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Poststreptococcal glomerulonephritis: getting to know an old enemy

The streptococcus, in addition to its ability to cause disease by direct tissue invasion and toxin production, is also responsible for immunologically mediated sequelae to the acute infection in the form of rheumatic fever and poststreptococcal glomerulonephritis (PSGN). Over the centuries these combined manifestations have been responsible for considerable morbidity and mortality. Although the immunologically mediated diseases are now rare in the UK, this is not so in other societies [1,2]. These diseases are also of importance because of the insight they may give into more general immunopathological mechanisms. For instance, we remain ignorant of the immunopatho-genesis of most forms of glomerulonephritis. The study of PSGN, in which there is a clearly defined initiating event, should facilitate an analysis of pathogenesis, and may provide clues as to the mechanisms involved in other forms of glomerulonephritis. There are a number of different ways in which the immune response to streptococcal infection may cause immunopathology. The production of anti-streptococcal antibodies that cross-react with constituents of cardiac muscle may play a role in rheumatic fever [3]. The strain-defining M protein has the ability to act as a superantigen, with different types of M protein activating distinct families of T cells defined by the use of particular V gene family products in their T cell receptors [4]; T cell stimulation with cytokine production may play a part in the inflammation in the kidney. In the case of PSGN, the generally accepted mechanism is that of a planted antigen. A streptococcal c omponent which has affinity for glomerular structures is deposited there during the early phase of a streptococcal infection. With the onset of the host immune response 10–14 days after infection, antibody attaches to the ‘planted’ antigen in the glomerulus and initiates the characteristic proliferative glomer ulonephritis. Direct activation of complement by the strep tococcal component may also play a role, with the release of phlogistic peptides C3a, C5a during activation, and the interaction of activated components with incoming neutrophils, to cause release of lysosomal proteins (see below). The general validity of the planted antigen model is supported by the key observation that streptococcal antigens can be identified in glomeruli from renal biopsies obtained early in the natural history of PSGN by staining with convalescent sera [5]. They are not detectable later in the course of the disease, presumably because they are obscured or removed by components of the host immune system. The obvious question arises as to the precise nature of the streptococcal antigen(s) involved in this mechanism. Three criteria have been proposed that should be met by potential nephritogenic antigens [6]: the antigen should be found only in nephritogenic strains; the antigen should be identifiable within the glomerulus; and antibodies should be present to the antigen in convalescent sera. To this could be added a fourth criterion, namely the ability of the candidate antigen to induce an appropriate glomerulonephritis in an experimental model. Given that only certain strains of streptococci, as defined by their M protein, are nephritogenic, the M protein was an obvious candidate. However, the development during convalescence of an antibody that probably identifies the nephritogenic antigen is independent of the M type of the precipitating infection [7]. In addition, the observation that one episode of PSGN provides lasting immunity against a second episode argues for the existence of a common immunizing nephritogenic antigen other than the variable M protein. The history of other more plausible candidate antigens is somewhat confusing. A number of streptococcal proteins which, to a variable extent, meet the criteria outlined above have been identified. These include an extract from disrupted streptococci termed endostreptosin [8,9]. Characterization of this protein shows it to have a mol. wt of 45 kD, and a PI of between 5 .6 and 5.9. The streptococcal protein termed preabsorbing antigen, on which further studies are reported in this issue of the journal [10], was initially described as being derived from the endostreptosin complex [11]. It is therefore not surprising that it has rather similar characteristics, with a mol. wt of 43 kD and a PI of 4 .7. Meanwhile, a separate group defined a protein termed nephritogenic strainassociated protein (NSAP) [12]. This protein also had a mol. wt of 46 kD and was initially shown to have a PI of 4 .75 [13]. At first sight, the obvious conclusion that NSAP was the same as preabsorbing antigen was discounted by the fact that they had different N terminal sequences [11,13], with NSAP appearing to be a streptokinase. Subsequent work failed to detect unique reactivity to streptococcal streptokinase in either the sera or renal biopsy specimens of patients with acute PSGN [14]; the authors interpreted the sequence data showing the presence of a streptokinase as evidence for the presence of two distinct proteins, namely NSAP on the one hand and a streptokinase on the other. Thus the difference in N terminal sequence does not rule out the identity of NSAP and preabsorbing antigen. The most recent development has been a report from the same group that described NSAP of yet another 46-kD protein secreted by nephritogenic strains of streptococci that binds to human plasmin, termed nephritis plasmin binding protein (NPBP) [15]. Sequencing of this protein suggests Clin Exp Immunol 1997;107:8–10