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PubMed2006

Cryopyrin activates the inflammasome in response to toxins and ATP.

A crucial part of the innate immune response is the assembly of the inflammasome, a cytosolic complex of proteins that activates caspase-1 to process the proinflammatory cytokines interleukin (IL)-1beta and IL-18. The adaptor protein ASC is essential for inflammasome function, binding directly to caspase-1 (refs 3, 4), but the triggers of this interaction are less clear. ASC also interacts with the adaptor cryopyrin (also known as NALP3 or CIAS1). Activating mutations in cryopyrin are associated with familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, diseases that are characterized by excessive production of IL-1beta. Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels. The release of IL-1beta in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was also found to be dependent on cryopyrin. In contrast to Asc-/- macrophages, cells deficient in the gene encoding cryopyrin (Cias1-/-) activated caspase-1 and secreted normal levels of IL-1beta and IL-18 when infected with Gram-negative Salmonella typhimurium or Francisella tularensis. Macrophages exposed to Gram-positive Staphylococcus aureus or Listeria monocytogenes, however, required both ASC and cryopyrin to activate caspase-1 and secrete IL-1beta. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes.

Adenosine Triphosphate↗

PubMed2000

Gender differences in the regulation of P450 aromatase expression and activity in human adipose tissue.

OBJECTIVE: To investigate the hormonal regulation of P450 aromatase activity (responsible for the conversion of C19 androgens to C18 oestrogens) in human adipose tissue from men and pre- and post-menopausal women. SUBJECTS: Subcutaneous abdominal adipose tissue was obtained from 19 subjects: six pre-menopausal females (mean age 41.8+/-(s.e.m.) 2.5; mean weight 76.01+/-5.6 kg), eight post-menopausal females (mean age 59.9+/-2.0; mean weight 63.5+/-2.6 kg), and five males (mean age 35.8+/-8.8; mean weight 78.5+/-7.8 kg) undergoing elective or cosmetic surgery. MEASUREMENTS: Cell viability and cell size were determined using staining techniques. RT-PCR was used to confirm the presence of aromatase. The regulation of aromatase activity was characterized using androstenedione as a substrate in a tritiated water release assay. Aromatase activity was analysed in abdominal subcutaneous stromal cells (ASC) and mature adipocytes (AD) cultured in serum-free medium with cortisol (10-6-10-7 M), insulin (500 nM) or a combination of both. RESULTS: In ASC aromatase activity increased in females from 14.5+/-1.7 to 29. 3+/-2.6 pmol/mg/h (n=14, P<0.05) and to 25.2+/-2.1 pmol/mg/h with cortisol (10-7 M) and insulin, respectively (P<0.05). In males ASC basal aromatase activity (20.5+/-4.2 pmol/mg/h; n=5) was inhibited by cortisol (10-7 M) alone (12.3+/-1.8 pmol/mg/h) and in combination with insulin (6.6+/-1.2 pmol/mg/h; men vs women, P<0.005). Aromatase activity in mature adipocytes was stimulated by cortisol plus insulin (P<0.05) with no gender-specific differences. Treatment of ASC from both pre- and post-menopausal females with cortisol alone (10-6 M; 10-7 M) or in combination with insulin demonstrated significantly different aromatase regulation compared with male aromatase stromal cell regulation (P<0.05); however there were no differences in aromatase regulation between pre- and post-menopausal females either in stromal cells or adipocytes. CONCLUSION: This study shows intrinsic gender differences in the regulation of aromatase, suggesting that differential enzyme regulation may affect sex steroid metabolism to alter the pattern of fat distribution between the sexes.

Adipocytes↗

PubMed2002

Delayed and reduced adaptive humoral immune responses in children with shigellosis compared with in adults.

We hypothesized that increased susceptibility to Shigella infection, increased severity of disease and high mortality in children compared with adults were consequences of insufficient adaptive immune responses. Antigen-specific immune responses were studied in paediatric patients (n = 38, 2-10 years) with shigellosis and compared with those of adult patients (n = 30, 18-45 years). Peak frequencies of antigen (invasion plasmid coded antigen B, Ipa-B; lipopolysaccharide, LPS)-specific immunoglobulin (IgM)-antibody secreting cells (ASC) were seen within 3-5 days after the onset of diarrhoea in children, while peak IgA- and IgG-ASCs were obtained 8-10 days later in line with adults. Antigen-specific ASC responses in children ranged between 2 and 4% of the total ASC responses, in contrast to 8-15% in adults. The kinetics of LPS-specific IgG subclass titres was different in younger children (2.5-5 years) (IgG1 > IgG2 > IgG4 > IgG3) compared with in older children (6-8 years) (IgG2 > IgG1 >IgG3 > IgG4) and adults. Secretory IgA levels in stool peaked 8-10 days after onset in both adults and children. However, a rapid induction of stool LPS-specific IgA, IgA1 and IgA2 occurred in adult patients within 3-5 days of onset, while in children, this was delayed by 8-10 days. Similarly, higher number of tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma expressing cells in vitro were seen in adult patients in response to antigens (LPS and Ipa-B) in the acute stage in contrast to paediatric patients. Thus, paediatric patients with shigellosis have reduced and delayed adaptive immune responses compared with adult patients.

