40 induced fibroblast proliferation. Costimulation with L-CD40 L and IFN-γ, resulted in maximal proliferation. Engagement of fibroblasts CD40 increased the IL-l-induced production of granulocyte macrophage-colony stimulating factor and macrophage inflammatory protein-Iα MIP-lα, CD40L activated fibroblasts showed decreased levels of CD40, but only marginal alterations of other cell-surface antigens. Taken together, the present results indicate that fibroblasts express functional CD40 and suggest a possible role of CD40L expressing cells, such as activated T cells and mast cells, in the development of synovium hyperplasia. [ABSTRACT FROM AUTHOR]

In this paper we review different aspects of B cell development on the path from the proB cell to the memory B cell and the plasmocyte. Emphasis is given to the positive and negative selection effects mediated by the changing forms of the surface immunoglobulin (Ig) receptor under successive microenvironments. Positive selection is linked to λ chain expression at the pro- and preB cell slage in fetal liver and bone marrow. Negative selection takes place when surface (s)IgM is being cross- linked by autoantigens before the immature B cell can leave, or after it has left, the bone marrow. After somatic mutation, major expansion becomes possible for B cells with high-affinity sIg receptors. This takes place in the germinal centres of the secondary lymphoid organs in the context of major histocompatibility complex (MHC) restriction and provided the necessary T cell help is given. Kinetic data on B cell replenishment in the rodent models are used to draw a schematic view of an established B cell repertoire. [ABSTRACT FROM AUTHOR]

The arihritogenic properties of adjuvant oil upon percutaneous administration in DA rats was investigated. Groups of rats were administered single or repeated percutaneous applications of Freund's incomplete adjuvant (FIA) or olive oil on shaved skin with or without prior abrasion of the skin. Control rats were shaved and abrased only. A transient arthritis developed in 8/16 animals after repeated applications of FIA on abrased skin. The incidence of arthritis increased to 7/8 animals when FIA was repeatedly administered via filter paper on abrased skin and covered with a bandage. Histological examination of the arthritic joints showed proliferation of the synovial lining layer, infiltration of mononuclear cells and polymorphonuclear cells in the subsynovial tissue. Some bone and cartilage destruction was also seen. Repeated treatment with olive oil on abrased skin induced joint swelling in 3/15 animals, which did not, however, correspond to any microscopically observable signs of inflammation. Also, a single application of FIA on abrased skin or repeated applications of FIA without abrasion induced arthritis, although with low penetration, whereas control animals had no clinical signs of joint involvement. These findings demonstrate that percutaneous administration of adjuvant oil can cause arthritis in genetically susceptible animals. [ABSTRACT FROM AUTHOR]

IL-6, an important mediator of the acute phase response, has been implicated in the pathogenesis of rheumatoid arthritis (RA). Many cell types including macrophages, T cells. H cells, endothelial cells and fibroblasts can produce this cytokine and production is largely regulated at the level of gene transcription or mRNA stabilization. In this paper we have first measured the levels of IL-6 activity in synovial fluid (SF) and serum from patients with RA and then localized IL-6-producing cells in the synovium by in situ hybridization combined with immunophenotyping. Patients with RA had raised levels of IL-6 in both SF and serum compared with patients with osteoarthritis and age-matched healthy controls. in individual RA patients tested serially after admission to hospital, serum IL6 was initially raised and, unexpectedly. increased with clinical improvement, in situ hybridization of IL-6 mRNA showed positive cells both in the lymphocyte-rich aggregates and adjacent to small blood vessels. With immunophenotyping it was found that cells containing IL-6 mRNA were often in contact with CD 14+ tissue macrophages and double immunophenotyping revealed that immuno- reactive IL-6 was often associated with synovial T cells. [ABSTRACT FROM AUTHOR]

The article presents various research papers, published in an earlier issue of the journal "Clinical & Experimental Immunology". One of the abstract talk about functional activities of sera from normal individuals with a range of C4A and C4B concentrations. Human C4 consists of two distinct highly polymorphic proteins C4A and C4B. Pre-eclampaia continues to be one of the most frequently encountered complications of human pregnancy with immune complexes being considered as an aetiological factor. If pre-eclampsia is indeed an immune complex disorder, then it might be expected that as with other "connective tissue" diseases, precipitation of clinical symptoms may be heralded by a reduction of Erythrocyte CRl (ECRl) expression.

The article presents various research papers related to complement deficiencies, published in an earlier issue of the journal "Clinical & Experimental Immunology". One of the abstracts talk about acquired deficiency in C1-inhibitor associated with an undifferentiated gastric adenocarcinoma. Acquired deficiency in C1-inhibitor (C1-INH) clinically manifests similar to hereditary angioedema and is usually associated with a B cell malignancy or is sometimes characterized by an autoantibody towards the C1-INH molecule.

