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1.
Mucosal Immunol ; 9(4): 884-93, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26509875

RESUMO

Whole-saliva IgA appears like an attractive noninvasive readout for intestinal immune induction after enteric infection or vaccination, but has failed to show consistent correlation with established invasive markers and IgA in feces or intestinal lavage. For reference, we measured antibodies in samples from 30 healthy volunteers who were orally infected with wild-type enterotoxigenic Escherichia coli. The response against these bacteria in serum, lavage, and lymphocyte supernatants (antibody-in-lymphocyte-supernatant, ALS) was compared with that in targeted parotid and sublingual/submandibular secretions. Strong correlation occurred between IgA antibody levels against the challenge bacteria in sublingual/submandibular secretions and in lavage (r=0.69, P<0.0001) and ALS (r=0.70, P<0.0001). In sublingual/submandibular secretions, 93% responded with more than a twofold increase in IgA antibodies against the challenge strain, whereas the corresponding response in parotid secretions was only 67% (P=0.039). With >twofold ALS as a reference, the sensitivity of a >twofold response for IgA in sublingual/submandibular secretion was 96%, whereas it was only 67% in the parotid fluid. To exclude that flow rate variations influenced the results, we used albumin as a marker. Our data suggested that IgA in sublingual/submandibular secretions, rather than whole saliva with its variable content of parotid fluid, is a preferential noninvasive proxy for intestinal immune induction.


Assuntos
Anticorpos Antibacterianos/metabolismo , Escherichia coli Enterotoxigênica/imunologia , Infecções por Escherichia coli/imunologia , Imunoglobulina A/metabolismo , Intestinos/imunologia , Glândula Parótida/metabolismo , Saliva/metabolismo , Biomarcadores/metabolismo , Células Cultivadas , Meios de Cultivo Condicionados/metabolismo , Infecções por Escherichia coli/diagnóstico , Fezes , Humanos , Imunidade nas Mucosas , Linfócitos/imunologia , Sensibilidade e Especificidade
2.
Mucosal Immunol ; 7(3): 511-20, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24064668

RESUMO

Human immunoglobulin A (IgA) comprises two IgA subclasses, IgA1 and IgA2, whose distribution has been shown by immunohistochemistry to be different in various body compartments. In comparison with systemic immune compartments, we investigated the IgA switch profiles at the molecular level in salivary and lacrimal glands, nasal mucosa, and proximal and distal gut mucosa. Direct switching from IgM to IgA1 or IgA2 predominated in all immune compartments analyzed. Similar composition of the Sµ-Sα1 and Sµ-Sα2 junctions was observed, including microhomology usage, which suggested that there is no major difference in the actual recombination mechanism utilized during IgA subclass switching. The proportion of IgA1/IgA2 switch recombination events largely paralleled the previously published immunohistochemical representation of IgA1(+) and IgA2(+) plasma cells, implying that the local subclass distribution generally reflects precommitted memory/effector B cells that have undergone IgA subclass switching before extravasation at the effector site. The extremely low or undetectable levels of activation-induced cytidine deaminase (AID) and Iα-Cµ circle transcripts in intestinal lamina propria samples as compared with Peyer's patches suggest that the cellular IgA subclass distribution outside of organized gut-associated lymphoid tissue is only to a minor extent, if at all, influenced by in situ switching.


Assuntos
Sistema Imunitário/fisiologia , Imunoglobulina A/genética , Imunoglobulina A/imunologia , Switching de Imunoglobulina , Mucosa/imunologia , Adolescente , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos B/metabolismo , Criança , Humanos , Mucosa Intestinal/imunologia , Pessoa de Meia-Idade , Mucosa/metabolismo , Mutação , Adulto Jovem
3.
Benef Microbes ; 4(1): 67-82, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23257015

RESUMO

There is currently a major focus on the role of the gut barrier function in balancing mucosal immune responses. Increased epithelial permeability for exogenous antigens is a crucial primary or secondary event in the pathogenesis of several disorders affecting body surfaces and beyond. The epithelial gate-keeper function is determined by the individual's age (e.g. preterm vs. term infant), diet, genetics, mucus composition, interactions between mast cells, nerves and neuropeptides, concurrent infection, the commensal microbiota and the epithelium-shielding effect of secretory IgA (SIgA) antibodies provided by breast milk or produced in the individual's gut. The integrity of the epithelial barrier furthermore depends on homeostatic regulatory mechanisms, including mucosal induction of regulatory T cells, where commensal microbiota-host interactions apparently play decisive roles. Thus, both extrinsic and intrinsic factors have been identified that may have an impact on the dynamics of the epithelial cell-cell junctions in the gut and thereby increase or reduce paracellular permeability. Experiments have shown that SIgA normally cooperates with innate defence factors to protect the epithelium and reinforce its barrier function. In the absence of SIgA commensal gut bacteria overstimulate innate epithelial immunity at the expense of expression of genes that regulate fat and carbohydrate metabolism, resulting in an epithelial gene signature that correlates with the development of lipid malabsorption. This shows that the intestinal epithelial barrier is a cross-road between defence and nutrition, and that SIgA is essential to keep the balance between these two functions.


