Downregulation of IFN-gamma production in patients with recurrent vaginal candidiasis.

BACKGROUND: Recurrent vaginal candidiasis (RVC) is an important health problem with unknown pathogenesis. Although impairment of the T-cell response is associated with persistent or recurrent candidiasis, data on immunologic responses in patients with RVC are controversial. OBJECTIVES: To evaluate the T-cell response in patients with RVC and the ability of cytokines and cytokine antagonists to modulate IFN-gamma production in cultures stimulated with Candida albicans antigens. METHODS: Participants in the study included 13 patients with RVC and 7 control women with sporadic candidiasis. Cytokines were determined by ELISA in supernatants of mononuclear cells with C albicans, purified protein derivative, or tetanus toxoid antigen. RESULTS: IFN-gamma production was absent or low in 11 of 13 women (84.6%) with RVC. Absent or low IFN-gamma production was specific to C albicans antigens (189 +/- 389 pg/mL), because high IFN-gamma levels were found in cultures stimulated with purified protein derivative (739 +/- 774 pg/mL) or tetanus toxoid antigens (1085 +/- 546 pg/mL). Monoclonal antibody anti-IL-10 enhanced IFN-gamma levels (750 +/- 753 pg/mL), and IL-10 suppressed this cytokine production in patients with sporadic candidiasis. CONCLUSIONS: Mononuclear cells from patients with RVC stimulated with C albicans antigen have low or absent IFN-gamma production. IL-10 plays an important role in downregulation of the T-cell response in these patients.     

Local immune responsiveness following intravaginal challenge with Candida antigen in adult women at different stages of the menstrual cycle.

Recurrent vulvovaginal candidiasis (RVVC) is a significant problem in women of childbearing age and is most often caused by Candida albicans that asymptomatically colonizes mucosal tissues. Although some form of local immune dysfunction is postulated to precipitate bouts of RVVC, the normal protective vaginal host response to C. albicans is poorly understood. In an effort to stimulate the natural adaptive response to yeast in healthy women without a history of VVC, commercial Candida skin test antigen was introduced intravaginally and changes in cytokines/immunomodulators were monitored in vaginal lavage fluid pre- and post-antigen challenge. In an earlier pilot study using small numbers of women without controlling for stages of the menstrual cycle, we reported elevated cytokines in vaginal secretions of antigen challenged women. The present study, however, that employed a similar design in a large number of women during each stage of the menstrual cycle showed no evidence of local immune stimulation, including changes in Th and proinflammatory cytokines, IgE, histamine, and prostaglandin, despite a natural modulation of vaginal cytokines over the course of the menstrual cycle. Taken together, these results suggest that either some form of vaginal immunoregulation/tolerance is evident in response to yeast or that more advanced clinical designs are required to detect the normal protective vaginal response to C. albicans.     

Expression of IL-18 mRNA and secretion of IL-18 are reduced in monocytes from patients with atopic dermatitis

BACKGROUND: Nasal polyps (NPs) are characterized by eosinophilic inflammation and often coexist with asthma. However, the role of atopy and IgE in NP pathogenesis is unclear. OBJECTIVE: We sought to determine whether there is an association between total and specific IgE to a variety of allergens in polyp and nonpolyp tissue and markers of eosinophilic inflammation or skin test results. METHODS: Homogenates were prepared from nasal tissue of 20 patients with NPs and 20 patients without NPs and analyzed for concentrations of IL-5, IL-4, eotaxin, leukotriene (LT) C4/D4/E4, sCD23, and histamine (ELISA). Eosinophil cationic protein (ECP), tryptase, and total and specific IgE for inhalant allergens and Staphylococcus aureus enterotoxins were measured (ImmunoCAP). RESULTS: The concentrations of total IgE, IL-5, eotaxin, ECP, LTC4/D4/E4, and sCD23 were significantly higher in NP tissue compared with nonpolyp tissue. Total IgE was significantly correlated to IL-5, ECP, LTC4/D4/E4, and sCD23 and to the number of eosinophils in NPs. On the basis of the presence of specific IgE antibodies in tissue, 3 NP groups were defined. NP group 1 demonstrated no measurable specific IgE, and NP group 2 selected specific IgE. The third group demonstrated a multiclonal specific IgE, including IgE to S aureus enterotoxins, a high total IgE level, and a high prevalence of asthma. CONCLUSIONS: These studies suggest that there is an association between increased levels of total IgE, specific IgE, and eosinophilic inflammation in NPs, which may be of relevance in the pathophysiology of nasal polyposis. Similarly, the presence of specific IgE to staphylococcal enterotoxins A and B also points to a possible role of bacterial superantigens.     

