Page 825 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 797

PATHOGENESIS OF KAWASAKI DISEASE such as intercellular adhesion molecule-1, vascular cell adhesion
molecule-1, and E-selectin, suggesting that endothelial cell
The incidence of KD is highest in East Asian countries, such as activation could perpetuate and potentiate the inflammatory
Japan, Korea, and Taiwan. The incidence in Japanese children milieu. IFN-γ and TNF-α increase the expression of class I major
is 10-fold higher compared with that in the United States. histocompatibility complex (MHC) antigens and induce MHC
Japanese data show a seasonal variation in incidence, with an class II expression, resulting in antigen presentation to T cells.
increase seen in the winter; furthermore, siblings of patients with In one study of 24 patients with idiopathic PAN, macrophages
KD are at increased risk of disease compared with the general and CD4 T lymphocytes were the predominant cell types found
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population, and the risk of sibling patients is increased among in lesions. T lymphocytes were more abundant in nerve biopsy
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patients whose parents previously had the disease. KD shows specimens compared with muscle biopsy specimens (52% vs
geographical clustering, with shared clinical features between 35%; p < 0.001), whilst macrophages were predominant in muscle
clusters of disease. These findings suggest a role for an infectious specimens (45% vs 33%; p = 0.005). Histologically, T lympho-
environmental trigger, together with genetic susceptibility. Several cytes were distributed throughout the vessel wall, whereas
disease susceptibility genes have been identified, including genes macrophages predominated in the periphery. 70
that affect the function of molecules involved in the calcineurin- In HBV-induced PAN, there is direct injury to the vessel wall
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nuclear factor of activated T cells (NFATs) pathway; transforming as a result of viral replication and deposition or in situ formation
growth factor-β (TGF-β) lipopolysaccharide-induced endothelial of immune complexes, which activate complement, thereby
cell inflammation pathways; and genes encoding Fcγ receptors, recruiting and activating neutrophils. The immunological process
such as ITPKC, FAM167-BLK, CD40, FCGR2A, HLA, CASP3, usually occurs within 6 months of HBV infection. During the
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TGFB2, TGFBR2, SMAD3, and PLCB4/PLCB1. CD40 and active phase of disease, complement levels are low, consistent
FCGR2A have been associated with disease susceptibility in with complement consumption resulting from immune complex
Europeans. deposition.
SNPs identified within the ITPKC and PLCB4/PLCB1 genes Alterations in the MEFV gene (encoding pyrin) may represent
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are associated with the risk of coronary artery aneurysms. ITPKC an important susceptibility factor for PAN. Pyrin is critically
and CASP3 SNPs are associated with lack of response to intra- important in regulating IL-1β production; mutations of pyrin
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venous immunoglobulin (IVIG) treatment. ITPKC is a negative may be associated with loss of regulation of inflammatory
2+
regulator of T-cell activation via downregulation of the Ca / pathways via apoptosis and IL-1β release, resulting in augmented
NFAT signaling pathway. The SNP located in the intron of ITPKC inflammation, similar to patients with familial Mediterranean
regulates splicing, decreasing negative regulation of T cells and fever, who can be carriers of MEFV mutations. 71
leading to increased T-cell activation and IL-2 production. 63
TNF-α, nuclear factor-κB (NF-κB), IL-17, TGF-β, interferon-γ PATHOGENESIS OF CRYOGLOBULINEMIC
(IFN-γ), granulocyte–colony-stimulating factor (G-CSF), IL-1β, VASCULITIS
IL-6, follistatin-like protein 1, and TLR2 are reported to be
elevated in patients with KD. 64,65 In the acute phase of disease, The pathological hallmark of cryoglobulinemic vasculitis is
circulating IL-17 levels and IL-17–induced cytokinesis are deposition of cold-precipitating Igs in small vessels, resulting in
increased, suggesting an imbalance between Th17 and Tregs. vascular inflammation and damage. In most patients, chronic
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Th17 levels are higher in children with coronary lesions. There HCV infection is the trigger, but cryoglobulinemic vasculitis
is evidence for marked activation of cytotoxic and Th lymphocytes can also occur in the context of other chronic infections and in
and dendritic cells, with upregulation of type I IFN responses, some autoimmune rheumatic diseases and lymphoproliferative
supporting a possible viral etiology of KD, based on a transcrip- disorders.
tomic study of patients who died or who were undergoing heart HCV plays several important roles in the pathogenesis of
transplantation. 67 cryoglobulinemic vasculitis. HCV glycoproteins interact directly
KD has been suspected to be triggered by bacterial or viral with B-cell surface receptors, lowering the activation threshold
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infections, but no single causative agent has been identified. It and resulting in polyclonal activation and expansion of B cells.
has been suggested that superantigens (SAgs) are implicated. Circulating, clonally expanded B cells produce monoclonal
Several microorganisms can produce SAgs, including bacteria IgM rheumatoid factor (RF). Mixed cryoglobulins contain a
(e.g., staphylococci, streptococci, mycobacteria, Mycoplasma, monoclonal IgM RF directed against the Fc segment of IgG and
Yersinia, Lactobacillus) and viruses (e.g., Epstein-Barr virus). polyclonal IgG. When IgM RF is exposed to cold conditions, it
SAg-producing bacteria have been isolated from children with undergoes conformational changes resulting in cryoprecipitation.
acute KD, including TSST-1 producing S. aureus and pyrogenic Cold-insoluble immune complexes are formed predominantly
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exotoxin–producing Streptococcus. In a mouse model involving by IgM RF linked to IgG (which, in turn, is bound to HCV
injections of intraperitoneal Lactobacillus casei, disease could core protein). Cryoglobulinemic vasculitis should be considered
not be induced in recombinase activating gene-1–deficient mice, an antigen-driven disease, because HCV persistence ensures
implicating T cells as critical drivers of the disease process. 69 sustained lymphoid proliferation and continued cryoglobulin
production.
PATHOGENESIS OF POLYARTERITIS NODOSA C1q protein levels and C1q binding are significantly increased
in cryoglobulinemic vasculitis. C1q is required for binding of
The pathogenesis of idiopathic PAN is unknown; clinical immune complexes to endothelial cells. Although mixed cryo-
responses to immunosuppressive therapy strongly support an globulins can be detected in up to 60% of patients with chronic
underlying immunological mechanism. Elevated levels of IL-2, hepatitis C, cryoglobulinemic vasculitis occurs only in a minority,
IL-8, IFN-γ, TNF-α, and IL-1β have been reported in PAN, as suggesting that host factors must be equally important in the
well as elevated levels of circulating soluble adhesion molecules, pathogenesis of the disease.