Adaptation, Physiological↗

PubMed2000

Absence of lipopolysaccharide high-dose paralysis in B-cell responses: implications for the one-signal theory.

Over 20 years ago, Coutinho and Möller reported that high concentrations of LPS were paralytic for the development of antibody secreting cells (ASC). This data was used to explain bell-shaped dose-response curves observed for antihapten antibody formation in response to haptenated LPS. In turn, this bell curve was used to formulate the one-signal model of B cell activation, which argued that antigen signalling was generally unimportant to B cell responses. The present paper re-examines LPS dose-response curves and finds results that do not support the view that high doses of LPS inhibit B cell differentiation to ASC. If high-dose paralysis is not an attribute of LPS stimulation, then the bell-shaped dose curve for hapten-specific ASC originally observed by Coutinho and Möller required an alternative explanation. Through the use of haptenated Ficoll, it was possible to show that the generation of LPS-induced antitrinitrophenol ASC could be inhibited by antigen presented on an inert substrate. Thus, the transmission of surface Ig-mediated (antigen) signals at higher concentrations can explain the antihapten bell-shaped dose curves, in contradiction to the conclusions of the one-signal model.

Animals↗

PubMed2000

Regulation of lipopolysaccharide-induced B-cell activation: evidence that surface immunoglobulin mediates two independently regulated signals.

An antigen-specific B cell response can be induced by low concentrations of haptenated lipopolysaccharide (LPS), whereas high concentrations are inhibitory. Two explanations have been proposed for the latter phenomenon. In the first, specific surface Ig focuses LPS to the B cell membrane, where high local concentrations of the mitogen become paralytic for B cell responses. In the alternative, transmission of an antigen signal at higher concentrations of hapten LPS actively inhibits the development of antibody secreting cells (ASC). In the present paper, the immunosuppressant cyclosporine A (CsA) was used to attempt to distinguish between these two models. Cyclosporine A did not block the inhibitory effects of goat anti-IgM (galphaIgM) on development of ASC induced by LPS and therefore was unsuitable for testing between the two models. However, surprisingly, in the presence but not the absence of CsA, even low concentrations of galphaIgM became inhibitory for LPS-induced B cell proliferation. Thus, a CsA-insensitive signal could inhibit both B cell proliferation and the development of ASC. In contrast, the CsA-sensitive signal induced by sIg required high concentrations of galphaIgM for triggering and enhanced the LPS proliferative response without affecting development of ASC. Evidence is presented that these two signals are regulated independently, suggesting that together they may transmit information about the physical form of an antigen to the B cell.

Animals↗

PubMed2004

Melatonin prevents disruption of hepatic reactive oxygen species metabolism in rats treated with carbon tetrachloride.

We reported that melatonin prevents the progression of carbon tetrachloride (CCl4)-induced acute liver injury in rats possibly by attenuating enhanced lipid peroxidation and reduced glutathione depletion. Herein, we examined the effect of melatonin on the changes in hepatic reactive oxygen species (ROS) metabolism in rats with a single intraperitoneal injection of CCl4 (1.6 g/kg body weight); the intent was to clarify the therapeutic mechanism of the indoleamine on CCl4-induced acute liver injury. Rats with and without CCl4 treatment received a single oral dose of melatonin (10, 50 or 100 mg/kg body weight) 6 hr after CCl4 treatment. Hepatic concentrations of ascorbic acid (ASC) and vitamin E (VE) and hepatic activities of superoxide dismutase (SOD), catalase (CAT), Se-glutathione peroxidase (Se-GSH-Px), glutathione reductase (GSSG-R), glucose-6-phosphate dehydrogenase (G-6-PDH), and xanthine oxidase (XO) were determined 6 and 24 hr after CCl4 treatment. The liver of CCl4-treated rats showed reductions in ASC concentrations, and SOD activity and an increase in G-6-PDH activity at 6 hr after treatment and further decreases in ACS concentrations and SOD activity and also further increase in G-6-PDH activity in addition to decreases in CAT and GSSG-R activities and increases in VE concentrations and XO activity at 24 hr after treatment. Melatonin attenuated the reductions in hepatic ASC concentrations and SOD, CAT and GSSG-R activities and the increase in hepatic XO activity in a dose-dependent manner without affecting either hepatic Se-GSH-Px activity or the increased hepatic VE concentration and G-6-PDH activity at 24 hr after CCl4 treatment. No dose of melatonin influenced hepatic ACS and VE concentrations and SOD, CAT, Se-GSH-Px, G-6-PDH, and XO activities in CCl4-untreated rats. These results indicate that melatonin postadministered at pharmacological doses prevents the disruption of hepatic ROS metabolism associated with ASC, SOD, CAT, GSSG-R, and XO, in addition to reduced glutathione, in CCl4-treated rats.

