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PubMed2007

Rab27a is a key component of the secretory machinery of azurophilic granules in granulocytes.

Neutrophils kill micro-organisms using microbicidal products that they release into the phagosome or into the extracellular space. The secretory machinery utilized by neutrophils is poorly characterized. We show that the small GTPase Rab27a is an essential component of the secretory machinery of azurophilic granules in granulocytes. Rab27a-deficient mice have impaired secretion of MPO (myeloperoxidase) into the plasma in response to lipopolysaccharide. Cell fractionation analysis revealed that Rab27a and the Rab27a effector protein JFC1/Slp1 (synaptotagmin-like protein 1) are distributed principally in the low-density fraction containing a minor population of MPO-containing granules. By immunofluorescence microscopy, we detected Rab27a and JFC1/Slp1 in a minor subpopulation of MPO-containing granules. Interference with the JFC1/Slp1-Rab27a secretory machinery impaired secretion of MPO in permeabilized neutrophils. The expression of Rab27a was dramatically increased when promyelocytic HL-60 cells were differentiated into granulocytes but not when they were differentiated into monocytes. Down-regulation of Rab27a in HL-60 cells by RNA interference did not affect JFC1/Slp1 expression but significantly decreased the secretion of MPO. Neither Rab27a nor JFC1/Slp1 was integrated into the phagolysosome membrane during phagocytosis. Neutrophils from Rab27a-deficient mice efficiently phagocytose zymosan opsonized particles and deliver MPO to the phagosome. We conclude that Rab27a and JFC1/Slp1 permit MPO release into the surrounding milieu and constitute key components of the secretory machinery of azurophilic granules in granulocytes. Our results suggest that the granules implicated in cargo release towards the surrounding milieu are molecularly and mechanistically different from those involved in their release towards the phagolysosome.

Animals↗
PubMed1975

Synthesis of immunoglobulins and 15 other proteins by diseased human kidneys.

In an effort to determine the synthetic capacity of human kidneys for serum proteins, pieces of both kidneys removed at operation prior to transplantation were placed in organ culture. Incubation with 14C labelled amino acids and subsequent radioimmunoelectrophoresis with antisera to all five classes of immunoglobulins showed synthesis of IgG by all 5 pairs of kidneys of IgA and IgE by 4, and of IgM by 2. None synthesized IgD. Radioimmunoelectrophoresis with specific antisera to 15 non-immunoglobulin proteins revealed synthesis of lactoferrin and uromucoid while several other serum proteins, such as alpha1 antitrypsin and alpha2 macroglobulin, known for their binding properties, showed apparent synthesis. No evidence for secretory component synthesis was seen despite positive immunofluorescent localization in the tubular cells. Further, Zn alpha2 and beta2GP I also showed positive immunofluorescence but negative synthesis. It seems possible that these latter proteins may not be synthesized by the tubular cells but rather may be actively excreted or reabsorbed by them.

Blood Proteins↗
PubMed1996

Encapsulated follicular thyroid carcinoma exhibiting glandular and spindle cell components. A case report.

We describe an unusual case of a thyroid carcinoma exhibiting glandular and sarcomatous features. The tumor occurred in a 16-year-old girl. Histologic study of the resected thyroid gland revealed an encapsulated tumor composed predominantly of glandular structures and some solid areas. In the glandular areas, the tumor cells showed a cribriform growth pattern, and neither colloid secretion into the lumen nor clear-cut cytologic features suggestive of papillary or follicular thyroid carcinoma were observed. In the solid areas, tumor cells became spindled and showed a sarcomatous arrangement with occasional whorl formation. A transition from the glandular areas to the solid ones was observed. Immunohistochemical study revealed that tumor cells were positive focally for epithelial membrane antigen, cytokeratin and secretory component. Thyroglobulin was positive only in a few and limited areas of the glandular component. Calcitonin was negative throughout the tumor. The histologic and immunohistochemical evidence indicates that this tumor is of thyroid origin and is probably derived from thyroid follicular cells. The histology of this tumor is unique, so we report this case briefly.

Adenocarcinoma, Follicular↗
PubMedDate not supplied

[D-penicillamine-induced IgA deficiency in the therapy of Wilson's disease].

Serum IgA deficiency was first noted in a 10 year old boy 8 months after the onset of D-penicillamine therapy. Special immunological examinations revealed a deficiency of the secretory component of IgA while cellular functions of T- and B-lymphocytes were normal. The patient showed discrete clinical signs compatible with IgA deficiency. Regular control of patients with Morbus Wilson and D-penicillamine treatment should include measurement of serum immunoglobulin levels.

Agammaglobulinemia↗
PubMed1987

Studies on the origin and composition of IgA in rat tears.

