Types Of Multinucleated Giant Cells Research Articles

Multinucleation resets human macrophages for specialized functions at the expense of their identity.

Macrophages undergo plasma membrane fusion and cell multinucleation to form multinucleated giant cells (MGCs) such as osteoclasts in bone, Langhans giant cells (LGCs) as part of granulomas or foreign-body giant cells (FBGCs) in reaction to exogenous material. How multinucleation per se contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrate comparative transcriptomics with functional assays in purified mature mononuclear and multinucleated human osteoclasts, LGCs and FBGCs. Strikingly, in all three types of MGCs, multinucleation causes a pronounced downregulation of macrophage identity. We show enhanced lysosome-mediated intracellular iron homeostasis promoting MGC formation. The transition from mononuclear to multinuclear state is accompanied by cell specialization specific to each polykaryon. Enhanced phagocytic and mitochondrial function associate with FBGCs and osteoclasts, respectively. Moreover, human LGCs preferentially express B7-H3 (CD276) and can form granuloma-like clusters invitro, suggesting that their multinucleation potentiates T cell activation. These findings demonstrate how cell-cell fusion and multinucleation reset human macrophage identity as part ofan advanced maturation step that confers MGC-specific functionality.

Multinucleated Giant Cells: Current Insights in Phenotype, Biological Activities, and Mechanism of Formation.

Monocytes and macrophages are innate immune cells with diverse functions ranging from phagocytosis of microorganisms to forming a bridge with the adaptive immune system. A lesser-known attribute of macrophages is their ability to fuse with each other to form multinucleated giant cells. Based on their morphology and functional characteristics, there are in general three types of multinucleated giant cells including osteoclasts, foreign body giant cells and Langhans giant cells. Osteoclasts are bone resorbing cells and under physiological conditions they participate in bone remodeling. However, under pathological conditions such as rheumatoid arthritis and osteoporosis, osteoclasts are responsible for bone destruction and bone loss. Foreign body giant cells and Langhans giant cells appear only under pathological conditions. While foreign body giant cells are found in immune reactions against foreign material, including implants, Langhans giant cells are associated with granulomas in infectious and non-infectious diseases. The functionality and fusion mechanism of osteoclasts are being elucidated, however, our knowledge on the functions of foreign body giant cells and Langhans giant cells is limited. In this review, we describe and compare the phenotypic aspects, biological and functional activities of the three types of multinucleated giant cells. Furthermore, we provide an overview of the multinucleation process and highlight key molecules in the different phases of macrophage fusion.

Monocyte Subsets Have Distinct Patterns of Tetraspanin Expression and Different Capacities to Form Multinucleate Giant Cells.

Monocytes are able to undergo homotypic fusion to produce different types of multinucleated giant cells, such as Langhans giant cells in response to M. tuberculosis infection or foreign body giant cells in response to implanted biomaterials. Monocyte fusion is highly coordinated and complex, with various soluble, intracellular, and cell-surface components mediating different stages of the process. Tetraspanins, such as CD9, CD63, and CD81, are known to be involved in cell:cell fusion and have been suggested to play a role in regulating homotypic monocyte fusion. However, peripheral human monocytes are not homogenous: they exist as a heterogeneous population consisting of three subsets, classical (CD14++CD16−), intermediate (CD14++CD16+), and non-classical (CD14+CD16+), at steady state. During infection with mycobacteria, the circulating populations of intermediate and non-classical monocytes increase, suggesting they may play a role in the disease outcome. Human monocytes were separated into subsets and then induced to fuse using concanavalin A. The intermediate monocytes were able to fuse faster and form significantly larger giant cells than the other subsets. When antibodies targeting tetraspanins were added, the intermediate monocytes responded to anti-CD63 by forming smaller giant cells, suggesting an involvement of tetraspanins in fusion for at least this subset. However, the expression of fusion-associated tetraspanins on monocyte subsets did not correlate with the extent of fusion or with the inhibition by tetraspanin antibody. We also identified a CD9High and a CD9Low monocyte population within the classical subset. The CD9High classical monocytes expressed higher levels of tetraspanin CD151 compared to CD9Low classical monocytes but the CD9High classical subset did not exhibit greater potential to fuse and the role of these cells in immunity remains unknown. With the exception of dendrocyte-expressed seven transmembrane protein, which was expressed at higher levels on the intermediate monocyte subset, the expression of fusion-related proteins between the subsets did not clearly correlate with their ability to fuse. We also did not observe any clear correlation between giant cell formation and the expression of pro-inflammatory or fusogenic cytokines. Although tetraspanin expression appears to be important for the fusion of intermediate monocytes, the control of multinucleate giant cell formation remains obscure.

