Acute poststreptococcal glomerulonephritis (APSGN) is the most common postinfectious renal disease following group A streptococci (GAS) infection, and the first form of glomerular disease in which immunological mechanisms were suspected to play a role. In fact, its evolution is characterized by a serum sickness-like latent period followed by hypocomplementemia and nephritis (Nordstrand et al., 1999). Researchers originally believed that the pathogenic mechanism underlying APSGN was the renal deposition of CICs. This theory was consistent with the clinical picture: the elevated serum levels of IgG and IgM in a high percentage of patients; the pattern of CIC levels, which are high during the acute phase and usually return to normal within 6-9 months after the attack, but linger in patients with persisting hematuria and proteinuria (Lin, 1982); and the finding of extracellular streptococcal antigens typical of nephritogenic strains in the patients' CICs (Friedman et al., 1984). However, various findings in recent decades have shed doubt on this hypothesis. For example, increased CIC titers have also been found in the sera of patients with other types of streptococcal disease. In APSGN patients, streptococcal antigens are present in CICs, but not in ICs eluted from kidney biopsies; the latter are endogenous complexes containing IgG that have probably been modified enzymatically by a streptococcal product (McIntosh et al., 1978; Rodriguez-Iturbe et al., 1980). The glomerular deposition of preformed ICs would cause complement activation by the classical pathway, but the presence of properdin in the kidney and the fact that C3 deposition precedes that of IgG indicate that complement activation occurs before IgG is deposited, possibly by the alternative pathway.
At present, the prevailing theory is that deposition in the glomeruli of a streptococcal antigen common to nephritogenic strains induces an inflammatory process by activating complement in situ, followed by C3 deposition, immune response activation, tissue destruction, IgG deposition, and amplification of the inflammatory reaction (Nordstrand et al., 1999). IgG deposition may be caused by autoantibodies to glomerular epitopes (e.g., cryptic epitopes exposed after tissue damage or epitopes that cross-react with streptococcal antigens, i.e., molecular mimicry), CICs, and/or antibodies to already planted streptococcal antigens. Accordingly, several streptococcal products have been suggested as possible nephritogenic agents, with different mechanisms of action. (i) M proteins (surface molecules that confer resistance to phagocytosis) may be antigenically cross-reactive with the glomerular basement membrane (GBM) and directly bind its constituents (Glurich et al., 1991); some M-like proteins can act like Fc receptors (FcR) and strains carrying these FcR-like M proteins can induce circulating anti-IgG antibodies, thus contributing to IC formation in APSGN (Burova et al., 2003). (ii) Preabsorbing antigen (PA-Ag), a streptococcal antigen able to activate the complement cascade via the alternative pathway, can induce the deposition of C3 (without IgG) in the glomeruli of rabbits (Yoshizawa et al., 1997). (iii) Streptococcal pyrogenic esotoxin B (Spe-B), an extracellular plasmin-binding protein secreted by nephritis-associated GAS, has been found only in kidney biopsies from APSGN patients; it could contribute to the disease pathogenesis either behaving like a planted antigen or blocking the inactivation of plasmin, as SpeB-bound plasmin is not inactivated by a2-antiplasmin (Cu et al., 1998). (iv) Streptokinase is a 46-kDa extracellular protein that plays a role in the streptococ-cal invasion of tissues due to its ability to convert plasminogen to plasmin. In a mouse model its presence was necessary for APSGN induction by a GAS nephritis isolate and it was detected in the glomeruli as early as 4 days after infection. Its ability to target the glomeruli seems to be restricted to nephritogenic strains, and streptokinase from nephritis isolates binds more tightly to human glomeruli than non-nephritis-associated streptokinases. Here again the deposited protein could play a role in the initiation of the disease process, and ICs might be involved in the later stages of the disease (Nordstrand et al., 1998). (v) Nephritis-associated plasmin receptor (NAPlr) with glycolytic activity (streptococcal glyc-eraldehyde-3-phosphate dehydrogenase) has been found in glomeruli from kidney biopsies of APSGN patients, but not in controls. It could contribute to the pathogenesis of the disease by maintaining activated plasmin in the glomeruli and playing a role in complement activation (Yoshizawa et al., 2004). (vi) During nephritogenic GAS infection, neuraminidase is produced and neuraminidase-treated leukocytes accumulate preferentially in the kidney. Furthermore, neu-raminidase could induce changes in IgG molecules, and render them immunogenic (McIntosh etal., 1978; Marin et al., 1997). (vii) Streptococcal eno-lase is a recently discovered cross-reactive antigen located on the surface of GAS. It may play an important role in the initiation of autoimmune diseases linked to streptococcal infection. There is a cross-reactivity between streptococcal enolase and human enolase, and patients with acute rheumatic fever have higher levels of antibodies that react with human and bacterial enolase than those with strepto-coccal pharyngitis or healthy subjects (Fontan et al., 2000), suggesting that strep-tococcal enolase may induce autoantibodies via molecular mimicry. In fact, a-enolase is a target of autoantibodies in several autoimmune disorders with renal involvement, such as systemic lupus erythematosus (SLE) and mixed cryoglobu-linemia (MC) (Pratesi et al, 2000).
Thus, after having been considered a prototypic CIC-mediated form of glomerulonephritis, the autoimmune nature of APSGN has been challenged by several findings; rather than the pathogenetic mechanism underlying APSGN, CICs could represent an epiphenomenon in GAS infection.
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