Experiments were carried out to quantify the proportion of IgA in rat tears that arrives from the circulating IgA pool in the blood, as opposed to that supplied by local synthesis in the lacrymal gland. Rats were injected subcutaneously with an IgA-secreting rat hybridoma cell line (91c), which was allowed to grow in vivo, in order to raise the levels of plasma IgA of known antibody specificity. In rats where serum 91c IgA concentrations had built up to 0.3 mg/ml or more, unstimulated tears contained 91c antibody activity of a molecular weight range that corresponded to that of the polymeric sizes of IgA, and was associated with secretory component. The concentrations of IgA in tear samples were about 0.3% of those in matched serum samples. Thus, a plasma contribution is made to the IgA in tears, but greater than 99% of the tear IgA is synthesized locally in the lachrymal gland.

Animals↗
PubMed1988

Proliferative and secretory activity in the pregnant and lactating human breast.

In this study the proliferative and secretory activity of human pregnant and lactating breast has been examined. 17 cases of pregnant tissue were obtained, comprising 9 from first trimester, 6 from the second and 2 from the third, together with 3 cases of lactating breast. Proliferation, measured by 3H thymidine autoradiography, gave a constant Thymidine labelling index of approximately 6% during the first 20 weeks, with a reduction by 50% thereafter. Levels of 0.2% were seen during lactation. Morphological assessment showed a high frequency of both mitosis and apoptosis throughout gestation. Although mitotic frequency did reduce with time, values were more variable than thymidine labelling. The reduction in thymidine uptake halfway through pregnancy coincided with generalised morphological lactational differentiation and the major immunocytochemical expression of alpha-lactalbumin. However, cytoplasmic expression of the secretory component of IgA was generalised and marked even during the first trimester and was closely related to increased proliferation and general synthetic cellular activity. These and other observations support a complex relationship of autocrine and paracrine factors in addition to the customary endocrine ones for breast regulation.

Adolescent↗
PubMed2004

In vitro adhesion and invasion inhibition of Shigella dysenteriae, Shigella flexneri and Shigella sonnei clinical strains by human milk proteins.

BACKGROUND: Shigella is the etiological agent of shigellosis, a disease responsible for more than 500,000 deaths of children per year, in developing countries. These pathogens colonize the intestinal colon, invade, spreading to the other enterocytes. Breastfeeding plays a very important role in protecting infants from intestinal infections. Amongst milk compounds, glycosylated proteins prevent the adhesion of many enteropathogens in vitro. The aim of this work was to determine the effect of human milk proteins on the colonization potential of Shigella dysenteriae, S. flexneri and S. sonnei. To fulfill this purpose, pooled milk samples from five donors, were fractionated by gel filtration and affinity chromatography. Using tissue culture, the milk fractions obtained were tested in Shigella adhesion and invasion assays. RESULTS: Our revealed showed that both adhesion and invasion of Shigella species were inhibited by low concentration of secretory immunoglobulin A, lactoferrin and free secretory component. This work also showed that, these proteins bind to superficial and whole-cell Shigella proteins. CONCLUSIONS: Our findings suggest that human milk may act inhibiting adhesion and, consequently, invasion of Shigella, thereafter preventing shigellosis in infants.

Antibodies, Bacterial↗
PubMed1984

[Comparative analysis of systemic and local immunity in selective IgA deficiency].

The levels of serum and salivary immunoglobulins and serum antibodies to 5 different antigens (diphtheria toxoid, Escherichia coli and Shigella sonnei O-antigens, bovine serum albumin and ovalbumin), as well as heterohemagglutinins , were studied in 29 persons with complete or partial IgA deficiency. In 27% of cases an increase in the level of serum IgA was observed, such increase occurring more frequently in complete than in partial IgA deficiency. A rise in the level of serum antibodies, especially those to alimentary and enterobacterial antigens, was established; the degree of this rise was not correlated with the degree of disturbances in the systemic synthesis of IgA. In complete IgA deficiency not only serum, but also salivary IgA was absent; in some cases saliva contained no secretory component as well. In partial IgA deficiency the level of salivary IgA was normal. The characteristic features of systemic and local immunity in a varying degree of disturbances in the synthesis of IgA are discussed.

Adolescent↗
PubMed1988

Effects of the long-acting somatostatin analogue SMS 201-995 in an infant with intractable diarrhea.

The long-acting somatostatin analogue SMS 201-995 was administered to a six-month-old infant with intractable diarrhea after failure of conventional treatment. During eight weeks of treatment, the secretory component of the diarrhea was positively influenced with a reduction of daily stool weight and stool sodium concentration. Plasma levels of growth hormone were markedly, and levels of insulin, IGF I, gastrin, pancreatic polypeptide, VIP, and neurotensin moderately decreased. Linear growth was also inhibited. The patient unexpectedly died from fulminant colitis at a time, when the dosage had been reduced from 18 to 3.5 micrograms/kg/day. The relationship, if any, between therapy with SMS 201-995 and the colitis remained unclear. It is concluded that SMS 201-995 can be effective in reducing secretory diarrhea in infants. However, further studies are necessary to assess the safety of its administration in this age group.

