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PubMed1992

Should granulomas be excised in children with long-term tracheotomy?

We reviewed 265 rigid bronchoscopies performed in 50 children with tracheotomy-dependent subglottic stenosis (25 congenital, 25 acquired). Granulomas developed in 40 children (80%) and were unrelated to age, sex, race, gastroesophageal reflux, tracheotomy duration, or type of stenosis. The incidence of small to medium, large, and obstructing granulomas at endoscopy was 28%, 6%, and 0%, respectively. Compared with a baseline finding of no granuloma at preceding bronchoscopy, the odds of granuloma recurrence were 3.0 after an unexcised granuloma (95% confidence interval [CI], 1.1 to 8.4), 4.1 after granuloma excision (95% CI, 1.4 to 11.9), and 7.3 after expansion surgery (95% CI, 1.1 to 49.2). Considering the low incidence of large or obstructing granulomas, and the failure of granuloma excision to diminish recurrence, we do not recommend interval excision of nonobstructing granulomas in children with stable tracheotomies.

Bronchoscopy↗
PubMedDate not supplied

Proline trapping in granulomas, the site of collagen biosynthesis in murine schistosomiasis.

Proline, a critical substrate for collagen synthesis, is increased in liver undergoing fibrosis. In mice with schistosomiasis, the incorporation of proline into collagen occurs within liver granulomas. To study the interaction of liver cells and granulomas in the development of fibrosis, we assayed the enzymes that catalyze the formation and degradation of proline in isolated granulomas and liver. Two sequential enzymes involved in the formation of proline from arginine are ornithine-delta-aminotransferase and delta-pyrroline-5-carboxylate (P5C) reductase. Activities of both these enzymes in granulomas were approximately 10% of those in liver, expressed on the basis of DNA content. The enzymes involved in degradation of proline are proline oxidase and P5C dehydrogenase; both are present in liver cells. In isolated granulomas, activity of proline oxidase was minimal, and P5C dehydrogenase activity was absent. These findings suggest that the metabolism of proline within granulomas differs greatly from that in liver cells. Earlier studies showed that exogenous proline enters granulomas and is rapidly incorporated into collagen. The combined findings raise the possibility that granulomas serve as a proline trap. Proline can enter this compartment and can be incorporated into collagen; however, proline within granulomas cannot readily be diverted into other pathways by degradation.

Animals↗
PubMed1996

Localization of alpha 2-macroglobulin protein and messenger RNA in rat liver fibrosis: evidence for the synthesis of alpha 2-macroglobulin within Schistosoma mansoni egg granulomas.

alpha 2-Macroglobulin (alpha 2M) in the rat is a strong-reacting acute-phase protein with potent protease-inhibiting and cytokine-binding properties. Production of alpha 2M is ascribed mainly to liver parenchymal cells. In the present study, we investigated, by means of immunohistochemistry and in situ hybridization, whether fibrosis in the rat liver induced by Schistosoma mansoni eggs leads to local production of alpha 2M. alpha 2M protein and messenger RNA (mRNA) in the unaffected liver tissue, as well as serum values of alpha 2M, were comparable in control rats and egg-injected rats, at 1, 3, and 8 weeks after injection of the eggs. alpha 2M was homogeneously distributed across the liver lobule. In contrast, at the sites of the granulomas, a strong increase in alpha 2M was observed. alpha 2M mRNA was expressed by granuloma cells, but not by the surrounding liver parenchymal cells. Within the granulomas, alpha 2M protein was present in numerous spindle-shaped cells and was diffusely distributed in the extra-cellular matrix. Using double-staining techniques, a subpopulation of the alpha 2M-positive cells in the granulomas appeared to be desmin-positive, suggesting a myofibroblast origin. In addition, parenchymal cells directly surrounding the granulomas contained alpha 2M protein in approximately 50% of the granulomas 1 week after injection of the eggs. In situ hybridization on consecutive sections revealed that these parenchymal cells showed only background activity of alpha 2M mRNA, suggesting uptake of alpha 2M-protein by these parenchymal cells and previous activation of alpha 2M by proteases within the granuloma. The significance of the present study is that alpha 2M is produced locally at sites of inflammation and liver fibrosis, without measurable increase of serum levels of alpha 2M. Unexpectedly, alpha 2M present at the sites of the granulomas is not produced by the liver parenchymal cells, but rather by granuloma cells.

