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P Brandtzaeg

Publications and source records attributed to P Brandtzaeg.

At least 19 recordsLinked to original sources
PubMed2001

The J chain is essential for polymeric Ig receptor-mediated epithelial transport of IgA.

Local production of secretory (S)IgA provides adaptive immunologic protection of mucosal surfaces, but SIgA is also protective when administered passively, such as in breast milk. Therefore, SIgA is a potential candidate for therapeutic administration, but its complex structure with four different polypeptide chains produced by two distinct cell types complicates recombinant production. The J chain is critical in the structure of SIgA because it is required for efficient polymerization of IgA and for the affinity of such polymers to the secretory component (SC)/polymeric (p)IgR. To better understand the role of the J chain in SIgA production, we have generated various mutant forms of the human J chain and analyzed the function of these mutants when coexpressed with IgA. We found that the C terminus of the J chain was not required for the formation of IgA polymers, but was essential for the binding of pIgA to SC. Likewise, we found that two of the intrachain disulfide bridges (Cys(13):Cys(101) and Cys(109):Cys(134)) were also required for the binding of pIgA to SC but, interestingly, not for IgA polymerization. Conversely, the last intrachain disulfide bridge (Cys(72):Cys(92)) was not essential for either of these two J chain functions. Finally, we demonstrated that the presence of only Cys(15) or Cys(69) was sufficient to support polymerization of IgA, but that these polymers were mostly noncovalently stabilized. Nevertheless, these polymers bound free SC with nearly the same affinity as pIgA containing wild-type J chain, but were transcytosed by pIgR-expressing polarized epithelial cells at a reduced efficiency.

Animals↗
PubMed2001

Identification of residues within the extracellular domain 1 of bovine Fc gamma 2R essential for binding bovine IgG2.

Neutrophils and monocytes in cattle express a novel class of immunoglobulin Fc receptor, specific for bovine IgG2 (bIgG2), termed bFc gamma 2R. In cows, the ability of neutrophils to kill immunoglobulin-opsonized microorganisms appears to depend largely on this subclass, whose interaction with bFc gamma 2R initiates the killing process. bFc gamma 2R is a transmembrane glycoprotein consisting of two extracellular immunoglobulin-like domains, followed by a 19-amino acid membrane-spanning region and a short cytoplasmic tail. Although related to other mammalian Fc gamma Rs, bFc gamma 2R belongs to a novel gene family that includes the human killer cell inhibitory receptor and Fc alpha RI (CD89) proteins. We have shown previously (Morton, H. C., van Zandbergen, G., van Kooten, C., Howard, C. J., van de Winkel, J. G., and Brandtzaeg, P. (1999) J. Exp. Med. 189, 1715-1722) that like these proteins (and unlike other Fc gamma Rs), bFc gamma 2R binds bIgG2 via the membrane-distal extracellular domain 1 (EC1). In this present study, we introduced mutations into the predicted loop regions of the EC1 domain and assayed the resulting bFc gamma 2R mutants for their ability to bind bIgG2. Our results indicated that the bIgG2 binding site lies within the predicted F-G loop region of the EC1 domain. Furthermore, single amino acid mutational analysis of this region identified Phe-82 and Trp-87 as being critical for bIgG2 binding.

Amino Acid Sequence↗
PubMed2001

Cloning and sequencing of a cDNA encoding the bovine FcR gamma chain.

Phagocytic cells of the immune system express specific receptors for the Fc region of immunoglobulins (FcRs). In humans, most FcRs for IgG (FcgammaR), IgA (FcalphaR) and IgE (FcvarepsilonR) consist of an immunoglobulin (Ig) -binding subunit associated with a specialized signaling molecule, the FcR gamma chain. The FcR gamma chain is crucial for the transmission of intracellular signals following receptor ligation. In cattle, however, although four distinct complimentary DNAs (cDNAs) encoding IgG-binding subunits have been described (corresponding to bovine FcgammaRI, FcgammaRII, FcgammaRIII, and Fcgamma2R), virtually, nothing is known about signal transduction via bovine FcRs. Therefore, in this study, a cDNA encoding the bovine FcR gamma chain was cloned. The cDNA is 258 base pairs long and encodes a protein of 85 amino-acids. The mature protein shows high homology with the FcR gamma chains from several other species. Interestingly, the cytoplasmic domain of the bovine FcR gamma chain is one amino-acid shorter than those previously described. Cloning of a cDNA encoding, the bovine FcR gamma chain will allow for a better understanding of signal transduction processes triggered by bovine FcRs.

