High Serum Immunoglobulin Research Articles

Zonula occludens toxin acts as an adjuvant through different mucosal routes and induces protective immune responses.

Zonula occludens toxin (Zot) is produced by Vibrio cholerae and has the ability to increase mucosal permeability by reversibly affecting the structure of tight junctions. Because of this property, Zot is a promising tool for mucosal drug and antigen (Ag) delivery. Here we show that Zot acts as a mucosal adjuvant to induce long-lasting and protective immune responses upon mucosal immunization of mice. Indeed, the intranasal delivery of ovalbumin with two different recombinant forms of Zot in BALB/c mice resulted in high Ag-specific serum immunoglobulin G titers that were maintained over the course of a year. Moreover, His-Zot induced humoral and cell-mediated responses to tetanus toxoid in C57BL/6 mice and protected the mice against a systemic challenge with tetanus toxin. In addition, we found that Zot also acts as an adjuvant through the intrarectal route and that it has very low immunogenicity compared to the adjuvant Escherichia coli heat-labile enterotoxin. Finally, by using an octapeptide representing the putative binding site of Zot and of its endogenous analogue zonulin, we provide evidence that Zot may bind a mucosal receptor on nasal mucosa and may mimic an endogenous regulator of tight junctions to deliver Ags in the submucosa. In conclusion, Zot is a novel and effective mucosal adjuvant that may be useful for the development of mucosal vaccines.

Serum immunoglobulin levels at onset: association with the prognosis of childhood idiopathic thrombocytopenic purpura.

Between 1981 and 2000, 87 patients with new diagnoses of idiopathic thrombocytopenic purpura (ITP) were admitted to the pediatric department of Kobe City General Hospital or Nishi-Kobe Medical Center. The patients' clinical records were analyzed for the relationships of disease outcome to serum immunoglobulin levels and other factors, including sex, onset age, and initial platelet counts. The disease of 22 patients became chronic, and of the 65 patients with an acute form of the disease, 27 exhibited levels of immunoglobulin G (IgG), IgA, or IgM above the 97.5% confidence limits of the age-matched control subjects. However, only 2 patients with the chronic form of the disease showed elevated serum immunoglobulin levels. The presence of antecedent specific viral infections was also associated with the acute disease form. In predicting the prognosis of childhood ITP, high serum immunoglobulin levels at initial presentation can be considered a good prognostic marker for the acute form of the disease.

Urinary leukotriene E4 in preschool children with acute clinical viral wheeze.

Cysteinyl leukotrienes (cystLTs) are important mediators of wheeze in atopic asthma, but the role of cystLTs in the pathogenesis of preschool viral wheeze (PVW) is unclear. Therefore, evidence for increased production of cystLTs in PVW was sought. Urinary leukotriene E4 (uLTE4) and serum total immunoglobulin (Ig)E were measured in children (1-5 yrs) with PVW during an acute attack (n=44) and in the convalescent phase (n=19), and compared with normal controls (n=15). The effect of atopic sensitisation was assessed in a separate group of atopic controls (n=6) in whom only uLTE4 was measured. The levels of uLTE4 were similar in normal and atopic controls and increased in acute PVW (median (interquartile range) 165 (101-285) versus 125 (82-163) ng x mM creatinine(-1)). Stratification by IgE showed that whereas uLTE4 was increased in 23 children with acute PVW and IgE > 95th percentile (median 211 (118-312) ng x mM creatinine(-1)), uLTE4 was not increased in the 21 children with acute PVW and IgE < or = 95th percentile. In the convalescent phase, uLTE4 fell in the subgroup with high IgE but not in the subgroup with low IgE. It is concluded that increased cysteinyl leukotriene production during acute preschool viral wheeze is associated with high serum immunoglobulin E.

