Involvement of the IP-10 chemokine in sarcoid granulomatous reactions

The accumulation of T cells and monocytes at sites of ongoing inflammation represents the earliest step in the series of events that lead to granuloma formation in sarcoidosis. In this study, we evaluated the pulmonary production of IFN-inducible protein 10 (IP-10), a CXC chemokine that stimulates the directional migration of activated T cells. Striking levels of IP-10 were demonstrated in the bronchoalveolar lavage (BAL) fluid of 24 patients with pulmonary sarcoidosis and lymphocytic alveolitis, as compared with patients with inactive disease or control subjects. A positive correlation was demonstrated between IP-10 levels and the number of sarcoid CD45R0+/CD4+ cells in the BAL. Immunochemistry, performed with an anti-human IP-10 polyclonal Ab in lymph nodes displaying prominent sarcoid granulomas, showed that cells bearing IP-10 were mainly epithelioid cells and CD68+ macrophages located inside granulomatous areas. Macrophages recovered from the BAL of sarcoid patients stained positive for IP-10 protein. Furthermore, alveolar macrophages isolated from sarcoid patients with T cell alveolitis and cultured for 24 h in presence of IFN-gamma secreted definite levels of IP-10 capable of inducing T cell chemiotaxis. Interestingly, alveolar lymphocytes recovered from patients with active sarcoidosis were CD4+ T cells expressing Th1 cytokines (IL-2 and IFN-gamma) and high levels of CXCR3. Taken together, these data suggest the potential role of IP-10 in regulating the migration and activation of T cells toward sites of sarcoid inflammatory process and the consequent granuloma formation.     

Extrinsic allergic alveolitis: a review for the practitioner

Extrinsic allergic alveolitis (EAA) or hypersensitivity pneumonitis (HP) is a clinical syndrome characterised by an inflammatory, partly granulomatous, immune disorder involving interstitial and alveolar spaces secondary to inhalation of organic substances. The disorder is mainly due to occupational exposure, farmer's lung being the best-known example. Acute, subacute or chronic forms can be clinically differentiated. Given the fact that chronic forms may present a pattern of irreversible pulmonary fibrosis, clinicians must be aware of the diagnosis of EAA in every situation where the history shows a potential antigenic exposure. Prevention should be reinforced by increasing individual protective measures and by improving techniques used at the workplace.     

Pulmonary hypersensitivity to Ramin (Gonystylus bancanus)

Transient airways obstruction associated with reduction in the transfer factor (diffusing capacity) of the lungs is reported in a patient with a clinical syndrome in keeping with extrinsic allergic alveolitis after exposure to Ramin dust (Gonystylus bancanus). The alterations in pulmonary function were consistently demonstrated on testing the patient in his working environment and were reproduced in the laboratory after inhalational challenge. The importance of the temporal relationship of changes in pulmonary function to contact with suspected allergenic material is emphasized.     

Respiratory pathology in the agricultural environment

Farmers are usually exposed to a wide variety of noxious organic or chemical substances. This explains why agriculture is probably one of the occupations where prevalences of respiratory diseases are the highest. Some diseases such as extrinsic allergic alveolitis, allergic asthma, silo filler's disease or pesticides-related fibrosis are classic and well described. Others, more recently identified although probably more frequent, remain often unrecognized. This is notably the case of agricultural chronic bronchitis and of organic dust toxic syndrome. Sometimes, these respiratory pathologies are intricate and lead to a complex presentation where signs of irritation or inflammation of the respiratory tract, bronchial hyperreactivity and chronic bronchial obstruction are mixed.     