Animals↗

PubMed2002

Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease.

Prevalence and clinical relevance of antibodies to soluble liver antigen (tRNP((Ser)Sec)/SLA) in autoimmune hepatitis (AIH) have been investigated using partially purified or prokaryotically expressed antigen. The aim of this study was to improve the detection of anti-tRNP((Ser)Sec)/SLA by establishing an immunoassay that was able to identify antibodies directed to conformational epitopes and to investigate the clinical implication of this autoantibody in autoimmune liver disease. By using eukaryotically expressed tRNP((Ser)Sec)/SLA as target in a radioligand assay (RLA), 81 patients with autoimmune liver disease (AILD) (33 type 1 AIH, 31 type 2 AIH, and 17 autoimmune sclerosing cholantitis [ASC]), 147 pathologic, and 56 healthy controls were investigated. RLA results were compared with those obtained using a commercial enzyme-linked immunosorbent assay (ELISA) and immunoblot. Reactivity to tRNP((Ser)Sec)/SLA was present in 58% of patients with type 1 and type 2 AIH, 41% with ASC, but in only 3 pathologic controls. RLA was similarly disease-specific but remarkably more sensitive than ELISA and immunoblot. A prospective study showed that anti-tRNP((Ser)Sec)/SLA-positive patients run a severe clinical course, having worse histology, needing longer to achieve remission, relapsing and requiring liver transplantation or dying more frequently than anti-tRNP((Ser)Sec)/SLA negative patients. Anti-tRNP((Ser)Sec)/SLA production was favored by the possession of DR3 and A1-B8-DR3 in AIH type 1 and ASC, and prevented by the possession of A2 in all 3 types of AILD, particularly in type 2 AIH. In conclusion, anticonformational tRNP((Ser)Sec)/SLA reactivity is frequent in type 1 and type 2 AIH and ASC, defining patients with a worse prognosis.

Autoantibodies↗

PubMed2000

Kinetics of circulating antibodies, immune complex and specific antibody-secreting cells in tuberculosis patients during 6 months of antimicrobial therapy.

OBJECTIVE: During the follow-up of a group of patients with active tuberculosis, the predictive potential of several antibody-based assays was evaluated in monitoring treatment efficacy. DESIGN: Eleven patients with bacteriologically documented pulmonary tuberculosis and two patients with tuberculosis pleurisy were studied over a period of 6 months, from the day before treatment to its completion. The kinetics of the humoral response to Mycobacterium tuberculosis was determined by the number of specific circulating antibody secreting cells (ASC) (ELISPOT assay), as well as the titres of specific circulating antibody and specific antibody present in circulating immune complexes (quantitative ELISA). RESULTS: Follow-up ELISPOT assays, performed after initiation of tuberculosis therapy showed a rapid increase of ASC, during the first week, followed by rapid 3-10 fold decline of ASC in 12 of 13 patients tested. This decline occurred more rapidly than the mycobacterial culture conversion. In contrast, follow-up of ELISA assays did not give relevant information in assessing the outcome of treatment. CONCLUSION: In comparison with direct detection of tubercle bacilli in sputum samples, the rapid clearance of specific circulating ASC occurring early on after the onset of therapy could suggest a potential usefulness of ELISPOT in monitoring therapeutic response.

Adult↗

PubMed2002

Lecithin-cholesterol acyltransferase activity during maturation of human preovulatory follicles with different concentrations of ascorbate, alpha-tocopherol and nitrotyrosine.

