Etiology

After almost 40 years of investigation following description of KD, we know a great deal about the epidemiology, pathology, pathogenesis of the disease and there is a fairly effective, although less than elegant, therapy available in the form of IVIG. The etiology of KD, however, remains an enigma.

As discussed previously, clinical and epidemiological factors favor an infectious etiology, but, as yet, a single microbial pathogen has not been consistently associated with the disease. A very abridged list of microbial and environmental agents that have been proposed as causes for KD is found in Table 6.

The two most heavily investigated areas in the last 10-15 years have been a bacterial toxin-mediated cause versus a viral pathogen etiology.

Superantigen-mediated etiology

The possibility of a superantigen (SA) being implicated in the cause of KD was prompted by the observation that the illness is associated with marked activation of T lymphocytes and monocytes/macrophages. The differences between SA and conventional antigen are compared in Table 7. Early studies showed significantly elevated levels of Vp2+ and Vp8.1+ T cells in patients with KD [95, 96]. Subsequently, Leung et al. [97] published a case

Table 7. Comparison of the Effect of Conventional and Superantigens

Conventional antigen

Processed by antigen presenting all (APC). Presented as a peptide on the APC surface in association with MHC II molecule.

Interacts with the variable (V), joining (J) and diversity (D) portions of the a and ß chains of the T cell receptor (TCR).

Recognized by the few sensitized T-cells with receptors for the antigen resulting in a limited more specific immune response.

Superantigen

Directly bind to class II MHC molecules on the APC and TCR.

Binding restricted to the specificity of the variable regions of the p chain (Vp) of TCR.

Activates a specific set of Vp families resulting in activation of a large portion of T-cells causing a much more intense immune response.

control study on the presence of bacterial colonization with Staphylococcus aureus organisms capable of producing toxic shock syndrome toxin (TSST). They found a significant association between colonization with toxin secreting S. aureus and the KD patients. Subsequent studies seemed to confirm the association [95, 98, 99]. A prospective multicenter trial assessing KD patients and controls for SA-producing staphylococcal and streptococcal bacteria (TSST-1, staphylococcal enterotoxins B and C, and streptococcal pyrogenic exotoxins A and C) were undertaken. Overall, isolation rates of SA-producing bacteria between KD patients and controls were not different statistically. A subset of patients with organisms expressing superantigens that stimulate Vp2+ T cell receptor families of T cells were found significantly more often in the KD group [100]. Other investigations have not confirmed the SA hypothesis, however [101-104]. More recent serological studies suggest a role in the pathogenesis of KD for TSST-1 staphylococcal enterotoxin B and streptococcal pyrogenic exotoxins A and C [105-107].

The role of SA in the etiology of KD remains controversial [108].

Conventional antigen/viral etiology

An alternative hypothesis to the superantigen theory is that KD results from infection with an as yet unidentified viral pathogen. Central to this idea is that the immunological response is oligoclonal in response to a conventional antigen rather than a polyclonal response as seen with a challenge by SA. A series of studies have compiled evidence to support this proposition.

An unexpected observation from an immunohistochemical study of coronary arteries taken from infants and young children who had died in the acute phase of KD initiated this line of investigation. [109, 110]. IgA-secret-ing plasma cells were found infiltrating the vascular wall, pancreatic ducts and kidneys of 100% of KD patients compared to none of the age-matched control patients. This observation was intriguing in view of the relative immaturity of the systemic IgA response in infancy as compared to a fully developed and more robust secretory IgA response at this age. A polyclonal response to an SA might engender infant B cells to respond with a predominantly IgM reaction. A viral or other microbe presented to a mucosal site in a similar patient might stimulate vigorous IgA response [111]. Also observed was a heavy infiltration of IgA-secreting plasma cells in the upper respiratory tract of KD patients as compared to controls [112].

Subsequently, the same investigators demonstrated that the vascular IgA response was oligoclonal in nature and, therefore, probably resulted from stimulation by a conventional antigen, not a superantigen [112]. As a next step, the group developed synthetic antibody from prevalent IgA gene sequences found in acute-phase KD arterial tissue. They then exposed the tissues to the antibody and detected antigen in the respiratory epithelium of proximal bronchi from lungs and in subsets of invading macrophages from the myocardium of other inflamed tissues. The strength of the antigen signal paralleled the concentration of IgA plasma cell infiltration. These findings were not present in tissue from non-KD control patients [113]. Spheroid bodies were seen in the region between the nucleus and apical surface of ciliated epithelium of the proximal bronchi. Similar bodies were seen in the splenic and lymph node tissues. Evaluation of these tissues was undertaken using light microscopy (LM) and transmitting electron microscopy (TEM) focusing on areas containing the spheroid bodies [114]. LM revealed round-to-oval intracytoplasmic perinuclear inclusion bodies in medium-sized bronchi. They stained with both eosin and hematoxylin, suggesting they contained both protein and nucleic acid. TEM showed regular electron-dense inclusion bodies in the perinuclear region of ciliated bronchial epithelial cells resembling aggregates of viral proteins and nucleic acids that are found in respiratory tissues during infection with RNA viruses [114].

A recent report of association between newly described human corona-virus [115, 116] and KD raised hope that the etiology of KD had finally been identified [117]. Unfortunately, a series of reports from Japan and Taiwan and the United States found no consistent association between the new RNA respiratory virus and KD [118-121].

Thus, the search for the etiology of KD continues. Hopefully, with the application of histochemical and molecular techniques described above, the cause will soon be identified, possibly among the many new viral agents being identified at an increasing rate [122, 123].

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