Immunoreactive substances of mycobacteria.

1 he perturbations that mycobacterial components inflict on elements of the immune system are so profound, so varied, and so unique that a wellknown British scientist of Wildeian wit (but, in my experience, of Shavian disposition) once observed, in a paraphrase of Voltaire, that "If the tubercle bacillus were to disappear from the face of the earth it would be necessary to create it afresh — in order to serve as an immunological tool" (9). Indeed, the overt physiologic consequences of the disease process itself are sensu stricto direct manifestations of these varied perturbations: the tubercle or tuberculous granuloma (2, 10-13); caseation and caseation necrosis, regarded as the most "characteristic feature of the tubercle (2); and thus, the massive tissue destruction that derives from the inordinate hypersensitization to its own antigenic components that the tubercle bacillus provokes. As reviewed by Crowle (14), " . there is experimental evidence that the delayed hypersensitivity to tuberculoprotein . is a hazardous aspect of the pathogenesis of tuberculosis and plays a direct role in cavity formation. " Thus, were it not for this hypersensitization, tuberculosis might well be a benign sort of disease. Even though lipid-free immunoreactive polysaccharides and proteins are reviewed in this paper, because a principal thrust of my own research efforts has been devoted to studies on mycobacterial lipids, their structures, and biologic activities, I am prone to see an indelible imprint of a lipid moiety as contributing to the expression of almost any immunoreactive mycobacterial substance. Is this a justifiable view or merely imaginary? Certainly there is support for its validity. If the least common denominator of immunoadjuvant activity in bacterial cell wall is simply TV-acyl-muramyl-L-alanyl-D-isoglutamine (muramyl dipeptide, MDP) (Figure 1), then why, despite its almost monotonous distribution among a host of microorganisms, are its effects seemingly so profound essentially only among (CMN) corynebacteria-mycobacteria-nocardia genera? Lederer, of course, has pondered the same question and has suggested that in these "other bacteria the peptidoglycan may be covered by other constituents (lipopolysaccharide, teichoic acids, etc.) and therefore cannot react with . (appropriate receptors) on the macrophage membrane" (5). We suggest that as appealing as this interpretation might be, it seems weak and unconvincing. It seems unlikely that all of the MDP component would be so effectively covered or masked. On the other hand, the alternative that we consider may be more persuasive, and is subject to testing. There is certainly evidence of an often unexpressed reluctance on the part of investigators to abandon completely the conviction that the lipids of CMN cell walls have a role in eliciting at least some of the immunologically mediated phenomena that have been documented, and this reluctance recently has been translated into ever-widening research efforts to establish such influences. Some of these studies are reviewed in the present paper, and it can be anticipated, owing to my own bias, that the role of lipids in the biologic expression of immunoactivity will be emphasized. Figure 1, adapted from (5) and (8) and modified to incorporate at least some of the wall-associated mycobacterial lipids, embraces many of the most important immunoreactive substances that have been described in mycobacteria. The rationale for representing the free (unbound) lipids as being intimately associated with the cell wall was detailed in an earlier publication (8); see also (2). Among the extractable free lipids of various mycobacteria can be found the prominently immunoreactive substances Wax D, the phosphatidylinositol mannosides, the sulfatides, cord factor, and the mycosides. It is these substances to which the bulk of this review is devoted.