The enzyme lecithin-cholesterol acyltransferase (LCAT) transfers an acyl chain from lecithin to cholesterol or oestradiol, thus playing a crucial role in reverse cholesterol transport and follicular synthesis of potent long-lived oestrogens. The mechanism of catalysis is biphasic, as it is based on a phospholipase and an esterifying activity. Sulfhydryl groups were previously reported to be required for the esterification step. Lecithin-cholesterol acyltransferase has previously been shown to be inhibited by thiol oxidants such as peroxynitrite. Peroxynitrite also converts tyrosine to nitrotyrosines. In the present study, high levels of nitrotyrosine associated with low LCAT activity, and vice versa, were found in human preovulatory follicular fluids. Follicular fluids were also analysed for oestradiol (E) and progesterone (P) concentrations. The E/P ratio, which decreases as ovulation approaches, was used to evaluate the maturation status of each follicle. Enzyme activity was negatively correlated with the E/P ratio. Ascorbate (Asc) and alpha-tocopherol (Toc) were titrated in follicular fluid and plasma to evaluate their accumulation or consumption in the follicle. High LCAT activity was found in follicular fluids where Asc and Toc had accumulated, whereas lower activity was associated with Asc and Toc consumption. The consumption of both antioxidants was positively correlated with the E/P ratio. The results suggest that as follicle maturation progresses, Toc and Asc concentrations increase in follicular fluid, thus protecting LCAT from oxidative damage and loss of activity.

Ascorbic Acid↗

PubMed2002

1-Cys peroxiredoxin overexpression protects cells against phospholipid peroxidation-mediated membrane damage.

1-Cys peroxiredoxin (1-cysPrx) is a novel antioxidant enzyme able to reduce phospholipid hydroperoxides in vitro by using glutathione as a reductant. This enzyme is widely expressed and is enriched in lungs. A fusion protein of green fluorescent protein with 1-cysPrx was stably expressed in a lung-derived cell line (NCI-H441) lacking endogenous enzyme. Overexpressing cells (C17 or C48) degraded H(2)O(2) and t-butylhydroperoxide more rapidly and showed decreased sensitivity to oxidant stress as measured by (51)Cr release. On exposure to (*)OH generated by Cu(2+)-ascorbate (Asc), overexpressing cells compared with H441 showed less increase in thiobarbituric acid-reactive substance and phosphatidylcholine hydroperoxide content. This effect was reversed by depletion of cellular glutathione. Diphenyl-1-pyrenoylphosphonium fluorescence, used as a real-time probe of membrane phospholipid peroxidation, increased immediately on exposure to Cu(2+)-Asc and was abolished by preincubation of cells with Trolox (a soluble vitamin E) or Tempol (a radical scavenger). The rate of diphenyl-1-pyrenoylphosphonium fluorescence increase with Cu(2+)-Asc exposure was markedly attenuated in C17 and C48 cells as compared with H441. Annexin V-Cy3 was used to detect phosphatidylserine translocation from the inner to outer leaflet of the plasma membrane. Cu(2+)-Asc treatment induced phosphatidylserine translocation within 2 h in H441 cells but none was observed in C48 cells up to 24 h. These results indicate that 1-cysPrx can scavenge peroxides but in addition can reduce peroxidized membrane phospholipids. Thus, the enzyme can protect cells against oxidant-induced plasma membrane damage, thereby playing an important role in cellular defense against oxidant stress.

Amino Acid Sequence↗

PubMed2000

A longevity assurance gene homolog of tomato mediates resistance to Alternaria alternata f. sp. lycopersici toxins and fumonisin B1.

The phytopathogenic fungus Alternaria alternata f. sp. lycopersici (AAL) produces toxins that are essential for pathogenicity of the fungus on tomato (Lycopersicon esculentum). AAL toxins and fumonisins of the unrelated fungus Fusarium moniliforme are sphinganine-analog mycotoxins (SAMs), which cause inhibition of sphingolipid biosynthesis in vitro and are toxic for some plant species and mammalian cell lines. Sphingolipids can be determinants in the proliferation or death of cells. We investigated the tomato Alternaria stem canker (Asc) locus, which mediates resistance to SAM-induced apoptosis. Until now, mycotoxin resistance of plants has been associated with detoxification and altered affinity or absence of the toxin targets. Here we show that SAM resistance of tomato is determined by Asc-1, a gene homologous to the yeast longevity assurance gene LAG1 and that susceptibility is associated with a mutant Asc-1. Because both sphingolipid synthesis and LAG1 facilitate endocytosis of glycosylphosphatidylinositol-anchored proteins in yeast, we propose a role for Asc-1 in a salvage mechanism of sphingolipid-depleted plant cells.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Silencing mediator of retinoid and thyroid hormone receptors and activating signal cointegrator-2 as transcriptional coregulators of the orphan nuclear receptor Nur77.

