Granulomatous Lung Inflammation Research Articles

Doxycycline aggravates granulomatous inflammation and lung microstructural remodeling induced by Schistosoma mansoni infection

Although doxycycline exhibits immunomodulatory properties, its effects on pulmonary infection by Schistosoma mansoni remain overlooked. Thus, we investigated the impact of this drug on lung granulomatous inflammation and microstructural remodeling in a murine model of schistosomiasis. Swiss mice were randomized in four groups: (i) uninfected, (ii) infected with S. mansoni and untreated, (iii) infected treated with praziquantel (Pzq; 200 mg/kg), and (iv) infected treated with Dox (50 mg/kg). Pz was administered in a single dose, and Dox for 60 days. S. mansoni induced marked granulomatous lung inflammation, which was associated to cytokines upregulation (IL-2, IL-4, IL-10, IFN-γ, TNF-α, and TGF-β), neutrophils and macrophages recruitment, alveolar collapse, lung fibrosis, and extensive depletion of elastic fibers. These parameters were attenuated by Pzq and aggravated by Dox. Exudative/productive granulomas were predominant in untreated and Dox-treated animals, while fibrotic granulomas were more frequent in Pzq-treated mice. The number and size of granulomas in Dox-treated animals was higher than untreated and Pzq-treated mice. Dox treatment inhibited the increase in MMP-1 and MMP-2 activity but upregulated myeloperoxidase and N-acetylglucosaminidase activity compared to untreated and Pzq-treated animals. Dox and Pzq exerted no effect on elastin depletion and upregulation of elastase activity. Together, our findings indicated that Dox aggravated granulomatous inflammation, accelerating lung microstructural remodeling by downregulating MMP-1 and MMP-2 activity without impair neutrophils and macrophages recruitment or elastase activity. Thus, Dox potentiates inflammatory damage associated with lung fibrosis, elastin depletion and massive alveolar collapse, profoundly subverting lung structure in S. mansoni-infected mice.

Granulomatous lung inflammation is nanoparticle type-dependent

ABSTRACTBackground: Nanoparticles are increasingly suspected as a strong etiologic factor of granuloma formation. Aim of the Study: The aim of our study was to compare lung inflammatory response and histology changes following exposure of mice to two widely used nanoparticles: carbon nanotubes (MWCNT) and cadmium-based nanoparticles (QDOT705) in an attempt to better our understanding of granulomatous inflammation. Materials and Methods: Various groups of mice were included: control mice and mice that were intranasally instilled with QDOT or MWCNT. At defined time points post-challenge, bronchoalveolar lavages (BALs) and lung tissues were collected to study inflammatory and histologic changes. Results: Analyses of lung BAL fluids and tissues of nanoparticles-challenged mice in comparison to controls found: (1) increased cellularity in BALs, (2) increase of total protein concentration, LDH activity and proteolytic activity in BALs; (3) patchy granulomas, (4) macrophages, CD3 ± T, Treg and B cell infiltration in granulomatous areas; and (5) altered regulation of key inflammatory mediators and receptors. Importantly, these changes were nanoparticle type-dependent. Conclusion: Our work enhances understanding of nanoparticles-induced lung inflammatory and histological changes that result in granuloma formation. We provide compelling evidence that not only exposure to nanoparticles leads to granulomatous lung inflammation, but the severity of this latter is nanostructure type-dependent. Of importance, while nanotechnology has the potential to revolutionize various fields including medicine, nanoparticles form the potential for an entirely new lung health risk that it is necessary to take seriously into consideration by setting up and/or reinforcing adequate safety measures.

IL-13 Immunotoxin Accelerates Resolution of Lung Pathological Changes Triggered by Silica Particles in Mice