Health Effect of Polychlorinated Biphenyls and Related Compounds

Polychlorinated biphenyls (PCBs) and dioxins have polluted the environment for about 50 years and parts of them have transferred to human being through food chain. Humans are already contaminated with chlorinated compounds at relatively high levels. Yusho PCB poisoning occurred at Northern Kyushu in 1968 and the patients have been suffering from various symptoms for 35 years. High concentrations of toxic PCBs and polychlorinated dibenzofurans in the patients have been very gradually decreased to the levels of only 2 to 6 times higher than those of normal persons. Typical Yusho symptoms of acneiform eruption, dermal pigmentation and increased eye discharge were very gradually recovered with lapse of several years. However, enzyme and/or hormone-mediated signs of high serum triglyceride, high serum thyroxin, immunoglobulin disorder and others are persistently maintained for more than 30 years. Recent tolerable daily intake of dioxins were determined from their hormone-like activities, such as decreased sperm count, immune suppression, increased genital malformation and neurobehavioral effects in the offspring of animals. PCBs are important factors on considering dioxin toxicities to human for the reason that half the dioxin toxicity in normal persons consists of the toxicity of coplanar PCBs. Recent epidemiological studies have reported that higher levels of PCBs and related compounds in the human body associated with various health effects, such as lowering intelligence quotient levels, disorder of thyroid gland, higher rate of endometriosis in women, declining thyroid hormone levels, higher rate of diabetes in pregnant women, lowering age at menarche, and altering play behavior in children at school age.

A nontoxic chimeric enterotoxin adjuvant induces protective immunity in both mucosal and systemic compartments with reduced IgE antibodies.

A novel nontoxic form of chimeric mucosal adjuvant that combines the A subunit of mutant cholera toxin E112K with the pentameric B subunit of heat-labile enterotoxin from enterotoxigenic Escherichia coli was constructed by use of the Brevibacillus choshinensis expression system (mCTA/LTB). Nasal immunization of mice with tetanus toxoid (TT) plus mCTA/LTB elicited significant TT-specific immunoglobulin A responses in mucosal compartments and induced high serum immunoglobulin G and immunoglobulin A anti-TT antibody responses. Although TT plus native CT induced high total and TT-specific immunoglobulin E responses, use of the chimera molecule as mucosal adjuvant did not. Furthermore, all mice immunized with TT plus mCTA/LTB were protected from lethal systemic challenge with tetanus toxin. Importantly, the mice were completely protected from influenza virus infection after nasal immunization with inactivated influenza vaccine together with mCTA/LTB. These results show that B. choshinensis-derived mCTA/LTB is an effective and safe mucosal adjuvant for the induction of protective immunity against potent bacterial exotoxin and influenza virus infection.

HLA DRB1*0405-DQB1*0401 haplotype is associated with autoimmune pancreatitis in the japanese population

Autoimmune pancreatitis is a distinctive disease entity characterized by high serum immunoglobulin G4 concentrations. Because of the close association between some autoimmune diseases and particular alleles of major histocompatibility complex genes, we investigated the association between HLA alleles and autoimmune pancreatitis. HLA-A, -B, -C, -DR, and -DQ gene typing and HLA-DRB1, -DQB1, and -DPB1 allele typing were performed by the polymerase chain reaction sequence-specific primers method and the restriction fragment length polymorphism method, respectively, in 40 patients with autoimmune pancreatitis, 43 patients with chronic calcifying pancreatitis, and 201 healthy subjects. In patients with autoimmune pancreatitis compared with healthy subjects, we found a significant increase in DR4 (73% vs. 44%, corrected P = 0.01) and DRB1*0405 (58% vs. 21%, corrected P = 0.000026) and DQ4 (58% vs. 26%, corrected P = 0.001) and DQB1*0401 (58% vs. 21%, corrected P = 0.000017). The DRB1*0405-DQB1*0401 haplotype in autoimmune pancreatitis showed no significant association with any HLA class I antigens, in contrast to the B54-DRB1*0405-DQB1*0401 haplotype reported in autoimmune hepatitis. The frequencies of DRB1*0405 and DQB1*0401 were significantly high in patients with autoimmune pancreatitis compared with chronic calcifying pancreatitis. It is probable that DRB1*0405-DQB1*0401 haplotype is associated with autoimmune pancreatitis in the Japanese population.