Assuntos
Imunidade nas Mucosas , Mucosa Intestinal/fisiologia , Fenômenos Fisiológicos da Nutrição , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo
4.
Clin Microbiol Infect ; 17(12): 1875-81, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21745258

RESUMO

A longitudinal, prospective study was conducted intermittently in Norway, from 1999 to 2008, to investigate the Candida colonization rates and species distributions in the tonsillopharyngeal and faecal flora in: (i) children with cancer; (ii) children with cystic fibrosis (CF); and (iii) healthy children. The effect of antibiotic treatment on Candida colonization was also studied, and we looked for changes in antifungal susceptibility over time within each child and between the different groups of children. In total, 566 tonsillopharyngeal swabs and 545 faecal samples were collected from 45 children with cancer, 37 children with CF, and 71 healthy, age-matched controls. The overall colonization rate with Candida was not significantly higher in the two groups of children undergoing extensive treatment with broad-spectrum antibiotics than in healthy controls. Approximately one-third of the cancer patients had a total lack of Candida colonization or had only one Candida-positive sample, despite multiple samples being taken, treatment with broad-spectrum antibiotics, long hospital stays, and periods with neutropenia. Children with CF had the highest prevalence of Candida albicans. Amoxycillin, azithromycin, third-generation cephalosporins and oral vancomycin resulted in a significantly increased Candida colonization rate. Phenoxymethylpenicillin, second-generation cephalosporins, metronidazole, trimethoprim-sulphamethoxazole, ciprofloxacin, penicillinase-resistant penicillins and inhaled tobramycin or colistin showed minimal effects on the Candida colonization rate. We found no evidence of development of antifungal resistance over time.


Assuntos
Candida/classificação , Candidíase/epidemiologia , Fibrose Cística/complicações , Neoplasias/complicações , Adolescente , Antibacterianos/uso terapêutico , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candida/isolamento & purificação , Criança , Pré-Escolar , Fezes/microbiologia , Humanos , Lactente , Estudos Longitudinais , Testes de Sensibilidade Microbiana , Noruega/epidemiologia , Tonsila Palatina/microbiologia , Faringe/microbiologia , Prevalência , Estudos Prospectivos
5.
Benef Microbes ; 1(3): 211-27, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21831758

RESUMO

In the process of evolution, the mucosal immune system has generated two layers of anti-inflammatory defence: (1) immune exclusion performed by secretory IgA (and secretory IgM) antibodies to modulate or inhibit surface colonisation of microorganisms and dampen penetration of potentially dangerous antigens; and (2) suppressive mechanisms to avoid local and peripheral hypersensitivity to innocuous antigens, particularly food proteins and components of commensal bacteria. When induced via the gut, the latter phenomenon is called 'oral tolerance', which mainly depends on the development of regulatory T (Treg) cells in mesenteric lymph nodes to which mucosal dendritic cells (DCs) carry exogenous antigens and become conditioned for induction of Treg cells. Mucosally induced tolerance appears to be a rather robust adaptive immune function in view of the fact that large amounts of food proteins pass through the gut, while overt and persistent food allergy is not so common. DCs are 'decision makers' in the immune system when they perform their antigen-presenting function, thus linking innate and adaptive immunity by sensing the exogenous mucosal impact (e.g. conserved microbial molecular patterns). A balanced indigenous microbiota is required to drive the normal development of both mucosa-associated lymphoid tissue, the epithelial barrier with its secretory IgA (and IgM) system, and mucosally induced tolerance mechanisms including the generation of Treg cells. Notably, polymeric Ig receptor (pIgR/SC) knock-out mice that lack secretory IgA and IgM antibodies show reduced epithelial barrier function and increased uptake of antigens from food and commensal bacteria. They therefore have a hyper-reactive immune system and show predisposition for systemic anaphylaxis after sensitisation; but this development is counteracted by enhanced oral tolerance induction as a homeostatic back-up mechanism.