Candida albicans-secreted aspartic proteinases modify the epithelial cytokine response in an in vitro model of vaginal candidiasis

Secreted aspartyl proteinases (Saps) are important virulence factors of Candida albicans during mucosal and disseminated infections and may also contribute to the induction of an inflammatory host immune response. We used a model of vaginal candidiasis based on reconstituted human vaginal epithelium (RHVE) to study the epithelial cytokine response induced by C. albicans. In order to study the impact of the overall proteolytic activity and of distinct Sap isoenzymes, we studied the effect of the proteinase inhibitor pepstatin A on the immune response and compared the cytokine expression pattern induced by the wild-type strain SC5314 with the pattern induced by Sap-deficient mutants. Infection of RHVE with the C. albicans wild-type strain induced strong interleukin 1alpha (IL-1alpha), IL-1beta, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, gamma interferon, and tumor necrosis factor alpha responses in comparison with cytokine expression in noninfected tissue. Addition of the aspartyl proteinase inhibitor pepstatin A strongly reduced the cytokine response of RHVE. Furthermore, SAP-null mutants lacking either SAP1 or SAP2 caused reduced tissue damage and had a significantly reduced potential to stimulate cytokine expression. In contrast, the vaginopathic and cytokine-inducing potential of mutants lacking SAP4 to SAP6 was similar to that of the wild-type strain. These data show that the potential of specific Saps to cause tissue damage correlates with an epithelium-induced proinflammatory cytokine response, which may be crucial in controlling and managing C. albicans infections at the vaginal mucosa in vivo.     

IgE, IgA and IgG antibodies and delayed skin response towards Candida albicans antigens in atopies with and without saprophytic growth

Immunoblotting and RAST were used to analyse IgE, IgA and IgG responses to antigens of Candida albicans. These were compared with the delayed skin response and C. albicans carriage in 40 atopic subjects. The majority of the atopic patients showed a strong IgG and IgA antibody response towards mannan, a carbohydrate, but only occasionally to proteins. Altogether 22 of the 40 patients showed specific IgE towards C. albicans by immunoblotting. The IgE response was mainly towards proteins, particularly to ones with molecular weights of 29 kD and 46 kD, and only in eight out of 22 IgE-positive subjects towards mannan. The IgG and IgA responses to mannan and the total IgE response towards C. albicans assessed by RAST showed an association with C. albicans carriage, whereas the delayed skin response showed an inverse relationship. The immunological parameters characteristic of C. albicans carriage were found to be C. albicans-specific depressed delayed skin response and elevated IgE, IgA and IgG responses. This situation in the atopics presenting such parameters may favour simultaneous sensitization and exposure by colonization. The degree of sensitization may be sufficiently high to produce symptomatic allergy, such as asthma, in some individuals during occasional overgrowth of C. albicans, e.g. due to antibiotic therapy.     

Candida-specific Th1-type responsiveness in mice with experimental vaginal candidiasis.

The role of systemic cell-mediated immunity (CMI) as a host defense mechanism in the vagina is poorly understood. Using a murine pseudoestrus model of experimental vaginal candidiasis, we previously found that animals given a vaginal inoculum of viable Candida albicans blastoconidia acquired a persistent vaginal infection and developed Candida-specific delayed-type hypersensitivity (DTH) responses. The present study was designed to characterize the peripheral CMI reactivity generated from the vaginal infection in mice and to determine whether pseudoestrus is a prerequisite for the induction of peripheral CMI reactivity. Mice treated or not treated with estrogen and given a vaginal inoculum of C. albicans blastoconidia were examined for 4 weeks for their vaginal Candida burden and peripheral CMI reactivity, including DTH responsiveness and in vitro Th1 (interleukin-2 [IL-2], gamma interferon [IFN-gamma]/Th2 (IL-4, IL-10)-type lymphokine production in response to Candida antigens. Results showed that although mice not treated with estrogen before being given a vaginal inoculum of C. albicans blastoconidia developed only a short-lived vaginal infection and harbored significantly fewer Candida CFU in the vagina compared with those given estrogen and then infected; DTH reactivity was equivalent in both groups. In vitro measurement of CMI reactivity further showed that lymph node cells from both estrogen- and non-estrogen-treated infected mice produced elevated levels of IL-2 and IFN-gamma in response to Candida antigens during the 4 weeks after vaginal inoculation. In contrast, lymph node cells from the same vaginally infected mice showed no IL-10 production and only small elevations of IL-4 during week 4 of infection. These results suggest that mice with experimental vaginal candidiasis develop predominantly Th1-type Candida-specific peripheral CMI reactivity and that similar patterns of Th1-type reactivity occur in mice regardless of the persistence of infection and the estrogen status of the infected mice.     

