Detection of Multiple Superantigen Genes in Stools of Patients with Kawasaki Disease

doi:10.1016/j.jpeds.2009.03.013

The Journal of Pediatrics

Volume 155, Issue 2, August 2009, Pages 266-270

https://doi.org/10.1016/j.jpeds.2009.03.013 Get rights and content

Objectives

To investigate whether superantigens (SAgs) are involved in the development of Kawasaki disease (KD) by examining SAg genes in the stool of patients with KD.

Study design

Stool specimens were obtained from 60 patients with KD and 62 age-matched children (36 children with acute illness and 26 healthy children). Total DNA was extracted from these stool samples. Using polymerase chain reaction, we examined genes of 5 SAgs: streptococcal pyrogenic exotoxin-A (SPE-A), SPE-C, SPE-G, SPE-J, and toxic shock syndrome toxin-1.

Results

At least 1 of the 5 SAg genes was detected in 42 (70%) specimens from patients with KD, 14 (38.9%) from the febrile group, and 7 (26.9%) from the healthy group. The detection rate between subjects with and without KD was of at least 1 of the 5 SAg genes (P < .001), and more than 2 SAg genes were significantly different (P = .002).

Conclusions

SAg may be involved in the development of KD; data suggest that multiple SAgs may trigger KD.

Section snippets

Patients and Stool Samples

The study was approved by the Ethics Committee of Wakayama Medical University (Wakayama, Japan). Informed consent was obtained from the parents of the patients. Sixty patients who fulfilled the diagnostic criteria for KD¹⁴ and were admitted to our hospital between June 2004 and June 2007 were enrolled consecutively.

Stool specimens were obtained from the 60 patients with KD at the acute stage of the disease (KD group) and from 62 age-matched children without KD: 36 with acute illnesses (febrile

Results

Patients with KD, febrile control children, and healthy control children had similar sex ratios (male:female) (34:26, 18:18, and 13:13) and mean ages (24.6, 25.9, and 25.5 months, respectively). The stools were collected from the patients with KD at a mean of 5.7 days from disease onset. Although not significantly different, the concentrations of DNA extracted from stools of healthy control children (m = 59.7 ng/μL) were slightly higher than those of patients with KD (m = 37.8 ng/μL) and

Discussion

It is still controversial whether the etiology of KD may involve a conventional antigen or a SAg.¹⁶ We have investigated SAgs derived from S pyogenes as causative agents of KD because the main symptoms of KD are similar to those of streptococcal infection. Although investigations have indirectly linked SAgs with KD, few articles have detected either SAgs themselves or SAg-producing bacteria in patients with KD).¹¹ We sought to detect SAg genes as antigenic agents in stool specimens because all

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Cited by (29)