Acute-Phase Reaction↗
PubMed1982

An immunoperoxidase study of immunological factors in high immune and low resistance granulomas in leprosy.

The epithelioid cell granuloma in high resistant tuberculoid (TT) leprosy was contrasted with the pure macrophage granuloma of anergic lepromatous leprosy (LL) by evaluating various immunological factors operating in these lesions. The immunoperoxidase technique using antisera to immunoglobulin IgG, IgM, complement C3, C3d and C1q and other products of macrophage secretion, lysozyme, plasminogen, a1 antitrypsin and C-reactive protein and of Ia antigens revealed peak levels in tissues of most of these factors in both types of granuloma. The tuberculoid response was linked to low antigenic load and Ia-like antigen and the lepromatous response was secondary to a high antigenic load in the absence of Ia antigen. Complement and other mediators were found intracellularly in both tuberculoid and lepromatous granulomas, but extracellularly only in tuberculoid lesions. This may indicate local hypersensitivity in the tuberculoid granuloma. It is suggested that the mediators in LL macrophages remain bound to lipids of mycobacterial degenerations in the phagocytic vacuole. Secretory cells were differently sited in the two types of granulomas: peripheral in epithelioid cell lesions and central around capillaries over the whole lesion in pure macrophage granulomas of LL. In tuberculoid leprosy many of the central vessels in the granuloma were obliterated. C1q was found in fibroblasts. However, the marked absence of fibrosis in any of the lesions of leprosy, except following severe reactions, casts some doubt on the link which has been postulated between epithelioid cells and fibroblasts as an explanation of fibrosis in granulomas.

Complement System Proteins↗
PubMed1993

Lymphokine regulation of granuloma formation in murine schistosomiasis mansoni.

The pathology in schistosomiasis mansoni is primarily due to hepatic and intestinal granuloma formation around deposited eggs and subsequent fibrosis. The intensity of the granulomatous response is dependent on the lymphokines produced by T cells in response to soluble egg antigens (SEA). The present study examined the relationship of three inflammatory lymphokines, IL-2, IL-4, and IFN-gamma in granuloma formation during the acute stage of the murine infection. Repeated injections of anti-IL-2 or anti-IL-4 mAbs in vivo significantly diminished pulmonary granuloma formation in infected mice and demonstrated that both IL-2 and IL-4 were involved during the period of peak granuloma formation. Administration of anti-IL-2 mAb decreased IL-2, but not IL-4 production, while anti-IL-4 mAb treatment decreased both IL-2 and IL-4 production by splenic T cells. Administration of anti-IFN-gamma mAb to infected mice significantly increased pulmonary granuloma formation and increased the production of both IL-2 and IL-4 by splenic T cells. Repeated injections of graded doses of recombinant IFN-gamma given to mice between 6 and 8 weeks of infection decreased pulmonary granuloma formation as well as IL-2 and IL-4 production by splenic T cells. These data demonstrate that the regulation of lymphokines, IFN-gamma, IL-2, and IL-4, is important in influencing the intensity of granuloma formation. IL-2 and IL-4 appear to play a proinflammatory role in granuloma formation, while IFN-gamma may downregulate splenic IL-2 and IL-4 production and, more importantly, the corresponding inflammatory granuloma formation.

Animals↗
PubMed1987

Granulomatous pancreatitis--granulomas in chronic pancreatitis.

