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1.  Role of Activating FcγR Gene Polymorphisms in Kawasaki Disease Susceptibility and Intravenous Immunoglobulin Response 
Background
A functional polymorphism in the inhibitory IgG-Fc receptor FcγRIIB influences intravenous immunoglobulin (IVIG) response in Kawasaki Disease (KD) a vasculitis preferentially affecting the coronary arteries in children. We tested the hypothesis that the polymorphisms in the activating receptors (Fcγ RIIA, Fcγ RIIIA and Fcγ RIIIB) also influence susceptibility, IVIG treatment response, and coronary artery disease (CAD) in KD patients.
Methods and Results
We genotyped polymorphisms in the activating FcγRIIA, FcγRIIIA and FcγRIIIB genes using pyrosequencing in 443 KD patients, including 266 trios and 150 single parent-child pairs, in northwest US and genetically determined race with 155 ancestry information markers. We used the FBAT program to test for transmission disequilibrium and further generated pseudo-sibling controls for comparisons to the cases. The FcγRIIA-131H variant showed an association with KD (p = 0.001) with ORadditive = 1.51 [1.16–1.96], p = 0.002) for the primary combined population, which persisted in both Caucasian (p = .04) and Asian (p = .01) subgroups and is consistent with the recent genome-wide association study. We also identified over-transmission of FcγRIIIB-NA1 among IVIG non-responders (p = 0.0002), and specifically to Caucasian IVIG non-responders (p = 0.007). Odds ratios for overall and Caucasian non-responders were respectively 3.67 [1.75–7.66], p = 0.0006 and 3.60 [1.34–9.70], p = 0.01. Excess NA1 transmission also occurred to KD with CAD (ORadditive = 2.13 [1.11–4.0], p = 0.02).
Conclusion
A common variation in FcγRIIA is associated with increased KD susceptibility. The FcγRIIIB-NA1, which confers higher affinity for IgG compared to NA2, is a determining factor for treatment response. These activating FcγRs play an important role in KD pathogenesis and mechanism of IVIG anti-inflammatory.
doi:10.1161/CIRCGENETICS.111.962464
PMCID: PMC3444514  PMID: 22565545
coronary disease; pediatrics; Kawasaki disease; IVIG treatment response; FcγR
2.  DC-SIGN gene promoter variants and IVIG treatment response in Kawasaki disease 
Background
Genetic variants in the inhibiting FcγRIIB mediate anti-inflammatory responses and influence IVIG refractoriness (IVIG-R). However, these variants are rare in Asian and Hispanic populations so other genes in the pathway could be potentially involved. IVIG is ineffective in mice lacking SIGN-R1, a related molecule to human DC-SIGN. Further, DC-SIGN is a known receptor for sialylated Fc, the component responsible for the anti-inflammatory action of IVIG. Thus, we hypothesized that DC-SIGN would also be involved in the pathway of IVIG response in Kawasaki Disease (KD) patients.
Findings
A case-control approach was performed to examine the differential distribution of five single nucleotide polymorphisms (SNPs) in DC-SIGN promoter with IVIG-R among White (158 vs. 62), Asian (64 vs. 12) and Hispanic (55 vs. 20) KD patients. Distinct differences in allele frequency distributions of several variants in the DC-SIGN promoter were observed in the three ethnic groups. Further, Asians with the major allele “A” in rs2287886 were more likely (OR = 1.76, p = 0.04) to be IVIG non-responder, but this allele is a minor allele in other two ethnic groups, where the association was not apparent.
Conclusions
DC-SIGN can potentially complement the role of FcγRIIB in the anti-inflammatory cascade involved in the IVIG response mechanism.
doi:10.1186/1546-0096-11-32
PMCID: PMC3847673  PMID: 24006904
Kawasaki disease; IVIG treatment response; FcγR; Coronary artery disease; DC-SIGN
3.  Passively Administered Pooled Human Immunoglobulins Exert IL-10 Dependent Anti-Inflammatory Effects that Protect against Fatal HSV Encephalitis 
PLoS Pathogens  2011;7(6):e1002071.
HSV-1 is the leading cause of sporadic encephalitis in humans. HSV infection of susceptible 129S6 mice results in fatal encephalitis (HSE) caused by massive inflammatory brainstem lesions comprising monocytes and neutrophils. During infection with pathogenic microorganisms or autoimmune disease, IgGs induce proinflammatory responses and recruit innate effector cells. In contrast, high dose intravenous immunoglobulins (IVIG) are an effective treatment for various autoimmune and inflammatory diseases because of potent anti-inflammatory effects stemming in part from sialylated IgGs (sIgG) present at 1–3% in IVIG. We investigated the ability of IVIG to prevent fatal HSE when given 24 h post infection. We discovered a novel anti-inflammatory pathway mediated by low-dose IVIG that protected 129S6 mice from fatal HSE by modulating CNS inflammation independently of HSV specific antibodies or sIgG. IVIG suppressed CNS infiltration by pathogenic CD11b+ Ly6Chigh monocytes and inhibited their spontaneous degranulation in vitro. FcγRIIb expression was required for IVIG mediated suppression of CNS infiltration by CD45+ Ly6Clow monocytes but not for inhibiting development of Ly6Chigh monocytes. IVIG increased accumulation of T cells in the CNS, and the non-sIgG fraction induced a dramatic expansion of FoxP3+ CD4+ T regulatory cells (Tregs) and FoxP3− ICOS+ CD4+ T cells in peripheral lymphoid organs. Tregs purified from HSV infected IVIG treated, but not control, mice protected adoptively transferred mice from fatal HSE. IL-10, produced by the ICOS+ CD4+ T cells that accumulated in the CNS of IVIG treated, but not control mice, was essential for induction of protective anti-inflammatory responses. Our results significantly enhance understanding of IVIG's anti-inflammatory and immunomodulatory capabilities by revealing a novel sIgG independent anti-inflammatory pathway responsible for induction of regulatory T cells that secrete the immunosuppressive cytokine IL-10 and further reveal the therapeutic potential of IVIG for treating viral induced inflammatory diseases.
