Clinical relevance of Küttner tumour and IgG4-related dacryoadenitis and sialoadenitis.

OBJECTIVES: Küttner tumour (KT), so-called chronic sclerosing sialoadenitis, is characterised by concomitant swelling of the submandibular glands secondary to strong lymphocytic infiltration and fibrosis independent of sialolith formation. However, recent studies have indicated that some patients with KT develop high serum levels of IgG4 and infiltration of IgG4-positive plasma cells, namely IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease. The aim of this study was to clarify the clinical and pathological associations between KT and IgG4-DS. MATERIALS AND METHODS: Fifty-four patients pathologically diagnosed with KT or chronic sialoadenitis were divided into two groups according to the presence or absence of sialolith (KT-S (+) or KT-S (-), respectively). RESULTS: There were no significant differences in the clinical findings, including the mean age, sex and disease duration, between the two groups. All patients in the KT-S (+) group showed unilateral swelling without infiltration of IgG4-positive plasma cells or a history of other IgG4-related diseases (IgG4-RD), while those in the KT-S (-) group showed bilateral swelling (37.5%), strong infiltration of IgG4-positive plasma cells (87.5%) and a history of other IgG4-RD (12.5%). CONCLUSIONS: These results suggest an association between the pathogeneses of KT-S (-) and IgG4-DS, but not KT-S (+).

Overexpression of inducible nitric oxide synthase and accumulation of 8-OHdG in nasopharyngeal carcinoma.

AIMS: Nitric oxide (NO), produced by inducible NO synthase (iNOS), has been suggested to cause oxidative stress, leading to 8-hydroxydeoxyguanosine (8-OHdG) accumulation and subsequent transversion mutation of DNA. The aim was to evaluate iNOS expression and the status of oxidative stress in nasopharyngeal carcinoma (NPC). METHODS AND RESULTS: Seventy-three cases of NPC were investigated to examine the immunohistochemical expression of iNOS, 8-OHdG and latent membrane protein-1 (LMP-1) and Epstein-Barr virus-encoded small RNA (EBER) expression using in situ hybridization. iNOS mRNA expression and p53 gene mutations were also assessed. Overexpression of iNOS, LMP-1 and EBER was observed in 62 (84.9%), 28 (38.4%) and 53 (72.6%) cases respectively. p53 gene mutation was found in 10 of 73 (13.7%) cases. Immunohistochemical iNOS expression was associated with the 8-OHdG labelling index, iNOS mRNA expression and p53 gene alteration (P < 0.0001, P = 0.016 and 0.0082 respectively). CONCLUSIONS: Our present findings suggest that the expression of iNOS induces oxidative stress in NPC. Although the presence of p53 mutation was associated with iNOS overexpression, the type of acid-base change of p53 was transition, but not transversion, which suggests that the p53 gene is not the direct target of DNA damage by 8-OHdG accumulation.

Sarcoidosis of the tongue: a case report.

A case of sarcoidosis involving the tongue is described in a 48-year-old Japanese man. A definite diagnosis of sarcoidosis was made for the clinical lesion and pathological examinations. Sarcoidosis is a multisystem granulomatous disease that may affect any organ. Sarcoidosis of the tongue is particularly rare.

Renal cell carcinoma with rhabdoid features: an aggressive neoplasm.