Granulomatous pancreatitis can be described only in infectious granulomas and pancreatic involvement by systemic granulomatosis. The presence of classical chronic tryptic pancreatitis in addition to individual sarcoidosis granulomas in one of our cases of sarcoidosis, shows that pancreatitis in a patient with generalized granulomatosis should not necessarily be considered granulomatous pancreatitis. A variety of foreign-body granulomas found in the pancreas may be explained by previous surgical operations, and other foreign bodies introducted iatrogenically. Occasionally, the pancreas in chronic pancreatitis contains granulomas that must be considered foreign body granulomas, although the causal foreign body cannot be identified. We believe that we can identify inspissated secretion that has passed out of the ductal system into the interstitium as the foreign body responsible. It is not possible to establish whether such iatrogenic measures as manipulations of the duct with back-up of the secretion within the ductal system, has any causative involvement in this secretion oedema. However, the absorption of the individual parenchymal secretions is impaired to such a degree that any extravasated remain "in situ" for a lengthy period. The absorption of the aqueous constituents leads to inspissation, so that it can finally be absorbed only through the formation of foreign body granulomas. The same granulogenic property in highly scarred pancreatic parenchyma is also recognizable in the abnormal degradation mode of normally absorbable Ethibloc, and in the excessive arterial and periarterial reactions following angiography. The presence of granulomas within the parenchyma of the pancreas in chronic pancreatitis, many of which have been induced by endogenous and/or exogenous foreign bodies would not lead us to refer to a granulomatous pancreatitis, since the remaining sections of the parenchyma manifest typical necroses and scar foci of chronic pancreatitis. We would characterize these granulomas by the term "granulomas in chronic pancreatitis", and differentiate this from granulomatous pancreatitis.

Chronic Disease↗
PubMed1996

Intravascular granuloma induced by intravenous inoculation of Cryptococcus neoformans.

In rodents an intravenous administration of viable Cryptococcus (C.) neoformans cells frequently resulted in attachment of intravascular cryptococcal granulomas to inner walls of the large to medium-sized veins of various organs, including the lungs, liver and spleen. In order to elucidate the pathogenesis of granulomatous changes, the cells composing the intravascular granulomas were observed by electron microscopic peroxidase (PO) cytochemistry. The granuloma composing cells could be divided into the following four types according to the pattern of endogenous peroxidase activity: exudate macrophage (M phi, type I), PO-negative M phi (type II), resident M phi (type III) and other inflammatory cells (type IV). In the intravenous granulomas of the lung, the percentages of composed cells were 39.0% for type I, 57.9% for type II, 0% for type III and 3.1% for type IV. By contrast, in the interstitial granulomas in the lung, type III M phi s, possibly derived from alveolar M phi s, played a significant role in granuloma formation. This may indicate that the intravascular granuloma is almost composed of macrophages derived from monocytes rather than alveolar macrophages. The expression of ICAM-1 on endothelia of the pulmonary veins was examined by immunoelectron microscopy. An immunogold labeling index was significantly augmented on the surface of endothelia in response to intravenous challenge of C. neoformans. The intravascular granuloma demonstrates that the monocytes develop into the granuloma-composing macrophages and suppress the cryptococcal activities even in the peripheral blood resulting in an assistance of endothelial functions.

Animals↗
PubMed2005

Subcutaneous granuloma annulare of the penis in 2 adolescents.

Granuloma annulare (GA) is a benign inflammatory disorder of unknown etiology characterized histologically by dermal palisading granulomas with central degeneration of collagen (necrobiosis). There is a rare subcutaneous clinical variant, this occurring more frequently in children than in adults and very rarely involves the penis. We describe 2 cases of penile subcutaneous GA developing in adolescent boys who to our knowledge has not previously been described in literature. Both were initially treated with surgical excision. Circumcision was performed on one of the boys, with subsequent improvement with the resolution of most of the nodules. Granuloma annulare of the penis is very rare, with only 7 cases reported to date [Narouz N, Allan PS, Wade AH. Penile granuloma annulare. Sex Transm Infect 1999;75(3):186-7; Trap R, Wiebe B. Granuloma annulare localised to the shaft of the penis. Scand J Urol Nephrol 1993;27(4):549-51; Laird SM. Granuloma annulare of the penis. Genitourin Med 1992;68(4):277; Hillman RJ, Waldron S, Walker MM, et al. Granuloma annulare of the penis. Genitourin Med 1992;68(1):47-9; Kossard S, Collins AG, Wegman A, et al. Necrobiotic granulomas localised to the penis: a possible variant of subcutaneous granuloma annulare. J Cutan Pathol 1990;17(2):101-4] and no previous reports in children or adolescents to our knowledge. All except one of the cases reported so far were of the subcutaneous (nodular) form of GA.