Amino Acid Sequence↗
PubMed2001

The CCR7 ligand elc (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment.

Lymphocyte homing to secondary lymphoid tissue is defined by a multistep sequence of interactions between lymphocytes and endothelial cells in high endothelial venules (HEVs). After initial selectin-mediated tethering and rolling, firm adhesion of lymphocytes requires rapid upregulation of lymphocyte integrin adhesiveness. This step is mediated in part by the HEV-derived chemokine SLC (secondary lymphoid-tissue chemokine, or CCL21) that binds to the CC chemokine receptor (CCR)7 on lymphocytes. However, the CC chemokine ELC (Epstein-Barr virus-induced molecule 1 ligand chemokine, or CCL19) shares the same receptor, and ELC transcripts have been observed in the T cell areas of lymphoid organs. Here, we show that perivascular ELC is transcytosed to the luminal surfaces of HEVs and enables efficient T cell homing to lymph nodes. In situ hybridization on sections of human tonsil showed no ELC mRNA in HEVs, but immunostaining revealed ELC protein in cytoplasmic vesicles of HEV cells. Furthermore, ELC injected into the footpads of mice entered the draining lymph nodes and was presented by HEVs. Finally, intracutaneous injections of ELC in mice lacking functionally relevant ELC and SLC (plt/plt mice) restored T cell trafficking to draining lymph nodes as efficiently as SLC. We conclude that perivascular ELC is transcytosed to the luminal surfaces of HEVs and participates in CCR7-mediated triggering of lymphocyte arrest.

Animals↗
PubMed2001

M cell pockets of human Peyer's patches are specialized extensions of germinal centers.

M cells in follicle-associated epithelium of Peyer's patches (PP) mediate antigen entrance into the underlying lymphoid tissue. To investigate the functional potential of B cells in this unique microcompartment, the expression of co-stimulatory molecules necessary for B-T cell interaction was examined in histologically normal human PP by three-color immunohistochemistry. In the M cell areas, CD80 / CD86 expression was much more frequent on memory (sIgD(-)CD20(+)) B cells than on naive (sIgD(+)CD20(+)) B cells. M cell areas identified by such co-expression of CD20 and CD80 / CD86 were always spatially related to germinal centers (GC). Contrary to the GC B cell phenotype (sIgD(-)CD20(+)CD80 / 86(hi)CD10(+)Bcl-2(-)), however, M cell-associated B cells with a high level of CD80 / CD86 were CD20(lo)CD10(-)Bcl-2(+), and adjacent memory T cells (CD3(+)CD45R0(+)) often expressed CD40L (CD154). Autologous peripheral blood B-T cell cocultures with purified protein derivative as antigen showed that the sIgD(-)CD80 / CD86(hi)CD20(lo) phenotype could indeed be generated during cognate B-T interactions, concurrent with CD40L up-regulation on memory T cells. Thus, this M cell-associated phenotype might result from B-T cell interactions in the course of antigen presentation by memory B cells, with subsequent CD40 engagement by CD40L-expressing cognate memory T cells. We propose that this M cell-associated event contributes to memory B cell survival and diversification of intestinal immunity, representing a specialized limb of GC function.

Antigens, CD↗
PubMed2001

Plasmacytoid dendritic cells (natural interferon- alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions.