Author Summary
We show that fatal HSV encephalitis (HSE) is caused by excessive brainstem inflammation. Once brainstem inflammation is initiated, antiviral drugs that inhibit only viral replication are ineffective in protecting against fatal HSE. Infusion of high doses of pooled human IgG (IVIG) is an effective anti-inflammatory treatment for various autoimmune diseases. One anti-inflammatory mechanism depends on sialylated IgGs (sIgG) present in limiting amounts (1–3%) in IVIG, hence the need for high doses of IVIG. We discovered a novel anti-inflammatory pathway mediated by low doses of IVIG independent of sIgG that prevented fatal HSE by suppressing CNS inflammation. The non-sIgG fraction of IVIG induced regulatory CD4+ T cells that produced the immunosuppressive cytokine IL-10 in the brainstem. Importantly, we show that IL-10 is critical for suppressing the generation of pathogenic inflammatory macrophages. Thus, IVIG has a remarkable ability to balance the host inflammatory responses to virus infection and thereby promotes virus clearance without bystander damage to the CNS, accounting for survival of all infected mice. Overall, our results provide important new insights in understanding IVIG's anti-inflammatory activity and further reveal its potential for use in treatment of viral inflammatory diseases.
doi:10.1371/journal.ppat.1002071
PMCID: PMC3107211  PMID: 21655109
4.  Intravenous immunoglobulins modulate neutrophil activation and vascular injury through FcγRIII and SHP-1 
Circulation Research  2012;110(8):1057-1066.
Rationale
Intravascular neutrophil recruitment and activation are a key pathogenic factor that contributes to vascular injury. Intravenous immunoglobulin (IVIG) has been shown to have a beneficial effect in systemic inflammatory disorders; however, the mechanisms underlying IVIG’s inhibitory effect on neutrophil recruitment and activation are not understood.
Objective
We studied the mechanisms by which IVIG exerts protection from neutrophil-mediated acute vascular injury.
Methods and Results
We examined neutrophil behavior in response to IVIG in vivo using real time intravital microscopy. We found that an antibody that blocks both FcγRIII and its inhibitory receptor counterpart, FcγRIIB, abrogated the inhibitory effect of IVIG on leukocyte recruitment and heterotypic RBC interactions with adherent leukocytes in wild-type mice. In the context of sickle cell disease, the blockade of both FcγRIIB and III abrogated the protective effect of IVIG on acute vaso-occlusive crisis caused by neutrophil recruitment and activation. Analysis of FcγRIIB- and FcγRIII-deficient mice revealed the predominant expression of FcγRIII on circulating neutrophils. FcγRIII mediated IVIG-triggered inhibition of leukocyte recruitment, circulating RBC capture, and enhanced Mac-1 activity, whereas FcγRIIB was dispensable. In addition, FcγRIII-induced IVIG anti-inflammatory activity in neutrophils was mediated by recruitment of Src homology 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1). Indeed, the protective effect of IVIG on leukocyte recruitment and activation was abrogated in SHP-1-mutant mice.
Conclusions
FcγRIII, a classical activating receptor, has an unexpected inhibitory role on neutrophil adhesion and activation via recruitment of SHP-1 in response to IVIG. Our results identify SHP-1 as a therapeutic target in neutrophil-mediated vascular injury.
doi:10.1161/CIRCRESAHA.112.266411
PMCID: PMC3351009  PMID: 22415018
neutrophils; vascular injury; FcγRIII; IVIG; SHP-1
5.  Is High-Dose Aspirin Necessary in the Acute Phase of Kawasaki Disease? 
Korean Circulation Journal  2013;43(3):182-186.
Background and Objectives
We sought to determine whether high-dose aspirin is necessary for the acute therapy of Kawasaki disease (KD) in the intravenous immunoglobulin (IVIG) era.
Subjects and Methods
Two groups of KD patients treated during the different periods were included. Study group (n=51, treated with IVIG without concomitant use of aspirin in the acute phase) was compared with control group (n=129, treated with IVIG plus high-dose aspirin) with regard to the response to IVIG, duration of fever after IVIG completion, time to C-reactive protein (CRP) <3 mg/dL, and the incidence of coronary artery lesions (CALs).
Results
There was no difference between the groups in age, sex, and duration of fever before treatment. Pre-IVIG laboratory measures also did not differ from each other. IVIG-resistant cases were 8 (15.7%) in study group and 22 (17.1%) in control group (p=1.000). Mean duration of fever after IVIG completion in IVIG-responsive patients was 13.3±13.5 hours in study group compared to 6.2±8.3 hours in control group (p=0.000). The mean time to decrease in CRP was 4.0±1.7 days in study group and 4.1±2.2 days in control group (p=0.828). There were 2 (3.9%) patients with CALs in study group and 10 (7.8%) in control group (p=0.514).