Adolescent↗
PubMed2001

Role of granulocyte/macrophage colony-stimulating factor in zymocel-induced hepatic granuloma formation.

To examine the role of granulocyte/macrophage colony-stimulating factor (GM-CSF) in inflammatory granuloma formation, we injected GM-CSF-deficient (GM-CSF(-/-)) mice and wild-type (GM-CSF(+/+)) mice intravenously with 2 mg of zymocel, and mice were killed at various intervals for examination. In GM-CSF(-/-) mice, we demonstrated a marked delay of zymocel-induced hepatic granuloma formation until 5 days after zymocel injection with a rapid reduction in numbers of granulomas at 10 days until their disappearance. In the early phase of granuloma formation, monocyte infiltration and differentiation of monocytes into macrophages were impaired in GM-CSF(-/-) mice compared with GM-CSF(+/+) mice. The percentages of [(3)H]thymidine-labeled macrophages at 2 days after zymocel injection were lower in the GM-CSF(-/-) mice than in the GM-CSF(+/+) mice. The DNA nick-end-labeling method demonstrated increased numbers of apoptotic cells in and around hepatic granulomas of GM-CSF(-/-) mice from 8 days after zymocel injection, and electron microscopy detected apoptotic bodies. Granuloma macrophage digestion of glucan particles and activation of macrophages were similar in the two types of mice. In situ hybridization demonstrated expression of GM-CSF mRNA in the endothelial cells, hepatocytes, and some granuloma cells in the GM-CSF(+/+) mice but not in the GM-CSF(-/-) mice. These results provide evidence that GM-CSF is important for the influx of monocytes into hepatic granulomas, for differentiation of monocytes into macrophages, and for proliferation and survival of macrophages within hepatic granulomas.

Animals↗
PubMed2004

Prevalence of hepatic granulomas in chronic hepatitis B.

An increasing frequency of hepatic granulomas, up to 10%, in chronic hepatitis C patients is reported, and their presence is considered to be a predictor of treatment success. However, there is only one prevalence study on granuloma in chronic hepatitis B, and its significance for treatment outcome is unknown. We aimed to determine the prevalence of hepatic granulomas in a larger group of chronic hepatitis B patients and to compare their presence with the response to interferon therapy. Biopsy specimens of chronic hepatitis B patients were reevaluated for the presence of hepatic granulomas. All patients with hepatic granuloma were screened for other granulomatous diseases by tuberculin skin test, chest X-ray and computed tomography, venereal disease research laboratory, Brucella agglutination tests, and exposure to hepatotoxic agents. We screened 663 cases of chronic hepatitis B. Hepatic granulomas were found in 10 cases (1.5%). The granulomas could not be ascribed to any other reason. Of the 10 patients with hepatic granulomas, 4 responded to interferon therapy, 2 dropped out, and 4 were nonresponders. We conclude that hepatic granuloma is a rare finding in chronic hepatitis B and its presence does not seem to predict the response to interferon therapy.

Adult↗
PubMed2007

An in vitro model of the leukocyte interactions associated with granuloma formation in Mycobacterium tuberculosis infection.

The principal defense of the human host against a Mycobacterium tuberculosis infection is the formation of granulomas, organized collections of activated macrophages, including epithelioid and multinucleated giant cells, surrounded by lymphocytes. This granuloma can sequester and contain the bacteria preventing active disease, and if the granuloma is maintained, these bacteria may remain latent for a person's lifetime. Secretion of a variety of chemoattractant cytokines following phagocytosis of the bacilli by the macrophage is critical not only to the formation of the granuloma but also to its maintenance. To investigate this process of early granuloma formation, we developed an in vitro model composed entirely of human cells. Combining blood lymphocytes and autologous macrophages from healthy purified protein derivative skin test-negative individuals and mycobacteria resulted in the formation of small, rounded aggregate structures. Microscopic examination found macrophage-specific CD68(+) epithelioid macrophages and small round CD3(+) lymphocytes that in complex resembled small granulomas seen in clinical pathology specimens. Acid-fast staining bacteria were observed between and possibly within the cells composing the granulomas. Supernatants from the infected cells collected at 24 and 48 h and 5 and 9 days after infection were analyzed by a multiplexed cytokine bead-based assay using the Luminex 100 and were found to contain interleukin (IL)-6, IL-8, interferon-gamma and tumor necrosis factor-alpha, cytokines known to be involved in human granuloma formation, in quantities from two-fold to 7000-fold higher than supernatants from uninfected control cells. In addition, chemotaxis assays demonstrated that the same supernatants attracted significantly more human peripheral blood mononuclear cells than those of uninfected cells (P<0.001). This model may provide insight into the earliest stages of granuloma formation in those newly infected.