Assuntos
Imunidade nas Mucosas , Imunoglobulina A Secretora/imunologia , Imunoglobulina M/imunologia , Mucosa Intestinal/microbiologia , Metagenoma , Animais , Homeostase , Humanos , Mucosa Intestinal/imunologia , Camundongos
6.
Allergy ; 65(5): 561-70, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-19886928

RESUMO

BACKGROUND: Mucosal immunity protects the epithelial barrier by immune exclusion of foreign antigens and by anti-inflammatory tolerance mechanisms, but there is a continuing debate about the role of secretory immunoglobulins (SIgs), particularly SIgA, in the protection against allergy and other inflammatory diseases. Lack of secretory antibodies may cause immune dysfunction and affect mucosally induced (oral) tolerance against food antigens. METHODS: We used polymeric Ig receptor (pIgR) knockout (KO) mice, which cannot export SIgA or SIgM, to study oral tolerance induction by ovalbumin (OVA) feeding and for parenteral antigen sensitization in the same animal. RESULTS: Remarkable systemic hyperreactivity was observed in pIgR KO mice, as 50% died after intradermal OVA challenge, which was not seen in similarly sensitized and challenged wild-type (WT) mice. Oral tolerance induced by OVA completely protected the sensitized pIgR KO mice against anaphylaxis and suppressed antibody levels (particularly IgG1) as well as delayed-type hypersensitivity (DTH) to OVA. Delayed-type hypersensitivity to a bystander antigen, human serum albumin, was also suppressed and T-cell proliferation against OVA in vitro was reduced in tolerized compared with non-tolerized pIgR KO mice. This effect was largely mediated by CD25+ T cells. Adoptive transfer of splenic putative regulatory T cells (CD4+ CD25+) obtained from OVA-fed pIgR KO mice to naïve WT mice mediated suppression of DTH against OVA after sensitization of the recipients. CONCLUSION: Compensatory regulatory T-cell function becomes critical in pIgR-deficient mice to avoid the potentially catastrophic effects of systemic immune hyperreactivity, presumably resulting from defective secretory antibody-mediated immune exclusion of microbial components.


Assuntos
Hipersensibilidade Tardia/imunologia , Tolerância Imunológica/imunologia , Imunidade nas Mucosas/imunologia , Receptores de Imunoglobulina Polimérica/deficiência , Transferência Adotiva , Animais , Ensaio de Imunoadsorção Enzimática , Feminino , Hipersensibilidade Alimentar/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/imunologia , Receptores de Imunoglobulina Polimérica/genética , Receptores de Imunoglobulina Polimérica/imunologia , Linfócitos T Reguladores/imunologia
7.
Scand J Immunol ; 70(6): 505-15, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19906191

RESUMO

Prevention of infections by vaccination remains a compelling goal to improve public health. Most infections involve the mucosae, but the development of vaccines against many of these pathogens has yet to be successful. Mucosal vaccines would make immunization procedures easier, be better suited for mass administration, and most efficiently induce immune exclusion - a term coined for non-inflammatory antibody shielding of internal body surfaces - mediated principally by secretory immunoglobulin A (SIgA). The exported antibodies are polymeric, mainly IgA dimers (pIgA) - produced by local plasma cells stimulated by antigens that target the mucosae. SIgA was early shown to be complexed with an epithelial glycoprotein - the secretory component (SC). In 1974, a common SC-dependent transport of pIgA and pentameric IgM was proposed. From the basolateral surface, pIg-SC complexes are taken up by endocytosis and finally extruded into the lumen. Membrane SC is now referred to as polymeric Ig receptor (pIgR). In 1980, it was shown to be synthesized as a larger transmembrane protein - first cloned from rabbit and then from human. Mice deficient for pIgR showed that this is the only receptor responsible for epithelial transport of IgA and IgM. In the gut, induction of B cells occurs in gut-associated lymphoid tissue, particularly the Peyer's patches, but also in mesenteric lymph nodes. Plasma cell differentiation is accomplished in the lamina propria to which the memory/effector cells home. The airways also receive such cells from nasopharynx-associated lymphoid tissue - but by different homing receptors. Such compartmentalization is a challenge for development of mucosal vaccines.


Assuntos
Imunidade nas Mucosas , Imunoglobulina A Secretora/imunologia , Imunoglobulina M/imunologia , Vacinação/métodos , Vacinas/administração & dosagem , Vacinas/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Homeostase/imunologia , Humanos , Tolerância Imunológica/imunologia , Imunoglobulina A Secretora/metabolismo , Imunoglobulina M/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/imunologia , Camundongos , Mucosa/imunologia , Transporte Proteico/imunologia , Coelhos
8.
Mucosal Immunol ; 1(1): 11-22, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19079156

RESUMO

The production of immunoglobulin A (IgA) in mammals exceeds all other isotypes, and it is mostly exported across mucous membranes. The discovery of IgA and the realization that it dominates humoral mucosal immunity, in contrast to the IgG dominance of the systemic immune system, was early evidence for the distinct nature of mucosal immunology. It is now clear that IgA can function in high-affinity modes for neutralization of toxins and pathogenic microbes, and as a low-affinity system to contain the dense commensal microbiota within the intestinal lumen. The basic map of induction of IgA B cells in the Peyer's patches, which then circulate through the lymph and bloodstream to seed the mucosa with precursors of plasma cells that produce dimeric IgA for export through the intestinal epithelium, has been known for more than 30 years. In this review, we discuss the mechanisms underlying selective IgA induction of mucosal B cells for IgA production and the immune geography of their homing characteristics. We also review the functionality of secretory IgA directed against both commensal organisms and pathogens.