The effect of a 50 Hz magnetic field on cognitive function in humans

Accumulation of eosinophils in the lung with concomitant tissue damage are defining histopathologic features of human asthma. Through degranulation and the release of proinflammatory proteins such as major basic protein (MBP), eosinophils may perpetuate this inflammatory response. We investigated the extent of eosinophil degranulation in a murine model of allergic pulmonary inflammation. In this paradigm, the mice develop pulmonary eosinophilia, mucus hypersecretion, tissue damage, and airway edema and hyperreactivity. To evaluate the degree of eosinophil degranulation, we used a polyclonal antibody to murine MBP (mMBP) to perform dot blot analysis of bronchoalveolar lavage (BAL) cells and fluids, and immunohistochemical fluorescent analysis of lung tissue sections. After ovalbumin antigen challenge, we were unable to detect immunoreactive mMBP in the BAL fluids from either nonsensitized or sensitized mice. However, after lysis of the recoverable BAL cells, we were able to detect mMBP by immunoblot analysis, with the levels of immunoreactive mMBP directly related to the number of recoverable eosinophils. We also examined paraffin-embedded, lung tissue sections for patterns of mMBP deposition. Whereas lung sections from allergic mice revealed prominent peribronchial eosinophilia after antigen challenge, tissue sections from nonsensitized animals rarely displayed eosinophils. Despite the presence of numerous eosinophils, no immunohistologic evidence of extracellular mMBP could be found in antigen-challenged allergic mice. Furthermore, rechallenged allergic mice displayed a significant increase in the number of recruited pulmonary eosinophils but all immunoreactive mMBP was still intracellular. We conclude that the recruited pulmonary eosinophils have not substantially degranulated. These results suggest that, in this murine model of allergic inflammation, eosinophil degranulation and release of mMBP does not contribute to the observed pulmonary inflammation and airway hyperreactivity.     

Scintigraphic evaluation of 67GA citrate in the comprehensive study of diffuse pulmonary lesions

Scintigraphic evaluation of 67Ga citrate was made in 102 patients with diffuse pulmonary lesions (DPL) of various genesis. There was respiratory sarcoidosis in 40 patients, exogenous allergic alveolitis in 47, idiopathic fibrosing alveolitis in 3, histiocytosis X in 6, and carcinomatosis in 6. Radionuclide findings indicated that the radioagent accumulated in intrathoracic lymph nodes of the mediastinum and partially in the lung tissue in 75.5% of cases at the acute stage of the disease, negative results were in 24.5%, as explained by the fact that the studies were conducted at remission or in the presence of pneumosclerosis. Reexaminations of DPL patients using 67Ga citrate may yield objective information on the treatment performed and, if the latter fails, correct it.     

Management of nevus spilus

BACKGROUND: Granulomatous gastritis is a rarely observed pathological diagnosis. This condition often mimics gastric adenocarcinoma clinically, resulting in gastric resection. However, granulomatous gastritis has long been viewed as a benign process not observed in association with adenocarcinoma of the stomach. This article describes a patient with granulomatous gastritis occurring in close proximity to an area of superficially invading gastric adenocarcinoma. METHODS: Acid-fast stains, fungal stains, standard cultures, tuberculosis cultures, and a VDRL serum test were all obtained. Both upper endoscopy and colonoscopy were performed. Chest radiographs were taken and pulmonary consultation was obtained. RESULTS: The gastric samples obtained from resection showed no evidence of foreign body reaction. The acid-fast stains, fungal stains, cultures, and VDRL were all negative. Endoscopic exams did not show granulomatous inflammation in any other part of the gastrointestinal tract. No pulmonary disease was evident on radiographic or pulmonary exam. CONCLUSION: Isolated granulomatous gastritis is a diagnosis of exclusion. The findings in this patient do not support a diagnosis of Crohn's disease, tuberculosis, sarcoidosis, syphilis, histoplasmosis, berylliosis, or foreign-body reaction. This is a unique case suggesting an association between isolated granulomatous gastritis and metaplastic mucosal changes.     