Adult↗
PubMed2001

Choroidal granulomas in systemic sarcoidosis.

PURPOSE: To evaluate the clinical course, including response to therapy, of patients with macular and peripapillary choroidal granulomas secondary to systemic sarcoidosis. METHODS: This is a retrospective case study and literature review. Nine patients with choroidal granulomas were identified. Eight patients had a tissue biopsy confirming sarcoidosis; one was diagnosed from clinical history and typical gallium scan. Ocular examinations included fundus examination, fluorescein angiography, and visual field examination. Eight patients had magnetic resonance imaging (MRI) scans looking for intracranial granulomas. Treatment consisted of oral prednisone in eight patients (one with concomitant subconjunctival triamcinolone); one patient received no treatment because of good vision and granuloma in the nasal retina. Variables studied included visual acuity (VA), response of granulomas to treatment, time to recurrence, and associated anterior segment findings. RESULTS: Eight of nine patients had a solitary lesion whereas one had multifocal involvement. The granulomas ranged in size from one half to four disk diameters. Eight patients had blurry vision; one was asymptomatic. All nine patients had hilar adenopathy and/or pulmonary parenchymal disease. No patient had nonocular neurologic symptoms and in eight patients who underwent MRI examination no intracranial granulomas were detected. Of the eyes that were treated (n = 8) all had decrease in the size of the choroidal mass at an average of 4 months of treatment. Two had complete resolution. Mean follow-up was 29.2 months. At the time of initial diagnosis only one patient had an active anterior uveitis. Five of nine patients had at least one recurrence. Mean time to recurrence was 7.6 months after discontinuing oral prednisone. The VA at presentation ranged from 20/30 to 20/300. Final VA was 20/30 or better in all patients. CONCLUSIONS: Choroidal granulomas related to systemic sarcoidosis respond well to oral corticosteroids. They may recur but good vision can be maintained. They are not typically associated with concomitant iritis and also do not appear to be associated with intracranial granulomas.

Administration, Oral↗
PubMed2004

Bacterial DNA within granulomas of patients with Crohn's disease--detection by laser capture microdissection and PCR.

OBJECTIVES: We previously reported the use of laser capture microdissection (LCM) and PCR to detect the presence of Mycobacterium paratuberculosis DNA in granulomas of patients with Crohn's disease. While this does not imply a cause-effect relationship, it may influence the disease process because bacterial DNA has immunomodulatory effects. The aim of this study was to determine whether DNA from nonmycobacterial commensals, such as Escherichia coli, is also increased in the granulomas of Crohn's disease. METHODS: Archival tissue from 15 surgical cases of Crohn's disease and 10 non-Crohn's granulomatous bowel disease controls were examined. Granulomas were isolated using LCM, and the extracted DNA was examined for presence of E. coli DNA by nested PCR amplification of a 135 base-pair segment of the uidA gene. RESULTS: E. coli DNA was detected in microdissected granulomas in 12/15 Crohn's disease patients and in 1/10 non-Crohn's control granulomas (p < 0.001). Also, E. coli DNA was detected in 8/15 Crohn's full-thickness sections and in 4/10 control full-thickness sections. CONCLUSIONS: E. coli DNA may be detected more frequently in Crohn's granulomas than in other non-Crohn's bowel granulomas. This may indicate a tendency for lumenal bacteria to colonize inflamed tissue, or may be due to increased uptake of bacterial DNA by gut antigen presenting cells. In light of previous detection of M. paratuberculosis DNA in Crohn's granulomas, the nonspecific nature of the type of bacterial DNA present in granulomas is evidence against any one bacterium having a significant causative role in Crohn's disease.