Conclusion
Although high-dose aspirin shortens the duration of fever, treatment without aspirin in the acute phase has no influence on the response to IVIG, resolution of inflammation, or the development of CALs. In the IVIG era, high-dose aspirin may provide little benefit to the treatment in the acute phase of KD.
doi:10.4070/kcj.2013.43.3.182
PMCID: PMC3629244  PMID: 23613695
Kawasaki disease; Aspirin; Therapeutics
6.  Treatment Response in Kawasaki Disease Is Associated with Sialylation Levels of Endogenous but Not Therapeutic Intravenous Immunoglobulin G 
PLoS ONE  2013;8(12):e81448.
Objectives
Although intravenous immunoglobulin (IVIG) is highly effective in Kawasaki disease (KD), mechanisms are not understood and 10-20% of patients are treatment-resistant, manifesting a higher rate of coronary artery aneurysms. Murine models suggest that α2-6-linked sialic acid (α2-6Sia) content of IVIG is critical for suppressing inflammation. However, pro-inflammatory states also up-regulate endogenous levels of β-galactoside:α2-6 sialyltransferase-I (ST6Gal-I), the enzyme that catalyzes addition of α2-6Sias to N-glycans. We asked whether IVIG failures correlated with levels of α2-6Sia on infused IVIG or on the patient’s own endogenous IgG.
Methods
We quantified levels of α2-6Sia in infused IVIG and endogenous IgG from 10 IVIG-responsive and 10 resistant KD subjects using multiple approaches. Transcript levels of ST6GAL1, in patient whole blood and B cell lines were evaluated by RT-PCR. Plasma soluble (s)ST6Gal-I levels were measured by ELISA.
Results
There was no consistent difference in median sialylation levels of infused IVIG between groups. However, α2-6Sia levels in endogenous IgG, ST6GAL1 transcript levels, and ST6Gal-I protein in serum from IVIG-resistant KD subjects were lower than in responsive subjects at both pre-treatment and one-year time points (p <0.001, respectively).
Conclusions
Our data indicate sialylation levels of therapeutic IVIG are unrelated to treatment response in KD. Rather, lower sialylation of endogenous IgG and lower blood levels of ST6GALI mRNA and ST6Gal-I enzyme predict therapy resistance. These differences were stable over time, suggesting a genetic basis. Because IVIG-resistance increases risk of coronary artery aneurysms, our findings have important implications for the identification and treatment of such individuals.
doi:10.1371/journal.pone.0081448
PMCID: PMC3855660  PMID: 24324693
7.  Immunomodulation by IVIg and the Role of Fc-Gamma Receptors: Classic Mechanisms of Action after all? 
Intravenous IgG (IVIg) contains polyclonal immunoglobulin G (IgG) from thousands of donors. It is administered at a low dose at regular intervals as antibody replacement therapy and at a higher dose as immunomodulatory treatment in various auto-immune or auto-inflammatory diseases. The working mechanism of immunomodulation is not well understood. Many different explanations have been given. During the last decade, we have focused on classical antibody binding via the Fc-domain of the IgG molecules to the common IgG receptors, i.e. the Fcγ receptors (FcγRs). Variation in the genes encoding human FcγRs determines function as well as expression among immune cells. As described here, NK cells and myeloid cells, including macrophages, can express different FcγR variants, depending on the individual’s genotype, copy number variation (CNV), and promoter polymorphisms. B-cells seem to only express the single inhibitory receptor. Although these inhibitory FcγRIIb receptors are also expressed by monocytes, macrophages, and only rarely by NK cells or neutrophils, their presence is unlikely to explain the immunomodulatory capacity of IVIg, nor does the sialylation of IgG. Direct IVIg effects at the level of the activating FcγRs, including the more recently described FcγRIIc, deserve renewed attention to describe IVIg-related immunomodulation.
doi:10.3389/fimmu.2014.00674
PMCID: PMC4301001  PMID: 25653650
IgG; Fc gamma receptors; immunomodulation; IVIg; mechanisms of action
8.  Management of Kawasaki disease 
Kawasaki disease (KD) is an acute self-limiting inflammatory disorder, associated with vasculitis, affecting predominantly medium-sized arteries, particularly the coronary arteries. In developed countries KD is the commonest cause of acquired heart disease in childhood. The aetiology of KD remains unknown, and it is currently believed that one or more as yet unidentified infectious agents induce an intense inflammatory host response in genetically susceptible individuals. Genetic studies have identified several susceptibility genes for KD and its sequelae in different ethnic populations, including FCGR2A, CD40, ITPKC, FAM167A-BLK and CASP3, as well as genes influencing response to intravenous immunoglobulin (IVIG) and aneurysm formation such as FCGR3B, and transforming growth factor (TGF) β pathway genes. IVIG and aspirin are effective therapeutically, but recent clinical trials and meta-analyses have demonstrated that the addition of corticosteroids to IVIG is beneficial for the prevention of coronary artery aneurysms (CAA) in severe cases with highest risk of IVIG resistance. Outside of Japan, however, clinical scores to predict IVIG resistance perform suboptimally. Furthermore, the evidence base does not provide clear guidance on which corticosteroid regimen is most effective. Other therapies, including anti-TNFα, could also have a role for IVIG-resistant KD. Irrespective of these caveats, it is clear that therapy that reduces inflammation in acute KD, improves outcome. This paper summarises recent advances in the understanding of KD pathogenesis and therapeutics, and provides an approach for managing KD patients in the UK in the light of these advances.
doi:10.1136/archdischild-2012-302841
PMCID: PMC3888612  PMID: 24162006
Infectious Diseases; Rheumatology
9.  Clinical Outcomes of Initial Dexamethasone Treatment Combined with a Single High Dose of Intravenous Immunoglobulin for Primary Treatment of Kawasaki Disease 
Yonsei Medical Journal  2014;55(5):1260-1266.
