Evidence of lectin complement pathway activation in poststreptococcal glomerulonephritis

Abstract

To the Editor: Although many morphologic, clinical, and serologic features of acute poststreptococcal glomerulonephritis (APSGN) suggest that APSGN is an immune complex disease, the precise nature of the antigen-antibody system remains undefined, and complement activation is primarily through the alternative rather than the classical (immune complex) pathway. Recently the third complement activation pathway, termed the “lectin pathway” (LP) had been described with starter molecules consisting of mannose-binding lectin (MBL)1.Turner M.W. Mannose-binding lectin: the pluripotent molecule of the innate immune system.Immunol Today. 1996; 17: 532-540Abstract Full Text PDF PubMed Scopus (654) Google Scholar and two MBL-associated serine proteases, MASP-12.Matsushita M. Fujita T. Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease.J Exp Med. 1992; 176: 1497-1502Crossref PubMed Scopus (531) Google Scholar and MASP-23.Thiel S. Vorup-Jensen T. Stover C.M. Schwaeble W. Laursen S.B. Poulsen K. Willis A.C. Eggleton P. Hansen S. Holmskov U. Reid K.B.M. Jensenius J.C. A second serum protease associated with mannan-binding lectin that activates complement.Nature. 1997; 386: 506-510Crossref PubMed Scopus (718) Google Scholar. With respect to infectious disease, LP is vital as a first line of host defense, because of its immunoglobulin-independent opsonising ability. In this letter, we report evidence of LP activation in a case of typical APSGN. A 16-year-old man presented with nausea and macrohematuria 2 weeks from onset of pyrexia and sore throat. Body weight was increased about 6 kg from his usual weight and blood pressure was elevated. Laboratory data indicated the presence of leukocytosis (18,300/μl) and renal insufficiency (blood urea nitrogen of 43.8 mg/dl, serum creatinine of 1.7 mg/dl). Serology revealed high titer of antistreptolysin O (2865 IU/ml, normal range 10–320) and hypocomplementemia (C3 < 1 mg/dl, normal range 45–95; C4 29 mg/dl, normal range 15–55; and CH50 39.5 U/ml, normal range 31.3–46.2). Urinary red blood cell count was> 100/high power field and urinary protein was 0.51 g/day. Oral bacampicillin 1500 mg per day was administered for 10 days. Gradually, clinical and laboratory findings returned to normal. Four weeks from the onset of symptoms renal biopsy was performed. Biopsy specimens demonstrated the typical histology of APSGN. All 16 glomeruli had increased numbers of mesangial and endothelial cells, which filled Bowman's space. Neutrophils had infiltrated the capillary lumen. Immunofluorescence microscopy revealed the deposition of C3c and C3d in a mesangial pattern, but no deposition of IgG, IgA, IgM, fibrinogen, C1q and C4c. Immunohistological studies were performed with anti-human MBL mouse monoclonal antibody (MoAb), anti-human MASP-1 mouse MoAb and anti-human C4d MoAb. The staining patterns of MBL and C4d Figure 1 were strong in all five glomeruli and seemed to be located at mesangial cells and/or the area of infiltration of neutrophils. MASP-1 was positively stained at the same area, but more weakly than MBL. MBL recognizes high-mannose and N-acetyl-glucosamine (GlcNAc) residues on a wide range of microorganisms. APSGN follows infection of the throat or skin with group Aβ-hemolytic streptococci and cell wall polysaccharides carry GlcNAc as the antigenic determinants. It seems likely that MBL recognizes this pathogen and subsequently activates complement, although direct evidence of the binding has not been reported. Also, MBL is capable of recognizing galactosamine radicals to a lesser degree; thus, there is a small possibility that MBL might bind to glomerular cells that had these carbohydrates surfaced by streptococcal neuraminidase. In any event, we propose that LP activation is a major contributor to renal damage in APSGN, because MASP-1 directly activates C34.Matsushita M. Fujita T. Cleavage of the third component of complement (C3) by mannose-binding protein-associated serine protease (MASP) with subsequent complement activation.Immunobiol. 1995; 194: 443-448Crossref PubMed Scopus (122) Google Scholar and MASP-2 activates C43.Thiel S. Vorup-Jensen T. Stover C.M. Schwaeble W. Laursen S.B. Poulsen K. Willis A.C. Eggleton P. Hansen S. Holmskov U. Reid K.B.M. Jensenius J.C. A second serum protease associated with mannan-binding lectin that activates complement.Nature. 1997; 386: 506-510Crossref PubMed Scopus (718) Google Scholar. Both events are followed by activation of the alternative pathway, resulting in the strong deposition of C3 break down products. In addition, lectin recognition (innate immunity) is important at the very early stage in pathogen invasion, until the antigen-antibody system (acquired immunity) awakens. Thus, the evidence of LP activation in APSGN may explain the pathogenesis of this disease.