Genetic Variants of the Receptors for Thromboxane A2 and IL-4 in Atopic Dermatitis

Thromboxane A2 (TXA2) is an arachidonate metabolite which is considered to relate to chronic inflammation in atopic diseases characterized by elevated immunoglobulin E productivity. The elevation of immunoglobulin E levels involves many molecules including interleukin-4 (IL-4) and interleukin-4 receptor alpha chain (IL-4Rα). To assess whether genetic variants of TXA2 receptor, IL-4 and IL-4Rα genes relate to the elevation of serum immunoglobulin E levels in patients with atopic dermatitis (AD), we conducted an association study of genetic polymorphisms of TXA2 receptor (795C/T), IL-4 (−589C/T), and IL-4Rα (Ile50Val) in a Japanese population (n = 789). The TXA2 receptor 795TT genotype strongly related to AD with high serum immunoglobulin E concentrations. AD patients with both TXA2 receptor 795TT genotype and the IL-4Rα Ile50/Ile50 genotype showed the greatest immunoglobulin E concentrations. These results suggest TXA2 receptor polymorphism strongly interacts with IL-4Rα polymorphism as a major determinant of high serum immunoglobulin E levels in AD.

A Polymorphism in the Human UGRP1 Gene Promoter That Regulates Transcription Is Associated with an Increased Risk of Asthma

Several traits associated with asthma phenotypes, such as high total serum immunoglobulin E and bronchial hyperresponsiveness, have been linked by numerous genome-screen studies and linkage analyses to markers on human chromosome 5q31-q34. In the present article, we describe UGRP1 (encoding uteroglobin-related protein 1) as one of asthma-susceptibility genes that is located on chromosome 5q31-q32. UGRP1 is a homodimeric secretory protein of 17 kDa and is expressed only in lung and trachea. The G --> A polymorphism was identified at -112 bp in the human UGRP1 gene promoter. The -112A allele is responsible for a 24% reduction in the promoter activity in relation to the -112G allele, as examined by transfection analysis. Electrophoretic mobility-shift analysis revealed that an unknown nuclear factor binds to the region around -112 bp. The binding affinity with the -112A oligonucleotide was reduced by approximately one half, as compared with the -112G oligonucleotide. In a case-control study using 169 Japanese individuals (84 patients with asthma and 85 healthy control individuals), those with a -112A allele (G/A or A/A) were 4.1 times more likely to have asthma than were those with the wild-type allele (G/G).

Aspergillus fumigatus-induced allergic airway inflammation alters surfactant homeostasis and lung function in BALB/c mice.

The differential regulation of pulmonary surfactant proteins (SPs) is demonstrated in a murine model of Aspergillus fumigatus (Af )-induced allergic airway inflammation and hyperresponsiveness. BALB/c mice were sensitized intraperitoneally and challenged intranasally with Af extract. Enzyme-linked immunosorbent assay analysis of serum immunoglobulin (Ig) levels in these mice showed markedly increased total IgE and Af-specific IgE and IgG1. This was associated with peribronchial/perivascular tissue inflammation, airway eosinophilia, and secretion of interleukin (IL)-4 and IL-5 into the bronchoalveolar lavage fluid (BALF). Functional analysis revealed that in comparison with nonsensitized mice, allergic sensitization and challenge resulted in significant increases in acetylcholine responsiveness. To analyze levels of SPs, the cell-free supernate of the BALF was further fractionated by high-speed (20,000 x g) centrifugation. After sensitization and challenges, the pellet (large-aggregate fraction) showed a selective downregulation of hydrophobic SPs SP-B and SP-C by 50%. This reduction was reflected by commensurate decreases in SP-B and SP-C messenger RNA (mRNA) expression of the lung tissue of these animals. In contrast, there was a 9-fold increase in SP-D protein levels in the 20,000 x g supernate without changes in SP-D mRNA. The increased levels of SP-D showed a significant positive correlation with serum IgE (r = 0.85, P < 0.001). Tissue mRNA and protein levels of SP-A in either the large- or the small-aggregate fractions were unaffected. Our data indicate that allergic airway inflammation induces selective inhibition of hydrophobic SP synthesis accompanied by marked increases in the lung collectin SP-D protein content of BALF. These changes may contribute significantly to the pathophysiology of Af-induced allergic airway hyperresponsiveness.

