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Bronchoalveolar lavage is an invaluable means of accurately evaluating the inflammatory and immune processes in the human lung. Sarcoidosis is a multisystem disorder characterized by heightened immune processes at sites of disease activity. The lung is most commonly involved. Although granulomas are charactaristic pathologic features of this disease, a number of studies suggest that the initial lesion in the lung is a T-cell alveolitis (an accumulation of T-cellls in the lung). There are a lot of findings that show abnormal functions of alveolar macrophages obtained by bronchoalveolar lavage in the release of various monokines and arachidonic acid metabolites and metabolize oxygen. In this review, the abnormalities of alveolar macrophages implicated in pulmonary T-cell alveolitis and fibrosis are reviewed and their potential roles in the lungs are discussed., 間質性肺疾患の肺病変の検討は気管支肺胞洗浄法の開発により病巣よりの免疫担当細胞を容易に得られるようになり近年急速に発展した。一方では分子生物学の進歩はこれらの細胞の産生する各種サイトカイン、代謝産物の分離と、その作用機序を明らかにした。そしてサルコイドーシスの肺病巣の免疫担当細胞においても細胞表面抗原の発現異常、外来抗原の貪食・消化の異常、サイトカインの産生・放出の異常、活性酸素の産生・放出の異常、アラキドン酸代謝の異常時、多岐にわたって多くの成績が報告されている。本論文では免疫担当細胞のうち、特に肺マイクロファージの機能異常とサ症の初期病変と考えられる肺胞へのリンパ球の異常集積、alveolitis形成および胞隔の線維化との関与について検討をおこない、本症の発症機序について考察を加えた。

Muramyl dipeptide (MDP) is a minimal structure necessory for various biological activities of bacterial cell wall peptidoglycans. MDP induces in guinea pigs the granulomas containing macrophages and epithelioid cells differentiated from macrophages. This suggests that MDP differentiates macrophages into epithelioid cells. This study was undertaken to gain an insight into the mechanism of activation and differentiation of macrophage induced by MDP. For this purpose, the effect of MDP on macrophage DNA synthesis was studied in view of the generally accepted fact that DNA synthesis is decreased when cells differentiate. Guinea pig peritoneal exudate macrophages actively incorporated ^3H-thymidine into trichloroacetic acidin soluble fraction in vitro without macrophage proliferating factors. The incorporation of ^3H-Thymidine was almost completely inhibited by aphidicolin, an inhibitor of DNA polymerase-α and an autoradiograph showed heavy labeling in nuclei of about 200% of macrophage populations. These results indicate that the observed thymidine incorporation reflected a DNA synthesis for replication. When macrophage was stimulated by MDP, the ^3H-Thymidine incorporation was markedly suppressed while ^C-glucosamine incorporation and production of monokine were increased. The suppression of ^3H-thymidine incorporation by MDP was not due to the decrease in thymidine transport through the cell membrane. An autoradiograph revealed that MDP decreased markedly the number of macrophages whose nuclei were labeled by ^3H-Thymidine. These resuts indicate that suppresion of ^3H-thymidine incorporation by MDP was due to a true inhibition of DNA synthesis. Among the three tested enzymes involved in DNA synthesis, only thymidine kinase activity decreased progressively in parallel with the decline in ^3H-Thymidine incorporation. Cyclic AMP and PGE_2,both of which are increased in amount in macrophage by MDP stimulation, suppressed DNA synthesis of macrophage. Phorbol myristic acid (PMA), ionomycin and debutyryl cyclic GMP failed to affect the ^3H-Thymidine incorporation. Inhibitors of cyclic AMP-dependent protein kinase considerably reduced the suppressive effect on ^3H-Thymidine incorporation. These results suggest that cyclic AMP or cyclic AMP-dependent protein kinase might be play an important role in suppression of ^3H-Thymidine incorporation. Concerning various analogs of MDP, a close correlation was observed among the capacities of activating macrophages, suppressing DNA synthesis and inducing epithelioid granuloma formation. These findings suggest that suppression of DNA synthesis by MDP may be induced by macrophage activation and represent an initial event during the differentiation of macrophage for epithelioid cells.

Toxic shock syndrome(TSS)は,ブドウ球菌外毒素産生が誘因となり発症,高熱や多臓器障害を特徴とする重篤な疾患である.ブドウ球菌外毒素はスーパー抗原としてT細胞に作用,活性化,さらに種々のサイトカイン産生を誘導,これらのサイトカインがTSSの病態形成に重要な役割を果たすことが示唆されている.われわれは白血病の寛解導入中にTSSを発症した1例を経験し,炎症性サイトカインの動態について検討した.患児は化学療法導入後間もなくから,発熱,意識障害,肝腎機能低下,循環不全,全身紅斑を認め,回復期に特徴的な皮膚剥脱が観察された.急性期に炎症性サイトカインであるTNF-α, IL-1β, IL-6の高値に加え, IFN-γの著増が認められ,これらの値は症状の改善とともに急速に正常化した. TSSの発症には炎症性サイトカイン,特にIFN-γをはじめとするT細胞由来サイトカインの過剰産生が重要な役割を果たしていることが示された. Toxic shock syndrome (TSS) is an acute, multisystem illness characterized by high fever, circulatory failure, desquamative skin lesion and multiple organ damage. It is usually associated with a focus of infection with staphylococcus aureus and its exotoxins have been considered to be the major contributing agents in the pathogenesis of TSS. Recently, it has become clear that most of the staphylococcal exotoxins acts as superantigens, activating a large fraction of T cells at the same time. The production of various cytokines induced by these toxins have been implicated in the development of TSS. We recently experienced a case of TSS in a 15-year-old boy. The characteristic features of the illness developed shortly after the introduction of anti-leukemic chemotherapy for acute myelocytic leukemia. Rapid deterioration of the clinical conditions was associated with high fever, circulatory failure, and evidence of liver damage. Oliguria and increase of BUN were also evident. Generalized erythematous skin lesion appeared at the peak of the illness. The patient's clinical condition recovered after short period of supportive therapy and the characteristic desquamation appeared during the convalescence. Staphylococcus aureus was recovered from the swollen lymph node in the neck. Antibody titers against TSST-1 and SEB remained high during the illness and did not show any appreciable change. There was no expansion or deletion of T cells with a particular Vβ repertoire during the course of illness. Although no specific toxin was found to be responsible, the characteristic clinical pictures were diagnostic of TSS. Patient's altered defense and the chemotherapy might have changed the growth and toxin producing profiles of the preexisting bacteria. Serum cytokine levels were measured during the acute stage of the illness. Not only monokine like IL-1β, TNFα and IL-6, but also IFNγ levels were markedly elevated during the acute stage of the illness. These cytokine levels returned quickly to normal values within a few days. The data indicated that the excessive production of the T cell derived cytokines, such as IL-2 and IFN-γ, play major roles in the development of the characteristic clinical picture of TSS.