Although the existence of anti-inflammatory alternatively activated macrophages (aamphi) has been accepted widely based on in vitro studies, their in vivo location, phenotype, and function still are ...debated. Gaucher disease (GD) is caused by a genetic deficiency in the lysosomal enzyme glucocerebrosidase and is characterized by accumulation of glycosphingolipids in so-called Gaucher cells (GCs). By using immunohistochemical analysis, we investigated whether this results in an aamphi phenotype. GCs are macrophage-like cells, expressing acid phosphatase, CD68, CD14, and HLA class II, but not CD11b, CD40, or dendritic cell markers. GCs show infrequent immunoreactivity for mannose receptor GCs did not express proinflammatory cytokines such as tumor necrosis factor alpha and monocyte chemoattractant protein 1, but did express the aamphi markers CD163, CCL18, and interleukin-1 receptor antagonist. Furthermore, CD36 and signal receptor protein alpha, involved in lipid uptake, also were observed on GCs. Thus, GCs represent a distinctive population of myeloid cells that resemble aamphi but differ from previously described in vitro aamphi.
Different
Lactobacillus strains are frequently used in consumer food products. In addition, recombinant lactobacilli which contain novel expression vectors can now be used in immunotherapeutic ...applications such as oral vaccination strategies and in T cell tolerance induction approaches for autoimmune disease. Both for food and clinical applications of lactobacilli, proper selection of wild type strains is crucial.
For that purpose, eight different common
Lactobacillus strains were analysed with respect to mucosal induction of pro- and anti-inflammatory cytokines, IgA-producing plasma cells in the gut, as well as systemic antibody responses against a parenterally administered antigen. Immunohistochemical analysis of cytokine-producing cells in the gut villi showed no significant induction of the cytokines IL-1α, IFN-γ, IL-4 or IL-10 after oral administration of wild type
Lactobacillus strains. In contrast, oral administration of
L. reuteri and
L. brevis induced expression of the proinflammatory/Th1 cytokines TNF-α, IL-2 and/or IL-1β. Oral administration of these two strains and
L. fermentum also significantly enhanced the IgG response against parenterally administered haptenated chicken gamma globulin (TNP–CGG). The five other strains did not show this adjuvanticity.
L. reuteri induced relatively high levels of IgG2a compared to
L. murines, a nonadjuving
Lactobacillus strain.
These findings imply that different
Lactobacillus strains induce distinct mucosal cytokine profiles and possess differential intrinsic adjuvanticity. This suggests that rational
Lactobacillus strain selection provides a strategy to influence cytokine expression and thereby influence immune responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The pathogenesis of Langerhans cell histiocytosis (LCH) remains poorly understood. To further elucidate LCH pathogenesis, we analyzed the expression of 10 cytokines relevant to cellular recruitment ...and activation at the protein level in 14 patients and identified the lesional cells responsible for cytokine production in situ by immunohistochemistry. The cytokines investigated included the hematopoietic growth factors interleukin-3 (IL-3), IL-7, and granulocyte-macrophage colony-stimulating factor (GM-CSF); the lymphocyte regulatory cytokines IL-2, IL-4, and IL-10; the inflammatory regulators IL-1α and tumor necrosis factor-α (TNF-α); and the effector cell-activating cytokines IL-5 and interferon-γ (IFN-γ). In all specimens, CD1a+ histiocytes (LCH cells) and CD3+ T cells produced large amounts of cytokines, creating a true cytokine storm. IL-2, IL-4, IL-5, and TNF-α were produced exclusively by T cells, whereas only IL-1α was produced by LCH cells. Equal numbers of LCH cells, T cells, and macrophages produced GM-CSF and IFN-γ. Equal numbers of LCH cells and macrophages produced IL-10, whereas IL-3 was produced by T cells and macrophages. IL-7 was only produced by macrophages. Eosinophils, present in some specimens, were partially responsible for the production of IL-5, IFN-γ, GM-CSF, IL-10, IL-3, and IL-7. Expression of all cytokines, abundant in most biopsies, was irrespective of age, gender, or site of biopsy. These findings emphasize the role of T cells in LCH. The juxtaposition of T cells and LCH cells suggests that both cells interact in a cytokine amplification cascade, resulting from stimulation of autocrine and paracrine stimulatory loops. This cascade can be linked directly to the development of LCH through recruitment, maturation, and proliferation of LCH cells. The cytokines studied are known to be involved in the development of other characteristic features of LCH, such as fibrosis, necrosis, and osteolysis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We investigated the role of CD40-CD40 ligand (CD40L) interactions in multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). Activated helper T cells expressing CD40L (gp39) ...surface protein were found in MS patient brain sections, but not in brain tissue sections of normal controls or patients