A localized vaginal allergic response in women with recurrent vaginitis

In women with recurring vaginitis, treatment of a vaginal Candida infection is not always accompanied by an alleviation of symptoms, and infection frequently reappears after termination of the chemotherapeutic agent. To determine whether an allergic reaction might be involved in symptom prolongation and susceptibility to reinfection, sera and vaginal washes from patients were examined for specific IgE antibodies. With RAST modified to ELISA, anti-Candida albicans IgE was identified in 18.8% of saline vaginal washes, but in only 6.1% of sera, obtained from 64 patients. Similarly, 25% of 16 patients were positive for vaginal fluid IgE, but only 6.3% had serum IgE to their partners' seminal fluid. The detection of specific IgE antibodies vaginally but not in the peripheral circulation suggested the occurrence of a localized vaginal hypersensitivity response. Vaginal fluid-derived IgE antibodies reactive with contraceptive spermicides or present in the particulate fraction of saline vaginal washes were also identified. Vaginal fluids with IgE antibodies also contained detectable levels of prostaglandin E2. A vaginal allergic response can predispose to recurrent Candida infection by inducing prostaglandin E2 synthesis that suppresses cell-mediated immune responses.     

Evidence of an affinity threshold for IgE‐allergen binding in the percutaneous skin test reaction

BACKGROUND: Atopy is an aberrant immune response involving allergen-specific IgE production, though serum IgE concentration is not an entirely reliable diagnostic tool, particularly for epidemiological and genetic studies. There is no clear correlation between IgE and other indicators of atopy such as skin prick tests (SPT)s, and physiological associations are difficult to justify in cases with detectable IgE but negative SPT results. OBJECTIVE: IgE reflects the number of molecules available to produce an atopic response, but the degree of the response is determined by the binding strength (affinity) between receptor-bound IgE and the allergen. We sought to determine if there was an association between binding affinity and SPT results in people with histories of atopy. METHODS: Standard SPTs (whole allergen extracts) were administered to people with histories of sensitivities to ragweed and house dust mite. The concentrations and affinities of serum allergen-specific IgEs were determined using the purified allergens Amb a 1 and Der p 1. RESULTS: There was a positive correlation between weal area and allergen-specific IgE among SPT-positive donors. However, for those individuals with detectable amounts of allergen-specific IgE, there was considerable overlap of IgE values between SPT-positive and -negative groups. Among sensitized donors, IgE-allergen interactions were characterized by two or three specific reactions of very high affinity (K(A) range 10(8) -10(11) M). Negative SPT reactions were associated with lowered IgE binding affinities to major allergens. This delimited two groups with atopic disorders: specific IgE(+)/ SPT(+) and specific IgE(+)/SPT(-). CONCLUSION: The product of antibody affinity and concentration, which we define as antibody capacity (CAP = K(A) x IgE), is more informative with regard to describing allergen sensitivity than antibody concentration alone. Antibody binding capacity provides physiological evidence of atopy in some subjects who do not test positively by common methods and suggests an affinity threshold to produce a positive SPT reaction.     

Cytokine and Chemokine Production by Human Oral and Vaginal Epithelial Cells in Response to Candida albicans

Oropharyngeal and vaginal candidiases are the most common forms of mucosal fungal infections and are primarily caused by Candida albicans, a dimorphic fungal commensal organism of the gastrointestinal and lower female reproductive tracts. Clinical and experimental observations suggest that local immunity is important in host defense against candidiasis. Accordingly, cytokines and chemokines are present at the oral and vaginal mucosa during C. albicans infections. Since mucosal epithelial cells produce a variety of cytokines and chemokines in response to microorganisms and since C. albicans is closely associated with mucosal epithelial cells as a commensal, we sought to identify cytokines and/or chemokines produced by primary oral and vaginal epithelial cells and cell lines in response to C. albicans. The results showed that proinflammatory cytokines were produced by oral and/or vaginal epithelial cells at various levels constitutively with considerable interleukin-1alpha (IL-1alpha) and tumor necrosis factor alpha, but not IL-6, produced in response to C. albicans. In contrast, Th1-type (IL-12 and gamma interferon) and Th2-type-immunoregulatory (IL-10 and transforming growth factor beta) cytokines and the chemokines monocyte chemoattractant protein 1 and IL-8 were produced in low to undetectable concentrations with little additional production in response to C. albicans. Taken together, these results indicate that cytokines and chemokines are variably produced by oral and vaginal epithelial cells constitutively, as well as in response to C. albicans, and are predominated by proinflammatory cytokines.     