AIMS: Only a few reports on renal cell carcinoma with rhabdoid features have been published. This study was performed to investigate the clinicopathological characteristics of renal cell carcinomas with rhabdoid features. METHODS AND RESULTS: Among 253 cases of renal cell carcinoma in adults, eight cases with rhabdoid features were detected. Rhabdoid areas ranged from 10% to 90% of each of the cases. Seven of the eight cases were TNM stage III or IV, and four of the eight cases died within 8 months of surgery. Immunohistochemically, the rhabdoid areas were positive for CAM 5.2 (4/8), AE1/AE3 (6/8), epithelial membrane antigen (6/8) and vimentin (8/8), and negative for myogenetic markers (0/8). The mean MIB-1 labelling index in the rhabdoid areas was higher than that in the definite carcinomatous areas. Ultrastructurally, perinuclear whorls of intermediate filaments were demonstrated in three of the eight cases using paraffin-embedded blocks. CONCLUSIONS: The rhabdoid areas in renal cell carcinoma have histological, immunohistochemical and ultrastructural similarities to malignant rhabdoid tumours. Renal cell carcinoma with rhabdoid features is a highly aggressive neoplasm and its malignant behaviour may be due to the high cell-proliferative activity of the rhabdoid areas. Rhabdoid features in renal cell carcinoma may represent the endpoint of clonal evolution of renal cell carcinoma (especially in clear cell type cases).

Subcellular distribution of cytokeratin and vimentin in malignant rhabdoid tumor: three-dimensional imaging with confocal laser scanning microscopy and double immunofluorescence.

Malignant rhabdoid tumor (MRT) is a highly aggressive neoplasm that mostly occurs in childhood, characterized histologically by rhabdoid cells as shown by eosinophilic intracytoplasmic inclusions. Although it is known that rhabdoid cells co-express cytokeratin (CK) and vimentin, the distribution patterns of these two kinds of intermediate filaments and structural relationship between them are still not known. We investigated the subcellular distribution of CKs 8 and 18 and vimentin in MRT cell lines (Tm87-16, STM91-01, TTC549, and TC289) using confocal laser scanning microscopy and double immunofluorescence, in addition to ultrastructural examination. Vimentin was diffusely expressed in the cytoplasm of MRT cells, focally forming a filamentous network. In contrast, CKs 8 and 18 were partially expressed in the cytoplasm of MRT cells, forming globules or a few vague agglomerates. Three-dimensional images in TC289 cells revealed distinct distribution patterns of cytokeratin and vimentin, showing agglomerates of cytokeratins within the vimentin filament network. We conclude that these globules and agglomerates of CKs 8 and 18 correspond with the characteristic ultrastructural finding, showing cytoplasmic bundles of intermediate filaments concentrated in whorled arrays.

Cytokeratin subunits of inclusion bodies in rhabdoid cells: immunohistochemical and clinicopathological study of malignant rhabdoid tumor and epithelioid sarcoma.

Extrarenal malignant rhabdoid tumor (MRT), which is recognized as being histologically similar to renal MRT, is characterized by the presence of "rhabdoid cell" (RC) and a highly aggressive biological behavior. Recently it has been proposed that "proximal variant" of epithelioid sarcoma (ES), whose morphology is similar to that of MRT, actually has a more aggressive clinical course than classical type ES. Detailed immunohistochemical analysis of cytokeratin (CK) subunits was performed in 3 cases of extrarenal MRT, 3 cases of renal MRT, and 11 cases of ES comprising 2 "proximal variants" and 9 classical types. Renal and extrarenal MRTs showed positive immunoreactivity for both CK8 and CK18. Classical type ESs were diffusely positive, not only for CK8 and CK18, but also for other cytokeratin subunits including CK4, 6, 10, 13, 16, 17, and "high-molecular-weight" CKs (CK1, 5, 10, and 14). On the other hand, proximal ES revealed limited immunohistochemical reactivity for cytokeratins, compared with classical ES. In conclusion, the inclusion bodies of RCs show immunoreactivity confined to CK8, CK18, and vimentin. Furthermore, ES has additional CK expressions, while proximal ES possesses characteristics intermediate between those of classical ES and those of external MRT.

Expression of intercellular adhesion molecules in epithelioid sarcoma and malignant rhabdoid tumor.