with other neurological diseases. CD40L-positive cells were co-localized with CD40-bearing cells in active lesions (perivascular infiltrates). Most of these CD40 bearing cells proved to be of the monocytic lineage (macrophages or microglial cells), and relatively few were B cells. To functionally evaluate CD40-CD40L interactions, EAE was elicited in mice by means of proteolipidpeptide immunization. Treatment with anti-CD40L monoclonal antibody completely prevented the developmental of disease. Furthermore, administration of anti-CD40L monoclonal antibody, even after disease onset, shortly before maximum disability score was reached led to dramatic disease reduction. The presence of helper T cells expressing CD40L in brain tissue of MS patients and EAE animals, together with the functional evidence provided by successful experimental prevention and therapy in an animal model, indicates that blockade of CD40-CD40L-mediated cellular interactions may be a method for interference in active MS.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
BACKGROUND: Pregnancy is associated with changes in the immune system. Although previous studies have focussed mainly on adaptive immunity, there are indications that components of innate immunity, ...such as mannose-binding lectin (MBL), are associated with pregnancy outcome. Although this would suggest that pregnancy also involves adaptations in innate immunity, there are few studies in this area. Therefore, we aimed to determine whether MBL concentrations and the following steps in complement pathway activation are influenced by pregnancy. METHODS: MBL and Ficolin-2 concentrations, MBL–MBL-associated serine protease (MASP) complex activity, MBL pathway activity and classical complement pathway activity were determined by enzyme-linked immunosorbent assay (ELISA) in sera from pregnant women (n = 32) during each trimester and post-partum. MBL genotyping was performed by PCR. RESULTS: During pregnancy, MBL concentrations increased to 140% interquartile range (IQR) 116–181%, P < 0.0001. This increase was already present at 12 weeks of pregnancy and was most pronounced in the high-production AA-genotype. Directly Post-partum MBL concentrations dropped to 57% of baseline (IQR 44–66%, P < 0.0001). Variations in MBL levels were reflected by similar changes in the following steps of complement activation, r > 0.93 (P < 0.01). Ficolin-2 levels and classical complement pathway activity were not similarly influenced by pregnancy. CONCLUSIONS: Pregnancy and the post-partum period profoundly influence MBL serum concentration and MBL complement pathway activity.
Dendritic cells are thought to regulate tolerance induction vs immunization by transferring Ags and peripheral signals to draining lymph nodes (LN). However, whether myelin Ag transfer and ...presentation in LN occurs during demyelinating brain disease is unknown. In this study, we demonstrate redistribution of autoantigens from brain lesions to cervical LN in monkey experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS). Immunohistochemical analysis revealed significantly more cells containing myelin Ags in cervical LN of monkeys with EAE compared with those of healthy control monkeys. Myelin Ags were observed in cells expressing dendritic cell/macrophage-specific markers, MHC class II, and costimulatory molecules. Moreover, these cells were directly juxtaposed to T cells, suggesting that cognate interactions between myelin-containing APC and T cells are taking place in brain-draining LN. Indeed, myelin Ag-reactive T cells were observed in cervical LN from marmosets and rhesus monkeys. Importantly, these findings were paralleled by our findings in human tissue. We observed significantly more myelin Ag-containing cells in LN of individuals with MS compared with those of control individuals. These cells expressed APC markers, as observed in marmosets and rhesus monkeys. These findings suggest that during MS and EAE, modulation of T cell reactivity against brain-derived Ags also takes place in cervical LN and not necessarily inside the brain. A major implication is that novel therapeutic strategies may be targeted to peripheral events, thereby circumventing the blood-brain barrier.
Summary
Background Ustekinumab is a fully human anti‐p40 monoclonal antibody which neutralizes interleukin (IL)‐12 and IL‐23, thereby interfering with T‐helper (Th)1/Th17 pathways and keratinocyte ...activation, and is highly effective in the treatment of psoriasis. During ustekinumab treatment, some of our patients noticed reduced koebnerization of noninvolved skin and less new plaque formation.
Objectives To determine whether ustekinumab improves psoriasis‐related gene expression and tape‐strip responses in noninvolved skin.
Methods Before and 4 weeks after ustekinumab treatment, noninvolved skin was tape‐stripped. After 5 h, biopsies were taken from untouched and tape‐stripped skin. The mRNA expression of psoriasis‐related markers such as NGF, GATA3 and IL‐22RA1, and several antimicrobial peptides (AMP) was quantified. Leucocyte counts and a broad range of inflammatory serum proteins were analysed to gain insight into the systemic alterations.
