Corticosteroids restore the balance between locally produced Th1 and Th2 cytokines and immunoglobulin isotypes to normal in sarcoid lung.

In this study, we have investigated the balance between Th1- and Th2-like activity in the lungs in sarcoidosis and have determined the effect of corticosteroid treatment on this. Twenty-one patients with acute untreated sarcoidosis were investigated by bronchoalveolar lavage (BAL) and compared with 11 normal volunteers. Sixteen of the sarcoid patients required corticosteroid therapy and seven of these were reinvestigated after 2-3 months' treatment. In order to assess Th1- and Th2-like activity in the lungs, IgG subclasses and IgE were measured in BAL fluid and serum, and IL-2, IL-4 and interferon-gamma (IFN-gamma) in BAL. In patients with untreated sarcoidosis, albumin-corrected BAL/serum ratios for IgG4 and IgE were significantly reduced (IgG4, 1.04 +/- 0.18 (mean +/- s.e.m.); IgE 9.58 +/- 3.11) compared with those in normal controls (IgG4 5.3 +/- 0.72, P < 0.001; IgE 67.7 +/- 28.9, P < 0.01). Estimates of actual levels of immunoglobulins produced in the lungs were also made and showed extremely high levels of total IgG in sarcoid patients (39.56 +/- 8.2 mg/l) compared with controls (1.17 +/- 0.5 mg/l, P < 0.001). Although there was no difference between the groups in amount of IgG4 locally produced, the proportion of total IgG which was IgG4 was greatly reduced in those with sarcoidosis (1.6 +/- 0.4% compared with 38.5 +/- 3.2%; P < 0.001). Lavage levels of IL-4 were also reduced in sarcoid patients (IL-4 2.103 +/- 0.21 pg/ml) compared with those in normals (IL-4 6.8 +/- 1.05; P < 0.001). Levels of IL-2 were lower (7.63 +/- 0.51 pg/ml compared with 9.4 +/- 0.95 pg/ml), but this difference was not significant. IFN-gamma, however, could not be detected above 0.4 pg/ml in any of the normal lavage fluid, but was detectable in 12/21 patients with sarcoidosis (chi2 = 7.74; P < 0.001). These changes reverted towards normal on treatment with oral corticosteroids. The mean albumin-corrected BAL/serum ratio for IgG4 before treatment was 0.88 +/- 0.33 compared with 5.5 +/- 2.1 (P < 0.05) on treatment, and for IgE before treatment 9.52 +/- 2.15 compared with 50.8 +/- 17.9 (P < 0.05) on treatment. Total IgG produced in the lung fell from 26.16 +/- 7.9 to 6.12 +/- 2.4 mg/l (P < 0.001) on treatment, and the proportion of IgG4 locally produced rose from 2.3 + 0.8% to 23.9 +/- 6.1% (P < 0.01). The mean level of IL-4 in lavage before treatment was 2.53 +/- 0.34 pg/ml compared with 4.7 +/- 0.34 (P < 0.001) on treatment. Levels of IL-2 also rose significantly on treatment from 8.74 +/- 0.95 pg/ml before to 14.44 +/- 1.38 pg/ml (P < 0.001) on treatment. Levels of IFN-gamma fell from 1.65 +/- 0.43 pg/ml before treatment to undetectable levels in all patients (P < 0.001) on treatment. These results demonstrate an imbalance between Th1- and Th2-like activity in the lungs in sarcoidosis, with suppression of Th2 and increase in Th1. Corticosteroid therapy restores the normal balance between Th1 and Th2 cytokines and immunoglobulins in the lungs, suggesting an effect on local immune regulation.

T-cell cytokines may control the balance of functionally distinct macrophage populations.

As monocytes differentiate into mature macrophages, subsets emerge that exhibit stimulatory, suppressive or phagocytic potential. These functionally distinct subsets can be discriminated using monoclonal antibodies RFD1 and RFD7. As examples of all these subsets have been repeatedly identified within the macrophage pool in a variety of organs the overall functional capacity of this pool will depend on the relative balance of these subpopulations. This study investigates whether this balance present in mature macrophage populations can be regulated by the local influence of T-cell-derived cytokines. The dose-dependent effect of cytokines interferon-gamma (IFN-gamma), interleukins (IL) IL-2, IL-4 and IL-10 on the phenotype and function of monocyte-derived macrophages was determined. Subsets of mature cells were quantified by identifying RFD1- RFD7- stimulatory cells (D1+); RFD1- RFD7+ phagocytes (D7+) and RFD1+ RFD7+ suppressive cells (D1 D7+). IFN-gamma and IL-4 increased the relative proportions of D1+ stimulatory cells and upregulated HLA-DR expression. IFN-gamma also increased the capacity of the mature macrophage pool to stimulate T-cell proliferation. IL-10 reduced the proportions of D1+ stimulatory cells while promoting the differentiation of D7+ phagocytes and D1/D7+ suppressive cells. IL-10 induced changes also reduced the functional capacity of the mature populations to stimulate T cells in auto and allogenic mixed lymphocyte reactions (MLR). IL-2 had no effect on differentiation of monocytes. Thus IL-4 and IFN-gamma are seen to induce the development of stimulatory macrophages while IL-10 promotes differentiation of monocytes to mature phagocytes and suppressive macrophages. It is concluded that mature macrophage phenotype is 'plastic' and under the control of T-cell-derived mediators. Furthermore, within the differentiating monocytes, phenotypic change appears to carry with it functional change, thus retaining the relationship between antigen expression and activity in the mature macrophage populations.