We clinicopathologically evaluated 31 cases of epithelioid sarcoma (ES; 25 'classical' type and six 'proximal variant' type) and six cases of malignant rhabdoid tumor (MRT; three extrarenal and three renal). We also did immunohistochemical studies on 12 classical and three proximal variant cases of ES, and six cases of MRT, to clarify the differences in biological behavior in these tumors. E-cadherin, beta-catenin and CD34 expression was evaluated. We also carried out mutational analysis of exon 3 of the beta-catenin gene by polymerase chain reaction-single-strand conformation polymorphism analysis. In ES, the 5- and 10-year survival rates were 71.1 and 55.3%, respectively. A high mitotic rate (>15/10 high-power fields) was significantly correlated with a poor overall survival rate in ES (P = 0.0248). E-cadherin expression was observed in nine cases (69.2%) of ES and in four cases (66.7%) of MRT. Most of these tumors showed aberrant E-cadherin expression. Seven cases (46.7%) of ES were positive for CD34, although none of the cases of MRT were CD34 positive. Eleven cases (73.3%) of ES were positive for beta-catenin, which was localized to the cellular membrane, whereas all of the cases of MRT were beta-catenin negative. Mutational analysis for the beta-catenin gene was done in nine cases of ES and six cases of MRT, however, genetic alteration was not found. From our results, we conclude that beta-catenin membranous expression could be a useful marker for distinguishing ES, including the proximal variant, from MRT.

Mutations of the p53 gene in malignant rhabdoid tumors of soft tissue and the kidney: immunohistochemical and DNA direct sequencing analysis.

Malignant rhabdoid tumor (MRT) is characterized by the presence of intracytoplasmic eosinophilic inclusions composed of whorls of intermediate filaments. This tumor was originally described as an entity of the abortive type of Wilms' tumor in childhood. Recently, it has been proved that these rhabdoid cells can be observed in various types of malignant tumors, including soft tissue sarcoma or carcinoma. To investigate the oncogenesis of this tumor, we examined the p53 gene alteration by means of immunohistochemical analysis and DNA direct sequencing in three cases of malignant rhabdoid tumor (MRT) of the soft tissue and three cases of MRT of the kidney. All the cases of MRT of the soft tissue and two of the cases of MRT of the kidney showed immunopositivity for p53 protein. Among them, one of the cases of MRT of the soft tissue and two of the cases of MRT of the kidney showed missense mutations of the p53 gene. These results strongly suggest that p53 gene alterations may have an important role to play in the aggressive biological behavior and poor prognosis of this tumor.

Opsonizing antibodies (IgG1) up-regulate monocyte proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and IL-6 but not anti-inflammatory cytokine IL-10 in mycobacterial antigen-stimulated monocytes-implications for pathogenesis.

Cachexia is one of the prominent features of advanced tuberculosis (TB) seen in association with increased expression of the monokine TNF-alpha. Several mycobacterial proteins, including PPD, stimulate TNF-alpha secretion from monocytes. Host factors that may play a role in cytokine expression from monocytes remain largely unknown. One such factor is the opsonizing antibodies. Monocytes have high-affinity receptors (FcgammaI and FcgammaIII) for IgG1 and IgG3 antibodies that mediate antigen uptake. We have reported selective up-regulation of IgG1 (which bind to Fcgamma receptors) in advanced TB and have recently shown the ability of PPD-specific IgG1 antibodies to augment TNF-alpha expression in PPD-stimulated monocytes. These observations have now been extended to other cytokines with semipurified fractions from secreted antigens of Mycobacterium tuberculosis (containing 30 kD and 58 kD) that were devoid of lipids, glycolipids and carbohydrates. In the presence of heat-inactivated TB plasma containing known amounts of antigen-specific IgG1 antibodies, these fractions induced significantly increased TNF-alpha, IL-6 and IL-10 secretion. Absorption of IgG1 with Protein 'A' removed the augmenting activity for TNF-alpha and IL-6 secretion from the TB plasma samples. In the case of IL-10, removal of IgG1 resulted in increased rather than decreased IL-10 secretion. These results suggest a possible pathogenic role for antibodies in TB by enhancing proinflammatory and blocking down-regulatory cytokines such as IL-10 cytokines during the chronic phase of TB.

Rhabdoid features in leiomyosarcoma of soft tissue: with special reference to aggressive behavior.