Sarcoidosis: a pediatric perspective

Childhood sarcoidosis is a rare multisystemic granulomatous disease of unknown etiology. The clinical presentation can vary greatly depending upon the organs involved. Two distinct forms of sarcoidosis exist in children. Older children usually present with a multisystem disease similar to the adult manifestation, with frequent hilar lymphadenopathy and pulmonary infiltration. Early-onset childhood sarcoidosis is a unique form of the disease characterized by the triad of rash, uveitis, and arthritis in patients presenting before age 4 years. The diagnosis of sarcoidosis is confirmed by demonstrating a typical noncaseating granuloma on a biopsy specimen. The current therapy of choice for childhood sarcoidosis with multisystem involvement is corticosteroids. Methotrexate given orally in low doses is effective and safe and has steroid-sparing properties.     

Fluorine-18 deoxyglucose uptake in sarcoidosis measured with positron emission tomography

Regional pulmonary glucose metabolism (MRglu; mumol h-1 g-1), extravascular lung density (D(EV); g cm-3) and vascular volume (VB; ml cm-3) were measured in a single midthoracic transaxial slice (approximately 2 cm thick) using position emission tomography (PET) in seven patients with histologically proven sarcoidosis. The measurements were repeated 1-7 months later after steroid therapy (in two cases, no treatment) in order to assess MRglu as an index of inflammation and relate it to routine pulmonary function tests, chest radiography and serum angiotensin converting enzyme (SACE) levels. MRglu was computed from serial lung scans and peripheral venous blood samples for 60 min following an i.v. injection of 18F-2-fluoro-2-deoxy-D-glucose (18FDG). Both MRglu (which was increased in six of seven patients) and elevated SACE levels returned to normal in those patients treated with high-dose steroids. Regional vascular volume was normal in six of seven cases and did not change significantly with therapy. The high tissue density measured in all patients decreased significantly in two of three patients treated with 40 mg prednisolone daily. The abnormal MRglu observed in active sarcoidosis becomes normal pari passu with SACE levels during high-dose steroid therapy. We conclude that MRglu measured with 18FDG and PET may reflect "disease activity" in sarcoidosis in quantitative terms (per gram lung tissue) and in respect of disease distribution.     

Selection of T lymphocytes bearing limited TCR-Vbeta regions in the lung of hypersensitivity pneumonitis and sarcoidosis

Hypersensitivity pneumonitis (HP) and sarcoidosis are interstitial lung disorders (ILD) characterized by a lymphocytic alveolitis that, in the active phase of the disease, is sustained by different T-cell subsets, i.e., CD8+ cells in HP and CD4+ lymphocytes in sarcoid patients. To address the question of whether a bias in T-cell selection occurs in the lung of patients with HP and sarcoidosis, we analyzed the T-cell receptor beta chain variable region (TCR-Vbeta) repertoire by flow cytometry and polymerase chain reaction (PCR) analyses in blood and lung lymphocytes of 14 HP and 25 sarcoid patients. To verify whether these cells can be activated in vitro through the TCR, blood and lung lymphocytes were also assessed for their responsiveness to different superantigenic stimuli represented by staphylococcal enterotoxins, including SEA, SEB, SEC1, SEC2, SED, and SEE. Flow cytometry and PCR analyses demonstrated an overexpression of cells bearing Vbeta2, Vbeta3, Vbeta5, Vbeta6, and Vbeta8 gene segments in the lung of HP patients as compared with the peripheral blood. In sarcoid patients cells bearing Vbeta2, Vbeta5, and Vbeta6 gene segments in the lung of HP patients as compared with the peripheral blood. In sarcoid patients cells bearing Vbeta2, Vbeta5, and Vbeta6 gene segments were overrepresented in the lung rather than in the blood. Both in HP and sarcoid patients almost all T cells bearing the dominant Vbeta segment belonged to the T-cell subset that sustains the alveolitis, i.e., CD8 in HP patients and CD4 in sarcoid subjects. Follow-up studies demonstrated that the recovery of the alveolitis was characterized by the disappearance of cells bearing a limited T-cell repertoire. Interestingly, T-lymphocyte response to different superantigens demonstrated that the proliferation elicited by different staphylococcal toxins was more pronounced in the lung than in the blood. Taken together, our findings indicate a compartmentalization of cells bearing discrete Vbeta gene products in the pulmonary microenvironment and suggest that the expansion of specific Vbeta region subsets occurring in the lung might result from triggering by a specific antigen. In fact, the removal from exposure in HP patients or specific treatment in sarcoidosis resulted in the decrease of the overrepresented cell population accounting for the lymphocytic alveolitis.     