Fate of PCDF/PCB congeners and change of clinical symptoms in patients with Yusho PCB poisoning for 30 years

Two mass-food poisonings called Yusho and Yucheng occurred in Japan and Taiwan in 1968 and 1979, respectively. Blood samples from five Yusho patients and three Yucheng patients were collected several times from 1982 to 1998 and from 1980 to 1995, respectively, and analyzed for polychlorinated dibenzofurans (PCDF) and polychlorinated biphenyls (PCB) congeners. Fat base concentrations of 2,3,4,7,8-penta-CDF in the Yusho patients, which were responsible for about 70% of the dioxin toxicity, are estimated to be decreased from 60 ppb in 1969 to 800 ppt in 1997 with the median half-life of 2.9 years in the first 15 years after onset and 7.7 years in the next stage of 15 years. Typical Yusho symptoms of acneiform eruption, dermal pigmentation and increased eye discharge were very gradually recovered with lapse of several years. However, enzyme and/or hormone-mediated signs of high serum triglyceride, high serum thyroxin, immunoglobulin disorder and others are persistently maintained for 30 years.

Gluten sensitivity in sporadic and hereditary cerebellar ataxia

Gluten sensitivity, with or without classical celiac disease symptoms and intestinal pathology, has been suggested as a potentially treatable cause of sporadic cerebellar ataxia. Here, we investigated the prevalence of abnormally high serum immunoglobulin A (IgA) and IgG anti-gliadin antibody titers and typical human lymphocyte antigen (HLA) genotypes in 50 patients presenting with cerebellar ataxia who were tested for molecularly characterized hereditary ataxias. A high prevalence of gluten sensitivity was found in patients with sporadic (7/26; 27%) and autosomal dominant (9/24; 37%) ataxias, including patients with known ataxia genotypes indicating a hitherto unrecognized association between hereditary ataxias and gluten sensitivity. Further studies are needed to determine whether gluten sensitivity contributes to cerebellar degeneration in patients with hereditary cerebellar ataxia. Patients with hereditary ataxia (including asymptomatic patients with known ataxia genotype) should be considered for screening for gluten sensitivity and gluten-free diet trials.

Gluten sensitivity in sporadic and hereditary cerebellar ataxia

Gluten sensitivity, with or without classical celiac disease symptoms and intestinal pathology, has been suggested as a potentially treatable cause of sporadic cerebellar ataxia. Here, we investigated the prevalence of abnormally high serum immunoglobulin A (IgA) and IgG anti-gliadin antibody titers and typical human lymphocyte antigen (HLA) genotypes in 50 patients presenting with cerebellar ataxia who were tested for molecularly characterized hereditary ataxias. A high prevalence of gluten sensitivity was found in patients with sporadic (7/26; 27%) and autosomal dominant (9/24; 37%) ataxias, including patients with known ataxia genotypes indicating a hitherto unrecognized association between hereditary ataxias and gluten sensitivity. Further studies are needed to determine whether gluten sensitivity contributes to cerebellar degeneration in patients with hereditary cerebellar ataxia. Patients with hereditary ataxia (including asymptomatic patients with known ataxia genotype) should be considered for screening for gluten sensitivity and gluten-free diet trials. Ann Neurol 2001;49:540–543

Factors predictive of disease progression and death in AIDS‐related Kaposi's sarcoma

The natural history of Kaposi's sarcoma (KS) is poorly documented. We attempted to identify factors predictive of progression and survival in HIV-infected patients with KS and CD4+ cell counts greater than 100/microL. We studied retrospectively 78 HIV-infected patients diagnosed as having KS between 1989 and 1995. The following variables were assessed as potential predictors of progression and death, in a Cox proportional hazards model: age, sex, ethnic group, transmission group, site of the first KS lesions, duration of KS, concomitant opportunistic infections or malignancies, antiretroviral drug therapy (excluding protease inhibitors), antiherpes treatments, neutrophil counts, CD4+ and CD8+ cell counts, plasma HIV load, p24 antigenaemia, beta2-microglobulinaemia and immunoglobin A and G serum levels. During a median follow-up of 22 months (3-81 months), KS progressed in 66 of the 78 patients. The median survival time after progression was 68 months (9-126 months). Multivariate analysis identified only visceral KS, a high neutrophil count and a high serum immunoglobulin (Ig) level as independent predictors of progression (P < 0.05). Previous and concomitant opportunistic diseases (P = 0.003) and low CD4+ cell counts (P = 0.013) were independently associated with shorter survival; in contrast KS therapy did not independently influence survival. Progression of KS is predicted by markers of KS severity, while overall survival is best predicted by markers of immunodeficiency (opportunistic diseases and the CD4+ cell count).