Histological evaluation of the possible transformation of peripheral giant cell granuloma and peripheral ossifying fibroma: A preliminary study.

The objective of this study is to describe shared morphological features of peripheral giant cell granuloma (PGCG) and peripheral ossifying fibroma (POF) in detail and discuss the possible relationship between them. Ten intermediate cases with features resembling to both POF and PGCG were selected and type 3 and 1 collagen immunostainings were performed for evaluation of the connective tissue maturation. Immunohistochemical staining percentage (SP) for stromal cells in the slides of POF and PGCG counterparts of intermediate lesions was scored as 1 when the SP was above 10%, 2 when the SP was above 25%, 3 when the SP was above 50% and 4 when the SP was above 75%. Staining intensity (SI) of immunuhistochemical staining was graded and scored as 1 - mild, 2 - moderate, and 3 - severe. An immunoreactivity score was calculated by multiplying SP and SI. All intermediate lesions comprised osteoclast type multinucleated giant cells and partly mineralized hard tissue component. Parts of intermediate lesions resembling POF showed higher type 1 collagen immunoreactivity compared to the PGCG counterparts of intermediate lesions (P < 0.05). PGCG counterparts showed higher type 3 collagen immunoreactivity compared to the POF counterparts of the intermediate lesions (P < 0.05). POF may be a later stage lesion with morphologically more mature components. A possible transformation may be considered for these two lesions.

Pathophysiology of Giant Cell Formation in Giant Cell Tumor and Lesions: A Review

This review is intended to provide insight into the current state of understanding regarding the molecular and cellular mechanisms underlying the formation and function of various types of multinucleated giant cells. Present article mainly focus on various factors such as e.g. GCP/F, GM-CSF, Meltrin, MIP-1 that contribute to giant cell formation and function. This review focuses on recent efforts to develop a better understanding of the molecular and cellular biology of multinucleated giant cell formation and function.

Nonepithelial skin tumors with multinucleated giant cells

Recognition of the different types of multinucleated giant cells in neoplastic and pseudotumoral lesions of the skin may be helpful in the differential diagnosis of these tumors. In this review, we will analyze the different types of multinucleated giant cells that can be found in nonepithelial cutaneous tumors and, more importantly, the clinicopathological context in which they are found. Touton giant cells are typically present in juvenile xanthogranuloma, necrobiotic xanthogranuloma, and some subtypes of xanthomas. Giant cells with a ground glass appearance are typically present in the solitary reticulohistiocytoma and multicentric reticulohistiocytosis. Osteoclast-like cells are found in giant cell tumors (GCT) of soft parts, plexiform fibrohistiocytic tumor, and atypical fibroxanthoma. Floret-like cells are present in giant cell fibroblastoma, pleomorphic lipoma, multinucleate cell angiohistiocytoma, and giant cell collagenoma.

Sarcoidosis of Tongue

Sarcoidosis is a rare, acquired systemic granulomatous disease, with unknown etiology affecting multiple organs and tissue. A 40-year-old male with the previous history of pulmonary sarcoidosis was screened with the clinical presentation of erythematous and nodular lesion over the tongue. Incisional biopsies from the tongue revealed the presence of ‘noncaseating epithelioid cell granulomas with Langerhans type multinucleated giant cells’ histopathologically.The 24 hours urine calcium examination revealed increased calcium level of 538 mg suggestive of oral sarcoidosis. The patient is periodically reviewed to study the course of the disease and identify the systemic progression at the illness.

Xanthogranuloma in Adolescence

Xanthogranuloma in Adolescence

Localized persistent pulmonary interstitial emphysema

A 3-week-old premature female infant was referred to our institution with progressively worsening respiratory distress. She was born at 29 weeks’ gestational age with radiologic evidence of mild respiratory distress syndrome. She required only minimal supplemental oxygen until her third week of life, when she developed worsening respiratory distress requiring mechanical ventilation. A new chest radiograph (Fig. 1) demonstrated hyperinflation of the left hemithorax with coarse reticular markings throughout the left lung. Computed tomography (CT; Fig. 2) revealed innumerable cystic spaces of varying sizes occupying the entirety of the left upper lobe, with no appreciable normal lung parenchyma interposed. She failed to wean from mechanical ventilation and underwent an urgent left thoracotomy. The entire upper lobe was grossly involved with cystic lung pathology (Fig. 3). This was treated by an uncomplicated left upper lobectomy, and the patient was weaned from mechanical ventilation over the next 3 days. The histopathology (Fig. 4) demonstrated cyst-like cavities lined by an irregular layer of cells within the lung parenchyma. These cells were mostly mononuclear admixed with foreign body–type multinucleated giant cells. The cysts were interspersed with essentially normal-appearing pulmonary tissue. Occasional air spaces were questionably dilated, particularly at the periphery of the lung beneath the pleural surface. However, widespread emphysematous changes were not apparent; neither was there any significant intraalveolar or interstitial inflammatory cell infiltrate. These findings were diagnosed as localized persistent pulmonary interstitial em