Protein profile in bronchoalveolar lavage fluid from patients with sarcoidosis and idiopathic pulmonary fibrosis as revealed by SDS-PAGE electrophoresis and western blot analysis

So far bronchoalveolar lavage (BAL)-protein in interstitial lung disease (ILD) is evaluated by measuring concentrations of single proteins. Due to the high dilution of most proteins in BAL, analysis of protein profile has been disappointing. This study describes a new method to overcome this problem and to reveal a highly differentiated picture of BAL proteins. Eighteen patients with pulmonary sarcoidosis, 18 patients with idiopathic pulmonary fibrosis (IPF) and 22 patients with no clinical, roentgenologic or functional evidence of ILD underwent BAL. Total and differential cell count was performed. Normal values for the control group, a lymphocytic alveolitis in sarcoidosis and a granulocytic alveolitis in IPF-patients were found. Median total protein concentration in sarcoidosis showed an increase five times higher than that of the controls (150 mg 1(-1) and 27 mg 1(-1), respectively) with p < 0.001, IPF protein concentration (58 mg 1(-1)) exceeded twice the control values (0.01 > p > 0.001). Analysis of electrophoretic protein profile in controls with Western blot analysis and the biotin/streptavidin staining system revealed a highly differentiated range of bands. Staining with immunoglobulin antibody identified six bands. Four proteins with molecular weight < 21.000 dalton were present only in sarcoidosis patients. These proteins may be identical with fragmented serum proteins or different cell mediators detected in alveolar cell supernatants. Furthermore, in sarcoidosis the intensity and number of bands with molecular weight more than 67.000 dalton was increased. This gives strong evidence for an injury of the alveolar membrane integrity in the alveolitis during the course of sarcoidosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased expression of the monocyte differentiation antigen CD14 in extrinsic allergic alveolitis

Expression of the CD14 antigen was studied on alveolar macrophages in extrinsic allergic alveolitis (EAA), using immunocytochemistry and cytometry. Compared to control donors, EAA patients had higher percentages of My4 positive cells (40 versus 22%), and the antigen density was fourfold higher (410 versus 92 channels). Levels of soluble CD14 (sCD14) in serum were found to be increased in EAA patients with an average of 4.6 +/- 1.5 micrograms.ml-1 compared to 3.2 +/- 0.7 micrograms.ml-1 in controls. Follow-up of patients with antigen avoidance revealed a concomitant decrease of CD14 staining of alveolar macrophages (AMs) and of sCD14 in serum, whilst allergen exposure induces both parameters. These data are consistent with the concept that antigen contact upregulates CD14 expression on AMs in EAA, followed by shedding and increase of sCD14 in serum.     

The so-called interstitial pulmonary diseases (author's transl)

The so-called interstitial pulmonary diseases are considered diseases of the pulmonary parenchyma and discussed according to different pathogenesis and etiology. The disturbance of function is emphasized. On the examples of allergic alveolitis, fibrosing alveolitis, drug damage to the parenchyma and shock-lung the clinical appearances of diseases of pulmonary parenchyma are discussed. Diagnostic methods are described and the causes of faulty interpretation are examined.     