Crohn Disease↗
PubMed1995

Granulomas in primary sclerosing cholangitis.

Granulomas in liver biopsy specimens from adult patients with chronic ductopenic cholestatic liver disease are a characteristic feature of primary biliary cirrhosis. However, we found a similar combination of abnormalities in 7 out of 100 native livers (7%) from patients who had orthotopic liver transplantation for primary sclerosing cholangitis. In a control group of native livers from 100 patients with primary biliary cirrhosis, the prevalence of granulomas was exactly the same, 7%. In the primary sclerosing cholangitis group, 13 addition livers showed a granulomatous epithelioid cell response, with or without foreign body type giant cells, to extravasated bile. All granulomas were noncaseating and non-necrotizing; they consisted of epithelioid cells and often contained giant cells. Perigranulomatous lymphocytic infiltrates were generally mild to moderate. The granulomas involved portal tracts, scars, and hepatic parenchyma. Biopsy experience revealed that granulomas can be found in all stages of the disease. In contradistinction to the granulomas in primary biliary cirrhosis, the granulomas in primary sclerosing cholangitis did not represent granulomatous cholangitis--that is, they were not a feature of the duct destruction. The etiology of these lesions is not clear, but in some cases we found strong morphologic evidence that granulomas may form as a response to the leakage of bile or bile components. No evidence of infection or of sarcoidosis was found. Although adverse drug responses cannot be ruled out with certainty, review of the clinical histories made that mechanism unlikely. Thus, the presence of granulomas in chronic ductopenic cholestatic liver disease is not pathognomonic for primary biliary cirrhosis and, in rare instances (on average, in 3-4% of the biopsy samples), may be a feature of primary sclerosing cholangitis.

Adult↗
PubMed1996

Intercellular adhesion molecule 1 is the major adhesion molecule expressed during schistosome granuloma formation.

Endothelial cell adhesion molecules play a key role in inflammation by initiating leukocyte trafficking. One of the most complex inflammatory responses is the formation of a cellular granuloma. Expression of adhesion molecules during granuloma formation was investigated by using the murine host reaction to schistosome parasite eggs deposited in the liver as a model. By both immunohistochemistry and lymphocyte adhesion assays, the predominant interaction identified was between intercellular adhesion molecule 1 (ICAM-1) and its cognate integrin, leukocyte functional antigen 1 (LFA-1). ICAM-1 expression on sinusoidal endothelium was induced when eggs were first deposited in the liver, peaked in parallel with granuloma size, and was downregulated with modulation of the granuloma. Polyacrylamide beads coated with soluble parasite egg antigens could induce ICAM-1 expression on endothelial cells in vitro only in the presence of tumor necrosis factor alpha, a cytokine previously shown to be key to granuloma formation. A role for ICAM-1 in recruiting lymphocytes to the hepatic granuloma was also supported by the observation that lymphocytes preincubated with anti-LFA-1 antibody did not bind to granulomas in tissue sections. While ICAM-1 is the predominant adhesion molecule in schistosome egg granuloma formation in wild-type mice, when the ICAM-1 gene is knocked out, vascular cell adhesion molecule 1 is upregulated and granuloma formation is preserved.

Animals↗
PubMed2002

Interleukin-4 receptor alpha chain and STAT6 signaling inhibit gamma interferon but not Th2 cytokine expression within schistosome granulomas.