The article presents various research papers related to inhibitory proteins and non-lethal effects, published in an earlier issue of the journal "Clinical & Experimental Immunology". One of the abstracts talk about role of inhibitory membrane proteins in the complement dependent killing of trophoblast cells. Trophoblast cells are known to be highly resistant to killing by decidual NK cells. HRF20 is deficient in a patient suffering from paroxysmal nocturnal hemoglobinuria. This deficiency in HRF20 is not only on blood cells but also other tissues including endothelial cells and peripheral nerves.

This paper describes the spontaneous occurrence of an autoimmune uveoretinitis in nude (nu/nu) mice reconstituted when 4 weeks old by the grafting of rat embryonic thymus. The uveoretinitis was characterized histologically by progressive loss of the photoreceptor layer, observed in 4.0, 17.6, 42.9% and 71.4% of such mice at 3, 5, 7 and 12 months of age, respectively. Mice with uveoretinitis were shown to have serum IgG antibody reactive by indirect immunofluorescence with retinal photoreceptors, and with interphotoreceptor retinoid-binding protein (IRBP), but not retinal S-antigen, by immunoblotting and ELISA. A uveoretinitis could be adoptively transferred to syngeneic ungrafted nude mice by splenic CD4+ T cells from diseased animals. This is the first experimental model of a (T cell mediated) autoimmune uveoretinitis which develops spontaneously and which is not dependent upon deliberate sensitization with retinal antigens and adjuvants. [ABSTRACT FROM AUTHOR]

The present paper describes two new MoAbs, GHI/75 and VMP55, which were raised against a glycoprotein enriched lysate of hairy cell leukaemia. These antibodies recognized a new antigen or 72 kD (unreduced) and 83 kD (reduced) molecular weight. GHI/75 and VMP55 gave very strong staining of plasma cells, moderate labelling of circulating B cells but only weak staining of monocytes., some tissue macrophages and lymphoid cells. Neither antibody reacted with neutrophils or any non-haematopoietic cells. Both antibodies, however, strongly labelled the tumour cells in hairy cell leukaemia, multiple mycloma, plasmacytoma and lymphoplasmacytic lymphomas. No staining was seen of the neoplaslic cells in Hodgkin's disease, myctoid leukaemia or T cell lymphomas. The two antibodies. GHI/75 and VMP55. may be of value in the differential diagnosis of hairy cell leukaemias and plasma cell neoplasms. In addition, the ease with which their antigen can be purified provides the possibility for a detailed study of this molecule. [ABSTRACT FROM AUTHOR]

The article presents an index related to authors who contributed their papers in the 1991 issue of the journal "Clinical & Experimental Immunology." Some of the authors are F. Aiuti, C.E. Alers, G. Alexander, J. Alexander, L. Alviggi, N. Amos, L.L. Ballard, E.J. Brown, V.M. Holers, S.P. Ballou, R.P. Cleveland, V. Barnaba, L. Barreto, G. Bird, J. Blaser, G.D. Bompiani, J.P. Levy, E. Gomard, A. Gomez, J. Bourgault, B. Bierwolf, S.N. Breit, J.C. Brouet, B. Brown, E.J. Brown, M.W. Burns, R.D. Campbell and A. Capron.

In this paper we report studies undertaken to determine the contribution of seminal prostaglandins to some of the known immunosuppressive properties of human seminal plasma. Initial studies revealed that fractions of seminal plasma enriched in E series prostaglandins, obtained by reverse phase chromatography, had a pronounced inhibitory effect on the PHA-induced proliferation of peripheral blood lymphocytes and on the NK-cell-mediated lysis of K562 target cells. Additional investigations revealed that similar inhibitory effects could be achieved with purified PGE2 (10-6 to 10-9 M) and 19-OH PGE1 (10-6 to 10-7 M), both of which are present in uniquely high concentrations in human seminal plasma. In contrast, 19-OH PGF1 which is found in lower concentrations in semen was slightly stimulatory in proliferative assays and had no effect on NK-cell-mediated cytotoxicity. Removal of the seminal prostaglandins by absorption chromatography resulted in a dramatic decrease in immune suppressive activity. Further studies with fractions obtained by ion-exchange HPLC of desalted seminal plasma indicated that prostaglandins complexed with seminal proteins, and these too were immunosuppressive. The possible relevance of these results to sexually transmitted disease is discussed. [ABSTRACT FROM AUTHOR]