Purpose
To investigate the clinical effects of a single high dose intravenous immunoglobulin (IVIG) combined with initial dexamethasone as a primary treatment on Kawasaki disease (KD).
Materials and Methods
Between January 2008 and December 2010, we reviewed the medical records of 216 patients with complete KD patients that were admitted to a single medical center. 106 patients were treated with a single high dose of IVIG (2 g/kg) alone and 110 patients received IVIG and dexamethasone (0.3 mg/kg per day for three days).
Results
The combined IVIG plus dexamethasone patient group had a significantly shorter febrile period and duration of hospital stay (1.4±0.7 days vs. 2.0±1.2 days, p<0.001; 5.8±1.7 days vs. 6.9±2.5 days, p<0.001, respectively) than the IVIG alone group. The combined IVIG plus dexamethasone group required IVIG retreatment significantly less than the IVIG only group (12.7% vs. 32%, p=0.003). After completion of the initial IVIG, C-reactive protein levels in the combined IVIG plus dexamethasone group were significantly lower than those in the IVIG only group (2.7±4.0 mg/dL vs. 4.6±8.7 mg/dL, p=0.03). In the combined IVIG plus dexamethasone group, the incidence of coronary artery lesions tended to be lower without worse outcomes at admission after initial infusion of IVIG and in follow-up at two months; however, the differences were not significant (8.2% vs. 11.3%, p=0.22; 0.9% vs. 2.8%, p=0.29).
Conclusion
Initial combined therapy with dexamethasone and a single high-dose of IVIG resulted in an improved clinical course, in particular a shorter febrile period, less IVIG retreatment, and shorter hospital stay without worse coronary outcomes.
doi:10.3349/ymj.2014.55.5.1260
PMCID: PMC4108810  PMID: 25048483
Dexamethasone; high-dose intravenous immunoglobulin; combined therapy; Kawasaki disease
10.  Parameters to Guide Retreatment After Initial Intravenous Immunoglobulin Therapy in Kawasaki Disease 
Korean Circulation Journal  2011;41(7):379-384.
Background and Objectives
We sought to determine parameters to guide the decision of retreatment in patients with Kawasaki disease (KD) who remained febrile after initial intravenous immunoglobulin (IVIG).
Subjects and Methods
A total of 129 children with KD were studied prospectively. Patients were treated with IVIG 2 to 9 days after the onset of disease. Laboratory measures, such as white blood cell (WBC), percentage of neutrophils, C-reactive protein (CRP), and N-terminal pro-brain natriuretic peptide (NT-proBNP), were determined before and 48 to 72 hours after IVIG treatment. Patients were classified into IVIG-responsive and IVIG-resistant groups, based on the response to IVIG.
Results
Of a total of 129 patients, 107 patients (83%) completely responded to a single IVIG therapy and only 22 patients (17%) required retreatment: 14 had persistent fever and 8 had recrudescent fever. There was no significant difference between the groups in age, gender distribution, and duration of fever to IVIG initiation, but coronary artery lesions developed significantly more often in the resistant group than in the responsive group (31.8% vs. 2.8%, p=0.000). Compared with pre-IVIG data, post-IVIG levels of WBC, percentage of neutrophils, CRP, and NT-proBNP decreased to within the normal range in the responsive group, whereas they remained high in the resistant group. Multivariate logistic regression indicated that neutrophil counts, CRP, and NT-proBNP were independent parameters of retreatment.
Conclusion
Additional therapy at an early stage of the disease should be administered for febrile patients who have high values of CRP, NT-proBNP, and/or neutrophil counts after IVIG therapy.
doi:10.4070/kcj.2011.41.7.379
PMCID: PMC3152732  PMID: 21860639
Kawasaki disease; Intravenous immunoglobulins; Retreatment
11.  Predicting Factors for Refractory Kawasaki Disease 
Korean Circulation Journal  2010;40(5):239-242.
Background and Objectives
About 10-15% of Kawasaki disease (KD) is refractory to intravenous immunoglobulin (IVIG) therapy. This study was designed to investigate the predicting factors for refractory KD.
Subjects and Methods
We reviewed retrospectively the clinical records of 77 patients with typical KD admitted at Wonju Christian Hospital from January, 2005, to December, 2008. The variance of laboratory and demographic parameters between the IVIG-responsive group and IVIG-resistant group were analyzed. Thirteen patients with urinary tract infections were randomly collected as a febrile control group.