Plasmacytoid dendritic cell (P-DC) precursors in peripheral blood produce large amounts of interferon (IFN)-alpha/beta when triggered by viruses. However, when incubated with interleukin-3 and CD40 ligand, the same precursors differentiate into mature DCs that stimulate naïve CD4(+) T cells to produce Th2 cytokines. We recently reported that P-DCs accumulate in nasal mucosa of experimentally induced allergic rhinitis, supporting a role for this DC subset in Th2-dominated inflammation. Here we examined whether P-DCs accumulate in cutaneous lesions of lupus erythematosus (LE), a disorder associated with increased IFN-alpha/beta production. Our results showed that P-DCs were present in 14 out of 15 tissue specimens of cutaneous LE lesions, but not in normal skin. Importantly, the density of P-DCs in affected skin correlated well (r(s) = 0.79,P < 0.0005) with the high number of cells expressing the IFN-alpha/beta-inducible protein MxA, suggesting that P-DCs produce IFN-alpha/beta locally. Accumulation of P-DCs coincided also with the expression of L-selectin ligand peripheral lymph node addressin on dermal vascular endothelium, adding further support to the notion that these adhesion molecules are important in P-DC extravasation to peripheral tissue sites. Together, our findings suggested that P-DCs are an important source of IFN-alpha/beta in cutaneous LE lesions and may therefore be of pathogenic importance.

Antigens, Surface↗
PubMed2001

Nature and function of gastrointestinal antigen-presenting cells.

Antigen-presenting cells (APCs) of the human gut are heterogeneous, including both macrophages, a variety of dendritic cells and B cells. They are found both in gut-associated lymphoid tissue and in the mucosal lamina propria, especially beneath the surface epithelium. APCs have diverse phenotypes and therefore probably different functions in various locations; their expression levels of a variety of costimulatory molecules are most likely important for immunological decision making of stimulated T cells, either locally in the gut or in regional lymph nodes to which migrating APCs (dendritic cells) carry antigen. Thus, APCs are involved in active immunity as well as in induction of oral tolerance. However, their precise role in food allergy remains to be defined.

Animals↗
PubMed2001

Age-related changes in CCR9+ circulating lymphocytes: are CCR9+ naive T cells recent thymic emigrants?

The chemokine receptor CCR9 is reported to be predominantly expressed by thymocytes as well as by circulating gut-homing and resident T cells in the small intestinal mucosa. Its ligand thymus-expressed chemokine (TECK) is produced by thymic and small intestinal epithelium. Here we report that the proportion of circulating CCR9+ naive T cells (mostly CD4+) declines with age, from approximately 15% of all T cells at birth to around 1% in adults. The proportion of CCR9+ T cells lacking the classical gut-homing receptor alpha4beta7, was much higher in children than in adults. Therefore, circulating CD3+CCR9+CD45RA+ cells have most likely left the thymus quite recently. This notion was supported by the small number of CCR9+ naive T cells which was present shortly after thymectomy. Establishing a phenotypic marker for recent thymic emigrants might provide a powerful tool in the clinical assessment and follow-up after cancer chemotherapy, hematopoietic stem cell transplantation, and during antiretroviral treatment of human immunodeficiency virus (HIV)-infected patients.

Adolescent↗
PubMed2001

Complement activation directly induced by Helicobacter pylori.

BACKGROUND AND AIMS: Helicobacter pylori is a frequent gram-negative colonizer of the human stomach. Its interaction with complement may be involved in the pathogenesis of chronic gastritis, and was mechanistically studied in vitro. METHODS: Four H. pylori strains, 2 cytotoxin-associated genes (cag)A+ and 2 cagA-, were isolated from infected patients. Bacteria or purified H. pylori lipopolysaccharides (LPSs) were incubated with nonimmune serum at 37 degrees C; the activation products C3b/iC3b/C3c (C3bc) and terminal complement complex (TCC) were then quantified by immunoassays. The serum sensitivity of 1 strain (L01, cagA+) was tested by counting the numbers of colony-forming units. RESULTS: All strains and LPSs generated large amounts of C3bc and TCC. Blocking of the classic complement pathway by the calcium chelator ethylene glycol tetraacetic acid (EGTA) markedly reduced the complement products, suggesting that H. pylori and its LPSs directly engage the classic activation pathway. H. pylori was shown to be serum sensitive, but 30% or more nonimmune serum was necessary to induce marked killing. After 5 minutes, swelled bacteria coated with C3bc and TCC were shown. CONCLUSIONS: H. pylori is complement sensitive and activates the classic pathway even in the absence of specific antibodies. Released cell wall constituents such as LPSs can activate complement and may explain why this bacterium induces gastric pathology without invading the mucosa.