The recently described Ta1 antigen is expressed by activated T cells in vitro and in vivo, as observed in patients with certain immune-mediated diseases, such as multiple sclerosis. In this paper we report on the tissue distribution of the Ta1 antigen. Serological testing of human tumour cell lines and immunohistochemical analysis of human tissue sections revealed a reactivity of the anti-Ta1 antibody with normal and malignant tissues of the upper gastro-intestinal tract, the biliary tract, exocrine pancreas and kidney. SDS-PAGE analysis of immunoprecipitates from 125I-labelled cells, employing the anti-Ta1 antibody, yielded a 113-115 kD band from three serologically Ta1, positive tumour cell lines, from a serologically Ta1, negative human EBV-transformed B lymphoblastoid cell line, from peripheral blood mononuclear cells (PBMC) and, as previously described, a 105 kD band from PHA activated T cells (Fox et al., 1984). After endoglycosidase F treatment similar bands of 85 kD were precipitated from activated T cells and from tumour cell lines. It is therefore likely that very similar glycoproteins,, which differ only modestly in the size of carbohydrate chains, bear the Ta1 epitope on Ta1 positive tissues. [ABSTRACT FROM AUTHOR]

Evidence accumulated over the last decade concerning human and experimental models suggests that an immunopathological mechanism may be involved in the pathogenesis of chronic Chagas' disease. In this paper we demonstrate the existence of two different circulating IgG in chagasic patients which bind with myocardial β1 and spleen cell β2 adrenoceptors, acting as non-competitive inhibitors. Both chagasic IgG against β1 and β2 adrenoceptor increased intracellular levels of cAMP that could be blocked by specific β1 and β2 adrenoceptor antagonists. The specificity for β1 and β2 adrenoceplors and the independence of other tissue reactive antibodies was demonstrated by IgG absorption with turkey red blood cell (TRBC), human lymphocytes (HL) or guinea pig red blood cells (GPRBC). The F(ab')2 fraction acted similarly. This supports the specificity of β1 and β2 adrenoceptors to the chagasic IgG and the independence of the other tissue reactive antibodies, such as EVI system. The probable pathogenic role of both β1 and β2 adrenergic chagasic antibody is discussed. [ABSTRACT FROM AUTHOR]

Recently, we reported on the importance of food antigens on the pathogenesis of an experimentally-induced model of, and some patients with, IgA nephropathy. In this paper, the glomerular deposition of food antigens (casein, lactalbumin, peanut protein, soy bean protein, rice protein, ovalbumin) was investigated by an immunofluorescence technique in 28 patients with IgA nephropathy and 32 controls (ten with lupus nephritis, three with Henoch-Schoenlein purpura nephritis and 19 with other glomerulonephritis). Glomerular IgA deposition was demonstrated in all IgA nephropathy and Henoch-Schoenlein purpura nephritis, and in four lupus nephritis. Positive findings of food antigens, observed as mesangial pattern, were obtained in eleven cases (39.3%) with casein, 21 (75.0%) with soy bean protein and one (3.6%) with rice protein in IgA nephropathy, even though no such findings were seen in the control group. Eleven of 28 patients with IgA nephropathy were positive with soy bean protein alone, nine were positive with soy bean protein+casein, one was positive with soy bean protein + casein + rice protein, and one was positive with casein alone. The deposition of food antigens was not observed in six cases only. Furthermore, no correlation was noted between the deposition of food antigens and the deposition of IgA1, IgA2 or J chain, in vitro binding of the secretory component, or histopathological grades. These results suggest that the exact meanings of glomerular deposition are unclear. Food antigens are postulated, however, as possibly participating strongly in the pathogenesis and as being localized in the glomerular mesangium as an antigen in some patients with IgA nephropathy. [ABSTRACT FROM AUTHOR]

The binding of EPF to lymphocytes stimulates the release of soluble mediators, active in T cell dependent reactions, namely the rosette inhibition test and the adoptive transfer of contact sensitivity. On the basis of their ability to inhibit the delayed type hypersensitivity reaction in this latter assay, they have been classified as suppressor factors. This paper describes the identification of two EPF-induced suppressor factors. Unlike EPF which is neither species-restricted nor strain-restricted, these factors are genetically restricted in their action in the rosette inhibition test EPF-S1 (estimated Mr 14,000) is restricted to the I region of the mouse MHC, while EPF-S2 (estimated Mr 55,000) is restricted to a locus (or loci) outside the MHC. Like other antigen non-specific factors, release of these suppressor factors can be stimulated also by Con A. [ABSTRACT FROM AUTHOR]

Freshly isolated B cells from chronic lymphocytic leukaemia patients (B-CLL) have been previously shown to induce a strong proliferative response and high levels of NK-like activity in lymphocytes from healthy donors. The present paper deals with the origin, mitotic state, target spectrum and cell surface phenotype of the NK-like effectors generated after stimulation with B-CLL. Experiments using large granular lymphocytes (LGL) and T cells as responders demonstrated that most of the precursors of the newly generated NK-like effectors express the CD3 antigen. The induction of NK-like activity paralleled cell activation, as judged by blast transformation, thymidine uptake and appearance of cell surface activation markers. The newly generated NK-like effectors displayed a T cell phenotype and a broader target repertoire than native NK cells. [ABSTRACT FROM AUTHOR]