No effect of interleukin-2 on IgE levels given in addition to antiretroviral therapy in HIV-infected adults with CD4 >300 cells/mm3

HIV-infected patients may have frequent atopy caused by an imbalance of Th1 and Th2 cytokines. The objective of the present study was to investigate whether IL-2 given in addition to antiretrovirals (ARV) would result in lower IgE levels and less allergic symptoms. Patients naive to IL-2 (n=28) began IL-2 plus ARV and were followed for 12 months. IgE, eosinophil and CD4 counts, HIV RNA, symptom scoring, PFT and skin prick test (SPT) were performed. It was found that the baseline median CD4 and IgE were 386.5 cells/mm3 and 63.5 IU/ml, respectively. Four patients had allergic rhinitis (AR) and 61% had a positive SPT to at least 1 antigen. At month 12, patients had higher CD4 counts (p < 0.001) compared to the baseline; however, there were no differences in IgE levels, allergic symptom scores or HIV RNA. The eosinophil count was higher after IL-2 administration. It was concluded that IL-2 plus ARV resulted in higher CD4 counts but had no effect on atopy.     

Interleukin-18 and gamma interferon production by oral epithelial cells in response to exposure to Candida albicans or lipopolysaccharide stimulation

Oral candidiasis is a collective name for a group of disorders caused by the dimorphic fungus Candida albicans. Host defenses against C. albicans essentially fall into two categories: specific immune mechanisms and local oral mucosal epithelial cell defenses. Since oral epithelial cells secrete a variety of cytokines and chemokines in response to oral microorganisms and since C. albicans is closely associated with oral epithelial cells as a commensal organism, we wanted to determine whether interleukin-18 (IL-18) and gamma interferon (IFN-gamma) were produced by oral epithelial cells in response to C. albicans infection and lipopolysaccharide (LPS) stimulation. Our results showed that IL-18 mRNA and protein were constitutively expressed by oral epithelial cells and were down-regulated by Candida infections but increased following LPS stimulation. Both C. albicans and LPS significantly decreased pro-IL-18 (24 kDa) levels and increased active IL-18 (18 kDa) levels. This effect was IL-1beta-converting-enzyme dependent. The increase in active IL-18 protein levels promoted the production of IFN-gamma by infected cells. No effect was obtained with LPS. Although produced only at an early stage, secreted IFN-gamma seemed to be a preferential response by oral epithelial cells to C. albicans growth. These results provide additional evidence for the contribution of oral epithelial cells to local (direct contact) and systemic (IL-18 and IFN-gamma production) defense against exogenous stimulation such as C. albicans infection or LPS stimulation.     

Evaluation of IgE-sensitization to fungi in HIV-positive patients with eczematous skin reactions.

BACKGROUND: Human immunodeficiency virus infection is associated with declining immune function and polyclonal B-cell activation leading to elevated IgE-levels. In selected patient categories, increased total IgE may be associated with allergic diseases. Furthermore, a significant number of patients with low CD4+ cell numbers have various skin manifestations, eg, eczema and dermatophytosis. Patients with chronic fungal infections and a tendency to produce increased levels of specific IgE may become allergic and IgE-mediated mechanism may contribute to inflammatory reactions in the skin. OBJECTIVE: This study investigates IgE-sensitization of patients infected with human immunodeficiency virus to a panel of fungal extracts of Candida albicans, Fusarium moniliforme, Penicillium notatum, Pityrosporum ovale, and Trichophyton rubrum. METHODS: Fifteen HIV-positive patients with eczematous skin manifestations and five non-atopic healthy controls were evaluated by basophil histamine release and skin prick test with fungal extracts. The extracts were separated by sodium dodecylsulfate-polyacrylamide gel electrophoresis under reducing conditions and analyzed by IgE-immunoblotting with sera from the patients and controls. RESULTS: Thirteen of 15 patients (87%) released histamine to one or more of the fungi. Skin prick test was positive to one or more fungi in 7 (47%) patients. Patient sera revealed binding to a wide range of IgE-binding components present in the fungal extracts. The IgE response was most often directed against a 46-kD main protein in the Candida albicans extract. There was no correlation between total serum IgE, CD4+ cell counts, and frequency of IgE-sensitization to fungi. CONCLUSION: The human IgE response in HIV-infected patients appears to be polyspecific and may be directed against various fungi of which Candida albicans may be an important allergen. It is possible that the sensitization is due to frequent infections with Candida albicans in this patient population. No unspecific fungal reactions were noted among control patients. These results suggest that allergen-specific IgE-mediated mechanism may contribute to the pathogenesis of the eczematous skin reaction in HIV-infected patients.     