For the orphan nuclear receptor subfamily that includes Nur77 (NGFI-B), Nurr1, and NOR-1, no transcriptional coregulators have been identified thus far. In this report, we found that Ca(2+)/calmodulin-dependent protein kinase IV enhances Nur77 transactivation in cotransfections either alone or in synergy with AF2dependent coactivator ASC-2, whereas corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) is repressive. Interestingly, Nur77 interacted with SMRT but did not directly bind ASC-2, and accordingly, the putative AF2 core domain of Nur77 did not affect the Nur77 transactivation. SMRT harbors transferable repression domains that associate with various histone deacetylases. Surprisingly, histone deacetylase inhibitor trichostatin A was unable to block the repressive effect of SMRT while dramatically stimulating the Nur77 transactivation. These results suggest that SMRT and ASC-2 are specific coregulators of Nur77 and that SMRT may dynamically compete with a putative adaptor molecule, which links ASC-2 to Nur77, for the identical binding sites within Nur77 in vivo.

Animals↗

PubMedDate not supplied

Shamanism and altered states of consciousness: an introduction.

In this article, the issue of shamanism and altered states of consciousness (ASC) is reviewed from a cross-cultural and multidisciplinary perspective. It is suggested that in spite of considerable differences in the uses of these terms, there are conceptual and empirical grounds for distinction among different types of trance practitioners. The authors argue that shamanism is a cultural adaptation of hunting and gathering societies to the biological potential for ASC, and that the specific nature of that manifestation changes as societies become more complex. The role of ASC in understanding shamanic phenomena, the roots of religious experience, and the modern manifestations of the potential for trance are examined. Western cultural avoidance of ASC has inhibited understanding of these phenomena, and has prevented an integration of shamanistic and trance perspectives into the understanding human of psychology, consciousness, and knowledge of the world.

Culture↗

PubMed1998

The glucose/insulin system and vitamin C: implications in insulin-dependent diabetes mellitus.

The cellular uptake of vitamin C (ascorbic acid, ASC) is promoted by insulin and inhibited by hyperglycemia. If a rise in plasma ASC is uncoupled from insulin replacement in insulin-dependent diabetes mellitus (IDDM) then the degree of hyperglycemia could account for "tissue scurvy" in IDDM. Leukocyte ASC is lower in IDDMs compared with nondiabetics when vitamin C consumption is adequate and our data suggest that this is a variable component of the pathophysiology of IDDM. The complications of diabetes mellitus are believed to result from either the intracellular accumulation of sorbitol or the nonenzymatic glycoxidation of proteins or both. With respect to the abnormal cellular accumulation of sorbitol, vitamin C supplementation has been shown to be effective in several studies of adults with diabetes; the situation regarding the prevention of protein glycoxidations by supplementation is presently unclear. The roles of ASC as an aldose reductase inhibitor and a water soluble antioxidant in body fluids are potentially very important as adjuncts to tight glycemic control in the management of diabetes. Tissue saturation and maximal physiologic function in IDDM may require supplemental vitamin C intake.

Adult↗

PubMed1999

Effects of the correction of renal artery stenosis on blood pressure, renal function and left ventricular morphology.

The aim of this study was to evaluate the effect of renal artery stenosis (RAS) correction in hypertensive patients on 24 h SBP, 24 h DBP, creatinine clearance (GFR), urinary albumin excretion (UAE) and LV morphology and mass (LVMI). A total of 61 hypertensive patients with RAS undergoing PTRA and/or surgical treatment entered the prospective study. The final analysis was done in 44 patients (age range 45.8 +/- 16.2 years) with RAS (atherosclerosis (ASC) 31 patients, fibromuscular dysplasia (FMD) 12 patients, arteritis 1 patient) who underwent PTRA (34 patients) or surgical treatment (10 patients) and presented no Doppler signs of restenosis (or a new stenosis) during 1-year observation. The pre-interventional assessment repeated after 6 and 12 months included ABPM, GFR, UAE and echocardiography. The results were analysed in the combined group (CG) and in according aetiology. 24 h SBP and 24 h DBP decreased in all groups 6 months post-intervention and did not change further. Cure of HT was observed in 35% and 29% of ASC patients at 6 and 12 months respectively; and in 58% of FMD patients. Failure rate at 12 months was 48% in ASC against 25% in FMD. The mean GFR in CG was higher 12 months after intervention. The increase in GFR was noted in 45% of patients, the decrease in 25% of patients at 12 months. Normal values of UAE were found in 71% of patients, pre- and post-intervention alike. Mean LVMI and number of patients with LVH in CG decreased already during the initial 6 months post-intervention and did not change further. In conclusion, correction of RAS leads to cure of or improved control of hypertension in the majority of the patients with FMD, but in the ASC group in about half of cases no BP cure or improvement was seen. The renal function was improved or stable in two-thirds of patients after revascularization. Successful renal revascularization was followed by regression of LVH, which was evident within 6 months post-intervention.