Assuntos
Formação de Anticorpos/imunologia , Imunidade nas Mucosas/imunologia , Imunoglobulina A/imunologia , Nódulos Linfáticos Agregados/imunologia , Plasmócitos/imunologia , Células Precursoras de Linfócitos B/imunologia , Animais , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia
9.
Mucosal Immunol ; 1(1): 31-7, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19079158

RESUMO

Stimulation of mucosal immunity has great potential in vaccinology and immunotherapy. However, the mucosal immune system is more complex than the systemic counterpart, both in terms of anatomy (inductive and effector tissues) and effectors (cells and molecules). Therefore, immunologists entering this field need a precise terminology as a crucial means of communication. Abbreviations for mucosal immune-function molecules related to the secretory immunoglobulin A system were defined by the Society for Mucosal Immunolgy Nomenclature Committee in 1997, and are briefly recapitulated in this article. In addition, we recommend and justify standard nomenclature and abbreviations for discrete mucosal immune-cell compartments, belonging to, and beyond, mucosa-associated lymphoid tissue.


Assuntos
Imunoglobulina A/imunologia , Tecido Linfoide/imunologia , Mucosa/imunologia , Terminologia como Assunto , Animais , Humanos , Tecido Linfoide/anatomia & histologia , Mucosa/anatomia & histologia
10.
Clin Exp Immunol ; 152(2): 381-7, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18341610

RESUMO

Regulatory T cells (T(regs)) may inhibit immunity against cancer. Induction and expansion of T(regs) in the immunosuppressive microenvironment created by a growing tumour appear to be one of the mechanisms by which it can evade host defence. We studied the impact of CD25+ T(regs) in a B cell lymphoma model in which Rag2-/- mice received adoptive transfer of wild-type spleen cells with or without CD25+ cells, and concurrently subcutaneous inoculation of the B cell lymphoma cell line A20. We also examined the effect of engaging the glucocorticoid-induced tumour necrosis factor receptor (GITR) - an approach reported previously to abrogate the suppressive effects of T(regs). Mice that received spleen cells depleted of CD25+ T(regs) showed significantly slower tumour growth and increased survival compared with mice that received unsorted spleen cells. The T(reg)-depleted group also had significantly more CD8+ T cells infiltrating the tumours and higher levels of serum immunoglobulin G subclasses. The anti-GITR treatment had no significant effect on tumour growth, survival or immunoglobulin production. In the CD25-depleted group four of 10 mice developed clinical signs of autoimmunity, in contrast to none in the non-depleted group. Forkhead box P3+ T cells were found in tumour-draining lymph nodes in mice in the CD25-depleted group, suggesting an in vivo induction or expansion of rare transferred donor T(regs). Thus, our study showed that removal of CD25+ T(regs) enhanced anti-tumour immunity against local growth of a B cell lymphoma and that induction or expansion of T(regs) could be one mechanism by which the growing tumour evades immune surveillance.


Assuntos
Subunidade alfa de Receptor de Interleucina-2/análise , Depleção Linfocítica , Linfoma de Células B/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Anticorpos Monoclonais/imunologia , Divisão Celular , Modelos Animais de Doenças , Proteína Relacionada a TNFR Induzida por Glucocorticoide , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Imunofenotipagem , Linfócitos do Interstício Tumoral/imunologia , Linfoma de Células B/patologia , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Receptores de Fator de Crescimento Neural/imunologia , Receptores do Fator de Necrose Tumoral/imunologia , Baço/imunologia
11.
Thorax ; 63(8): 703-9, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18250182

RESUMO

BACKGROUND: In early childhood, the ability to mount protective immune responses in the airways is impaired, with increased risk of allergic sensitisation to inhaled allergens. Antigen presenting cells (APC) and regulatory T cells (Treg) are important modifiers of T cell immunity but little is known about their distribution in bronchial mucosa at this age. Here the subset distribution of APC and the appearance of Foxp3(+) Treg and bronchus associated lymphoid tissue (BALT) were examined immunohistochemically in children less than 2 years of age with chronic asthma-like symptoms of the lower airways. METHODS: Immunophenotyping was performed in situ on bronchial biopsy specimens obtained from 45 infants, 4-23 months of age, under investigation for airway disease. RESULTS: A well developed HLA-DR(+) network of APC was present in all samples, approximately 50% of the cells being CD68(+) macrophages and the remainder various subsets of dendritic cells. The density of HLA-DR(+) cells increased significantly with age but was not related to atopy, clinical symptoms or lung function. Comparing the density of APC subsets and clinical parameters, only the number of intraepithelial CD1a(+) dendritic cells was significantly increased in infants who had recently suffered a respiratory infection. BALT structures were identified in 22 children, with no relation to lung function, atopic status or human rhinovirus positivity. Plasmacytoid dendritic cells and Foxp3(+) Treg were located primarily within these isolated lymphoid follicles. CONCLUSION: A bronchial network of dendritic cells and macrophages develops quite rapidly after birth, apparently independent of clinical symptoms or atopy. The high frequency of BALT structures containing putative tolerogenic dendritic cells and Treg suggests that these lymphoid follicles play an important role in bronchial immune homeostasis during infancy.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Brônquios/imunologia , Linfócitos T Reguladores/imunologia , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunidade Celular , Imuno-Histoquímica , Lactente , Tecido Linfoide/imunologia , Masculino , Fenótipo , Infecções Respiratórias/imunologia
12.
Clin Exp Allergy ; 37(6): 856-64, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17517099