Absence of association between delayed type hypersensitivity to tuberculin and atopy in children in The Gambia

BACKGROUND: An inverse association between delayed type hypersensitivity to tuberculin and atopy has been observed in children, suggesting that exposure to mycobacteria may influence the immune response to allergens. OBJECTIVE: To investigate the relationship between tuberculin responses and atopy in children living in three different environments in The Gambia. METHODS: In this cross-sectional study a total of 507 school-aged children were recruited from rural, urban poor or urban affluent communities. They were assessed for skin responses to five common allergens and tuberculin, presence of bacille Calmette-Guérin (BCG) scar, presence of intestinal parasites, and total serum IgE. Atopy was defined as the presence of a skin prick test response > or = 3 x 3 mm to at least one allergen. RESULTS: The overall prevalence of atopy was 33% but there was a significant variation among the three study groups. The prevalence of atopy was 22% in urban poor, 36% in urban affluent, and 43% in rural children. Controlling for potential confounding factors, children in the rural community had a significantly higher odds ratio, 3.3 (95% confidence interval 1.8-6.0) of being atopic than children from the urban poor community. No association between atopy and tuberculin response or BCG scar was observed in any of the three groups. Serum IgE levels were higher among children of the urban poor group but were not associated with tuberculin response or BCG scar in any of the groups. CONCLUSION: Environmental factors have an important influence on the development of atopy in children in The Gambia but delayed type hypersensitivity to tuberculin is not a protective factor.     

Random allergen-specific IgE expression in atopic families: evidence for inherited "stochastic bias" in adverse immune response development to non-infectious antigens

The complex inherited human atopic diseases are associated with adverse IgE-mediated immune responses, notably allergen-specific IgE that presumably involves the input from one or more genes. However, gene searches have met with limited success, possibly because a causally direct gene input-trait outcome assumption is not valid for these immune responses. To test this assumption, we determined the probability distributions of quantitative IgE responses associated with atopy, and used these to determine the statistical interdependence among first-degree relatives (parent-child and sibling-sibling) from families with history of atopic asthma (total available N=1099). Each person was screened for asthma history, pulmonary responses by spirometry and atopic immune responses using serum total IgE and skin prick tests (SPT) to 14 allergens. Heritability estimates were made by variance components analysis for quantitative IgE traits. The serum total IgE distribution comprised statistically independent sub-sets when individuals were categorized as either SPT [-] or SPT [+], reflecting contributions from non-pathology associated basal IgE and pathology-associated allergen-specific IgE. However, heritability estimates were significant only for basal IgE, while total allergen-specific IgE production was a random variable independent of inheritance. Genes for specific IgE-mediated responses are not obligately inherited. Rather, gene products that modulate underlying stimulus-response coupling interactions and alter the probabilities influencing adverse immune responses are inherited, but an individual's specific pathologic outcome is a random variable. These results support a model of "stochastic bias" that "skews" an immune response to non-infectious antigens among people with an inherited predisposition for atopy.     