Instillation of silica into the lungs of rodents results in pathological changes that strongly mimic human silicosis, an occupational lung disease marked by restrictive airway obstruction, inflammation, and fibrosis. Because IL-13 is a pivotal proinflammatory and fibrogenic cytokine, we examined whether a recombinant immunotoxin comprised of human IL-13 and a mutated form of Pseudomonas exotoxin (IL-13-PE) might affect pathological features of experimental silicosis. Mice received a single intranasal instillation of silica particles and were treated with intranasal IL-13-PE every other day from days 21 to 27 postsilica. The sensitivity of putative cell targets to IL-13-PE was also assessed in in vitro settings. Upregulation of IL-13, its receptor subunits IL-13Rα1 and IL-13Rα2, and shared receptor IL-4Rα were associated with development of granulomatous lung inflammation triggered by silica. IL-13-PE inhibited silica-induced granuloma and fibrotic responses noted at 24 h and 15 d after the last treatment. Upregulation of TNF-α, TGF-β, and chemokines, as well as increased collagen deposition and airway hyperreactivity to methacholine were all clearly sensitive to IL-13-PE. In addition, IL-13-PE inhibited both IL-13-induced proliferation of cultured lung fibroblasts from silicotic mice and silica-induced IL-8 generation from A549 cells. In conclusion, our findings show that therapeutic treatment with IL-13-PE can reverse important pathological features caused by inhalation of silica particles, suggesting that this recombinant immunotoxin is a promising molecular template in drug discovery for the treatment of silicosis.

The role of PPARγ in carbon nanotube-elicited granulomatous lung inflammation

BackgroundAlthough granulomatous inflammation is a central feature of many disease processes, cellular mechanisms of granuloma formation and persistence are poorly understood. Carbon nanoparticles, which can be products of manufacture or the environment, have been associated with granulomatous disease. This paper utilizes a previously described carbon nanoparticle granuloma model to address the issue of whether peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear transcription factor and negative regulator of inflammatory cytokines might play a role in granulomatous lung disease. PPARγ is constitutively expressed in alveolar macrophages from healthy individuals but is depressed in alveolar macrophages of patients with sarcoidosis, a prototypical granulomatous disease. Our previous study of macrophage-specific PPARγ KO mice had revealed an intrinsically inflammatory pulmonary environment with an elevated pro-inflammatory cytokines profile as compared to wild-type mice. Based on such observations we hypothesized that PPARγ expression would be repressed in alveolar macrophages from animals bearing granulomas induced by MWCNT instillation.MethodsWild-type C57Bl/6 and macrophage-specific PPARγ KO mice received oropharyngeal instillations of multiwall carbon nanotubes (MWCNT) (100 μg). Bronchoalveolar lavage (BAL) cells, BAL fluids, and lung tissues were obtained 60 days post-instillation for analysis of granuloma histology and pro-inflammatory cytokines (osteopontin, CCL2, and interferon gamma [IFN-γ] mRNA and protein expression.ResultsIn wild-type mice, alveolar macrophage PPARγ expression and activity were significantly reduced in granuloma-bearing animals 60 days after MWCNT instillation. In macrophage-specific PPARγ KO mice, granuloma formation was more extensive than in wild-type at 60 days after MWCNT instillation. PPARγ KO mice also demonstrated elevated pro-inflammatory cytokine expression in lung tissue, laser-microdissected lung granulomas, and BAL cells/fluids, at 60 days post MWCNT exposure.ConclusionsOverall, data indicate that PPARγ deficiency promotes inflammation and granuloma formation, suggesting that PPARγ functions as a negative regulator of chronic granulomatous inflammation.

Antifungal activity of leaves of mangroves plant Acanthus licifolius against Aspergillus fumigatus

The antifungal activity of chloroform extract of leaves of Acanthus ilicifolius was evaluated in Aspergillus fumigatus infected mice. Swiss albino mice (60) were divided into five groups. All the groups were immunosuppressed with cyclophosphamide and cortisone acetate couple of days prior to intranasal inoculation with Aspergillus fumigatus conidia (106) in all the groups, except the first. Treatment was initiated at 24 h of fungal inoculation and continued up to day 14, and included amphotericin B (1 mg/kg orally) for group III and extract of Acanthus ilicifolius at 250 mg and 500 mg/kg for group IV and V, respectively. Groups I and II received sterile water orally for the same period. From each group, three mice were sacrificed after 1 h and the remaining mice on the 14th day of inoculation. One hour post-inoculation lung colony forming unit count confirmed the delivery of conidia into the lungs. Colony forming unit count, intensity of gross necropsy changes and histopathological changes were highest in group II. It improved in group III and also in groups IV and V in dose-dependent manner. Lesions were absent in the noninfected group. Lesions included maximum granulomatous inflammation of lung, multifocal diffused necrotic granulomas on kidney and moderate microgranulomas on liver. From this study, it was concluded that chloroform extract of Acanthus ilicifolius contains active principles that are absorbed after oral administration to produce systemic effects when given at 500 mg/kg dose.

