Inflammatory giant cells.

Giant cells are commonly seen in granulomas produced by a wide variety of known and unknown agents. It is widely accepted that giant cell formation results from fusion of mononuclear phagocytes. Both experimental and circumstantial evidence suggests that fusion takes place following the attachment of more than one macrophage to the same endocytic material. This view is in keeping with the consistent observation of giant cell formation in granulomas, where macrophages are actively ingesting material in close apposition to other macrophages. The experimental evidence for this view derives from the finding that if more than one macrophage is attached simultaneously to the same endocytic material in vitro, fusion results. Study of the phagocytic capacity of giant cells formed in vivo suggests that the same mechanism of fusion operates in granulomatous inflammation. Giant cell formation in granulomas thus appears to be the incidental result of macrophages ingesting material in close apposition to other macrophages. The material responsible for fusion may either be the visible particulate cause of granuloma formation or the denatured macromolecules formed by the inflammatory process.

The role of antibody in primary and reinfection BCG granulomas of rat skin.

Primary subcutaneous infection of rats with BCG leads to a three stage local reaction. There is first a short-lived simple granuloma corresponding with high levels of cell mediated immunity (CMI). This is followed by an explosive phase of necrosis and local Mycobacterial multiplication corresponding with low levels of CMI and high levels of circulating anti-BCG antibody. Finally the lesion resolves via an epithelioid cell granuloma as bacteria fall in number and CMI returns. Reinfection with BCG produces quite different lesions when initiated at different stages of the primary infection. Reinfection during the short first stage causes a self-healing epithelioid granuloma. Reinfection during the long second stage produces a florid necrotic, bacilli-laden lesion. Reinfection during the third stage produces only a vestigial, transient granuloma. It is suggested that the evolution of tuberculous lesions depends on the interplay of CMI, bacillary load and circulating antibody. A large antigenic load in the presence of high antibody titres causes necrosis and bacillary multiplication, whereas reduced bacterial numbers plus antibody and high CMI lead to compact granulomas and healing. The first situation may be analogous to immune complex disease in antigen excess and the second to complexes in antibody excess. An analogy is drawn between the reinfection experiments and natural infection after BCG vaccination in humans. It is postulated that BCG vaccination in man may be followed by a phase in which antibody is high relative to CMI. If because of high prevalence rates, natural infection with large doses of bacilli was more likely to occur at this time, the results might help to explain the failure of BCG prophylaxis in India and comparable countries, as opposed to its success in the UK.

Experimental granulomas induced by mycobacterial immune complexes in rats.

After BCG were complexed with homologous anti-BCG serum IgM was found to be firmly bound to the organisms. Preparations were made at antigen/antibody equivalence and at two-fold and four-fold antibody excess. They were injected subcutaneously into rats. At equivalence the mixtures provoked rapidly developing necrotic destructive lesions containing many bacilli. Injection of mixtures at antibody excess caused the rapid formation of epithelioid cell granulomas without necrosis and containing few bacilli. Compared with the injection of BCG alone, injection of comparable numbers of IgM-complexed bacilli at equivalence led to more rapid necrosis but also more rapid resolution of the granulomas which followed, Delayed-type skin reactions to PPD took longer to develop after injection of complexed BCG, usually as long as 4 weeks. The delay varied directly with the degree of antibody excess. This failure to detect cell mediated immunity was reflected in the histology of the draining lymph nodes which differed strikingly from that seen after injection of BCG alone. In animals injected with bacilli in excess antibody, epithelioid cell granulomas formed and viable bacilli were apparently eliminated before skin reactions to PPD developed. It is concluded that circulating immunoglobulin, perhaps IgM in particular, is likely to play a significant role in the pathogenesis of tuberculosis and similar diseases and that the relative ratio of antigen to antibody within the lesions may be crucial in influencing the balance between tissue destruction and healing.

Facsimile epithelioid cells obtained from stimulated peritoneal macrophages and their secretory activity in vitro.