Compared to wild-type (WT) mice, schistosome granulomas in Stat6 knockout (KO) mice lacked eosinophils and had Th1 features. Interleukin-4 (IL-4) acts through Stat6 in assisting Th2 cell development. The importance of Stat6 for Th2-cell development within schistosome granulomas had not been explored. Therefore we studied gamma interferon (IFN-gamma), IL-4, and IL-5 production in granulomas from Stat6 KO and WT mice. Dispersed granuloma cells from Stat6 KO and WT mice made similar amounts of IL-4 and IL-5. Only Stat6 KO granuloma cells released IFN-gamma. Granuloma T cells contained most of the IL-4, IL-5, and IFN-gamma mRNA and secreted these cytokines. In Stat6 KO mice, 16.6% of the granuloma cells were CD4(+). Of these, 10.7% stained for IFN-gamma and/or IL-4 by intracytoplasmic flow analysis. Few CD4(-) T cells stained positively. The IL-4-producing T cells did not stain for DX5 or with labeled alpha-GalCer CD1d tetramer, suggesting an absence of NK T cells. Thus, conventional Th cells in Stat6 KO granulomas produce IFN-gamma and Th2 cytokines. Stat6 limits IFN-gamma production but is unnecessary for Th2-cell development or localization within the granuloma.

Animals↗
PubMed2001

TGF-beta and IL-10 regulation of IFN-gamma produced in Th2-type schistosome granulomas requires IL-12.

Interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) regulate CD4+ T cell interferon-gamma (IFN-gamma) secretion in schistosome granulomas. The role of IL-12 was determined using C57BL/6 and CBA mice. C57BL/6 IL-4-/- granuloma cells were stimulated to produce IFN-gamma when cultured with IL-10 or TGF-beta neutralizing monoclonal antibody. In comparison, C57BL/6 wild-type (WT) control granuloma cells produced less IFN-gamma. IL-12, IL-18, and soluble egg antigen stimulated IFN-gamma release from C57BL/6 IL-4-/- and WT mice. IFN-gamma production in C57 IL-4-/- and WT granulomas was IL-12 dependent, because IL-12 blockade partly abrogated IFN-gamma secretion after stimulation. All granuloma cells released IL-12 (p70 and p40), and IL-12 production remained constant after anti-TGF-beta, anti-IL-10, recombinant IL-18, or antigen stimulation. C57 WT and IL-4-/- mouse granuloma cells expressed IL-12 receptor (IL-12R) beta1-subunit mRNA but little beta2 mRNA. TGF-beta or IL-10 blockade did not influence beta1 or beta2 mRNA expression. CBA mouse dispersed granuloma cells released no measurable IFN-gamma, produced IL-12 p70 and little p40, and expressed IL-12R beta2 and little beta1 mRNA. In T helper 2 (Th2) granulomas of C57BL/6 WT and IL-4-/- mice, cells produce IL-12 (for IFN-gamma production) and IL-10 and TGF-beta modulate IFN-gamma secretion via mechanisms independent of IL-12 and IL-12R mRNA regulation. We found substantial differences in control of granuloma IFN-gamma production and IL-12 circuitry in C57BL/6 and CBA mice.

Animals↗
PubMed2002

CD4+ TCR repertoire heterogeneity in Schistosoma mansoni-induced granulomas.

The hallmark of Schistosoma mansoni infection is the formation of liver granulomas around deposited ova. The initiation of granuloma formation is T cell-dependent since granulomas are not formed in their absence. We investigated whether a few T cells arrive to initiate the inflammatory lesion and subsequently expand locally, or whether a large repertoire of systemically activated T cells home to the delayed type hypersensitivity reaction induced by the ova. The TCR repertoire of single granulomas from the same liver were analyzed by PCR using Vbeta-specific primers and CDR3 analysis. Each granuloma has a very diverse TCR repertoire indicating that most of the T cells recruited to these lesions are activated systemically. At the same time, sequence analysis of individually sized CDR3 products from single granuloma indicate that a fraction of T cells expand locally at the lesion site. Using TCR transgenic mice containing a pigeon cytochrome c-specific T cell population or lymphocytic choriomeningitis virus infection tracked with lymphocytic choriomeningitis virus-specific tetramers, we demonstrated that nonspecific T cells home to the granuloma if they are activated. However, recombinase-activating gene 2(-/-) pigeon cytochrome c-specific TCR transgenic mice fail to form granulomas in response to S. mansoni ova even after T cell activation, suggesting a requirement for egg-specific T cells in the initiation of these inflammatory lesions. Understanding the mechanism of T cell recruitment into granulomas has important implications for the rational design of immunotherapies for granulomatous diseases.

Animals↗