Dysregulated Cytokine Expression by CD4+ T cells from Post-Septic Mice Modulates both Th1 and Th2-Mediated Granulomatous Lung Inflammation

Previous epidemiological studies in humans and experimental studies in animals indicate that survivors of severe sepsis exhibit deficiencies in the activation and effector function of immune cells. In particular, CD4+ T lymphocytes can exhibit reduced proliferative capacity and improper cytokine responses following sepsis. To further investigate the cell-intrinsic defects of CD4+ T cells following sepsis, splenic CD4+ T cells from sham surgery and post-septic mice were transferred into lymphopenic mice. These recipient mice were then subjected to both TH1-(purified protein derivative) and TH2-(Schistosoma mansoni egg antigen) driven models of granulomatous lung inflammation. Post-septic CD4+ T cells mediated smaller TH1 and larger TH2 lung granulomas as compared to mice receiving CD4+ T cells from sham surgery donors. However, cytokine production by lymph node cells in antigen restimulation assays indicated increased pan-specific cytokine expression by post-septic CD4+ T cell recipient mice in both TH1 and TH2 granuloma models. These include increased production of TH2 cytokines in TH1 inflammation, and increased production of TH1 cytokines in TH2 inflammation. These results suggest that cell-intrinsic defects in CD4+ T cell effector function can have deleterious effects on inflammatory processes post-sepsis, due to a defect in the proper regulation of TH-specific cytokine expression.

Novel Murine Model of Chronic Granulomatous Lung Inflammation Elicited by Carbon Nanotubes

Lung granulomas are associated with numerous conditions, including inflammatory disorders, exposure to environmental pollutants, and infection. Osteopontin is a chemotactic cytokine produced by macrophages, and is implicated in extracellular matrix remodeling. Furthermore, osteopontin is up-regulated in granulomatous disease, and osteopontin null mice exhibit reduced granuloma formation. Animal models currently used to investigate chronic lung granulomatous inflammation bear a pathological resemblance, but lack the chronic nature of human granulomatous disease. Carbon nanoparticles are generated as byproducts of combustion. Interestingly, experimental exposures to carbon nanoparticles induce pulmonary granuloma-like lesions. However, the recruited cellular populations and extracellular matrix gene expression profiles within these lesions have not been explored. Because of the rapid resolution of granulomas in current animal models, the mechanisms responsible for persistence have been elusive. To overcome the limitations of previous models, we investigated whether a model using multiwall carbon nanoparticles would resemble chronic human lung granulomatous inflammation. We hypothesized that pulmonary exposure to multiwall carbon nanoparticles would induce granulomas, elicit a macrophage and T-cell response, and mimic other granulomatous disorders with an up-regulation of osteopontin. This model demonstrates: (1) granulomatous inflammation, with macrophage and T-cell infiltration; (2) resemblance to the chronicity of human granulomas, with persistence up to 90 days; and (3) a marked elevation of osteopontin, metalloproteinases, and cell adhesion molecules in granulomatous foci isolated by laser-capture microdissection and in alveolar macrophages from bronchoalveolar lavage. The establishment of such a model provides an important platform for mechanistic studies on the persistence of granuloma.

Pulmonary adiaspiromycosis: The first reported case in Turkey

Adiaspiromycosis is a world wide airborne infection and is a pulmonary disease in humans caused by the fungus Chrysosporium parvum var crescens (Emmonsia parva) . It is caused by inhalation of spores of the saprophytic soil fungus. The spherules induce a granulomatous reaction, in which a single spherule is surrounded by a fibronecrotic and suppurative or fibrous granuloma. The disease can be localized and asymptomatic, or disseminated, occasionally severe, or even fatal. Reticulonodular infiltrates are the most common radiographic manifestations, with localized infiltrates occurring occasionally. We present a case with bilateral diffuse interstitial micronodular infiltration and granulomatous inflammation in the lung. The larvae of adiaspiromycosis visualized in the center of granulomatous inflammation by histopathologic examination of the lung biospy specimens. We aimed to discuss the very rare cause of diffuse interstitial and granulomatous inflammation of lung.