Mouse peritoneal macrophages collected after exposure to new born calf serum in vivo were found to have some of the morphological and ultrastructural features attributed to epithelioid cells. These features were accentuated by short term culture in vivo or in vitro. Three accepted varieties of epithelioid cell were reproduced, i.e., those with predominant rough ER, those with predominant smooth vesicles and the plasmacytoid variety. Cells resembling fibroblasts were not seen, nor were lymphoid cells. The facsimile epithelioid cells had considerable secretory activity for a range of macrophage enzymes. They retained the phagocytic capacity and the surface receptors of macrophages but to a reduced extent. It is suggested that epithelioid cells are a form of stimulated macrophage, especially effective in enzyme secretion and liable to appear after excitation of the cell membrane by pinocytosis rather than phagocytosis.

Inflammatory reactions in onchocerciasis: a report on current knowledge and recommendations for further study.

This report concerns the host's reactions to the presence of the parasite both in the course of the natural disease and during drug treatment. The various stages of Onchocerca volvulus are discussed in terms of the type of tissue reaction seen. The discussion then turns to basic hypotheses concerning the etiology of these reactions, emphasis being placed on the fact that while pathological changes are considerable in some locations there is a remarkable lack of reaction in others. Some of the mechanisms possibly involved in this apparent absence of host response are discussed, including anti-complement factors, poor antigenicity, acquisition of host antigen, immune tolerance, and blocking antibodies. In any study of the inflammatory response it is recommended that critical evaluations be made of histological material, haematological studies, the definition of the antigenic nature of O. volvulus, characterization of immunological reactivity of patients, and the definition of the migratory pathways of the parasite.The marked host reactions seen following chemotherapy, especially those related to the interaction of the drug diethylcarbamazine with microfilariae, are discussed at some length. The etiology of these reactions is considered and recommendations are made for the experimental elucidation of the mechanisms involved. Emphasis is placed on the necessity for detailed sequential histopathological and immunopathological studies in the definition of the tissue lesions found in onchocerciasis. Characterization of these lesions will assist greatly the approach to control of the adverse reactions seen during treatment.The use of anti-inflammatory agents in clinical trials is discussed and comments are made concerning the most suitable clinical situations for testing drugs and the types of drug that should be tested.

Neoplastic macrophages grown from human leukaemic monocytes.

Leucocyte suspensions from some cases of acute myelogenous leukaemia produced large numbers of macrophages when cultured in vitro. The macrophages increased steadily in number during the first 1-2 wk of culture. The increase was partly derived from division of the macrophages themselves, partly from augmentation from supernatant cells not adherent to the surface of the culture flask. This augmentation occurred mostly in the first 24 hr of culture. The leukaemic macrophages had many features of normal macrophages as regards light microscopy, surface receptors, phagocytic activity and cytochemistry. Under the electron microscope, however, they had many abnormal characteristics, all of which have been recorded previously as features of malignant transformation. Cultures containing the abnormal macrophages and their precursor cells caused local solid tumours when injected into immune-deprived mice. The tumours were composed of rather uniform cells many of which resembled neoplastic reticulum cells. It is concluded that human leukaemic monocytes or promonocytes can develop into macrophages with ultrastructural features of malignancy. This appears to be the first demonstration of the development of neoplastic macrophages. It is suggested that some lymph node tumours of man may be composed of similar neoplastic macrophages and their precursor cells.

Proliferation of macrophages in inflammation.

Proliferation of macrophages in chronic inflammatory loci is an essential part of granuloma development and as such helps to defend the host against dissemination of harmful microorganisms. Its induction seems to depend in part on local appearance of soluble mitogenic factors since sterile cell-free exudates will induce mitotic activity in vitro in a macrophage population otherwise unable to divide. Macrophage proliferation is probably checked and controlled by inherent restrictions on the number of divisions possible. This in turn probably depends on the rapid appearance of gross chromosomal defects, the effete cells being eliminated by their incorporation into multinucleate giant cells which then form non-viable polyploid cells.