A Neuronal NO Synthase (NOS1) Gene Polymorphism Is Associated with Asthma

Recent family-based studies have revealed evidence for linkage of chromosomal region 12q to both asthma and high total serum immunoglobulin E (IgE) levels. Among the candidate genes in this region for asthma is neuronal nitric oxide synthase (NOS1). We sought a genetic association between a polymorphism in the NOS1 gene and the diagnosis of asthma, using a case-control design. Frequencies for allele 17 and 18 of a CA repeat in exon 29 of the NOS1 gene were significantly different between 490 asthmatic and 350 control subjects. Allele 17 was more common in the asthmatics (0.83 vs 0.76, or 1.49 [95% CI 1.17–1.90], P = 0.013) while allele 18 was less common in the asthmatics (0.06 vs 0.12, or 0.49 [95% CI 0.34–0.69], P = 0.0004). To confirm these results we genotyped an additional 1131 control subjects and found the frequencies of alleles 17 and 18 to be virtually identical to those ascertained in our original control subjects. Total serum IgE was not associated with any allele of the polymorphism. These findings provide support, from case-control association analysis, for NOS1 as a candidate gene for asthma.

Comparaison des signes cliniques, radiographiques, biologiques et scintigraphiques dans l'arthrose érosive et non érosive de la main. Résultats après deux ans de suivi

Objectives. The primary objective was to compare the clinical, radiologic, laboratory, and scintigraphic features in 28 patients with erosive hand osteoarthritis and in 24 with nonerosive hand osteoarthritis. Other objectives were to evaluate clinical, radiographic, and scintigraphic progression in the two groups over a two-year period and to estimate the value of bone scintigraphy for predicting clinical and radiographic progression. Method. Prospective two-year study of 52 patients with hand osteoarthritis, of whom 28 had at least three subchondral erosions and 24 patients had no erosions. Results. The group with erosive disease had higher serum immunoglobulin G levels (14.53 ± 3.79 mg/L vs. 12.03 ± 4.01 mg/L; P< 0.05) and a higher radiographic index (91.81 ± 3.67 vs. 25.88 ± 12.81; P< 0.001), whereas the group with nonerosive disease had a higher rate of paresthesia (66.7% vs. 39.3%; P< 0.05) and higher values for the erythrocyte sedimentation rate (25.21 ± 20.86 vs. 13.21 ± 12.85; P< 0.05) and serum C-reactive protein level (8.82 ± 6.08 vs. 3.25 ± 6.92; P< 0.01). None of the other study parameters showed any significant differences, and both age and sex distribution were also similar in the two groups. At completion of the two-year follow-up, no changes versus baseline were found in any of the study parameters in the overall study population or in either of the two groups. The baseline scintigraphic index was significantly correlated with the radiographic index at baseline ( r = 0.497; P < 0.01) and at study completion ( r = 0.550; P < 0.001). Joints with a positive baseline scintigram were significantly more likely to show radiographic progression (21.09% vs. 6.68% in negative joints; P < 0.001) and joint tenderness exacerbation (21.22% vs. 13.73%; P < 0.001). Conclusion. These data suggest that bone scintigraphy may be useful for predicting clinical and radiographic progression of hand osteoarthritis with or without erosions.

Recognizing early asthma.

Asthma symptoms often develop during the first years of life. Longitudinal studies show that at least 40% of children with wheezing lower respiratory illnesses (LRIs) during the first 3 years of life still have wheezing episodes at 6 years of age. Thus, it is important to identify children at risk of developing asthma, and to distinguish these from those in whom early wheezing is likely to be transient. This is complicated, however, by the variable nature of asthma and the lack of specific and sensitive markers. Genetic markers and epidemiologic risk factors for asthma have been identified, but cannot be used to predict the development of asthma in an individual patient. Similarly, infants who subsequently develop asthma in childhood have higher serum immunoglobulin E (IgE) and peripheral eosinophil counts than those who do not develop asthma, but, again, these factors are not sufficiently sensitive and specific to allow identification of children at risk of developing asthma. An algorithm is presented that outlines possible criteria to determine the risk of developing asthma in infants.