The infectious complications of sarcoidosis: a current perspective

The incidence of indections requiring hospitalization was determined in 122 patients with sarcoidosis. The group was remarkably free of infection except for three patients with Aspergillus mycetoma occurring in areas of long-standing parenchymal involvement with cystic degeneration. There was a single instance of complicating pulmonary tuberculosis, and the only extrathoracic infection was a single instance of disseminated herpes zoster. This study confirms that aspergillosis, not tuberculosis, is currently the most common infectious complication of sarcoidosis. Although previous case reports have suggested an increased incidence of invasive fungal infection in patients with sarcoidosis, there is little to support this concept. None of the patients in the present study group developed these fungal infections during a mean 7.2-year follow-up. The clinical presentation of many of the previously reported cases suggests that the entire course of the granulomatous illness was infectious in nature rather than sarcoidosis with complicating infection.     

Two year observation of patients with chronic extrinsic allergic alveolitis during steroid treatment

In 53 patients (37 females, 16 males, aged 17-64) with chronic extrinsic allergic alveolitis after two years of prednisone treatment (40 mg as initial dose reduced to 20 mg after 6 weeks and to 15 mg after 6 months) the significant increase (p < 0.05) of mean values of FVC, FEV1 and DCO and of clinical improvement were observed. No radiological improvement was seen. Complete allergen cessation (16 patients) had very limited influence on pulmonary function parameters and chest X-ray picture, but clinical symptoms were diminished in comparison with patients who stayed on their farms and were potentially exposed to allergens.     

Ileal ureter

Clinically apparent involvement of the heart and nervous system occurs in a relatively small number of patients with sarcoidosis. The diagnosis of myocardial and neurological sarcoidosis is difficult because anatomic presence of granulomas without clinical dysfunction is an important feature of sarcoidosis. The chest radiography is abnormal in 8 of every 10 patients with myocardial or neurosarcoidosis. Serum angiotensin-converting enzyme and gallium uptake studies may provide some indication of the extent and severity of the granulomatous process. Corticosteriods are the mainstay of therapy but chloroquine or hydroxychloriquine, methotrexate, and azathioprine are also effective. Prognosis of myocardial and neurological sarcoidosis is poor.     

Canine airway responses to acetylcholine, prostaglandin F2alpha, histamine, and serotonin after chronic antigen exposure

Dose-response curves were obtained for aerosols of acetylcholine (ACh), prostaglandin F2alpha (PGF2alpha), histamine (H), and 5-hydroxytryptamine (5-HT) on pulmonary resistance (Rp) and dynamic lung compliance (Cdyn) in Ascaris-hypersensitive dogs. Previously, these animals had been subjected to chronic biweekly "allergic asthmatic" episodes by aerosol administration of Ascaris antigen. When examined either one week before or after antigen provocation the airways were not hyperreactive to ACh, H, or 5-HT but did demonstrate a modest hyperreactivity to PGF2alpha. When aerosol dose-response curves were obtained for these agonists immediately following an "allergic asthmatic" episode, the airways were hyporeactive to PGF2alpha, H, and 5-HT, but not to ACh. Studies with atropine indicated that the hyporeactivity was the result of decreased airway responsiveness to both direct and indirect effect of PGF2alpha and H. It is concluded that, in dogs, chronic antigen challenge is not accompanied by a general increase in airway reactivity to pharmacologic agents.     

Studies on the mechanisms involved in antigen-evoked pleural inflammation in rats: contribution of IgE and complement