Antidiarrheals↗
PubMed1978

Increased calcium-ion influx is a component of capacitation of spermatozoa.

Capacitation (modifications required for gamete fusion) is produced by incubating guinea-pig spermatozoa in vitro in a chemically defined medium. It is shown that during such incubation a net uptake of Ca2+ by the sperm occurs in two distinguishable phases. An initial loose association of Ca2+, possibly to surface sites, is unaffected by agents (Mg2+, inhibitors of mitochondiral function) that prevent or delay the exocytotic spermatozoal acrosome reaction. The time course of a secondary Ca2+ uptake parallels or slightly precedes the time course of the acrosome reaction. This parallelism is maintained during a variety of treatments that either expedite (local anaesthetics, ionophore A23187, Triton X-100) or delay (Mg2+, low external Ca2+) the acrosome reaction. We conclude that the secondary Ca2+ influx described herein apparently serves to link alterations of the spermatozoal membrane to subsequent contractile and secretory components of the capacitation sequence.

Acrosome↗
PubMedDate not supplied

[Secretory IgA and the antibacterial defenses of the respiratory tract (author's transl)].

The secretory IgA (IgA S) in bronchial mucus is produced by cells which are derived, at least in part, from the BALT (Bronchus Associated Lymphoid Tissue). The physico-chemical characteristics of IgA S (the amino-acid structure of the alpha chain, the secretory component and the J chain) explain three properties of this antibody which enable it to play its part as the first line of defense on the surface of the mucus, namely its resistance to proteolysis, its adherence and its ability to penetrate mucus. The role of IgA S in the antibacterial defense of the respiratory tract has been in doubt for some time because it does not follow the usual processes of antibacterial action, having neither opsonising nor lytic activity. It is thought at present that IgA S exerts its action in an individual way, more directly and peculiar to the secretory immune-apparatus. It acts by 1) causing agglutination of bacteria and by inhibiting their adsorption on the mucous membranes, 2) inhibiting bacterial reproduction and 3) by inactivating bacterial toxins. The combination of these three processes produces a surface defense system which inhibits bacterial penetration of the mucus. Despite the uncertainties which still exist, it is essential that the fundamental immunological data should be included in the complex picture of the mechanisms of defense of the respiratory tract.

Adhesiveness↗
PubMed1985

Serum levels of secretory immunoglobulin A in liver disease.

Secretory immunoglobulin A (sIgA) in serum was measured in patients with various liver diseases using enzyme immunoassay specific to sIgA. Marked elevation of the serum sIgA concentrations was found in liver diseases especially in intrahepatic or extrahepatic cholestasis. In chronic hepatitis and liver cirrhosis serum sIgA correlated significantly with leucine aminopeptidase (r = 0.69), GOT (r = 0.66), alkaline phosphatase (r = 0.55), and direct bilirubin (r = 0.42). In acute hepatitis their levels correlated significantly with total bilirubin (r = 0.59) and GPT (r = 0.55). In acute hepatitis and acute exacerbation of chronic hepatitis the major peaks of serum sIgA were observed later than those of liver enzymes. These results suggest two mechanisms working to elevate the serum sIgA levels in liver diseases. In chronic hepatitis, liver cirrhosis, and intrahepatic and extrahepatic cholestasis the raised serum sIgA probably reflects reflux of bile, a rich source of secretory component and sIgA, into circulation. In acute or chronic massive liver necrosis elevation of sIgA may be associated with liver regeneration. Serial measurement of serum sIgA with other conventional parameters will contribute much to the understanding of the pathophysiology of liver diseases.

Acute Disease↗
PubMed1982

Amniotic fluid secretory immunoglobulin A in normal pregnancy and in pregnancy complicated by rhesus isoimmunization.

Amniotic fluid levels of secretory immunoglobulin A (S-IgA) were measured by simple radial immunodiffusion according to the method of Mancini using a monospecific antiserum against the human secretory component. We examined 256 samples from healthy pregnant women and 149 samples from mothers suffering from rhesus isoimmunization. During normal pregnancy amniotic fluid S-IgA increased significantly and showed a loose correlation with the phospholipid levels. This was not observed in pregnancies complicated by rhesus isoimmunization.

Amniotic Fluid↗
PubMedDate not supplied

[Microecology and humoral immunity characteristics of the vagina in women with nonspecific inflammatory diseases of the genitals].