The presence of rhabdoid cells has been reported in various types of malignant neoplasms and has been determined to be a predictor of aggressive behavior of neoplasms regardless of tumor histogenesis. One hundred and thirteen cases of leiomyosarcoma, selected from 1800 soft tissue sarcomas, were reviewed on hematoxylin and eosin sections, and immunohistochemical staining when available, and seven cases with rhabdoid features were retrieved. Clinicopathologic differences were analyzed to compare between cases with rhabdoid features and those without rhabdoid features. In the seven cases with rhabdoid features, two were intra-abdominal, and the others arose in external soft tissues including muscle, subcutis, and cutis. Patient age ranged from 33 to 84 years, three were female, and four were male. Tumor size ranged from 3 to 22 cm. Clinical evidence showed no differences from those cases without rhabdoid features. Histologically, one of the abdominal cases was epithelioid leiomyosarcoma. Two of the 7 cases were better subclassified as pleomorphic leiomyosarcoma, in which rhabdoid cells are diffusely scattered. In cases other than those with pleomorphic leiomyosarcomas, foci of anaplastic areas were observed, and collections of rhabdoid cells were present in those areas. Immunohistochemical examination of the cases confirmed myogenic differentiation, and showed rhabdoid cells being positive for vimentin and desmin in the inclusion bodies, and diffusely so for muscle actin in the cytoplasm. After dividing all the cases of leiomyosarcoma by their location, prognostic analysis was performed. Leiomyosarcoma of external soft tissue with rhabdoid cells showed a tendency for poorer prognoses than cases without rhabdoid features. On the contrary, retroperitoneal cases did not. This study indicates that rhabdoid features are associated with aggressive biological behavior in leiomyosarcoma of the external soft tissue.

Decreased CD44H expression in early-stage tongue carcinoma associates with late nodal metastases following interstitial brachytherapy.

BACKGROUND: Late nodal metastases is a critical factor that worsens the prognosis of T1/T2N0 tongue cancer treated by interstitial brachytherapy. If we could better predict the patients at high risk for late nodal metastases developing before treatment, more appropriate choices of treatment could be selected. In recent studies of colon cancer, prostate cancer, and laryngeal cancer, CD44H has been postulated to be a metastasis suppressor. METHODS: On the basis of this phenomenon, we immunohistochemically evaluated the expression of CD44H in 38 cases of primary T1/T2N0 tongue cancer treated by interstitial brachytherapy. Formalin-fixed, paraffin-embedded biopsy specimens obtained before treatment were examined. RESULTS: The group that had late nodal metastases revealed a significantly lower (p =.0035) CD44H expression. CONCLUSIONS: A decreased CD44H expression may therefore be useful as a new predictor of late nodal metastases in patients with T1/T2N0 tongue carcinoma. For patients with a decreased CD44H expression, a partial glossectomy and an elective neck dissection may therefore be an appropriate treatment modality.

PPD-specific IgG1 antibody subclass upregulate tumour necrosis factor expression in PPD-stimulated monocytes: possible link with disease pathogenesis in tuberculosis.