Results Four weeks following a single ustekinumab injection, NGF showed a significant decrease, whereas GATA3 and IL‐22RA1 expression increased, indicative of reduced responsiveness to epidermal triggering. This was accompanied by an increase of the inflammation‐related serum proteins GPNMB, MST1 and TRADD. The baseline and tape‐strip‐induced mRNA expression of the AMP human β‐defensin‐2 (hBD‐2), S100A7 and LL‐37 remained unaltered. Clinically, after 4 weeks, eight out of 11 patients showed a 50% psoriasis area and severity index (PASI) improvement, which was accompanied by a significant reduction in serum hBD‐2 levels. No changes were noted in total leucocytes, C‐reactive protein and erythrocyte sedimentation rate.
Conclusions These findings indicate that ustekinumab reduces psoriasis‐related gene expression in noninvolved psoriatic skin, making it more resistant to exogenous triggering, without disturbing its antimicrobial response. In parallel, ustekinumab modulates important circulating inflammation‐related proteins.
What’s already known about this topic?
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Ustekinumab is an effective biologic for psoriasis.
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Psoriasis‐related gene expression levels in noninvolved psoriatic skin are elevated compared with healthy skin.
What does this study add?
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Ustekinumab improves psoriasis‐related gene expression in noninvolved psoriatic skin.
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Ustekinumab alters expression of inflammation‐related proteins in serum.
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Induction of antimicrobial peptides by tape‐stripping is not inhibited by ustekinumab.
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A weakness in our study is the limited number of patients studied; however, there are consistent results.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Transanal advancement flap repair has been advocated as the treatment of choice for high transsphincteric perianal fistulas, but fails in 1 of every 3 patients. Persistence of the fistula ...after flap repair might be the result of ongoing disease in the remaining fistula tract. In 10 specimens of the distal part of the fistula, microbiota was assessed by means of conventional microbiological culture and 16S rRNA gene sequencing. Proinflammatory bacterial peptidoglycan and recognition proteins were assessed by immunohistochemistry. Bacterial species were bowel derived, skin derived, or a combination of both. No mycobacterium species were identified. 16S rRNA gene sequencing failed to identify bacteria in all but 1 specimen, most likely as a result of low numbers of organisms. Peptidoglycan was detected in 90% of the patients, and a host response to peptidoglycan in 60%. Therefore, we suggest that peptidoglycan might play a role in the ongoing inflammation in perianal fistulas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Ectromelia virus (ECTV), a natural mouse pathogen and an orthopoxvirus, has been used to investigate the correlation between polarized type 1 or type 2 immune responses and resistance to disease in ...poxvirus infections by using well defined resistant and susceptible mouse strains. Our data show that distinct differences exist in the cytokine profiles expressed in resistant and susceptible mice infected with ECTV. Resistant C57BL/6 mice generate a type 1 cytokine response IFN-γ, IL-2, and tumor necrosis factor (TNF), within the first few days of infection, which is associated with strong cytotoxic T lymphocyte response (CTL) and recovery from ECTV infection. Susceptible strains of mice (BALB/c and A/J) on the other hand generate a type 2 cytokine response (IL-4 but little or no IFN-γ and IL-2), which is associated with a weak or an absent CTL response, resulting in uncontrolled virus replication and death. Although deletion of IL-4 function alone did not change the outcome of infection in susceptible mice, the loss of IFN-γ function in resistant mice abrogated natural killer (NK) cell and CTL effector functions resulting in fulminant disease and 100% mortality. Therefore, a clear link exists between the early production of specific type 1 cytokines, in particular, IFN-γ, the nature of the cellular immune response, and disease outcome in this virus model. This finding in the mousepox model raises the possibility that inappropriate cytokine responses may result in increased susceptibility to smallpox in humans.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Langerhans-cell histiocytosis (LCH) is caused by an uncontrolled pathogenic clonal proliferation of dendritic cells (DCs) with Langerhans-cell (LC) characteristics. LCH cells are arrested in an ...immature, partially activated stage and show a deviant regulation of cell division. Their aberrant interactions with T cells and the lesional microenvironment are typified by high level production of diverse cytokines. Chemokine and chemokine receptor patterns probably explain LCH predilection sites and lesion composition, reminiscent of chronic granulomatous inflammation. Recent advances in LCH immunology suggest that clonal changes in DCs might underlie the aberrant immune interaction with T cells, leading to a unique pathological picture, which combines features of carcinogenesis and chronic inflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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