ヒト末梢血単球由来の多核巨細胞

Multinucleated giant cells (MGC) are characteristic cells in granulomatous disorders such as sarcoidosis and leprosy. There are two types of MGC; foreign body-type and Langhans-type cells. The exact mechanisms of the formation and the functional significance of MGC are not determined, although their morphological features are well understood. MGC are also formed in vitro from peripheral blood mononuclear cells by stimulation with cytokines and lectins. Particularly IFN-gamma is considered to play a pivotal role in monocyte fusion. IL-3, IL-4, IL-13, and GM-CSF are other reported cytokines involved in MGC formation. In addition to such inflammatory mediators, a factor derived from the pathogens of granulomatous disorders may be necessary for MGC formation. Muramyl dipeptide, a peptidoglycan portion of bacterial cell walls, is one of the candidates and can preferentially induce Langhans-type cells in in vitro MGC formation system. Although the exact mechanisms of in vitro MGC formation remains unknown, cell surface molecules such as P2X7 receptor, integrins, CD98, and macrophage fusion protein are considered to be involved in fusion process. Monocytes of sarcoidosis patients expressed higher levels of P2X7 and had a higher ability to induce MGC than those of healthy controls. Effective agents for sarcoidosis such as tranilast, alloprinol, and captopril inhibited in vitro MGC formation, suggesting their therapeutic effects through the direct effects on monocytes. Thus, an in vitro MGC formation model would be a useful tool to understand the relevance of MGC in granulomatous disorders.

Syncytial giant cell component. Review of 55 renal cell carcinomas.

Different types of multinucleated giant cells (MGC) have been documented in tumors with osteoclast-like appearance, with trophoblastic differentiation or as tumoral malignant giant cells. A new variety of MGC has been described in renal cell carcinoma. In order to study the frequency, nature and significance of this cellular type, we have reviewed our files. To assess the presence, nature and significance of these MGC in renal cell carcinomas and associated histologic subtype. To review all malignant renal tumors diagnosed in the last 5 years in our hospital and to carry out a morphologic and immunohistochemical study in renal cell carcinomas with syncytial type MGC. 55 renal cell carcinomas were reviewed. Clear cell (conventional) renal cell carcinoma was the most common type encountered (40 cases); two of these cases showed syncytial type MGC and low grade malignancy. Microscopically the MGC contained from 5 to 40 nuclei. Immunohistochemically, mononucleated and multinucleated cells were positive for cytokeratin CAM 5.2, cytokeratin AE1/AE3 and weakly positive for vimentin. Histiocytic, muscular, neural markers, beta-HCG and alpha-fetoprotein were negative. The presence of syncytial type MGC in renal cell carcinomas is an exceptional event. Among 55 renal cell carcinomas we found two cases, both of which were of clear cell subtype and low grade malignancy. The MGC proved positive for epithelial markers and probably are the result of mononucleated tumoral cell fusion. We are unaware of the impact of this MGC in the outcome of patients; such cells appear in low grade carcinomas and do not seem to be of dismal prognosis.

Multinucleated Giant Cells in Bronchoalveolar Lavage

To determine the frequency, morphology and possible diagnostic significance of multinucleated giant cells (MGC) in bronchoalveolar lavage (BAL). Retrospectively we examined 671 BAL specimens. Enlarged cells having > or = 10 nuclei were defined as MGC. Cytomorphologic features were described. BAL specimens containing MGC were grouped according to clinicohistologic diagnosis into sarcoidosis, asbestosis, other interstitial lung diseases and different chronic, noninterstitial lung diseases. MGC were present in 10.7% of BAL specimens and occurred in low numbers. MGC were classified into Langhans' or foreign-body-type MGC (LF-MGC), alveolar macrophage-like MGC (AM-MGC) and nonspecific MGC (NS-MGC). LF-MGC were found most often in patients with sarcoidosis. AM-MGC were found in all groups of patients. NS-MGC were found most often in patients with asbestosis and other interstital lung diseases. MGC in BAL are not encountered frequently and are not numerous. Based on cytomorphologic features, three types of MGC can be distinguished.

