Pathology

Pathologically KD is a vasculitis of medium-sized vessels [52]. Studies from Japan have described four stages of pathology in the heart [53] (Tab. 4). The classification was based on the careful evaluation of 20 hearts taken from patients who had died of KD. Stages were based on the duration of illness at the time of death. The pathological description is considered unique and is distinguished from other vasculitis in the "medium-sized vasculitis" group, polyarteritis nodosa, in that the arterial inflammation does not affect vessels smaller than arteries [52]. Prior to the introduction and the availability of intravenous immunoglobulin (IVIG) for treatment of KD, 20-25% of children developed coronary artery aneurysms as a sequela [2].

Table 4. Pathology of the heart in KD [52]

Stage I (0-9 days): Acute perivasculitis and vasculitis of microvessels (arterioles, capillaries and vessels) and small arteries

Acute perivasculitis and end-arteritis of the three major coronary arteries (MCAs)

Pericarditis myocarditis

Inflammation of the atrioventricular conductor system Endocarditis with valvulitis

Stage II (12-25 days): Panvasculitis of the MCAs and aneurysm with thrombus in the stems

Myocarditis, coagulation necrosis, lesions of the conduction system

Pericarditis

Endocarditis with valvulitis

Stage III (28-31 days): Disappearance of inflammation in the microvessels

Granulation of the MCAs

Myointimal proliferation in the coronary and other medium-sized arteries

Stage IV (40 days to 4 years): Scarring with severe stenosis in the MCAs

Fibrosis of the myocardium Coagulation necrosis Lesions of the conduction system Endocardial fibroelastosis

Pathogenesis

The vasculitis of KD is clearly immunologically mediated and a wide variety of immunoregulatory abnormalities have been documented during the acute phase [54]. In a study of 21 children in the acute phase of KD, Leung and colleagues [54, 55] demonstrated a significant reduction in circulatory T8-positive (T8+) suppressor-cytotoxic T cells, increased activated T4+ helper cells and a proliferation of circulating activated B cells spontaneously secreting IgG and IgM. Furukawa et al. [56], in Japan, demonstrated activation of CD23+ monocytes/macrophages in the peripheral blood of patients with acute KD.

Immunopotent cellular activation is associated with a broad array of proinflammatory cytokines including TNF-a [57, 58], IL-1 [59], IFN-y [60] and IL-6 [61]. These mediators undoubtedly contribute to the high fever, discomfort and inflammatory changes during the acute phase but also facilitate the vascular injury.

Vascular endothelial cells become activated by cytokine stimulation and may induce or increase expression of endothelial cell surface antigens that promote functional changes such as leukocyte adhesion and antigen presentation. These changes may make endothelial cells more vulnerable to attack by cytotoxic IgM antibodies present in acute phase serum of KD [62]. Further evidence of immunological injury to coronary arteries derives from immunohistochemical studies demonstrating transmural infiltration of artery walls with CD45RO T lymphocytes (activated/memory T cells) with CD8 lymphocytes predominating over CD4 T cells [63]. Remarkably, T cell activation, cytokine excretion and other immunological perturbations are reversed by IVIG [64].

Numerous other immunoregulatory abnormalities have been observed during KD or have been suggested as possible contributors to the patho-genesis of the disease. Macrophage activation syndrome has been observed with KD [65]. CD25+ CD4+ regulatory T cells, which maintain immunologi-cal self tolerance and control immune responses to microbial invasion, have been shown to be reduced in acute KD patients more than normal controls, suggesting this might play a role in the disease [66].

Wang et al. [67] proposed that CD40 ligand (CD40L) might play a role in the pathogenesis of KD because they found CD40L expression on CD4+ T lymphocytes in patients with the acute disease. CD40L is a potent activator of the immune system and might enhance endothelial cell inflammation and vascular damage [67].

Several recent reports implicate vascular endothelial grown factor (VEGF) in the pathological findings associated with KD. VEGF is the primary growth factor for formation of blood vessels and is a vascular permeability factor. It may also be a driver of inflammation as it enhances mono-cyte chemotaxis in humans and increased the production of B cells in mice [68]. Several reports have documented significantly elevated levels of VEGF in the acute and subacute phases of KD [69-71]. VEGF induces expression of matrix metalloproteinases (MMP), which degrade extracellular matrix and basement membrane proteins such as collagen and elastin [68]. Gavin et al. [72] demonstrated MMP-2 and MMP-9 in the damaged arterial walls of children who died of KD. The same group subsequently demonstrated angiogenesis in acute KD aneurysms much earlier than previously reported, probably related to several angiogenesis factors including VEGF.

Thus, through such highly complex and intricate interactions of immu-nopotent cells, cytokines and other mediators, the inflammatory process results in vascular damage in KD.

Genetic influence of the pathogenesis of KD

Racial differences in incidence, families with multiple cases, and the apparent greater tendency for CAA to occur in some children but not in others

Table 5. Gene polymorphisms and single nucleotide polymorphisms (SNPs) in KD

Polymorphism or SNP

Susceptibility or risk factor

Reference

HLA Bw22J

Associated with KD in Japanese children

74, 75

HLABw51

Associated with KD in United States and Israel population

76, 77

HLABw44

Associated with KD during Boston epidemic

78

IFN-y gene

Over production of TNF-a

79

Monocyte chemoattractant protein 1 gene (MCP-1

Over production of MCP-1

80

TNF-a gene A/A at LT-x + 250

Over production of TNF-a

81

SLC11A1 gene 51-promoter (GT)n

Possible dysregulation of IL-1B or TNF-a

82

Genotype 1/11 fa IL1-Ra

Higher susceptibility of KD

83

Angiotensin converting enzyme genotype ID

Associated with KD

84

Vascular endothelial growth factor (VEGF) CGCC

Associated with KD

85

Angiotensin/converting enzyme genotype I/I

Associated with development of CAA

86

MHC-class-1-chain related gene A (MICA) allele 4A

Protective for development of CAA

87

Methylenetetrahydrofolate reductose (MTHFR) TT genotype

Protective for females and risk factor for males for CAA

88

CD14/-159 TT genotype

Associated with CAA

89

CD40 ligand (CD40L) SNP in intron 4

Associated with CAA in males

90

VEGF G allele

Associated with CAA

91

Matrix metalloproteinase-3 gene 6A/6A genotype

Associated with CAA

92

Fc x RIIa HR and RR alleles

May predict failure of IVIG therapy

93

Mannose-bending lectin (MBL)gene MBL2 genotype

May predict failure of IVIG therapy in < 1 year olds

94

are all observations that suggest there may be a genetic influence in the pathogenesis of KD. Many investigators are attempting to identify genetic factors that predispose to acquiring KD or its complications.

Many single-nucleotide polymorphisms (SNPs) have been identified that seem to be associated with susceptibility to KD or a risk factor for developing CAA. Table 5 lists 21 studies that identify polymorphisms or SNPs possibly associated with these or other risks.

Epidemiology and etiology of Kawasaki disease Table 6. Proposed etiological agents of KD

Infections Human herpes virus 6 & 8 Epstein-Barr virus Human parvovirus B-19 Retrovirus Adenovirus TT virus

Propionibacterium acnes Streptococcus mitis Leptospira Erlichia species

Staphylococcus aureus (TSST-1 positive) Chlamydia pneumoniae

The numerous known or candidate SNPs identified on multiple separate gene locations suggest that the genetic influence on pathogenesis, like the inflammatory process itself is highly complex [68]. New genetic markers will undoubtedly be identified in the future.

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