Results
Among 77 patients diagnosed with complete KD, 13 patients (16.9%) were IVIG-resistant. The febrile period and hospital days were significantly longer in the IVIG-resistant group than IVIG-responsive group (p<0.001, p=0.002). Serum levels of albumin and sodium were significantly lower in the IVIG-resistant group (p=0.025). The Kobayashi score could differentiate these two groups (p=0.015). Fewer lymphocytes was observed during the subacute phase in the IVIG-resistant group (p=0.032). Coronary arterial dilatations (CADs) were observed in 10.9% (7/64) of IVIG-responders and 38.5% (5/13) of IVIG-resistant patients (p=0.038).
Conclusion
The percentage of neutrophils and lymphocytes in patients with KD, in addition to known risk factors for refractory KD, may help predict IVIG-resistance in patients with KD.
doi:10.4070/kcj.2010.40.5.239
PMCID: PMC2877789  PMID: 20514335
Mucocutaneous Lymph Node Syndrome; Risk factors; Coronary arteries
12.  A Case of Kawasaki Disease with Coronary Aneurysm Responding to the 4th IVIG Treatment 
Case Reports in Cardiology  2014;2014:821812.
Kawasaki disease is an acute febrile illness that usually occurs in children younger than 5 years of age. The use of intravenous immunoglobulin (IVIG) within the first 10 days of illness has been shown to reduce the incidence of coronary artery aneurysms significantly. The relative roles of repeated doses of intravenous immunoglobulin (IVIG) are controversial in refractory Kawasaki disease (KD). Most experts recommend the second retreatment with IVIG, 2 g/kg in refractory KD. However, the dose-response effect of the third or fourth IVIG was uncertain. Although there have been a significant number of reports on new therapeutic options for refractory KD, such as steroid, infliximab, methotrexate, and other immunosuppressants, their effectiveness in reducing the prevalence of coronary artery aneurysms was unproven. We present here KD patient with small coronary artery aneurysm who is resistant to the third IVIG and steroid pulse therapy but showed improvement immediately after the infusion of the 4th IVIG on fever day 18.
doi:10.1155/2014/821812
PMCID: PMC4137746  PMID: 25161773
13.  FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications 
Nature reviews. Immunology  2010;10(5):328-343.
FcγRIIB is the only inhibitory Fc receptor. It controls many aspects of immune and inflammatory responses, and variation in the gene encoding this protein has long been associated with susceptibility to autoimmune disease, particularly systemic lupus erythematosus (SLE). FcγRIIB is also involved in the complex regulation of defence against infection. A loss-of-function polymorphism in FcγRIIB protects against severe malaria, the investigation of which is beginning to clarify the evolutionary pressures that drive ethnic variation in autoimmunity. Our increased understanding of the function of FcγRIIB also has potentially far-reaching therapeutic implications, being involved in the mechanism of action of intravenous immunoglobulin, controlling the efficacy of monoclonal antibody therapy and providing a direct therapeutic target.
doi:10.1038/nri2762
PMCID: PMC4148599  PMID: 20414206
14.  DC-SIGN (CD209) Promoter −336 A/G (rs4804803) Polymorphism Associated with Susceptibility of Kawasaki Disease 
The Scientific World Journal  2012;2012:634835.
Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. High-dose intravenous immunoglobulin (IVIG) is the most effective therapy for KD to reduce the prevalence of coronary artery lesion (CAL) formation. Recently, the α2, 6 sialylated IgG was reported to interact with a lectin receptor, specific intracellular adhesion molecule-3 grabbing nonintegrin homolog-related 1 (SIGN-R1) in mice and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) in human, and to trigger an anti-inflammatory cascade. This study was conducted to investigate whether the polymorphism of DC-SIGN (CD209) promoter −336 A/G (rs4804803) is responsible for susceptibility and CAL formation in KD patients using Custom TaqMan SNP Genotyping Assays. A total of 521 subjects (278 KD patients and 243 controls) were investigated to identify an SNP of rs4804803, and they were studied and showed a significant association between the genotypes and allele frequency of rs4804803 in control subjects and KD patients (P = 0.004 under the dominant model). However, the promoter variant of DC-SIGN gene was not associated with the occurrence of IVIG resistance, CAL formation in KD. The G allele of DC-SIGN promoter −336 (rs4804803) is a risk allele in the development of KD.
doi:10.1100/2012/634835
PMCID: PMC3354554  PMID: 22629172
15.  Hemolytic anemia following intravenous immunoglobulin therapy in patients treated for Kawasaki disease: a report of 4 cases 
Background
Hemolytic anemia is a rare but reported side effect of intravenous immunoglobulin (IVIG) therapy. The risk of significant hemolysis appears greater in those patients who receive high dose IVIG. The etiology is multifactorial but may relate to the quantity of blood group antibodies administered via the IVIG product.
Findings
We describe 4 patients with significant hemolytic anemia following treatment with IVIG for Kawasaki disease (KD). Direct antibody mediated attack as one of the mechanisms for hemolysis, in this population, is supported by the demonstration of specific blood group antibodies in addition to a positive direct antiglobulin test in our patients.
Conclusions
Clinicians should be aware of this complication and hemoglobin should be closely monitored following high dose IVIG therapy.
doi:10.1186/1546-0096-10-10
PMCID: PMC3353234  PMID: 22507284
Direct antiglobulin test; Isohemagglutinins; Retreatment
16.  Transcript abundance patterns in Kawasaki disease patients with IVIG resistance 
Human immunology  2010;71(9):865-873.
Intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) patients comprise at least 20% of treated patients and are at higher risk of coronary artery abnormalities. If identified early in the course of the disease, such patients may benefit from additional anti-inflammatory therapy. The aim of this study was to compare the transcript abundance between IVIG-resistant and – responsive KD patients to identify biomarkers that might differentiate between these two groups and to generate new targets for therapies in IVIG-resistant KD patients. We compared the transcript abundance profiles of whole blood RNA on Agilent arrays from acute and convalescent KD subjects and age-similar, healthy controls. KD subjects were stratified as IVIG-resistant or – responsive based on response to initial IVIG therapy. Transcript abundance was higher for IL-1 pathway genes (IL-1 receptor, interleukin receptor associated kinase, p38 mitogen-activated protein kinase), and MMP-8. These findings point to candidate biomarkers that may predict IVIG-resistance in acute KD patients. The results also underscore the importance of the IL-1 pathway as a mediator of inflammation in KD and suggest that IL-1 or its receptor may be reasonable targets for therapy, particularly for IVIG-resistant patients.
doi:10.1016/j.humimm.2010.06.008
PMCID: PMC2929310  PMID: 20600450
Kawasaki disease; gene expression; intravenous immunoglobulin
17.  FcγRIIB Regulation of BCR/TLR-Dependent Autoreactive B Cell Responses 
European journal of immunology  2010;40(10):2692-2698.
Summary
Crosslinking of FcγRIIB and the BCR by immune complexes (ICs) can downregulate antigen-specific B cell responses. Accordingly, FcγRIIB deficiencies have been associated with B cell hyperactivity in patients with SLE and mouse models of lupus. However, we have previously shown that murine IgG2a-autoreactive AM14 B cells respond robustly to chromatin- associated ICs through a mechanism dependent on both the BCR and endosomal TLR9, despite FcγRIIB coexpression. To further evaluate the potential contribution of FcγRIIB to the regulation of autoreactive B cells, we have now compared the IC-triggered responses of FcγRIIB-deficient and FcγRIIB-sufficient AM14 B cells. We find that FcγRIIB-deficient cells respond significantly better than FcγRIIB-sufficient cells when stimulated with DNA ICs that incorporate low affinity TLR9 ligand (CG-poor dsDNA fragments). AM14 B cells also respond to RNA-associated ICs through BCR/TLR7 coengagement, but such BCR/TLR7 dependent responses are normally highly dependent on IFNα costimulation. However, we now show that AM14 FcγRIIB-/- B cells are very effectively activated by RNA ICs without supplemental IFNα priming. These results demonstrate that FcγRIIB can effectively modulate both BCR/TLR9 and BCR/TLR7 endosomal-dependent activation of autoreactive B cells.
doi:10.1002/eji.200940184
PMCID: PMC3060940  PMID: 20809520
Autorective B cells; endogenous TLR ligands; inhibitory Fc receptor
18.  EVALUATION OF KAWASAKI DISEASE RISK SCORING SYSTEMS FOR INTRAVENOUS IMMUNOGLOBULIN RESISTANCE 
The Journal of pediatrics  2010;158(5):831-835.e3.
Objectives
To assess the performance of three risk scores from Japan that were developed to predict, in children with Kawasaki disease, resistance to intravenous immunoglobulin (IVIG) treatment.
Study design
We used data from a randomized trial of pulsed steroids for primary treatment of Kawasaki disease to assess operating characteristics of the three risk scores, and we examined whether steroid therapy lowers the risk of coronary artery abnormalities in patients prospectively classified as IVIG resistant.
Results
For comparability with published cohorts, we analyzed the data of 99 patients not treated with steroids (16% IVIG-retreated), and identified male sex, lower albumin and higher AST as independent risk factors for IVIG resistance. The Kobayashi score was similar in IVIG-resistant and responsive patients, yielding sensitivity=33% and specificity=87%. There was no interaction of high vs. low risk status by treatment received (steroid vs. placebo) using any of the three risk score algorithms.
Conclusion
Risk scoring systems from Japan have good specificity but low sensitivity for predicting IVIG resistance in a North American cohort. Primary steroid therapy did not improve coronary outcomes among patients prospectively classified as high risk for IVIG resistance.
doi:10.1016/j.jpeds.2010.10.031
PMCID: PMC3075321  PMID: 21168857
Kawasaki; pediatrics; inflammation; therapy
19.  Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease? 
Journal of Clinical Investigation  2005;115(1):155-160.
Intravenous Ig (IVIg) mediates protection from the effects of immune thrombocytopenic purpura (ITP) as well as numerous other autoimmune states; however, the active antibodies within IVIg are unknown. There is some evidence that antibodies specific for a cell-associated antigen on erythrocytes are responsible, at least in part, for the therapeutic effect of IVIg in ITP. Yet whether an IVIg directed to a soluble antigen can likewise be beneficial in ITP or other autoimmune diseases is also unknown. A murine model of ITP was used to determine the effectiveness of IgG specific to soluble antigens in treating immune thrombocytopenic purpura. Mice experimentally treated with soluble OVA + anti-OVA versus mice treated with OVA conjugated to rbcs (OVA-rbcs) + anti-OVA were compared. In both situations, mice were protected from ITP. Both these experimental therapeutic regimes acted in a complement-independent fashion and both also blocked reticuloendothelial function. In contrast to OVA-rbcs + anti-OVA, soluble OVA + anti-OVA (as well as IVIg) did not have any effect on thrombocytopenia in mice lacking the inhibitory receptor FcγRIIB (FcγRIIB–/– mice). Similarly, antibodies reactive with the endogenous soluble antigens albumin and transferrin also ameliorated ITP in an FcγRIIB-dependent manner. Finally, broadening the significance of these experiments was the finding that anti-albumin was protective in a K/BxN serum–induced arthritis model. We conclude that IgG antibodies directed to soluble antigens ameliorated 2 disparate IVIg-treatable autoimmune diseases.
doi:10.1172/JCI200522753
PMCID: PMC539200  PMID: 15630455
20.  Prediction of Resistance to Standard Intravenous Immunoglobulin Therapy in Kawasaki Disease 
Korean Circulation Journal  2014;44(6):415-422.