Langhans-type and foreign-body-type multinucleated giant cells in cutaneous lesions of sarcoidosis.

Multinucleated giant cells are characteristic of a monocyte-macrophage lineage in sarcoidosis and consist of two types of cells: Langhans-type with an arcuate arrangement of nuclei and a foreign-body type with random arrangement of nuclei. To compare these cells in the cutaneous lesions of sarcoidosis, we histologically and immunohistologically examined multinucleated giant cells in 25 scar infiltrations (cutaneous sarcoidosis with foreign bodies) and 30 cutaneous lesions of sarcoidosis without foreign bodies. Regardless of the presence or absence of foreign bodies, the cutaneous lesions had both types of multinucleated giant cells, usually with a predominance of the Langhans-type, although the numbers of total multinucleated giant cells were higher in scar infiltrations than in cutaneous sarcoidosis without foreign bodies, suggesting that their frequency is influenced by the microenvironment in sarcoidal lesions such as the presence of foreign bodies. Immunohistochemical studies using surface antigens of monocyte-macrophage lineage cells and adhesion molecules indicated that both types of multinucleated giant cells are formed from monocytes rather than tissue macrophages and are phenotypically the same cells with different distributions of nuclei.

腎うのｉｎｆｌａｍｍａｔｏｒｙ ｐｓｅｕｄｏｔｕｍｏｒの１例

We report a case of a 73-year-old man with inflammatory pseudotumor of the left renal pelvis. The tumor was histologically composed of spindle-shaped cells with mild atypia and some multinucleated giant cells, lymphocytes and plasma cells. Cytological features revealed spindle-shaped fibroblast-like cells with enlarged oval nuclei with slight atypia. These cells had thin nuclear membranes and a fine chromatin structure. Imprint smears also contained lymphocytes and foreign-body type multinucleated giant cells. Immunostaining was positive for α-SMA and vimentin. These features were thought to be compatible with those reported for inflammatory pseudotumor. Its cytological differential diagnosis was briefly discussed as well.

Ultrastructure of multinucleated giant cell apoptosis in foreign-body granuloma

To elucidate the role of apoptosis in the disappearance of multinucleated giant cells from the granulation tissue in cases of foreign-body granuloma, we induced a foreign-body reaction by implanting a collagen sponge into the dorsum of the rat and observed apoptotic changes within the multinucleated giant cells using electron microscopy. Two types of multinucleated giant cells were identified presenting apoptotic characteristics morphologically. One was characterized by apoptosis of only one nucleus, followed by cytoplasmic changes, rupture of the plasma membrane and necrosis evoking an inflammatory reaction. The other showed typical apoptotic changes in the majority or in all of the nuclei, followed by phagocytosis of the apoptotic syncytia. The results of the present study suggest that apoptosis occurring within only one nucleus might be triggered by overexpression of the p53 protein, because DNA abnormalities are confined to this single nucleus. In contrast apoptosis occurring simultaneously in the majority or all of the nuclei is most probably due to cell death caused by senescence.

Characteristics of giant cells and factors related to the formation of giant cells in myocarditis.

Giant cell myocarditis is a serious and frequently fatal inflammatory heart disease of which the etiology remains unknown. In the present study, we investigated the origin of multinucleated giant cells in myocarditis with the use of an experimental model. We also examined the factors relating to the formation of giant cells in myocarditis. Severe myocarditis characterized by the appearance of multinucleated giant cells was induced in Lewis rats by immunization with cardiac myosin in complete Freund's adjuvant. Two types of giant cells, foreign body giant cell-like and myocytelike, were observed in this myocarditis. Immunohistochemical studies revealed that both types of multinucleated giant cells were stained with OX42 and ED1 (macrophage markers) and were not stained with anti-desmin antibody and HHF35 (markers for muscle fibers). Therefore, it is likely that multinucleated giant cells in this myocarditis are derived from macrophages. During the course of the disease, the appearance of multinucleated giant cells was restricted to a period corresponding with the fulminant phase of inflammation. When the severity of the disease was modulated by immunization with various doses of the antigen, multinucleated giant cells appeared only in severe myocarditis after inoculation of a large dose of the antigen. Administration of immunoadjuvants also affected the formation of giant cells. Most of the rats injected with cardiac myosin in complete Freund's adjuvant developed giant cell myocarditis.(ABSTRACT TRUNCATED AT 250 WORDS)

Superficial eosinophilic gastritis in laboratory beagle dogs attributable probably to diet.

