Development of serum IgM antibodies against superantigens of Staphylococcus aureus and Streptococcus pyogenes in Kawasaki disease

Abstract

To serologically determine the association of microbial superantigens and the pathogenesis of Kawasaki disease (KD), we conducted a case-control study. Serum IgG and IgM antibodies against staphylococcal enterotoxin A (SEA), SEB, SEC, toxic shock syndrome toxin-1 (TSST-1), and streptococcal pyrogenic exotoxin A (SPEA) were measured by an enzyme-linked immunosorbent assay in 293 serum samples from 65 KD patients on clinical days 1-28 and 120 control samples. The administration of immunoglobulin products, which contain high concentrations of IgG antibodies against all the superantigens, directly elevated antitoxin IgG antibodies in KD patients. In contrast, antitoxin IgM antibodies were not detected in immunoglobulin products. Actually, we found a significant elevation of IgM antibodies against SEA in KD patients in the first (median titre: 0.020, P < 0.01 versus control), second (0.024, P < 0.001), third (0.030, P < 0.001) and fourth (0.038, P < 0.001) weeks, compared to the controls (0.015). Significant differences of IgM antibodies were also true for SEB, TSST-1, and SPEA throughout the first to fourth weeks, and for SEC throughout the second to fourth weeks. The prevalence of KD patients having high IgM titres (> mean + 2SD of control values) to the 5 superantigens was increased with the clinical weeks, and reached 29-43% of KD subjects at the fourth week. This is the first study that describes kinetics of IgM antibodies against superantigens and clarifies the serological significance throughout the clinical course of KD. Our results suggest that multiple superantigens involve in the pathogenesis of KD.

Fig. 1

Antitoxin IgG antibodies against superantigens of patients with Kawasaki disease (KD) prior to treatment and controls (C). SEA; staphylococcal enterotoxin A, SEB; staphylococcal enterotoxin B, SEC; staphylococcal enterotoxin C, TSST-1; toxic shock syndrome toxin-1, SPEA; streptococcal pyrogenic exotoxin A. Indicated are median (inner lines), 25/75 percentiles (boxes) and 10/90 percentiles (whiskers).

Fig. 2

Kinetic changes in antitoxin IgM antibodies against superantigens (a–e), and those of total serum IgM (f) in patients with Kawasaki disease and controls through the first to fourth weeks. (a) SEA; staphylococcal enterotoxin A (b) SEB; staphylococcal enterotoxin B (c) SEC; staphylococcal enterotoxin C (d) TSST-1; toxic shock syndrome toxin-1 (e) SPEA; streptococcal pyrogenic exotoxin A. Indicated are median (inner lines), 25/75 percentiles (boxes) and 10/90 percentiles (whiskers). *P < 0·01 (versus control), **P < 0·001 (versus control).

Fig. 3

Representative patients with Kawasaki disease who had high IgM antibodies against one (a, against staphylococcal enterotoxin A) or multiple (b, against 5 all toxins) superantigens. IVIG; intravenous immunoglobulin therapy. Open and closed circles, open and closed squares, and open triangle indicate staphylococcal enterotoxin A, staphylococcal enterotoxin B, staphylococcal enterotoxin C, toxic shock syndrome toxin-1, and streptococcal pyrogenic exotoxin A, respectively.

Fig. 4

Prevalence of patients having high antitoxin IgM antibodies against superantigens. Open and closed circles, open and closed squares, and open and closed triangles indicate staphylococcal enterotoxin A, staphylococcal enterotoxin B, staphylococcal enterotoxin C, toxic shock syndrome toxin-1, streptococcal pyrogenic exotoxin A, and any of the 5 superantigens, respectively.