Background and Objectives
Ten to twenty percent of children with Kawasaki disease (KD) do not respond to initial intravenous immunoglobulin (IVIG) treatment. If untreated, approximately 15% to 25% of KD patients have complications. The aim of this study was to find useful predictors of responsiveness to initial IVIG treatment in KD.
Subjects and Methods
We retrospectively reviewed medical records of 91 children diagnosed with KD at Myong Ji Hospital from March 2012 to April 2014. Before and after (24 hours to 36 hours) IVIG treatment, the following laboratory data were obtained: hemoglobin (Hb) level, white blood cell count, proportion of neutrophil, lymphocyte and eosinophil, platelet count, erythrocyte sedimentation rate (ERS), C-reactive protein (CRP), creatine kinase (CK), creatine kinase MB (CK-MB), and N-terminal pro-brain natriuretic peptide (NT-proBNP). Subjects were then divided into two groups: IVIG-responsive or IVIG-resistant.
Results
Of 91 patients, 11 (12%) required retreatment. By univariate analysis, before-IVIG laboratory parameters of white blood cell count, % neutrophil, ERS, CRP, sodium, CK, CK-MB, and NT-proBNP were significantly different between IVIG-responsive and IVIG-resistant patient groups. In the after-IVIG laboratory parameters, Hb level, white blood cell count, % neutrophil, % lymphocyte, CRP, CK, CK-MB, and NT-pro-BNP were significantly different between the two groups. While the mean-differences were not statistically significant, fractional change (FC)-CRP and FC-% neutrophil showed significant difference. By multivariate analysis, FC-CRP was confirmed to be an independent predictor for initial IVIG resistance.
Conclusion
Fractional change-C-reactive protein might be a useful and important value for predicting initial IVIG resistance in KD patients.
doi:10.4070/kcj.2014.44.6.415
PMCID: PMC4248614  PMID: 25469144
Kawasaki disease; Immunoglobulins, intravenous; Risk factors
21.  FcγRIIb Inhibits Allergic Lung Inflammation in a Murine Model of Allergic Asthma 
PLoS ONE  2010;5(2):e9337.
Allergic asthma is characterized by airway eosinophilia, increased mucin production and allergen-specific IgE. Fc gamma receptor IIb (FcγRIIb), an inhibitory IgG receptor, has recently emerged as a negative regulator of allergic diseases like anaphylaxis and allergic rhinitis. However, no studies to date have evaluated its role in allergic asthma. Our main objective was to study the role of FcγRIIb in allergic lung inflammation. We used a murine model of allergic airway inflammation. Inflammation was quantified by BAL inflammatory cells and airway mucin production. FcγRIIb expression was measured by qPCR and flow cytometry and the cytokines were quantified by ELISA. Compared to wild type animals, FcγRIIb deficient mice mount a vigorous allergic lung inflammation characterized by increased bronchoalveolar lavage fluid cellularity, eosinophilia and mucin content upon ragweed extract (RWE) challenge. RWE challenge in sensitized mice upregulated FcγRIIb in the lungs. Disruption of IFN-γ gene abrogated this upregulation. Treatment of naïve mice with the Th1-inducing agent CpG DNA increased FcγRIIb expression in the lungs. Furthermore, treatment of sensitized mice with CpG DNA prior to RWE challenge induced greater upregulation of FcγRIIb than RWE challenge alone. These observations indicated that RWE challenge upregulated FcγRIIb in the lungs by IFN-γ- and Th1-dependent mechanisms. RWE challenge upregulated FcγRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells. FcγRIIb deficient mice also exhibited an exaggerated RWE-specific IgE response upon sensitization when compared to wild type mice. We propose that FcγRIIb physiologically regulates allergic airway inflammation by two mechanisms: 1) allergen challenge mediates upregulation of FcγRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells by an IFN-γ dependent mechanism; and 2) by attenuating the allergen specific IgE response during sensitization. Thus, stimulating FcγRIIb may be a therapeutic strategy in allergic airway disorders.
doi:10.1371/journal.pone.0009337
PMCID: PMC2825267  PMID: 20179765
22.  Steroid pulse therapy for Kawasaki disease unresponsive to additional immunoglobulin therapy 
Paediatrics & Child Health  2011;16(8):479-484.
BACKGROUND:
The optimal management of Kawasaki disease (KD) unresponsive to intravenous immunoglobulin (IVIG) therapy remains unclear.
OBJECTIVE:
To prospectively evaluate the efficacy and safety of intravenous methylprednisolone pulse (IVMP) therapy in KD cases unresponsive to additional IVIG.