Stomach tissues from 222 beagle dogs, which were used for toxicological studies, were examined histopathologically. Out of 190 dogs fed the same diet, 185 had gastric lesions, whereas all of 32 dogs fed another diet were free from them. The gastric lesions were noted as an accumulation of eosinophils, infiltration of inflammatory cells including lymphocytes, plasma cells and histiocytes in the gastric lamina propria, formation of foreign body type multinucleated giant cells, focal desquamation and papillary proliferation of mucosal epithelium. The lesions were confined to the superficial layer of the antral and pyloric mucosa, and neither desmoplasia nor clinical signs were seen. Multinucleated giant cells often contained amphophilic foreign bodies of varying appearance with inconsistent reaction for periodic acid-Schiff (PAS), but no definite causal agents were detected.

Touton-like giant cells in periapical granulomas

Two types of multinucleated giant cells were observed in periapical granulomas--the foreign body type and the Touton type. In the Touton type, the nuclei were near the center of the cell, surrounded by foamy cytoplasm. Both types of giant cells reacted positively to lysozyme, alpha 1-antitrypsin and alpha 1-antichymotrypsin, indicating their histiocytic origin.

Human osteogenic sarcoma: fine structure of hard tissue areas.

The structure of hard tissue areas (with osteoid and calcified matrix) in 10 osteoblastic, chondroblastic, and fibroblastic osteogenic sarcomas was studied in the electron microscope. Neoplastic cells commonly associated with these areas and presumably actively involved in the production of hard tissue were osteoblast-like cells types 1 and 3, chondroblast-like cells type 1, and fibroblast-like cells, as defined and characterized in previous studies. The cells differed from those in soft tissue areas of osteogenic sarcomas in but one respect: they usually showed presence of irregular extrusions at their surfaces. Other types of osteoblast-like and chondroblast-like cells occurred rarely or not at all. Two types of multinucleated giant cells were recognized in these areas, one showing a fine structure reminiscent of that in osteoclasts, the other probably being of a neoplastic nature and engaged in the production of the calcifying matrix. The evidence suggested that neoplastic osteoblast-like, chondroblast-like, and fibroblast-like cells as well as certain multinucleated giant cells might all be involved in the mineralization process and/or the formation of osteoid in osteogenic sarcomas. Although phenotypically of highly variable appearance, all these different cells may thus functionally (and probably histogenetically) be closed related. The mineralization process in the tumor tissue appeared to be a modification of what occurs in normal ossification, possibly with an alternative or complementary pathway involving the production of spherical bodies with layered contents.

Comparative study on peroxidatic activity in inflammatory cells on cutaneous and peritoneal implants

Inflammatory reactions were evoked by simultaneous implantation of pieces of Melinex plastic in the subcutaneous tissue of the dorsum and in the peritoneal cavity of rats. The cellular composition of the Melinex-adherent cells and their peroxidatic (PO) activity were investigated in relation to the duration of implantation. Several striking differences were found between the subcutaneous and peritoneal implants. On the 7th and 14th days, multinucleated giant cells were abundantly present on the subcutaneous implants, whereas they were relatively rare on the peritoneal implants. The subcutaneous implants bore no mast cells and only a few eosinophilic granulocytes, but both types of cell were observed frequently on the peritoneal implants. Macrophages and multinucleated giant cells on the subcutaneous implants show PO activity only in the granules are PO negative. On the peritoneal implants three types of macrophages can be dintinguished: exudate macrophages which have PO activity restricted to granules or are PO-negative; macrophages with PO activity in granules and both the rough endoplasmic reticulum (RER) and nuclear envelope; and resident macrophages with PO activity only in the RER and nuclear envelope. In addition, two types of multinucleated giant cells are found, one with and the other without PO activity in the RER and nuclear envelope. Multinucleated giant cells with PO activity in the RER and nuclear envelope as well as exudate macrophages with PO activity in the RER and nuclear envelope were mainly found 32 h and 3 days after implantation of the Melinex in the peritoneal cavity. These findings are discussed in the light of current knowledge of the PO activity in macrophages and multinucleated giant cells. It is concluded that the appearance of PO activity in the RER and nuclear envelope of exudate macrophages and multinucleated giant cells is in all probability a transient phenomenon, and that there is no objective evidence to support the opinion that exudate macrophages with PO activity in the RER and nuclear envelope are transitional cells between exudate and resident macrophages.