Cachexia is a prominent feature of advanced tuberculosis, in association with increased expression of the monokine tumour necrosis factor (TNF)-alpha. Monocytes, have high affinity receptors (mannose, complement and Fc gamma1 and gamma111) which mediate antigen uptake and subsequent cytokine activation. Several mycobacterial proteins, including PPD, can stimulate TNF-alpha secretion from monocytes. However, the role of various receptors in stimulating or regulating TNF-alpha secretion is still unclear. We have previously shown selective augmentation of opsonic antibodies (IgG1 and IgG3) in tuberculosis patients with advanced pulmonary disease. We now analyse the role of opsonizing antibodies in modulating TNF-alpha expression in antigen stimulated monocytes. PPD was used as the prototypic mycobacterial antigen to stimulate monocytes from PPD skin test negative donors (n = 7) in the presence of plasma from tuberculosis patients (n = 8), containing known amounts of IgG1 and IgG3 anti-PPD antibodies. TNF-alpha secretion was enhanced in the presence of TB plasma (4/8) but not in the presence of control plasma. Using Spearman Rank analysis (two-tailed Fisher exact test), a significant correlation (rho = 0.762; P = 0. 04) was observed between IgG1 antibodies and enhancement of TNF-alpha secretion. No significant association was observed with IgG2 (rho = 0.310; P = 0.41), IgG3 (rho = 0.089; P = 0.81) or IgG4 (rho = - 0.357; P = 0.347) subclass antibodies. Absorption of IgG1 with protein 'A' removed the enhancement of TNF-alpha secretion activity from the plasma samples. Our results therefore indicate that IgG1 antibodies may enhance the chronic release of TNF-alpha in TB patients with progressive disease and, for the first time, show a direct link between disease pathogenesis and raised antibody levels.

Altered IL-1 expression and compartmentalization in monocytes from patients with AIDS stimulated with Mycobacterium avium complex.

The pathophysiologic basis for the exuberant intracellular growth of Mycobacterium avium complex (MAC) in AIDS patients is unclear but may relate to altered expression of modulatory cytokines. Interleukin (IL)-1, IL-6, and TNF-alpha expression by monocytes from AIDS patients and healthy subjects (HS) stimulated with isogeneic MAC strains (SmT, smooth-transparent, virulent; SmD, smooth-domed, avirulent) was examined. Spontaneous cytokine production was not observed in patients with AIDS. MAC strains induced less IL-1 alpha and IL-1 beta release in AIDS patients than HS (P < 0.05). The ratio of cell-associated to supernatant IL-1 alpha also was increased in AIDS patients (P = 0.03). IL-1 beta mRNA expression paralleled protein release in either group of subjects. In both HS and AIDS patients, stimulation with SmD induced more IL-1 and TNF-alpha release by monocytes compared to SmT. In AIDS patients, SmD also induced greater IL-6 release than SmT (P < 0.01). Alterations in monocyte expression and compartmentalization of the regulatory cytokines IL-1 and IL-6 may enhance bacterial replication and contribute to the pathogenesis of MAC infection in AIDS.

Induction of prostaglandin E2 by human monocytes infected with Mycobacterium avium complex--modulation of cytokine expression.

Prostanoids, including prostaglandin E2 (PGE2), suppress macrophage effector functions against Mycobacterium tuberculosis. PGE2 production by monocytes infected with Mycobacterium avium complex (MAC) and its effects on intracellular mycobacterial growth were examined. Freshly obtained monocytes from healthy subjects were stimulated with lipopolysaccharide or 10(7) organisms/mL of 4 MAC strains. PGE2 production in monocyte supernatants peaked at 48 h. Significantly higher levels of PGE2 were produced by monocytes infected with the mixed rough-smooth, flat, and transparent (SmT) morphotype strain 86m2096 (26.8 +/- 5.2 ng/mL) than by the more virulent LR114 SmT morphotype strain (2.4 +/- 0.6 ng/mL; P < .05, paired t test). When infected monocytes were incubated with 1 microgram/mL indomethacin (IM) for 2 days and then further stimulated with interferon-gamma, no effect on intracellular MAC growth was evident. IM increased tumor necrosis factor-alpha (1.7 +/- 0.4 vs. 2.3 +/- 0.3 ng/mL; P = .005, paired t test) but not interleukin-1 beta (8.2 +/- 1.7 vs. 8.7 +/- 2.1 ng/mL, P = .34) production by monocytes stimulated with lipopolysaccharide. These data suggest that MAC-induced PGE2 expression may modulate cytokine production and intracellular parasitism.

Evidence against a role for interleukin-10 in the regulation of growth of Mycobacterium avium in human monocytes.