Antibodies, Bacterial↗
PubMed2001

Inflammatory bowel disease: clinics and pathology. Do inflammatory bowel disease and periodontal disease have similar immunopathogeneses?

Inflammatory bowel disease (IBD) comprises two chronic, tissue-destructive, clinical entities Crohn disease (CD) and ulcerative colitis (UC) both apparently caused by immunological overreaction (hypersensitivity) to commensal gut bacteria. Under normal conditions the intestinal immune system shows a down-regulating tone ('oral tolerance') against dietary antigens and the indigenous microbiota. This local homeostasis is disturbed in IBD, leading to hyperactivation of T helper 1 (Th1) cells with abundant secretion of interferon-gamma and tumor necrosis factor (TNF) and production of IgG antibodies against commensal bacteria. In addition, UC includes genetically determined autoimmunity, particularly IgG1-mediated cytotoxic epithelial attack. Breaching of the epithelium is the best-defined event underlying abrogation of oral tolerance, but immune deviation caused by cytokines fiom irritated epithelial cells or subepithelial elements (for example, mast cells, natural killer cells, macrophages) may also be involved. Endogenous infection with local hypersensitivity likewise causes periodontal disease, reflecting 'frustrated' immune elimination mechanisms entertained by antigens from dental plaque. Altogether, perturbation of a tightly controlled cytokine network, with abnormal crosstalk between several cell types, apparently explains the progressive immunopathology of chronic inflammatory mucosal diseases in general. This adverse development will be influenced by numerous immunity genes, the dosage and potential pathogeniciy of commensal bacteria, general health, nutritional status, and psychological factors. Several targets for new therapy have tentatively been identified to block immunopathological mechanisms in IBD, and inhibition of TNF has a striking beneficial effect in CD, supporting a central role of this cytokine.

Animals↗
PubMed2001

CD89: the human myeloid IgA Fc receptor.

CD89 (Fc alphaRI) is the human myeloid IgA Fc receptor expressed on cells, such as neutrophils, eosinophils and monocytes/macrophages. Cross-linking of CD89 on these cells, by IgA-opsonised particles (e.g. bacteria, viruses) or anti-CD89 monoclonal antibodies, can trigger various immunological effector functions which are generally protective but may also cause harm to the body. CD89 is a transmembrane glycoprotein that binds both subclasses of IgA in all its molecular forms (i.e. monomeric, dimeric and secretory IgA) via a region of its membrane-distal EC1 domain. DNA studies have shown that the CD89 gene is located within the newly described leukocyte receptor cluster (LRC) on chromosome 19. CD89 is more closely related to the KIR and MIR proteins, whose genes are also found in the LRC, than to other human Fc receptors (FcRs). On myeloid cells, CD89 is able to associate with the immunoreceptor tyrosine-based activation motif (ITAM)-containing the FcR gamma chain, which is responsible for intracellular signaling via CD89. Recently, it has been suggested that some cells express CD89 in a form that does not associate with the FcR gamma chain. Although the biological relevance of this observation is not yet clear, it may explain certain anti-inflammatory/inhibitory effects attributed to IgA. Here we review current knowledge concerning the genetics, structure and biological function of CD89.

Animals↗
PubMed2000

Bioactive cytidine deaminase, an inhibitor of granulocyte-macrophage colony-forming cells, is massively released in fulminant meningococcal sepsis.