ApoE-Deficient Mice on Cholate-Containing High-Fat Diet Reveal a Pathology Similar to Lung Sarcoidosis

Sarcoidosis is a chronic disease of unknown etiology characterized by the formation of non-necrotizing epithelioid granulomas in various organs, especially in the lungs. The lack of an adequate animal model reflecting the pathogenesis of the human disease is one of the major impediments in studying sarcoidosis. In this report, we describe ApoE-/- mice on a cholate-containing high-fat diet that exhibit granulomatous lung inflammation similar to human sarcoidosis. Histological analysis revealed well-defined and non-necrotizing granulomas in about 40% of mice with the highest number of granulomas after 16 weeks on a cholate-containing high-fat diet. Granulomas contained CD4+ and CD8+ T cells, and the majority of the cells in granulomas showed immunoreactivity for the macrophage marker Mac-3. Cells with morphological features of epithelioid cells expressed angiotensin-converting enzyme, osteopontin, and cathepsin K, all characteristics of epithelioid and giant cells in granulomas of human sarcoidosis. Giant cells and nonspecific inclusions such as Schaumann's bodies and crystalline deposits were also detected in some lungs. Granulomatous inflammation resulted in progressive pulmonary fibrosis. Removal of cholate from the diet prevented the formation of lung granulomas. The observed similarities between the analyzed mouse lung granulomas and granulomas of human sarcoidosis, as well as the chronic disease character leading to fibrosis, suggest that this mouse model might be a useful tool to study sarcoidosis.

Sarcoid relapse with isolated kidney involvement

A 70-year-old Caucasian male presented with history of systemic symptoms lasting since several weeks including malaise, anorexia, weight loss, and low-grade fever. He had no other significant symptoms or clinical findings, physical examination was unrevealing, and vital parameters were normal. When the patient was 45 yeas old, a diagnosis of pulmonary sarcoid was made upon results of radiologic imaging tests, gallium-67 scanning, and the histological demonstration of non-caseating granulomas at a transbronchial lung biopsy. At that time, all other known causes of granulomatous lung inflammation were ruled out and complete recovery was achieved after 6 months of steroid treatment at tapering doses. Afterwards, he had several episodes of recurrent right flank pain, which were managed conservatively; 10 months before admission lithotripsy was performed and calcium oxalate urinary stones recovered. At that time, serum creatinine was 2.1 mg/dl (normal range 0.5-1.2 mg/dl), urea was 72 mg/dl (normal range 10-50 mg/dl), and calcium was 12.4 mg/dl (normal range 8.1-10.4 mg/dl). Follow-up laboratory results until 1 month before presentation revealed persistent mild hypercalcaemia, with calcium blood levels ranging from 10.6 to 11.2 mg/dl, and stable serum creatinine and urea levels; the other variables remained within normal ranges on each occasion. There was no personal and family history of hypertension or any other cardiovascular, metabolic or systemic disorders, and the patient denied alcohol use, toxic habits, or taking any other medications, including over-the-counter medications, or herbal remedies. On admission, laboratory analyses showed renal impairment with a glomerular filtration rate of 14 ml/min; serum creatinine was 4.1 mg/dl, urea was 106 mg/dl, and calcium was 14.4 mg/dl. Electrolytes, a complete blood count, uric acid, cholesterol, triglycerides, protein, amylase and lipase, liver function tests, intact parathyroid hormone, and the coagulation profile were all normal; the erythrocyte sedimentation rate was 50 mm/h. Urinalysis showed a pH of 6.5, a specific gravity of 1012, and the urine tested positive for occult blood; there were between 5 and 10 red cells and calcium oxalate crystals per high-power field with no white cells, casts, or bacteria. Cultures grew no pathogens and the 24h urinary protein excretion was < 500 mg. Complement was normal and search for autoantibodies, including antinuclear, antiphospholipid, and antineutrophil cytoplasmic antibodies, rheumatoid factor, cryoglobulins, and lupus anticoagulant was also negative; blood levels of angiotensin-converting enzyme (ACE) were not measured at this time. An electrocardiogram did not show any abnormalities and a chest

Production of granulomatous inflammation in lungs of rat pups and adults by Sephadex beads.