Interleukin-10 (IL-10) inhibits intracellular Mycobacterium avium killing by cytokine-activated murine macrophages and may have a role in pathogenesis. Cytokine activities in supernatants of M. avium-infected human monocytes were maximal at 6-24 h for tumor necrosis factor (TNF)-alpha and 24-48 h for IL-10. TNF-alpha and IL-10 production increased with increasing M. avium-to-monocyte infection ratios (20:1 to 200:1). TNF-alpha production by monocytes infected with smooth, domed, and opaque organisms at 200:1 exceeded that of monocytes infected with smooth, flat, and transparent M. avium (P < .01). IL-10 induction demonstrated considerable strain-to-strain variability and did not correlate with intracellular M. avium growth. IL-10 significantly inhibited TNF-alpha, IL-1 beta, and IL-6 production by M. avium-infected monocytes. Coculturing monocytes with IL-10 after M. avium infection did not affect intracellular M. avium growth. Differential induction of TNF-alpha may be a factor in the intracellular growth of M. avium in human monocytes. IL-10, however, played no apparent role in pathogenicity in this model.

Selective induction of transforming growth factor beta in human monocytes by lipoarabinomannan of Mycobacterium tuberculosis.

The induction of macrophage-deactivating (interleukin-10 [IL-10] and transforming growth factor beta [TGF-beta] and macrophage-activating (IL-1, IL-6, and tumor necrosis factor alpha [TNF-alpha] cytokines by lipoarabinomannan (LAM) from pathogenic Mycobacterium tuberculosis Erdman and H37Rv strains (ManLAM) and nonpathogenic mycobacteria (AraLAM) in human blood monocytes was examined. ManLAM was significantly less potent in induction of TNF-alpha, IL-1, IL-6, and IL-10 protein and mRNA, whereas its ability to induce TGF-beta was similar to that of AraLAM. Differences in induction of TNF-alpha mRNA by the two LAM preparations only became apparent at late time points of culture (24 h). The induction of TNF-alpha and IL-1 by purified protein derivative of M. tuberculosis was significantly stronger than that by ManLAM. Pretreatment of monocytes with ManLAM did not, however, interfere with cytokine induction by lipopolysaccharide or AraLAM. The extensive mannosyl capping of arabinose termini of ManLAM may underlie the lack of ability to induce some cytokines (IL-1, TNF-alpha, and IL-10) and the retained ability to induce TGF-beta. The latter may have a role in shifting the cytokine milieu in favor of survival of M. tuberculosis.

Enhanced production of TGF-beta by blood monocytes from patients with active tuberculosis and presence of TGF-beta in tuberculous granulomatous lung lesions.

The expression of TGF-beta, a molecule that affects both immune responsiveness and wound healing, was examined in blood monocytes and granulomatous lesions from patients with active pulmonary tuberculosis. The spontaneous release of TGF-beta was higher in culture supernatants of monocytes from patients as compared with those of healthy subjects by an ELISA (p < 0.0005). TGF-beta activity was also confirmed in a bioassay in supernatants from patients. Next, freshly isolated monocytes from patients with tuberculosis and matched subjects were examined for TGF-beta activity. Cytosmears of monocytes were stained with an Ab against TGF-beta 1 (anti-LC) or isotype-specific Ab by using an alkaline-phosphatase anti-alkaline phosphatase method. In contrast to monocytes from healthy individuals, 60 to 70% of monocytes from patients demonstrated cytoplasmic staining for TGF-beta (n = 3). Upon hypotonic lysis, monocytes from patients with tuberculosis contained immunoreactive TGF-beta (n = 3). By Northern blot analysis, monocytes from three of seven patients with tuberculosis had increased expression of TGF-beta mRNA as compared with concurrently examined monocytes from healthy subjects. Within the granulomas of lung sections from two patients with untreated tuberculosis, TGF-beta immunoreactivity was identified in the Langhan's giant cells mainly and to a lesser extent the epithelioid cells using anti-LC Ab and the peroxidase-anti-peroxidase technique. Thus, both blood monocytes and lung granuloma macrophages from patients with active tuberculosis express TGF-beta. Excess activity of this cytokine in blood monocytes may underlie the depressed T cell responses of patients with tuberculosis. Moreover, within the infected tissues excess TGF-beta activity may interfere with anti-mycobacterial mechanisms and effective granuloma formation.