Up-regulation of glomerular extracellular matrix and transforming growth factor-βbgr; expression in RF/J mice

RF/J mice were first reported as a murine model of spontaneous glomerulosclerosis by Gude and Lupton in 1960, but the precise histologic characteristics and immunopathological background of this mouse have not been investigated further. Measurements of serum levels of immunoglobulins, anti-single strand DNA (anti-ss-DNA) antibody, complement (C3), and circulating immune complex (IC) were performed. Analyses of glomerular histological and immunopathological lesions in association with the detection of mRNA expression of collagen IV, TGF-beta, matrix protein turnover related enzymes, matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2) and platelet-derived growth factor (PDGF) were also performed in young (10-week-old) and elderly (60-week-old) RF/J mice with age-matched BALB/C mice as the controls. High levels of serum IgA and IgG from as early as 20 weeks of age were noted in the RF/J mice. Serum anti-ss-DNA antibody of aged RF/J mice increased up to 23% of that of aged MRL-lpr/lpr mice, and serum C3 concentration significantly decreased with age, reaching lower levels than that of BALB/c mice. IgA-IC levels were significantly high compared to BALB/C mice both in the early and late stages of life, whereas IgG-IC levels were high only in mice younger than 20 weeks. Semiquantitative and quantitative analyzes of renal histopathological findings revealed significantly marked and age-related mesangial matrix expansion in RF/J mice, with increasing frequency of global glomerular sclerosis and tubulointerstitial damage. On the other hand, although precise measurements of glomerular cell numbers also showed an apparent augmentation in both young and old RF/J mice compared to BALB/C mice, glomerular cellularity decreased with age in RF/J mice. Immunohistochemical study revealed massive immunoglobulin deposition from a young age in association with significantly higher accumulation of matrix proteins, such as types I and IV collagen and laminin from the early stage of life. In addition, in these glomeruli, transforming growth factor-beta1 (TGF-beta1) was highly expressed both in young and old mice. The mRNA expression of MMP-2 was up-regulated only in the early stage of life. Although PDGF mRNA of RF/J mice was significantly up-regulated in the early stage of life, the differences between the mice disappeared in the late stage of life. These findings suggest that in RF/J mice, an immunopathological background inducing high serum immunoglobulin and IC levels from the early stage of life is closely related to mesangioproliferative glomerular lesions mediated by PDGF, and that development of massive extracellular matrix accumulation in glomeruli was induced by up-regulated expression of TGF-beta with inappropriate regulation of protein turnover-related enzyme production.

Role of laboratory values in determining disease activity in juvenile rheumatoid arthritis

Juvenile rheumatoid arthritis (JRA) is an autoimmune joint disease characterized by supression of disease activity. To confirm clinical criteria in determining disease activity, several laboratory parameters, such as haemoglobm level, leucocyte count, thrombocyte count, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), serum concentration of immunoglobulin and complement are considered important. This retrospective study was undertaken to find out whether the same correlation was also existed our patients trend. Bivariate analysis was used to study 113 episodes of disease activity in 46 patients with JRA from October 1983-0ctober 1997. Each episode of disease activity was clinically classified as either active or inactive according to American Rheumatism Assocation (ARA). It was found that CRP and disease activity correlated significantly (p=O.04). The disease activity was not associated with anemia, leukocytosis, thrombocytosis, increased level of ESR, high serum immunoglobulin concentration, or increased level of complement. Heterogenous origin in 3 types of IRA and limited study subjects may affect these results. In conclusion, besides clinical judgment of disease activity, CRP can be added and used as an objective measure of disease activity.