Adolescent↗

PubMed2002

Organ and non-organ specific autoantibody titres and IgG levels as markers of disease activity: a longitudinal study in childhood autoimmune liver disease.

No longitudinal study has investigated whether autoantibody titres and serum IgG levels correlate with disease activity in autoimmune liver disease. To determine this, we investigated prospectively 19 patients on 254 occasions between 10 months to 5 years from diagnosis. Nine had anti-nuclear and/or anti-smooth muscle antibody (ANA/SMA) positive autoimmune hepatitis (type 1 AIH), 5 liver kidney microsomal type 1 (LKM-1) positive AIH (type 2 AIH) and 5 ANA/SMA positive autoimmune sclerosing cholangitis (ASC). Correlation between IgG levels, titres of ANA, SMA and LKM-1 and levels of the organ specific autoantibodies anti-liver specific protein (anti-LSP), and anti-asialoglycoprotein receptor (anti-ASGPR) with biochemical evidence of disease activity, as measured by serum aspartate amino transferase (AST) levels, was sought during the course of the disease. AST levels correlated with levels of anti-LSP, anti-ASGPR and IgG in type 1 and 2 AIH, but not in ASC. Positive correlation with AST was also observed for LKM-1 titres in type 2 AIH and for SMA titres in type 1 AIH, but not in ASC. In both AIH and ASC, AST levels correlated with the T cell-dependent immune responses anti rubella IgG and anti tetanus toxoid IgG, but not with the T cell-independent IgG2 response to pneumococcal capsular polysaccaride. Our results indicate that measurement of organ and non-organ specific autoantibodies and IgG levels may be used to monitor disease activity in AIH.

Adolescent↗

PubMed2002

The intestinal chemokine thymus-expressed chemokine (CCL25) attracts IgA antibody-secreting cells.

Immunoglobulin A (IgA) provides protection against pathogens at mucosal surfaces. Chemotactic responses have been hypothesized to target IgA plasma cells involved in mucosal immune responses. We show here that thymus-expressed chemokine (TECK, CCL25) is a potent and selective chemoattractant for IgA antibody-secreting cells (ASC), efficiently recruiting IgA-producing cells from spleen, Peyer's patches, and mesenteric lymph node. Cells secreting IgA antibody in response to rotavirus, an intestinal pathogen, also respond well. In contrast, IgG- and IgM-ASC respond poorly. Epithelial cells in the small intestines, a principal site of IgA-ASC localization and IgA production in the body, highly and selectively express TECK. The migration of IgA-ASC to the intestinal epithelial cell chemokine TECK may help target IgA-producing cells to the gut wall, thus helping define and segregate the intestinal immune response.

Animals↗

PubMed2004

CCL28 controls immunoglobulin (Ig)A plasma cell accumulation in the lactating mammary gland and IgA antibody transfer to the neonate.

The accumulation of immunoglobulin (Ig)A antibody-secreting cells (ASCs) in the lactating mammary gland leads to secretion of antibodies into milk and their passive transfer to the suckling newborn. This transfer of IgA from mother to infant provides transient immune protection against a variety of gastrointestinal pathogens. Here we show that the mucosal epithelial chemokine CCL28 is up-regulated in the mammary gland during lactation and that IgA ASCs from this tissue express CCR10 and migrate to CCL28. In vivo treatment with anti-CCL28 antibody blocks IgA ASC accumulation in the mammary gland, inhibiting IgA antibody secretion into milk and the subsequent appearance of antibody in the gastrointestinal tract of nursing neonates. We propose that CCL28 is a key regulator of IgA ASC accumulation in the mammary gland and thus controls the passive transfer of IgA antibodies from mother to infant.

Animals↗