The complex cytological, microbiological and immunological examination of 90 female patients with nonspecific inflammatory diseases of the genital tracts and 30 clinically healthy women (the control group) was carried out. The examination revealed significant microbiocenosis changes in the lumen and the parietal area of the vagina, depending on the severity of the infectious process: a decrease in the level of lactobacilli, an increase in the content of opportunistic facultative anaerobic microorganism in the lumen and obligate anaerobic bacteria in the parietal area. Pronounced correlation between the content of opportunistic microorganisms and the levels of IgM and IgA, as well as secretory IgA and free secretory component in vaginal secretions in patients in patients with non-specific inflammatory diseases of the genital tracts has been revealed.

Anaerobiosis↗
PubMed2000

Absence of CD89, polymeric immunoglobulin receptor, and asialoglycoprotein receptor on human mesangial cells.

IgA nephropathy (IgAN) is characterized by raised serum IgA and predominant mesangial IgA deposits of polymeric nature. The expression of IgA receptor molecules in white blood cells and glomerular mesangial cells has recently attracted much attention in relation to the uptake of IgA by these cells. This study investigates the expression of IgA Fc receptor (Fc alphaR1 or CD89), asialoglycoprotein receptor (ASGPR), and polymeric Ig receptor (pIgR) in cultured glomerular mesangial cells. Using a sensitive nested reverse transcription-PCR, mRNA encoding for Fc alphaR1, pIgR, or the H2 chain of ASGPR was not demonstrated on human mesangial cells. U937, HepG2, and HT29 cell lines, used as positive controls, strongly expressed the Fc alphaR1, ASGPR, and pIgR mRNA, respectively, under similar experimental conditions. Flow cytometry also demonstrated the presence of surface proteins for Fc alphaR1, ASGPR, and pIgR on the respective control cell lines but not on human mesangial cells. Expression of Fc alphaR1 mRNA on cultured U937 cells was upregulated by tumor necrosis factor-alpha. However, tumor necrosis factor-alpha, interleukin-1beta, or transforming growth factor-beta failed to induce the expression of Fc alphaR1 on human mesangial cells. Human serum IgA or secretory IgA bound to human mesangial cells, HepG2, or the U937 cell line in a dose-dependent manner. The binding of purified IgA to human mesangial cells was not blocked by preincubation with human IgG, IgM, orosomucoid, asialo-orosomucoid, anti-CD89 antibody (My43), or anti-secretory component antibody. The present study concluded that there was an absence of Fc alphaR1, ASGPR, or pIgR on human mesangial cells. These findings suggest that the predominant binding of human IgA to human mesangial cells is mediated by other mechanisms.

Antibodies↗
PubMed1989

[Immunomorphological determination of secretory immunoglobulin A in the bronchial mucous membrane in chronic bronchitis].

The disappearance of the secretory immunoglobulin A in chronic bronchitis is shown to result from the disappearance of the epitheliocytes capable of secreting this substance. The secondary immunoglobulin A deficiency is followed by its accumulation in the basal epithelial cells. The absence of the secretory component probably prevents the immunoglobulin A diffusion to the epithelium surface this decreasing the local immunity against various antigens and the possibility of their elimination. It is suggested that the epithelial alterations described in patients with chronic bronchitis are among the causes for non-specific lung diseases to become chronic.

Adult↗
PubMed2001

Megalin in thyroid physiology and pathology.

Megalin, a member of the low density lipoprotein endocytic receptor family, is expressed on the apical surface of thyroid epithelial cells, directly facing the follicle lumen, where colloid is stored in high concentrations. Studies in vivo and with cultured thyroid cells have provided evidence that megalin expression on thyroid cells is TSH-dependent. Thyroglobulin (Tg), the major protein component of the colloid and the precursor of thyroid hormones, binds to megalin with high affinity and megalin mediates in part its uptake by thyrocytes. Tg internalized by megalin avoids the lysosomal pathway and is delivered by transepithelial transport (transcytosis) to the basolateral membrane of thyrocytes, from which it is released into the bloodstream. This process competes with pathways leading to thyroid hormone release from Tg molecules, which occurs following internalization of Tg molecules from the colloid by other means of uptake (fluid phase endocytosis or endocytosis mediated by low affinity receptors) that result in proteolytic cleavage in the lyosomes. During transcytosis of Tg, a portion of megalin (secretory component) remains complexed with Tg and enters the circulation, where its detection may serve as a tool to identify the origin of serum Tg in patients with thyroid diseases. Tg endocytosis via megalin is facilitated by the interaction of Tg with cell surface heparan sulfate proteoglycans, which occurs via a carboxyl terminal heparin binding site of Tg functionally related with a major megalin binding site. Although autoantibodies against megalin can be found in the serum of approximately 50% of patients with autoimmune thyroiditis, a role of megalin in this and other thyroid diseases remains to be established.

Animals↗