Allergen-induced interleukin-9 production in vitro: correlation with atopy in human adults and comparison with interleukin-5 and interleukin-13

BACKGROUND: The contribution of IL-9 to human atopy is supported by genetic studies. However, IL-9 production in response to allergen in vitro has been reported only in children. OBJECTIVE: Study IL-9 induction by allergen in adults, compare it with IL-5 and IL-13 and evaluate its association with atopy. METHODS: Peripheral blood mononuclear cell (PBMC) from control adults and from atopic patients were cultured with various allergens or phytohaemagglutinin (PHA) and secreted IL-5, IL-9 and IL-13 were measured by ELISA. RESULTS: IL-9 was produced in response to Dermatophagoides pteronyssinus (Der p) by PBMC from Der p-hypersensitive adults at levels equivalent to those induced by PHA but with slower kinetics. The induction of IL-9 was allergen specific, reflecting donor RAST profile. In Der p-triggered reactions of non-atopic and atopic subjects, IL-9 showed the highest selectivity for atopics, IL-5 and IL-13 being produced more frequently in non-atopic donors. Significant correlations with specific IgE titres were found for IL-9 with all allergens tested (Der p and two peptides of Bet v 1 birch allergen). For IL-5 and IL-13, they were in the same range for Der p but more variable for birch allergens. Patterns of cytokine production by individual patients in response to allergen reflected these differences: for Der p, IL-5, IL-9 and IL-13 productions were strongly correlated but for birch IL-5 differed from the latter two. The in vitro production of IL-9 reflected clinical hypersensitivity profiles and was higher in individuals with asthma than in those with disease limited to rhinitis and/or conjunctivitis. CONCLUSIONS: Allergen-triggered IL-9 production in vitro is an excellent marker for atopy in adults given its virtual absence in allergen-stimulated PBMC from non-atopic individuals and its correlation with allergen-specific IgE and asthma.     

Association of specific IgE to staphylococcal superantigens with the phenotype of chronic urticaria

It has been well established that bacterial superantigens lead to the induction and aggravation of chronic inflammatory skin diseases. We investigated the clinical significance of serum specific immunoglobulin E (lgE) to the staphylococcal superantigens staphylococcal enterotoxin A (SEA), staphylococcal enterotoxin B (SEB), and toxic shock syndrome toxin (TSST)-1 in patients with chronic urticaria (CU), focusing on the differences in these prevalences between aspirin-intolerant CU (AICU) and aspirin-tolerant CU (ATCU) patients. Aspirin sensitivity was confirmed by oral aspirin provocation test. There were 66 patients AICU and 117 patients ATCU in the study. Serum IgE antibodies specific for SEA, SEB, and TSST-1 were measured by the ImmunoCAP test and the patients were compared with 93 normal controls (NC). The prevalences of serum specific IgE to staphylococcal superantigens were significantly higher in CU than in NC patients (IgE to SEA, 13.7% vs. 5.4%; IgE to SEB, 12.0% vs. 4.3%; IgE to TSST-1, 18.0% vs. 6.5%; p<0.05, respectively). The patients with specific IgE to SEA, SEB, and TSST-1 had higher serum total IgE levels and higher rates of atopy. Significant associations were noted between the prevalence of specific IgE to SEA and SEB and the HLA DQB1*0609 and DRB1*1302 alleles in the AICU group. We confirmed that a sub-population of patients with CU possesses serum IgE antibodies to SEA, SEB, and TSST- 1. Particularly, the IgE immune response to TSST-1 is associated with aspirin sensitivity in CU patients.     

Local IgE production and positive nasal provocation test in patients with persistent nonallergic rhinitis

BACKGROUND: Allergic rhinitis is an IgE-mediated inflammatory disease of the nasal mucosa, which is usually diagnosed by typical symptoms, positive skin tests, and/or serum specific IgE antibodies to allergens. Despite suggestive symptoms of allergic rhinitis, some patients have a negative diagnostic test for atopy. OBJECTIVE: To evaluate in the nose the inflammatory response, specific IgE to Dermatophagoides pteronyssinus (DP), and the response to a nasal allergen provocation test with DP (NAPT-DP), in patients with persistent nonallergic rhinitis (PNAR) compared with patients with persistent allergic rhinitis (PAR) and healthy controls. METHODS: Fifty patients with PNAR, 30 with PAR to DP, and 30 healthy controls were studied by determining the nasal leukocyte-lymphocyte phenotype by flow cytometry (CD16, CD8, CD4, CD33, CD3, and CD45), nasal eosinophil cationic protein (ECP), albumin, total and specific IgE to DP, and NAPT-DP. RESULTS: The PNAR patients showed a similar leukocyte-lymphocyte phenotype in nasal lavage to the PAR patients and was different to the healthy controls. Within the PNAR group, 54% showed a positive NAPT-DP, with 22% of these having nasal specific IgE to DP. CONCLUSION: These data support the hypothesis that in persistent nonallergic rhinitis some patients may have local inflammation, nasal IgE production, and a positive response to a nasal allergen provocation test despite no evidence of systemic atopy. Further research is needed to evaluate the influence of other perennial allergens and/or immunologic mechanisms. CLINICAL IMPLICATIONS: The local production of IgE antibodies without systemic detection is a condition that should be considered in patients with PNAR.     