Colonial morphotype as a determinant of cytokine expression by human monocytes infected with Mycobacterium avium.

Mycobacterium avium is an intracellular pathogen that causes disseminated infection in patients with AIDS. Colonial morphotype (smooth-transparent (SmT) vs smooth-domed (SmD)) is a key determinant of virulence in mice and the capacity for replication in human monocytes. Some cytokines (IL-1 and IL-6) promote, whereas others (IFN-gamma and TNF) inhibit intracellular M. avium growth. The specific factors that determine virulence of M. avium, however, are not clear. In this study, we examined cytokine expression by human monocytes stimulated with isogeneic cloned isolates of M. avium. Monocytes were prepared from healthy donors and cultured with or without isogeneic M. avium for up to 7 days. Cytokine levels (IL-1, IL-6, and TNF-alpha) in monocyte supernatants and cell lysates were measured by immunoassay using an ELISA. The expression of cytokine mRNA by monocytes infected with M. avium also was determined by extracting total RNA and subjecting it to Northern blot analysis. Optimal cytokine release occurred at 24 h. SmD induced higher levels of the following cytokines in supernatants than SmT: IL-1 alpha (140 +/- 32 (mean +/- SE) vs 47 +/- 16 pg/ml, p < 0.02), IL-1 beta (4.0 +/- 0.9 vs 1.7 +/- 0.5 ng/ml, p < 0.01), and TNF-alpha (2725 +/- 546 vs 1464 +/- 409 pg/ml, p < 0.01). IL-6 production was comparable for both strains. SmD and SmT isolates induced comparable levels of steady state mRNA for IL-1 beta, TNF, and IL-6. Pulse-chase analysis indicated that differences in cytokine expression between SmT and SmD occurred in monocyte lysates at the earliest time point (immediately after pulse-labeling). The dissociation of the expression of specific mRNA from production of IL-1 and TNF suggests that translational capacity for the expression of certain cytokines was reduced by the more virulent SmT. Differential induction of cytokine may be a factor in the pathogenicity of M. avium strains isolated from patients with AIDS.

Inhibition of growth of Mycobacterium avium in murine and human mononuclear phagocytes by migration inhibitory factor.

Infections caused by Mycobacterium avium, the most common form of diseminated bacterial disease in AIDS patients, are difficult to treat because of their resistance to many antimycobacterial drugs. The results of the present study show that recombinant migration inhibitory factor, a 12-kDa molecule recently isolated by COS-1 cell expression screening of cDNA from a human T-cell hybridoma, has potent inhibitory activity on the growth of a panel of clinical isolates of M. avium within both bone-marrow-derived murine macrophages and cultured human blood monocytes. These cells cultured in recombinant migration inhibitory factor exhibit various signs of activation, including cell division, morphological changes such as evidence of substantial phagolysosomal fusion, and enhanced secretion of tumor necrosis factor.

Macrophages, mycobacteria and HIV: the role of cytokines in determining mycobacterial virulence and regulating viral replication.

The marriage of two scourges, one old (mycobacterial disease) and one new (HIV), has presented an enormous challenge to the medical and public health communities, and has stirred renewed interest in mechanisms for immune control of mycobacterial infection. Virulence of both M. avium and M. tuberculosis appears to be inversely related to the capacity of the microorganisms to induce production of protective cytokines in infected hosts. TNF alpha and IFN gamma are central to this process, and mycobacterial polysaccharides may be their main determinant. Despite these similarities, M. tuberculosis and M. avium cause illnesses at the polar extremes of HIV disease. Tuberculosis, occurring early in the course of HIV disease, may promote HIV replication in otherwise latently infected cells via induction of cytokines. As such, the potential exists for accelerated progression to AIDS due to the mutual synergy of these pathogens.