Although different models for rheumatoid arthritis have been studied, the pathogenesis in humans remains unknown. A possible mechanism is the crossreactivity between bacterial components and the target-tissue, the cartilage. The existence of this crossreactivity is supported by various data from clinical and experimental studies. Here we provide direct evidence that priming in vivo with cell wall fragments of Streptococcus pyogenes or Escherichia coli can induce a cellular and humoral anti-cartilage response in Balb/c mice in vitro. T cells isolated from these mice can be stimulated in vivo to proliferate by a variety of antigens among which arc the priming bacterium, an unrelated bacterium, small bacterial components and diverse antigens of cartilagenous origin. In bacterium-primed mice antibodies were also detected that displayed a reactivity to cartilage extract besides the reactivity to bacteria. A crossreactive response occurred in vivo in certain circumstances; a delayed type hypersensitivity reaction could be elicited in cell-wall-primed mice by challenge with cartilage extract. For the expression of this crossreactive response in vivo however, it was obligatory to attenuate the mouse's suppressor-circuit. In this paper we would suggest a mechanism for the pathology of chronic arthritis, based on repeated challenges with different bacterial stimuli. [ABSTRACT FROM AUTHOR]

This paper reports a study of the locomotor behaviour of the lymphocytes from 17 patients with chronic lymphocytic lcukaemia (CLL). The cells were studied both immediately after separation from blood and after culture for 24 to 48 h with a range of growth activators. Cells direct from blood were tested for polarization in fetal calf serum (FCS 20%), phorbol myristate acetate (PMA 10-7 M) and colchicine (10-5 M). The polarization of lymphocytes from CLL patients with high white cell (WBC) counts (> 10 × 109/litre) was very poor in FCS and PMA. though the cells from about half of these patients responded well to colchicine. The response of cells from patients with low white cell counts was the same as that of controls. The growth activators, PHA (1 /Lg/ml), anti-CD3 antibody (OKT3 25 ng/ml). Cowan strain Staphylococcus aureus (SAC: 15 × 107/ml) and PMA (10-8 M) induced an increase in the proportion of locomotor lymphocytes from controls and from CLL patients with low white cell counts during 4 h of culture. Cells from patients with high white cell counts showed very little increase in locomotor forms in any activator including PMA and the B cell mitogen SAC. This detect was seen in both polarization assays and collagen gel invasion assays. The findings suggest that CLL lymphocytes have a defect of locomotion demonstrable at two levels: (a) the cells fail to respond by polarizing immediately upon stimulation; colchicine treatment reverses this defect in some cases: (b) they also fail to acquire locomotor capacity during culture with activators of growth. [ABSTRACT FROM AUTHOR]

Corticosteroids have been reported to stimulate immunoglobulin (Ig) production by otherwise unstimulated peripheral blood mononuclear cells. In this paper we confirm that observation but report the necessity for an additional minor antigenic stimulus. Lymphocytes cultured with HB101, a complete medium not requiring serum supplement, did not increase Ig production after addition of hydrocortisone, but did if small concentrations (1-10%) of fetal calf serum were added. Various antigens such as Candida, tetanus, and albumin of different sources could substitute for fetal calf sera in allowing corticosteroids to stimulate Ig production in resting lymphocytes. We conclude that corticosteroids do not stimulate Ig production by lymphocytes de novo, rather, corticosteroids greatly enhance the Ig production stimulated by the foreign antigens present in fetal calf sera. [ABSTRACT FROM AUTHOR]

Peripheral blood mononuclear cells from patients with Sjögren's Syndrome spontaneously secrete autoantibodies to the La antigen when cultured in vitro. This paper reports that specific IgG autoantibody production in vitro is suppressed by pre-treatment of CD8+ enriched T cells with rabbit polyclonal antibodies to idiotypes borne by circulating autologous anti-La antibodies. Treatment of this T cell subpopulation with anti-idiotypes specific for circulating anti-La antibodies from other patients or for anti-DNA antibodies was without effect on anti-La antibody production. Similarly anti-La anti-idiotypes had no effect on the production of autoantibodies to other ribonucleoprotein antigens such as nRNP/Sm. These data show that CD8+ T cells are the main targets for anti-idiotypic control in vitro. We suggest that the relative deficit of these cells, plus a surfeit of CD4+ T cells at the site of the pathological lesion within the salivary gland permits localized production of autoantibodies. Thus, dysregulation of the idiotypic network could contribute to the pathogenesis of Sjögren's Syndrome. [ABSTRACT FROM AUTHOR]