Local Th1/Th2 cytokine production during experimental vaginal candidiasis: potential importance of transforming growth factor-beta.

Host defense mechanisms against vaginal Candida albicans infections are poorly understood. Despite the protective role of T helper (Th)1-type cell-mediated immunity (CMI) against mucosal C. albicans infections, studies using an estrogen-dependent murine model of vaginal candidiasis have shown a lack of effect of systemic Th1-type CMI against a vaginal C. albicans infection, and a lack of changes in local T cells during infection. In the present study, the local Thl- (interleukin [IL]-2, interferon [IFN]-gamma and IL-12) and Th2- (IL-4, IL-10 and transforming growth factor [TGF]-beta1) type cytokines were evaluated in vaginal tissue during an experimental C. albicans infection. Results showed constitutive expression of TGF-beta1 in vaginal tissue of naive mice that was two-fold higher than the levels of the other cytokines examined. These high levels of TGF-beta1 were further increased as a result of pseudoestrus and/or infection, and were corroborated at the messenger RNA level. Furthermore, the levels of TGF-beta in naive or infected mice were significantly higher in the vagina compared to other areas of the genital tract. Finally, TGF-beta1 predominated as well in the draining, but not non-draining, lymph nodes during infection. These results suggest that TGF-beta1, a potent immunoregulatory cytokine, may be important in the lack of demonstrable CMI at the vaginal mucosa against C. albicans.     

Parenchymal organ, and not splenic, immunity correlates with host survival during disseminated candidiasis

We examined the relationship between host survival and renal and splenic immune responses in a murine model of hematogenously disseminated candidiasis. Male BALB/c mice were infected via tail vein injection with wild-type C. albicans or with an isogenic, Deltaefg1/Deltaefg1 hypha-deficient mutant. Host survival, organ fungal burden, intracellular cytokine content of splenic and kidney lymphocytes, and whole-organ cytokine profiles were determined. Wild-type C. albicans induced type 2 splenocyte responses with both nonfatal and fatal inocula. In the kidney, conversely, wild-type inocula causing no or low mortality induced type 1 responses and 100% fatal inocula induced type 2 or interleukin-10 (IL-10)-dominant responses. Hypha-deficient mutant C. albicans caused no or low mortality while inducing type 1 responses in both the spleen and kidney. To our knowledge, this is the first demonstration that host survival during systemic infection correlates with the type of immune response engendered in a nonlymphoid, parenchymal organ and not with the response in the spleen. Furthermore, the results provide in vivo confirmation that hyphal formation by C. albicans induces type 2 or IL-10-dominant host responses in tissues.     

Inverse association between skin response to aeroallergens and Schistosoma mansoni infection

BACKGROUND: Helminthic infections and allergic disease are highly prevalent in many areas of the world. It is known that IgE antibodies are involved in the pathogenesis of both helminthiasis and atopy. However, the consequences of the presence of helminthic infections in atopic patients are still not completely understood. METHODS: Subjects infected by Schistosoma mansoni with more than 200 eggs/g of feces (n = 42) and uninfected subjects (n = 133) were selected from an endemic area of schistosomiasis. The history of allergy and results of the immediate hypersensitivity prick tests with inhalant allergen extracts were registered. Total IgE and IgE specific to S. mansoni and aeroallergens were measured in serum by ELISA. RESULTS: The proportion of individuals with a positive skin test to allergens was higher in the uninfected group (24.3%) than in the group with more than 200 eggs/g of feces (4.8%). The odds of atopy (defined as a positive test for at least one of the antigens) were 5 times higher (odds ratio = 7.0; 95% confidence interval = 1.6-31.1%; p = 0.01) in the uninfected group, after taking into account the potential influence of gender and age. While there was a tendency for higher total and S. mansoni-specific IgE levels in infected patients, an opposite trend, that is higher aeroallergen-specific IgE, was observed in uninfected subjects. CONCLUSIONS: There was a strong and statistically significant inverse association between the immediate skin test response to common aeroallergens and infection by S. mansoni. The results indicate that immediate hypersensitivity reactions may be suppressed in S. mansoni-infected individuals.