CD48 on blood leukocytes and in serum of asthma patients varies with severity.

BACKGROUND: CD48 is a membrane receptor (mCD48) on eosinophils and mast cells and exists in a soluble form (sCD48). CD48 has a pivotal role in murine asthma and in the proinflammatory interactions of mast cells with eosinophils via its ligand CD244. Thus, CD48 might be important in human asthma. METHODS: Therefore, two separate cohorts (IL and UK) comprising mild, moderate, and severe asthma and healthy volunteers were evaluated for blood leukocyte mCD48 expression and sCD48 in serum. Asthmatic bronchial biopsies were immunostained for CD48. sCD48 effect on CD244-dependent eosinophil activation was evaluated. RESULTS: Eosinophil mCD48 expression was significantly elevated in moderate while downregulated in severe asthma. mCD48 expression on B, T, and NK cells and monocytes in severe asthma was significantly increased. sCD48 levels were significantly higher in mild while reduced in severe asthma. sCD48 optimal cutoff values for differentiating asthma from health were identified as >1482 pg/ml (IL) and >1619 pg/ml (UK). In asthmatic bronchial biopsies, mCD48 was expressed predominantly by eosinophils. sCD48 inhibited anti-CD244-induced eosinophil activation. CONCLUSIONS: mCD48 and sCD48 are differentially expressed in the peripheral blood of asthma patients of varying severity. sCD48 inhibits CD244-mediated eosinophil activation. These findings suggest that CD48 may play an important role in human asthma.

Mast cell phenotype, TNFα expression and degranulation status in non-small cell lung cancer.

Mast cell infiltration of tumour islets represents a survival advantage in non-small cell lung cancer (NSCLC). The phenotype and activation status of these mast cells is unknown. We investigated the mast cell phenotype in terms of protease content (tryptase-only [MCT], tryptase + chymase [MCTC]) and tumour necrosis factor-alpha (TNFα) expression, and extent of degranulation, in NSCLC tumour stroma and islets. Surgically resected tumours from 24 patients with extended survival (ES; mean survival 86.5 months) were compared with 25 patients with poor survival (PS; mean survival 8.0 months) by immunohistochemistry. Both MCT and MCTC in tumour islets were higher in ES (20.0 and 5.6 cells/mm2 respectively) compared to PS patients (0.0 cells/mm2) (p < 0.0001). Both phenotypes expressed TNFα in the islets and stroma. In ES 44% of MCT and 37% of MCTC expressed TNFα in the tumour islets. MCT in the ES stroma were more degranulated than in those with PS (median degranulation index = 2.24 versus 1.73 respectively) (p = 0.0022), and ES islet mast cells (2.24 compared to 1.71, p < 0.0001). Since both MCT and MCTC infiltrating tumour islets in ES NSCLC patients express TNFα, the cytotoxic activity of this cytokine may confer improved survival in these patients. Manipulating mast cell microlocalisation and functional responses in NSCLC may offer a novel approach to the treatment of this disease.

Physical interactions between mast cells and eosinophils: a novel mechanism enhancing eosinophil survival in vitro.

BACKGROUND: Mast cells (MCs) and eosinophils (Eos) are the key effector cells of the allergic reaction. Although classically associated with different stages of the response, the cells co-exist in the inflamed tissue in the late and chronic phases in high numbers and are likely to cross-talk. While some mediators of MCs are known to affect Eos biology and vice versa, paracrine and physical interplay between the two cells has not been described yet. We aimed to investigate whether intercellular MC-Eos communication could take place in the allergic response and exert functional bidirectional changes on the cells. METHODS: Tissue sections from various allergic disorders were specifically stained for both cells. Human cord blood-derived MCs and peripheral blood Eos, co-cultured under different conditions, were studied by advanced microscopy and flow cytometry. RESULTS: Several co-localized MC-Eos pairs were detected in human nasal polyps and asthmatic bronchi, as well in mouse atopic dermatitis. In vitro, MCs and Eos formed stable conjugates at high rates, with clear membrane contact. In the presence of MCs, Eos were significantly more viable under several co-culture conditions and at both IgE-activated and steroid-inhibited settings. MC regulation of Eos survival required communication through soluble mediators but was even more dependent on physical cell-cell contact. CONCLUSIONS: Our findings provide the first evidence for a complex network of paracrine and membrane interactions between MCs and Eos. The prosurvival phenotype induced by this MC-Eos interplay may be critical for sustaining chronic allergic inflammation.

Macrophages within NSCLC tumour islets are predominantly of a cytotoxic M1 phenotype associated with extended survival.

There is a marked survival advantage for patients with nonsmall cell lung cancer (NSCLC) expressing high numbers of macrophages in their tumour islets. The primary aim of the present study was to determine the immunological phenotype of NSCLC-associated macrophages. CD68(+) macrophages expressing markers of a cytotoxic M1 phenotype or a noncytotoxic M2 phenotype were identified in the islets and stroma of surgically resected tumours from 20 patients with extended survival (median 92.7 months) and 20 with poor survival (median 7.7 months), using immunohistochemistry. The islet density of both M1 and M2 macrophages was markedly increased in extended compared with poor survival patients. In the extended survival group, M1 islet density was significantly increased compared with M2 density, 70% of islet macrophages were positive for M1 markers versus 38% for M2, and the islet:stromal ratio of M1 macrophages was markedly increased compared with M2. The 5-yr survival for patients with above and below median expression of M1 macrophages in the islets was >75 and <5%, respectively. Macrophages infiltrating the tumour islets in nonsmall cell lung cancer were predominantly of the M1 phenotype in patients with extended survival. The survival advantage conferred by islet macrophage infiltration may be related to their cytotoxic antitumour activity.