RESUMO

BACKGROUND: Elevated proliferative response to allergen in cord blood mononuclear cells (CBMCs) is related to subsequent allergy development of the neonate and has been suggested as a screening marker for high allergy risk. OBJECTIVE: To characterize the proliferating cells in CBMCs from a neonatal group influenced by maternal allergy compared with a control group without known allergic heredity. METHODS: CBMCs were stimulated with bovine beta-lactoglobulin (beta-LG) and proliferation was analysed by radioactive thymidine incorporation and expressed both as the traditional stimulation index (SI) and SI corrected by eliminating non-specific proliferation. After beta-LG combined with endotoxin stimulation, cellular expression of IL-4 and IFN-gamma mRNA was determined by quantitative RT-PCR and adhesion as well as chemokine receptors were analysed by three-colour flow cytometry in proliferating T cells (CD3+ Ki-67+). RESULTS: The percentage of CCR4+ cells correlated weakly with concurrent IL-4 expression (r(S)=0.5, P<0.05), while CXCR3 correlated strongly with IFN-gamma expression (r(S)=0.83, P<0.001). In the allergy risk group, the percentage of proliferating T cells expressing CCR4 or integrin alphaE (CD103) was significantly reduced compared with the control group, while CXCR5 and the corrected SI were relatively increased (CCR4: P=0.01; integrin alphaE: P=0.03; CXCR5: P=0.04; SI: P=0.04). CONCLUSION: Our results implied delayed maturation of immune functions involved in cellular migration, cell-cell interaction and immunoregulatory functions in neonates with hereditary allergy risk. The alterations observed in this subject group suggested that the corrected SI as well as proliferation of CCR4+, CXCR5+ or CD103+ T cells in allergen-stimulated CBMCs might serve as early screening markers for allergy risk.


Assuntos
Antígenos CD/imunologia , Proliferação de Células , Sangue Fetal/imunologia , Hipersensibilidade/imunologia , Cadeias alfa de Integrinas/imunologia , Troca Materno-Fetal/imunologia , Receptores de Quimiocinas/imunologia , Linfócitos T/imunologia , Adulto , Alérgenos/imunologia , Alérgenos/farmacologia , Animais , Antígenos CD/biossíntese , Complexo CD3/imunologia , Bovinos , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Endotoxinas/farmacologia , Feminino , Sangue Fetal/metabolismo , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Hipersensibilidade/congênito , Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Recém-Nascido , Cadeias alfa de Integrinas/biossíntese , Interferon gama/imunologia , Interleucina-4/imunologia , Antígeno Ki-67/imunologia , Lactoglobulinas/imunologia , Lactoglobulinas/farmacologia , Masculino , Gravidez , Receptores CCR4 , Receptores CXCR5 , Receptores de Quimiocinas/biossíntese , Linfócitos T/metabolismo
13.
Gut ; 55(9): 1240-7, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16484508

RESUMO

BACKGROUND AND AIMS: Patients with rheumatoid arthritis (RA) often feel there is an association between food intake and rheumatoid disease severity. To investigate a putative immunological link between gut immunity and RA, food antibodies were measured in serum and perfusion fluid from the jejunum of RA patients and healthy controls to determine the systemic and mucosal immune response. METHODS: IgG, IgA, and IgM antibodies to dietary antigens were measured in serum and jejunal perfusion fluid from 14 RA patients and 20 healthy subjects. The antigens originated from cow's milk (alpha-lactalbumin, beta-lactoglobulin, casein), cereals, hen's egg (ovalbumin), cod fish, and pork meat. RESULTS: In intestinal fluid of many RA patients, all three immunoglobulin classes showed increased food specific activities. Except for IgM activity against beta-lactoglobulin, all other IgM activities were significantly increased irrespective of the total IgM level. The RA associated serum IgM antibody responses were relatively much less pronounced. Compared with IgM, the intestinal IgA activities were less consistently raised, with no significant increase against gliadin and casein. Considerable cross reactivity of IgM and IgA antibodies was documented by absorption tests. Although intestinal IgG activity to food was quite low, it was nevertheless significantly increased against many antigens in RA patients. Three of the five RA patients treated with sulfasalazine for 16 weeks had initially raised levels of intestinal food antibodies; these became normalised after treatment, but clinical improvement was better reflected in a reduced erythrocyte sedimentation rate. CONCLUSIONS: The production of cross reactive antibodies is strikingly increased in the gut of many RA patients. Their food related problems might reflect an adverse additive effect of multiple modest hypersensitivity reactions mediated, for instance, by immune complexes promoting autoimmune reactions in the joints.