Granulomatous inflammation is a process that involves mononuclear leukocytes as well as other inflammatory cells. The heterogeneity of its appearance may be due to the variety of cytokines and chemokines that are involved. In this study, we compared granuloma formation and bronchoalveolar leukocyte differential in the lungs of rats (2- and 8-wk-old) that were treated intravenously with Sephadex beads. In addition, the kinetics of cytokine and chemokine production was determined in these groups. In adults, the beads caused lung granulomas associated with infiltration of eosinophils and neutrophils and increased eosinophil and neutrophil counts in the bronchoalveolar lavage fluid within 16 h. In pups, the granulomas were formed slowly and did not reach the size achieved in adults. Eosinophils and neutrophils were sparsely found in the periphery of the granulomas, even at 32 h. Pups were also unable to respond rapidly to Sephadex bead treatment with eosinophil and neutrophil infiltration in the bronchoalveolar lavage fluid. Tumor necrosis factor-alpha was significantly increased in both groups, but the cytokine was lower in pups than in adults. Interferon-gamma and eotaxin were increased only in adults, and IL-4 and regulated on activation, normal T cell expressed, and secreted was increased only in pups. In conclusion, the i.v. administration of Sephadex beads produced granulomatous inflammation in the lungs of adult rats, but pups were unable to respond as rapidly to the treatment. In addition, the difference in response between the two age groups was associated with the kinetics of cytokine and chemokine production.

Etanercept or Mycobacterium Lung Injury?-To the Editor

We are honored by the interest of Iseman and Fennely in our case, and we respect their vast knowledge and experience with acid-fast bacilli (AFB) and granulomatous inflammation. Teasing through the differential diagnosis for granulomatous lung inflammation can be challenging. Conclusions often are fraught with controversy,1 particularly when microorganisms are not identified in tissue stains. Temporal relationships in the clinical history help to define the likelihood of an applicable diagnosis.

Hexachlorobenzene-Induced Eosinophilic and Granulomatous Lung Inflammation Is Associated with in Vivo Airways Hyperresponsiveness in the Brown Norway Rat

We investigated whether the eosinophilic and granulomatous lung pathology that develops in Brown Norway (BN/SsNOlaHsd) rats upon feeding hexachlorobenzene (HCB) is associated with nonspecific in vivo airways hyperresponsiveness (AHR) to methacholine. To this end, female BN/SsNOlaHsd rats were exposed to diets with no supplementation or diets supplemented with 450 mg HCB per kg feed. On days 7 or 21 of exposure in vivo airways hyperresponsiveness to increasing concentrations of methacholine was assessed both by whole body plethysmography and by visual scoring. In addition, lungs were lavaged to count and differentiate lavage cells, and skin and lungs were processed for histology. Lungs of the control rats showed some scattered microgranulomas and by 3 weeks of control diet some rats showed rather extensive granuloma formation and perivascular and peribronchiolar infiltration of eosinophils, as well as increased responsiveness to methacholine. Oral exposure to HCB for 7 days caused a moderate perivasculitis, but no increase of total serum IgE levels and no AHR to methacholine was found. Prolonged HCB exposure for 21 days resulted in severe and extensive eosinophilic and granulomatous lung inflammation, a threefold increase of total serum IgE levels, and marked cholinergic AHR in all rats. Correlation analysis revealed a significant relation between the AHR and lung inflammation, as judged by granuloma formation and increased numbers of eosinophilic granulocytes in the lung interstitium, particularly around the bronchi and bronchioli. No correlation was observed between serum IgE levels and AHR. Data suggest that HCB induces AHR by stimulating eosinophilic lung inflammation and that the preexistent microgranulomas may predispose to development of the HCB-induced lung pathology.

Matrix metalloproteinases 2, 9, and 13, and tissue inhibitors of metalloproteinases 1 and 2 in experimental lung silicosis.

Exposure to silica induces granulomatous lung inflammation evolving to fibrosis through yet unclear pathogenic mechanisms. We examined the expression of extracellular matrix remodeling molecules: collagenase 3, gelatinases A and B, and TIMP-1 and TIMP-2 in experimental lung silicosis. Rats were instilled with 50 mg of silica and sacrificed after 15 and 60 d. At 60 d a significant increase in lung collagen content was found (170.2 +/- 34.4 versus 88.2 +/- 20.8 microgram/mg in controls, p = 0.01). Gelatin zymography of bronchoalveolar lavage fluid (BALF) from 15 and 60 d revealed bands of progelatinase A and progelatinase B, and lung tissue zymograms showed in addition, the active gelatinase A form at 15 d. By in situ hybridization and immunohistochemistry, early silicotic granulomas exhibited intense staining for all matrix metalloproteinases (MMPs) and TIMPs assayed. Labeling was restricted inside granulomas and surrounding areas. Late silicotic granulomas at 60 d showed lower MMP expression than did early lesions, and in highly fibrotic nodules scarce signal was usually found. TIMP-1 and TIMP-2 showed a moderate reduction in 60-d silicotic nodules. These findings suggest that an imbalance in the expression of MMPs and TIMPs may be implicated in extracellular matrix remodeling and basement membrane disruption during experimental lung silicosis.