Immune and non-immune mechanisms that determine vasculitis and coronary artery aneurysm topography in Kawasaki disease and MIS-C
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Citation Excerpt :
The pathogenesis of TSS itself has been viewed ultimately in terms of a type of capillary leak syndrome with multiorgan dysfunction with much of this, in turn, attributed to superantigen activation of a large proportion of T-cells [101,119]. This link is supported by some pieces of evidence of the presence of TSS toxin-producing staphylococcus and other bacterial superantigens in the majority of KD patients [119–122]. The absence of supportive evidence for the persistence of respiratory SARS-CoV-2 infection in MIS-C and MIS-A might have initially argued against a superantigen-driven process- given that no such antigen was recoverable.
The overlap between multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) including coronary artery aneurysms (CAA) and broadly shared gastrointestinal and mucocutaneous disease is poorly defined. In this perspective, we highlight common age-related extravascular epicardial microanatomical and immunological factors that might culminate in CAA expression in both MIS-C and KD. Specifically, the coronary vasa vasorum originates outside the major coronary arteries. Widespread inflammation in the epicardial interstitial compartment in shared between KD and MIS-C. Age-related changes in the neonatal and immature coronary vasculature including the impact of coronary artery biomechanical factors including coronary vessel calibre, age-related vessel distensibility, flow, and vessel neurovascular innervation may explain the decreasing CAA frequency from neonates to older children and the virtual absence of CAA in young adults with the MIS-C phenotype. Other KD and MIS-C features including mucocutaneous disease with keratinocyte-related immunopathology corroborate that disease phenotypes are centrally influenced by inflammation originating outside vessel walls but a potential role for primary coronary artery vascular wall inflammation cannot be excluded. Hence, common extravascular originating tissue-specific responses to aetiologically diverse triggers including superantigens may lead to widespread interstitial tissue inflammation characteristically manifesting as CAA development, especially in younger subjects. Given that CAA is virtually absent in adults, further studies are needed to ascertain whether epicardial interstitial inflammation may impact on both coronary artery physiology and cardiac conduction tissue and contribute to cardiovascular disease- a hitherto unappreciated consideration.
Streptococcal superantigens: Categorization and clinical associations
2014, Trends in Molecular Medicine
Superantigens are key virulence factors in the immunopathogenesis of invasive disease caused by group A streptococcus. These protein exotoxins have also been associated with severe group C and group G streptococcal infections. A number of novel streptococcal superantigens have recently been described with some resulting confusion in their classification. In addition to clarifying the nomenclature of streptococcal superantigens and proposing guidelines for their categorization, this review summarizes the evidence supporting their involvement in various clinical diseases including acute rheumatic fever.
The role of infection in Kawasaki syndrome
2013, Journal of Infection
Citation Excerpt :
Furthermore, a number of studies analysing the T lymphocyte receptor repertoire and the titres of antibodies against selected SAs have indirectly demonstrated that these proteins may be related to the development of KS.52,54–56 In addition, Suenaga et al. examined five SA genes in the stools of KS patients, febrile controls and healthy children,57 and found at least one of the genes in 42 specimens from the patients with KS (70%), in 14 from the febrile group (38.9%), and in seven from the healthy group (26.9%). The detection rate between subjects with and without KS was of at least one of the 5 SA genes (p < 0.001), and more than two SA genes were significantly different (p = 0.002), thus suggesting the direct involvement of SAs in the development of KS.
To analyse the evidence suggesting a possible infectious origin of Kawasaki syndrome (KS).
PubMed was searched for all of the studies published over the last 15 years using the key words “Kawasaki syndrome” or “mucocutaneous lymph node syndrome” and “infectious disease” or “genetics” or “vasculitis” or “pathogenesis”.
Various levels of evidence support the hypothesis that KS is a complex disease triggered by an infection due to one or more pathogens. Viruses or bacteria may be the primum movens, although no specific infectious agent can be considered definitely etiological. A number of genetic polymorphisms have been identified in subjects with KS, but none of them can currently be considered a real marker of susceptibility.
Various data suggest that KS is intimately related to infectious diseases and that its clinical expression is influenced by predisposing genetic backgrounds, but our knowledge of the infectious agent(s) involved and the genetic characteristics of susceptible children remains only partial. Further studies are needed to address the many still open questions concerning the disease.
Streptococcal toxic shock syndrome or Kawasaki disease? Two case studies of children with group A streptococcal pneumonia empyema
2011, Archives de Pediatrie
Nous rapportons les cas de 2 enfants ayant présenté une pleuropneumopathie à streptocoque du groupe A compliquée pour l’un d’un syndrome de Kawasaki et pour l’autre d’un syndrome de choc toxinique streptococcique. Ces 2 syndromes ont des critères clinicobiologiques bien définis, mais pourtant parfois difficiles à distinguer en pratique clinique, soulignant leur possible intrication physiopathologique. En cas de doute clinique entre l’un ou l’autre de ces diagnostics, la réalisation d’une échographie cardiaque à la recherche d’une atteinte coronarienne et la mise en place d’un traitement précoce associant immunoglobulines intraveineuses et antibiothérapie à visée antitoxinique (clindamycine) restent probablement la meilleure attitude à adopter.
We report 2 cases of children with group A streptococcus pyogenes pleuropneumonia, in one child associated with Kawasaki disease and in the other with streptococcal toxic shock syndrome. These 2 features, with theoretically well-defined clinical and biological criteria, are difficult to differentiate in clinical practice, however, likely due to their pathophysiological links. In case of clinical doubt, an echocardiography needs to be performed to search for coronary involvement and treatment including intravenous immunoglobulins, and an antibiotic with an anti-toxin effect such as clindamycin has to be started early.
Superantigens in dermatology
2011, Journal of the American Academy of Dermatology
Citation Excerpt :
In another study, the number of Vβ2 cells in the small intestinal mucosa in KD patients was increased compared with controls.89 Suenega et al90 studied stool samples from 60 patients with KD, 36 patients with acute febrile illness, and another 26 healthy controls. The samples were examined for SAg genes (TSST-1, SPE-A, SPE-C, SPE-G, and SPE-J) derived from bacteria present in the respiratory and gastrointestinal tracts.
Superantigens (SAgs) are virulent polypeptides that are produced by a variety of infectious organisms. They are capable of causing nonspecific T cell activation by circumventing normal antigen processing in the human host. The genetic makeup of the host plays a role in conferring susceptibility or protection against SAgs. They are linked to a variety of conditions, ranging from toxic shock syndrome to recurrent toxin-mediated perineal erythema. The early recognition of signs and symptoms of SAg-mediated illnesses is important to ensure prompt medical treatment.
Streptococcal infection and autoimmune diseases
2024, Frontiers in Immunology

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: Supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (2006-2008) and a grant from Japan Kawasaki Disease Research Center (2007).

: Presented in part at the Ninth International Kawasaki Disease Symposium, Taipei, Taiwan (April 2008).

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Original ArticleDetection of Multiple Superantigen Genes in Stools of Patients with Kawasaki Disease

Objectives

Study design

Results

Conclusions

Section snippets

Patients and Stool Samples

Results

Discussion

Lancet

J Pediatr

Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of fingers and toes in children: clinical observation of 50 cases

Jpn J Allergol

Results of 12 nationwide epidemiological incidence surveys of Kawasaki disease in Japan

Arch Pediatr Adolesc Med

ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms

Nat Genet

Selective expansion of T cells expressing T-cell receptor variable regions V beta 2 and V beta 8 in Kawasaki disease

Proc Natl Acad Sci U S A

Evidence for a superantigen mediated process in Kawasaki disease

Arch Dis Child

Relation of streptococcal pyrogenic exotoxin C as a causative superantigen for Kawasaki disease

Pediatr Res

Analysis of T-cell receptor V-beta 2 in peripheral blood lymphocytes as a diagnostic marker for Kawasaki disease

Infection

Selective increase of V beta 2 + T cells in the small intestinal mucosa in Kawasaki disease

Pediatr Res

T cell activation profiles in Kawasaki syndrome

Clin Exp Immunol

Possible relationship between streptococcal pyrogenic exotoxin A and Kawasaki syndrome in patients older than six months of age

Pediatr Infect Dis J

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

Clin Exp Immunol

Original Article
Detection of Multiple Superantigen Genes in Stools of Patients with Kawasaki Disease