Assuntos
Artrite Reumatoide/imunologia , Hipersensibilidade Alimentar/imunologia , Imunoglobulina A/análise , Imunoglobulina G/análise , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/etiologia , Reações Cruzadas , Proteínas Alimentares/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Hipersensibilidade Alimentar/complicações , Humanos , Imunidade nas Mucosas , Imunoglobulinas/análise , Mucosa Intestinal/imunologia , Jejuno/imunologia , Masculino , Pessoa de Meia-Idade , Sulfassalazina/uso terapêutico
14.
Clin Exp Immunol ; 139(2): 314-22, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15654830

RESUMO

Reduced microbial exposure in early life may contribute to the increase of atopic diseases in 'westernized' societies but the underlying mechanisms remain elusive. The objective of this study was to examine how exposure to bacterial lipopolysaccharide (LPS) during early antigen encounter might influence the maturation of neonatal lymphoid cells, and to define possible differences in this respect between neonates with high risk of allergy due to a family history (FH(+)) and controls with no apparent hereditary risk (FH(-)). Cord blood mononuclear cells from the FH(+) or FH(-) group were stimulated with pure LPS or beta-lactoglobulin (beta-LG) in the presence of LPS. T cell expression of chemokine receptors CCR4 and CXCR3 was determined by flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR). Cellular expression of interleukin (IL)-4 was analysed by quantitative RT-PCR, whereas interferon (IFN)-gamma was analysed by both quantitative RT-PCR and immunoassay. Stimulation with LPS, or beta-LG together with LPS, induced up-regulation of CCR4 (P < 0.05) and CXCR3 (P < 0.05). For CCR4, such up-regulation was related to the level of IL-4 produced by the same T cells (r(S) = 0.49, P = 0.03), while CXCR3 expression was negatively correlated with the IL-4 levels (r(S) = -0.56, P = 0.02). Compared with the FH(-) group, the FH(+) group showed a significantly lower capacity for generation of CCR4(+) T cells (mean percentage of total T cells: FH(+), 2.42%versus FH(-), 5.74%; P < 0.01), whereas induction of CXCR3 and IFN-gamma did not differ significantly between the two groups. When the immune system in early life encounters antigen together with LPS, the T cell potential for compartmentalized interaction with other immune cells might be increased by elevated CCR4- and CXCR3-expression levels. In neonates at hereditary allergy risk, this putative homeostatic mechanism could theoretically be jeopardized due to decreased up-regulation of CCR4. Conversely, Th1 responses to antigen in the presence of LPS did not appear to be reduced compared with controls.


Assuntos
Hipersensibilidade/genética , Interleucina-4/imunologia , Receptores de Quimiocinas/imunologia , Células Th2/imunologia , Estudos de Casos e Controles , Células Cultivadas , Exposição Ambiental , Citometria de Fluxo , Humanos , Hipersensibilidade/imunologia , Recém-Nascido , Interferon gama/imunologia , Lactoglobulinas/imunologia , Lipopolissacarídeos/farmacologia , Ativação Linfocitária , Receptores CCR4 , Receptores CXCR3 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Risco , Estatísticas não Paramétricas
15.
Gut ; 53(4): 487-93, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15016741

RESUMO

BACKGROUND: It is well documented that highly active antiretroviral therapy (HAART) restores systemic immunity to human immunodeficiency virus (HIV) but the effect of this treatment on the mucosal immune system is less clear. AIMS: Because future preventive or therapeutic vaccines against HIV may be administered by the mucosal route, we wished to evaluate the effect of HAART on the activation level and homeostasis of the intestinal B cell system. PATIENTS AND METHODS: Duodenal biopsy specimens were collected consecutively from infection prone HIV positive adults (n = 31), mostly with advanced AIDS. In situ two colour immunofluorescence staining was performed to quantify mucosal immunoglobulin (Ig) class and subclass producing immunocytes (plasmablasts and plasma cells). RESULTS: HIV positive patients had, on average, duodenal proportions of IgA (74.6%), IgM (19.5%), and IgG (3.4%) immunocytes similar to median values recorded in 11 HIV seronegative healthy controls but the total immunocyte number per mucosal section length unit (500 microm) was significantly increased in patients (median 175 v 120 cells/unit; p<0.008), mainly comprised of IgA (p<0.02) and IgG1 (median 81.8% of total IgG; p<0.02) isotypes. Patients receiving a successful HAART regimen tended to normalise their IgG1 proportion and showed significantly lower total duodenal IgA immunocyte number than those receiving no or insufficient antiretroviral treatment (p<0.005). CONCLUSION: Our study demonstrated that advanced AIDS patients hyperactivate their intestinal B cell system. HAART could significantly reverse this perturbation, suggesting restored ability of the mucosal immune system to control intestinal infections.


Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade , Linfócitos B/efeitos dos fármacos , HIV-1 , Mucosa Intestinal/efeitos dos fármacos , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Adulto , Fármacos Anti-HIV/farmacologia , Linfócitos B/imunologia , Contagem de Linfócito CD4 , Duodeno/efeitos dos fármacos , Duodeno/imunologia , Feminino , Sobreviventes de Longo Prazo ao HIV , Humanos , Imunidade nas Mucosas/efeitos dos fármacos , Imunoglobulinas/sangue , Mucosa Intestinal/imunologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Carga Viral , Microglobulina beta-2/sangue
16.
Int J Pediatr Otorhinolaryngol ; 67 Suppl 1: S69-76, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14662171

RESUMO

The lymphoid tissue of Waldeyer's ring, and particularly the nasopharyngeal tonsil (adenoids), appears to be functionally comparable to nasal-associated lymphoid tissue in rodents. Antigen-stimulated lymphoid follicles give rise to: (a) clonal B-cell expansion; (b) B-cell receptor affinity maturation; (c) positive selection of B cells according to receptor affinity for antigen; (d) differentiation to B memory cells and plasma cells; and (e) variable induction of the joining (J)-chain gene. B-cell differentiation is also important to promote downstream isotype switching of the immunoglobulin (Ig) heavy chain constant genes. For tonsillar B cells, this process gives mainly rise to IgG and IgA plasma cells, partially associated with J-chain expression. Because the J chain is a key peptide in the polymer structure of secretory IgA, tonsils and adenoids may provide B cells for mucosal effector sites. Thus, several observations suggest that these lymphoid organs generate polymeric IgA (pIgA)-expressing B cells that migrate to the upper airway mucosa, lacrimal glands and salivary glands. Accordingly, the nasal route of vaccination induces secretory IgA-dependent regional mucosal immunity and will also enhance systemic immunity. Although the pIgA-producing capacity of tonsillar B cells is considerably decreased in children with recurrent tonsillitis, a conservative attitude towards adenotonsillectomy appears immunologically desirable, particularly in the young age group.


Assuntos
Tonsila Faríngea/imunologia , Cirurgia Geral , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Otolaringologia , Tonsila Palatina/imunologia , Competência Profissional , Adenoidectomia/efeitos adversos , Tonsila Faríngea/metabolismo , Antígenos CD/imunologia , Comunicação Celular/fisiologia , Humanos , Imunoglobulina A/metabolismo , Imunoglobulina G/metabolismo , Imunoglobulina M/metabolismo , Linfócitos/imunologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Procedimentos Cirúrgicos Otológicos , Tonsila Palatina/metabolismo , Tonsilectomia/efeitos adversos
17.
Br J Dermatol ; 149(3): 484-91, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14510979

RESUMO

BACKGROUND: Normal skin contains no epidermal calprotectin. In biopsies from various inflammatory skin disorders, however, this antimicrobial protein occurs in the cytoplasm of keratinocytes. OBJECTIVES: To exclude the possibility of epidermal uptake of calprotectin from granulocytes and macrophages in diseased skin, we investigated whether cytokine-stimulated human keratinocytes can express calprotectin in vitro. METHODS: Keratinocytes from healthy individuals were cultured in serum-free keratinocyte medium. The cells were stimulated with different cytokines [interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-10 and IL-13], both separately and in various combinations. Cytoplasmic protein levels of calprotectin were measured by an enzyme-linked immunosorbent assay performed on fixed adherent keratinocytes, and mRNA expression was determined by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Calprotectin was produced by cytokine-stimulated keratinocytes, especially in response to combinations of the proinflammatory cytokines, which showed an additive upregulatory effect. When expression of mRNA for the light (MRP-8) and heavy (MRP-14) calprotectin chain was determined by RT-PCR, their respective levels were shown to be increased four- to ninefold and three- to fivefold after 24 h of combined stimulation with IFN-gamma and TNF-alpha. The time course of calprotectin production showed no significant elevation for the first 16 h but then increased and peaked after 36 h. CONCLUSIONS: Cultured human keratinocytes stimulated with proinflammatory cytokines produce calprotectin, suggesting that epidermal expression of this antimicrobial protein in diseased skin reflects compartmentalized synthesis rather than uptake from dermal inflammatory cells.