Immunoglobulin E (IgE) has been shown to play a critical role in the allergic late-phase reaction, which is marked by intense leukocyte infiltration and edema. In this study we assessed the allergic pleural inflammation triggered by intrapleural (i.pl.) challenge in sensitized rats. We examined pleural effluent from actively sensitized rats following anti-IgE monoclonal antibody (mAb) (MARE-1) provocation for protein exudation, neutrophil as well as eosinophil accumulation. Inflammatory changes triggered by antigen after passive sensitization with IgE mAb was also assessed for comparison. Total serum level of IgE was found to be about threefold increased 7-8 days post-active sensitization, remaining augmented for at least 30 days. Increased levels of peritoneal leukocyte-bound IgE and serum IgE with specificity to ovalbumin were also detected. Nevertheless, the anti-IgE challenge in 14-day actively sensitized was shown to be a weak stimulus of neutrophil and eosinophil accumulation, despite being able to cause intense protein extravasation. Similarly, antigen challenge of IgE-passively sensitized rats caused protein leakage that was comparable to that induced by anti-IgE mAb in actively sensitized rats but led to a much lower neutrophil/eosinophil infiltration. Also, blockade of complement with recombinant human soluble C receptor-1 (sCR1) treatment prevented actively sensitized rats from reacting to antigen with neutrophil and eosinophil recruitment without modifying protein extravasation. These data suggest that IgE and complement-mediated mechanisms probably account for the exudation and leukocyte infiltration that is characteristic of the pleural inflammatory response observed in actively sensitized rats.     

Role of immunoglobulin A monoclonal antibodies against P23 in controlling murine Cryptosporidium parvum infection

Cryptosporidium parvum is an important diarrhea-causing protozoan parasite of immunocompetent and immunocompromised hosts. Immunoglobulin A (IgA) has been implicated in resistance to mucosal infections with bacteria, viruses, and parasites, but little is known about the role of IgA in the control of C. parvum infection. We assessed the role of IgA during C. parvum infection in neonatal mice. IgA-secreting hybridomas were developed by using Peyer's patch lymphocytes from BALB/c mice which had been orally inoculated with viable C. parvum oocysts. Six monoclonal antibodies (MAbs) were selected for further study based on indirect immunofluorescence assay reactivity with sporozoite and merozoite pellicles and the antigen (Ag) deposited on glass substrate by gliding sporozoites. Each MAb was secreted in dimeric form and recognized a 23-kDa sporozoite Ag in Western immunoblots. The Ag recognized comigrated in sodium dodecyl sulfate-polyacrylamide gel electrophoresis with P23, a previously defined neutralization-sensitive zoite pellicle Ag. MAbs were evaluated for prophylactic or therapeutic efficacy against C. parvum, singly and in combinations, in neonatal BALB/c mice. A combination of two MAbs given prophylactically prior to and 12 h following oocyst challenge reduced the number of intestinal parasites scored histologically by 21.1% compared to the numbers in mice given an isotype-matched control MAb (P < 0.01). Individual MAbs given therapeutically in nine doses over a 96-h period following oocyst challenge increased efficacy against C. parvum infection. Four MAbs given therapeutically each reduced intestinal infection 34.4 to 42.2% compared to isotype-matched control MAb-treated mice (P < 0.05). One MAb reduced infection 63.3 and 72. 7% in replicate experiments compared to isotype-matched control MAb-treated mice (P < 0.0001). We conclude that IgA MAbs directed to neutralization-sensitive P23 epitopes may have utility in passive immunization against murine C. parvum infection.     

Effect of indomethacin and atropine in experimental asthma in conscious guinea pigs

Pulmonary mechanics were measured in unanesthetized guinea pigs sensitized to horseradish peroxidase (HRP) before and during two aerosolized challenges of this antigen. During the first challenge the pulmonary resistance increased in all animals. Prior to second challenge the animals received either atropine (0.2 mg/kg) or indomethacin (10 mg/kg) intraperitoneally. We found that during the second challenge the indomethacin group had an increase in pulmonary resistance slightly greater or similar to that during the first exposure to the antigen, while the animals treated with atropine had a significantly diminished response (P less than 0.05). In five guinea pigs sensitized to HRP but challenged with a nonspecific aerosal made up of rabbit albumin, we found that pulmonary resistance increased in some animals and that this increase could be partially blocked by atropine. These results show that indomethacin has no effect on this model of allergic airways disease. They also confirm the importance of the vagus nerves in allergic bronchoconstriction and in addition show that nonspecific hyperirritability can be induced in some animals by immunization.