Cytidine deaminase (CDD) catalyzes the hydrolytic deamination of cytidine, which thereby is converted to uridine. CDD is found in serum and different tissues, with particularly high concentrations in polymorphonuclear neutrophils (PMN). We measured the CDD levels in plasma from patients with systemic meningococcal disease. Thirty-seven patients had significantly higher plasma levels of CDD than did 29 healthy control subjects (P=.0001). CDD levels in plasma or serum increased from a median of 96 ng/mL in healthy control subjects to medians of 168 ng/mL in patients without persistent shock (n=23; P=.001) and 422 ng/mL in patients with fulminant meningococcal septicemia (n=14; P=.0001). In most patients with fulminant septicemia, CDD levels in plasma increased during the first 3-53 h after the initiation of therapy (P=.003). CDD alone had no immediate harmful effect when injected into mice during a 4-day period. CDD may modulate the stimulatory effect of colony-stimulating factors on PMN in patients.

Adolescent↗
PubMed2000

Mechanism of IL-4-mediated up-regulation of the polymeric Ig receptor: role of STAT6 in cell type-specific delayed transcriptional response.

The polymeric IgR (pIgR) mediates transport of dimeric IgA and pentameric IgM across mucosal epithelia, thereby generating secretory Abs. Its expression is up-regulated at the transcriptional level by IL-4 in HT-29 cells. In this study, we demonstrate that IL-4 mediates up-regulation of human pIgR through a 554-bp IL-4-responsive enhancer in intron 1. Mutation of a binding site for STAT-6 within this region abolished IL-4-induced enhancement, while an adjacent putative C/EBP site was dispensable. IL-4 treatment induced binding of STAT6 to the intronic STAT6 site, but cooperation with nearby upstream and downstream DNA elements was required for IL-4 responsiveness. Furthermore, IL-4-mediated increased transcription of the pIgR-derived enhancer, like the endogenous pIgR gene, required de novo protein synthesis. Interestingly, a conditionally active form of STAT6 sufficed to activate a pIgR-derived enhancer in HT-29 cells, but not in Cos-1 cells, suggesting a requirement for cell type-specific factors. Thus, STAT6 activation mediates a delayed transcriptional enhancement of pIgR by induction of a de novo synthesized protein that cooperates with STAT6 itself bound to its cognate DNA element in intron 1. This mechanism may represent a general strategy for how pleiotropic cytokines elicit cell type-specific transcriptional responses.

Animals↗
PubMed2000

Experimentally induced recruitment of plasmacytoid (CD123high) dendritic cells in human nasal allergy.

Recent evidence suggests that the previously enigmatic cell type designated plasmacytoid monocytes can function as dendritic cells and contribute substantially to both innate and adaptive immunity. This cell type has previously been described only in bone marrow, blood, and organized lymphoid tissue, but not at effector sites with direct Ag exposure such as the mucosae. Plasmacytoid dendritic cells (P-DCs) matured in vitro can induce T cells to produce allergy-promoting Th2 cytokines; therefore, their possible occurrence in nasal mucosa during experimentally elicited allergic rhinitis was examined. Patients with silent nasal allergy were challenged topically with relevant allergen daily for 7 days. Biopsy specimens as well as blood samples were obtained before and during such provocation, and P-DCs were identified by their high expression of CD123 (IL-3R alpha-chain), together with CD45RA. Our results showed that P-DCs were present in low and variable numbers in normal nasal mucosa but increased dramatically during the allergic reaction. This accumulation concurred with the expression of the L-selectin ligand peripheral lymph node addressin on the mucosal vascular endothelium. The latter observation was particularly interesting in view of the high levels of L-selectin on circulating P-DC precursors and of previous reports suggesting that these cells can enter organized lymphoid tissue via high endothelial venules (which express peripheral lymph node addressin constitutively). Together, our findings suggested that P-DCs are involved in the triggering of airway allergy and that they are directed to allergic lesions by adhesion molecules that normally mediate leukocyte extravasation in organized lymphoid tissue.

