Granulomatous diseases

In spite of extreme diversity in their aetiology, many of the major infectious and autoimmune diseases of man share the underlying histopathological characteristic of granuloma formation. This tissue response to chronic stimulation has been widely described in the context of human parasitic, neoplastic and autoimmune inflammatory stimuli and subjected to intricate dissection in many animal models of the same. A recent text devoted to describing the major granulomatous diseases runs to over 600 pages (James & Sumla 1999)! However, the interest afforded to the granulomatous response itself varies between extremes, as do the passions of those who investigate them. To some, these structures may be seen as mere end-stages of the immunological response, a default when all else fails. Some, on the other hand, view these structures with the same degree of respect most immunologists attach to the microanatomical organization of secondary lymphoid tissues.

Granulomas vary considerably in their degree of complexity, physical size and organization. Not surprisingly, their classification has attracted much attention, and a numbers of schemes have been described (Adams 1976; Warren 1976; Williams and Williams 1983; Ridley & Ridley 1983). The cornerstone of the granulomatous response, however, is the predominant involvement of mononuclear phagocytes. As granulomas develop, tissue-resident, as well as inflammatory mononuclear phagocytes become intimately acquainted, and these cells may develop highly differentiated epithelioid cell characteristics. In many cases, elegant multinucleate populations can be seen, distinct from the syncytia formed after viral infection as evident by their extended life-span. Accumulating lymphocytes, mainly T cells, contribute to the developing microarchitecture of the granuloma, often with characteristic patterns of subset organization relative to the core of mononuclear phagocytes and to each other. B lymphocytes, plasma cells, NK cells and neutrophils may all be present, though a relative paucity of neutrophils delineates these sites of inflammation from those associated with necrosis. At its extreme, the granuloma may serve as the focus for irreversible fibrotic reactions, but, even in less dramatic cases, a substantive degree of local tissue remodelling occurs. Never far from the thoughts of those investigating granulomas is the delicate balancing act necessary to achieve containment and/or elimination of pathogens or chronic irritants, but still limit the pathologic disturbance to normal tissue structure and function. This is particularly true as the era of defined clinical intervention comes closer (Maini et al. 1999), with the dissociation of the anti-infective vs. tissue-destructive aspects of granulomatous responses likely to be a major goal.

The developmental processes underlying granuloma formation still pose many questions in cell biology, immunology and inflammation. Although our understanding is progressing, research is often focused in a rather disease-specific way. Although there are undoubtedly fine details which are locally modified by the inducing stimulus, the commonality of various aspects of granuloma biology suggest core mechanistic issues will be conserved. However, it has been unusual to address these issues across both disease and discipline boundaries. In a recent meeting1, experts from a broad range of disciplines related to granuloma development were brought together to discuss recent advances. The papers presented at that meeting form the basis for the series of articles to appear in International Journal of Experimental Pathology over the coming months.