Assuntos
Citocinas/farmacologia , Queratinócitos/metabolismo , Complexo Antígeno L1 Leucocitário/metabolismo , Adulto , Células Cultivadas , Sinergismo Farmacológico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interferon gama/farmacologia , Interleucina-1/farmacologia , RNA/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima
18.
Allergy ; 58(9): 833-43, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12911410

RESUMO

BACKGROUND: Strategies to prevent children from developing allergy have been elaborated on the basis of state-of-the-art reviews of the scientific literature regarding pets and allergies, building dampness and health, and building ventilation and health. A similar multidisciplinary review of infant feeding mode in relation to allergy has not been published previously. Here, the objective is to review the scientific literature regarding the impact of early feeding (breast milk and/or cow's milk and/or formula) on development of atopic disease. The work was performed by a multidisciplinary group of Scandinavian researchers. METHODS: The search in the literature identified 4323 articles that contained at least one of the exposure and health effect terms. A total of 4191 articles were excluded mainly because they did not contain information on both exposure and health effects. Consequently, 132 studies have been scrutinized by this review group. RESULTS: Of the 132 studies selected, 56 were regarded as conclusive. Several factors contributed to the exclusions. The studies considered conclusive by the review group were categorized according to population and study design. CONCLUSIONS: The review group concluded that breastfeeding seems to protect from the development of atopic disease. The effect appears even stronger in children with atopic heredity. If breast milk is unavailable or insufficient, extensively hydrolysed formulas are preferable to unhydrolysed or partially hydrolysed formulas in terms of the risk of some atopic manifestations.


Assuntos
Aleitamento Materno , Hipersensibilidade/prevenção & controle , Animais , Humanos , Hipersensibilidade/genética , Fórmulas Infantis , Leite/efeitos adversos , Hipersensibilidade a Leite/etiologia , Medição de Risco
19.
Scand J Immunol ; 57(6): 506-16, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12791088

RESUMO

CD89, the human immunoglobulin A (IgA) Fc receptor (FcR), is a potential target for antibody-based therapeutics, but little is known about its expression and modulation in vivo. In this study, we examined the expression pattern of CD89 and its signalling subunit, the FcR gamma chain, on circulating myeloid cells and in various tissues. Our results showed a wide tissue distribution of CD89+ cells. Thus, CD89+ cells were evident as clusters in tonsils and appendix and scattered in varying numbers in lymph nodes, kidney, liver, intestinal mucosa, bronchoalveolar lavage and peritoneal fluid. Most CD89+ cells were identified as neutrophils with high levels of CD89. A few recently emigrated macrophages (CD14low), weakly positive for CD89, were occasionally found in the tissues and more often in the peritoneal fluid. The level of CD89 on neutrophils in tissues and peripheral blood was similar, whereas on monocytes it was much lower in the tissues than in blood, and it was absent on CD14-/CD68+ intestinal lamina propria macrophages. Conversely, we detected much higher levels of the FcR gamma chain in monocytes than in neutrophils, but the FcR gamma chain was also downregulated in tissue macrophages as well as in in vitro-differentiated monocyte-derived macrophages and dendritic cells. The implications of our current findings on the biological functioning of CD89 are discussed.


Assuntos
Antígenos CD/metabolismo , Células Mieloides/imunologia , Receptores Fc/metabolismo , Receptores de IgG/metabolismo , Diferenciação Celular , Células Dendríticas/imunologia , Regulação para Baixo , Humanos , Técnicas In Vitro , Macrófagos/imunologia , Monócitos/imunologia , Células Mieloides/citologia , Neutrófilos/imunologia , Distribuição Tecidual
20.
Dev Biol (Basel) ; 115: 39-48, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-15088774

RESUMO

Adaptive humoral immunity mediated by secretory antibodies appears to be desirable in the defence against mucosal virus infections. Specific secretory immunoglobulin A (SIgA) can inhibit initial pathogen colonization by performing immune exclusion both on the mucosal surface and within infected secretory epithelial cells without causing tissue damage. Like natural infections, live topical vaccines or adequate combinations of inactivated vaccines and mucosal adjuvants give rise not only to SIgA antibodies, but also to longstanding serum IgG and IgA responses. The intranasal route of vaccine application appears particularly attractive to achieve this result. The degree of protection after vaccination may range from complete inhibition of re-infection to reduction of symptoms. In this scenario it is generally difficult to determine unequivocally the relative importance of SIgA versus serum antibodies. However, infection models in knockout mice support the notion that SIgA exerts a decisive role in protection and cross-protection against influenza.


Assuntos
Imunidade nas Mucosas , Influenza Humana/imunologia , Anticorpos Antivirais/biossíntese , Humanos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Intestinos/imunologia , Tecido Linfoide/imunologia
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