Administration, Topical↗
PubMed2000

Fulminant meningococcal septicemia: dissociation between plasma thrombopoietin levels and platelet counts.

Thrombopoietin (TPO), interleukin (IL)-6, and platelets were measured serially in 9 patients with fulminant meningococcal septicemia and consumption coagulopathy. The results were compared with those of patients with meningococcal meningitis and mild meningococcemia (n=10) and with those of healthy control subjects (n=19). TPO levels in control subjects were below the detection limit (<63 pg/mL). In patients with fulminant meningococcal septicemia, the median TPO level on admission was 193 pg/mL (range, 133-401 pg/mL), and the level peaked within 3-7 days (median, 488 pg/mL; range, 239-1334 pg/mL). Platelet counts remained low, despite the elevated TPO levels. In patients with meningitis or meningococcemia, the median TPO level on admission was 112 pg/mL (range, <63-695 pg/mL), and the TPO level was not detectable within 48 h. Platelet counts for these patients remained within normal limits. Maximum IL-6 levels in patients with septicemia were observed on admission (median, 5317 pg/mL; range, 188-651,000 pg/mL) and increased earlier than TPO levels. In patients with fulminant septicemia, TPO level increases significantly whereas the level of circulating platelets does not.

Adult↗
PubMed2000

[Does reduced microbial exposure contribute to increased prevalence of allergy?].

Diseases associated with atopic allergy such as asthma, hay fever and eczema have increased dramatically in westernised societies over the last decades. Reduced microbial exposure during the first years of life, which we find in societies with a high standard of living, may be disadvantageous in terms of mucosal sensitisation to allergy. Recent studies have suggested an inverse relationship between allergic disorders and infections with intracellular pathogens including tuberculosis, measles, and hepatitis A. Because many intracellular pathogens generate predominantly a T helper 1 (Th1)-cell cytokine profile, and because Th1 and Th2 cell-mediated immune mechanisms are subjected to cross-regulation, it is possible that exposure to certain microorganisms may repress or abolish development of atopic allergy.

Animals↗
PubMed2000

Immunoglobulin A cell distribution in the human small intestine: phenotypic and functional characteristics.

We compared B-cell phenotypes in Peyer's patches and solitary lymphoid follicles (organized gut-associated lymphoid tissue, GALT) with those in jejunal or ileal lamina propria. In situ, immunostaining showed that small B cells of naive [surface immunoglobulin D-positive (sIgD+) CD27-] and memory (sIgD+/- CD27+) phenotypes occurred almost exclusively in GALT, whereas the lamina propria contained only scattered sIgA+ CD27+ memory cells. In contrast, B-cell blasts and plasma cells negative for CD20 and often also for CD19 but with strong expression of CD38, CD27 and cytoplasmic IgA (cIgA), dominated in the lamina propria but were scarce in GALT. By flow cytometry, the proportion of dispersed CD19+ B lymphocytes varied from 4 to 42% among jejunal mucosal samples; between 5 and 50% of these were sIgD+, suggesting a variable contamination with GALT cells. B-cell blasts and plasma cells, identified by their large size and strong expression of CD38, were regularly found (25-35% of the total mononuclear cell population). Distinction between B-cell blasts and mature plasma cells was made by the presence or absence of human leucocyte antigen (HLA) class II molecules, CD45RA, CD19 and surface immunoglobulin. No CD19+ B cells outside GALT expressed CD5, but a very small portion of the lamina propria B-cell blasts were positive for CD28. Dispersed sIgA+ lamina propria cells expressed low levels of CD40, proliferated on CD40 ligation and constitutively secreted IgA in vitro. We concluded that the lamina propria B-cell compartment consists mainly of B-cell blasts and plasma cells but also has scattered, small sIgA+ cells that can proliferate in response to CD40 ligation and may therefore function as local memory cells for recall antigens.

Adolescent↗