Giant cell formation in sarcoidosis: cell fusion or proliferation with non-division?

Abstract

Granulomas are inflammatory reactions featuring macrophages, epithelioid, T and multi-nucleated giant cells (MGC). Giant cells are present in a number of granulomatous reactions, but little is known about their formation and function, especially in man. We studied MGC in the granulomatous disorder sarcoidosis. In situ labelling of lymph nodes by means of [(3)H]-thymidine showed that proliferation and non-division of epithelioid cells leading towards giant cells was not observed in these granulomas. However, [(3)H]-uridine incorporation showed MGC with labelled as well as unlabelled nuclei in the same cell, pointing to a process of fusion of epithelioid cells to form giant cells. Apoptotic bodies were incidentally found in granulomas. A novel finding was that such bodies were statistically more often found in the close vicinity of MGC, but not within these cells. These apoptotic cells appeared to be CD4(+) lymphocytes or histiocytes. CD44 and CCR-5 involved in the process of fusion were expressed in MGC. In conclusion, MGC in sarcoidosis derive by cell fusion rather than by proliferation and non-division, and seem to play an active role in the induction of apoptosis in granulomas.

Fig. 1

Granuloma in which an apoptotic body (←) is seen in the vicinity of a Langhans type giant cell (haematoxylin and eosin staining, ×400).

Fig. 2

Regression analysis of Langans type (LH)- against foreign body type (FB)-multi-nucleated giant cells (MGC). % Langhans type = [the number of LH-MGC/total number of multinucleated giant cells (MGC)]× 100; % foreign body type = (the number of FB-MGC/total number of MGC) × 100.

Fig. 3

(a) Light microscopic appearance of a sarcoidosis lymph node section labelled with [³H]-thymidine. In the epithelioid cell granuloma two radio-labelled mononuclear cells (←) are seen, while a Langhans giant cell showed no radio-labelling [haematoxylin and eosin staining (H&E), ×400]. (b) In a granuloma section labelled with [³H]-uridine, a foreign body type giant cell is clearly visible in which some nuclei are radio-labelled (←) (H&E staining, ×1000).

Fig. 4

(a) Giant cell stained for Fas-ligand (Fas-L). Centre of the cell with no staining while the rim of the cell is Fas-L positive. Around the multi-nucleated giant cells (MGC) some Fas-L⁺ staining is also visible (Fas-L immunostaining, ×630). (b) CCR-5⁺ sarcoid granulomas within two CCR-5-negative FB-MGC (CCR-5 immunostaining, ×200). (c) Cell membrane of MGC stained positively for CD44. A CD44-negative apoptotic body is also visible (CD44 immunostaining, ×220). (d) LH-MGC in close contact with an apoptotic body (←). Inset (2·4×): Co-expression of caspase-3 (brown) and CD4 (blue) of this body is clearly visible (caspase-3/CD4 immuno-double-staining, ×400).