Increased glutathione and glutathione peroxidase in lungs of individuals with chronic beryllium disease.

Reactive oxygen species (ROS) are mediators of chronic tissue damage and fibrosis. Endogenous antioxidants may increase in response to oxidants and reduce tissue injury. We investigated the antioxidant response of the lungs to the chronic release of ROS, as occurs in the immune-specific granulomatous inflammation of chronic beryllium disease (CBD), and compared it with that in healthy controls and individuals exposed to cigarette smoke. The antioxidants superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione (GSH) were quantitated in lung epithelial lining fluid (ELF) and serum from control subjects (n = 10), cigarette smokers (n = 8), and individuals with CBD (n = 9). GPx activity and extracellular GPx (eGPx) protein were increased in the ELF of subjects with CBD in comparison with that of control subjects and smokers (eGPx in ELF: controls, 1.3 +/- 0.2 microgram/ml, smokers, 1.9 +/- 0.3 microgram/ml, CBD, 3.8 +/- 0.8 microgram/ml; p = 0.002; GPx U/ml ELF, controls 1.4 +/- 0.3, smokers 1.8 +/- 0.4, CBD, 4.5 +/- 1, p = 0.02). Smokers' ELF had higher levels of GSH than that of controls, but CBD patients' ELF contained much more GSH than that of either controls or smokers (p < 0.001). Increases in GSH were correlated with eGPx, indicating similar inducing mechanisms for these antioxidants. Thus, coordinate augmentation of the glutathione antioxidant system occurs in granulomatous lung inflammation.

Expression and localization of TIMP-1, TIMP-2, MMP-13, MMP-2, and MMP-9 in early and advanced experimental lung silicosis.

Chronic exposure to crystalline silica particles results in macrophagelymphocytic granulomatous lung inflammation, which is followed by abnormal and progressive accumulation of extracellular matrix. 1,2 However, the pathogenic mechanisms and the sequence of the pathological events leading to the fibrotic response have not been well defined. In this context, there is evidence suggesting an upregulation of a variety of fibrogenic cytokines such as tumor necrosis factor alpha (TNFα ) and transforming growth factor beta (TGFβ ), with increased synthesis and secretion of lung extracellular matrix components. 3,4 However, studies on matrix degradation are scanty.

Role of Extracellular Matrices, Matrix Receptors, and Cytokines in Granulomatous Lung Inflammation

Role of Extracellular Matrices, Matrix Receptors, and Cytokines in Granulomatous Lung Inflammation

Wegener's Granulomatosis, Lymphomatoid Granulomatosis, and Benign Lymphocytic Angiitis and Granulomatosis of Lung

Observations on 35 patients with pulmonary angiitis and granulomatosis show the value of separating pulmonary lesions of this type into three categories. Fifteen patients had Wegener's granulomatosis characterized by necrotizing granulomatous inflammation of lung, frequent upper airway and renal involvement, and responsiveness to cyclophosphamide. Nine had lymphomatoid granulomatosis characterized by necrotic atypical lymphoreticular infiltrates and frequent cutaneous and neurologic involvement, usually fatal despite intensive cytotoxic drug therapy. Eleven had benign lymphocytic angiitis and granulomatosis, in the past included in the above categories and characterized by nodular collections of mature lymphocytes and plasma cells, with predominantly pulmonary involvement and consistent responsiveness to chlorambucil. Wegener's granulomatosis and benign lymphocytic angiitis and granulomatosis were frequently associated with serum immunoglobulin elevations, with intact cell-mediated responses. Clinical and immunologic assessment was useful indistinguishing benign lymphocytic angiitis and granulomatosis from lymphomatoid granulomatosis.