耳下腺部の木村病５症例

We investigated five patients with eosinophilic granulomas of soft tissue in the parotid region. Four patients were male and one patient was female. Patient age ranged from 11 to 42. The patients had moderate to marked eosinophilia in the peripheral blood and high serum immunoglobulin IgE. The lesions of Kimura's disease showed intermediate intensity on T1-weighted MRI and high intensity on T2-weighted images. Four patients were treated with surgical excision of the swollen parts of the facial tumor and received various medication therapies post operatively. One patient was treated with medication therapies alone, without surgical excision. Three patients who underwent full surgical excision recovered without recurrence. The remaining two patients have had repeated recurrences. A combination of surgery and medication is usually effective. However, when combination therapy is not effective, radiation therapy may be an alternative to prevent recurrence of Kimura's disease.

ANIMAL MODELS OF ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS

Aspergillus fumigatus is a ubiquitously distributed fungus. 45,57 Spores can be found in the soil and in other organic substances such as hay, animal bedding, 100 compost, 50 wood, 27,64 and wool. 2 Mold growth that is dependent on the moisture and nutrients in the substrate is caused by the growth of A. fumigatus, other related fungi, and thermoactinomyces species. Depending on the ventilation and the quality of food and bedding, the concentration of A. fumigatus spores in the air can be very high in barns. 12,100 This organism (and other closely related species) is an opportunistic fungal pathogen for humans and animals, causing life-threatening systemic infections in immunocompromised patients (HIV-infected patients 46 ) and patients undergoing immunoablative treatment. 38 Alternatively, the fungus can colonize mucosal sites in predisposed patients (e.g., patients affected with cystic fibrosis 97 and other structural lung diseases) and in otherwise apparently normal individuals. A variety of proteins from A. fumigatus are highly antigenic and cause lung hypersensitivity responses in man and animals with or without colonization of lungs or sinuses. 45,56 Lung hypersensitivity responses to A. fumigatus may present as one of several distinct clinical entities. 56 Asthma presents as recurrent bouts of dyspnea caused by bronchoconstriction and is often, but not always, accompanied by high serum immunoglobulin E (IgE) levels and peripheral blood and tissue eosinophilia. Hypersensitivity pneumonitis, in contrast, is characterized by bouts of dyspnea caused by alveolar filling and pulmonary restriction, often in the setting of influenza-like symptoms (e.g., fever, fatigue). Serum IgE titers are often low in hypersensitivity pneumonitis, and eosinophilia, if present, is usually less than in asthma. Immunologically, asthma has been associated with an exaggerated response of T helper 2 (Th2) lymphocytes. 11 Th2 cells make a specific array of cytokines, most prominently IL-4 and IL-5. 73 IL-4 is a critical mediator of IgE synthesis, 73 and IL-5 is probably the most essential factor for eosinophil infiltration into the tissues. 19,74 IL-4 and IgE are thought to be instrumental for the activation of mast cells. 91 In contrast, hypersensitivity pneumonitis is characterized by neutrophil influx into the lungs at the acute phase and T cell and macrophage influx during the chronic phase of the disease. It is thought to be caused by excessive macrophage activation because of an immune complex-mediated Arthus reaction together with the response of T helper 1 lymphocytes (Th1). 86,87 Th1 cells mediate functions that are often antagonistic to functions mediated by Th2 cells. 73 Interferon gamma (IFN-γ), the most prominent cytokine made by Th1 cells, activates macrophages and promotes the secretion of IgG2a antibodies. 1 Hypersensitivity to A. fumigatus antigens in human patients can lead to allergic bronchopulmonary aspergillosis (ABPA). 56 Patients with ABPA resemble asthmatics and their airways may be colonized by A. fumigatus. The immunopathology of ABPA is characteristic of activated Th2 cells 14,48,95 ; however, IgG-mediated Arthus reactions 56 and autoimmune reactions 25 also can contribute to the pathogenesis. The study of animal models of ABPA allows comparative research of naturally occurring diseases. Both common and distinct pathologic features are of great interest because they serve to identify key elements in the pathogenesis. Animal model studies also afford research of experimentally induced diseases. Only experimentally induced diseases can be modeled in different ways (e.g., changing the genetic background, the route of sensitization) and altered by treatment with specific antibodies. Furthermore, animals with targeted gene-deletions or with insertion of transgenes can be studied. The purpose of this type of research is to identify the roles of specific cells, receptors, or soluble mediators in disease pathogenesis. The conclusions then are used to formulate hypotheses that have to be tested for their application to human disease.