METHODS:
KD patients who initially received IVIG (2 g/kg/24 h) and acetylsalicylic acid within nine days after disease onset were studied. Patients who did not respond received additional IVIG (2 g/kg/24 h), and those who still did not respond were given IVMP (30 mg/kg/day) for three days, followed by oral prednisolone. The response to treatment, echocardiographic findings and adverse effects were evaluated.
RESULTS:
Among 412 KD cases, 74 (18.0%) were treated with additional IVIG; 21 (28.4%) of the latter cases subsequently received IVMP followed by prednisolone. All cases became afebrile soon after IVMP infusion and did not have a high-grade fever during treatment with prednisolone for two to six weeks. Four weeks after disease onset, coronary artery lesions (CAL) were diagnosed according to the Japanese Ministry of Health and Welfare or the American Heart Association criteria in two of the 21 cases treated with IVMP plus prednisolone; among all 412 cases, three (0.7%) and eight (1.9%) had CAL according to each criteria, respectively. All CAL regressed completely one year after disease onset. Adverse effects of IVMP, such as hypothermia and sinus bradycardia, resolved spontaneously.
CONCLUSIONS:
In KD patients unresponsive to additional IVIG, IVMP promptly induced defervescence, and subsequent oral prednisolone suppressed recurrence of fever. IVMP followed by prednisolone therapy may prevent CAL, without severe adverse effects.
PMCID: PMC3202387  PMID: 23024586
Coronary artery lesions; Kawasaki disease; Nonresponders to intravenous immunoglobulin; Prednisolone; Steroid pulse
23.  Performance of 2004 American Heart Association Recommendations for Treatment of Kawasaki Disease 
Pediatrics  2010;125(2):e234-e241.
OBJECTIVE
The 2004 American Heart Association (AHA) statement included a clinical case definition and an algorithm for diagnosing and treating suspected incomplete Kawasaki disease (KD). We explored the performance of these recommendations in a multicenter series of US patients with KD with coronary artery aneurysms (CAAs).
METHODS
We reviewed retrospectively records of patients with KD with CAAs at 4 US centers from 1981 to 2006. CAAs were defined on the basis of z scores of >3 or Japanese Ministry of Health and Welfare criteria. Our primary outcome was the proportion of patients presenting at illness day ≤21 who would have received intravenous immunoglobulin (IVIG) treatment by following the AHA guidelines at the time of their initial presentation to the clinical center.
RESULTS
Of 195 patients who met entry criteria, 137 (70%) met the case definition and would have received IVIG treatment at presentation. Fifty-three patients (27%) had suspected incomplete KD and were eligible for algorithm application; all would have received IVIG treatment at presentation. Of the remaining 5 patients, 3 were excluded from the algorithm because of fever for <5 days at presentation and 2 because of <2 clinical criteria at >6 months of age. Two of these 5 patients would have entered the algorithm and received IVIG treatment after follow-up monitoring. Overall, application of the AHA algorithm would have referred ≥190 patients (97%) for IVIG treatment.
CONCLUSIONS
Application of the 2004 AHA recommendations, compared with the classic criteria alone, improves the rate of IVIG treatment for patients with KD who develop CAAs. Future multicenter prospective studies are needed to assess the performance characteristics of the AHA algorithm in febrile children with incomplete criterion findings and to refine the algorithm further.
doi:10.1542/peds.2009-0606
PMCID: PMC2896313  PMID: 20100771
Kawasaki disease; guidelines; diagnostic recommendations; cardiac disease; coronary aneurysm
24.  Interferon Regulatory Factor 5 Is Required For Disease Development In The FcγRIIB−/−Yaa and FcγRIIB−/− Mouse Models Of Systemic Lupus Erythematosus 1 
Polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are strongly associated in human genetic studies with an increased risk of developing the autoimmune disease systemic lupus erythematosus. However, the biological role of IRF5 in lupus pathogenesis has not previously been tested in an animal model. In this study we show that IRF5 is absolutely required for disease development in the FcγRIIB−/−Yaa and FcγRIIB−/− lupus models. In contrast to IRF5-sufficient FcγRIIB−/−Yaa mice, IRF5-deficient FcγRIIB−/−Yaa mice do not develop lupus manifestations and have a phenotype comparable to wildtype mice. Strikingly, full expression of IRF5 is required for the development of autoimmunity as IRF5-heterozygotes had dramatically reduced disease. One effect of IRF5 is to induce the production of the type I interferon IFN-α, a cytokine implicated in lupus pathogenesis. To address the mechanism by which IRF5 promotes disease, we evaluated FcγRIIB−/−Yaa mice lacking the type I interferon receptor IFNAR1. Unlike the IRF5-deficient and IRF5-heterozygous FcγRIIB−/−Yaa mice, IFNAR1-deficient FcγRIIB−/−Yaa mice maintained a substantial level of residual disease. Furthermore, in FcγRIIB−/− mice lacking Yaa, IRF5-deficiency also markedly reduced disease manifestations indicating that the beneficial effects of IRF5 deficiency in FcγRIIB−/−Yaa mice are not due only to inhibition of the enhanced TLR7 signaling associated with the Yaa mutation. Overall, we demonstrate that IRF5 plays an essential role in lupus pathogenesis in murine models and that this is mediated through pathways beyond that of type I interferon production.
doi:10.4049/jimmunol.0901748
PMCID: PMC2858062  PMID: 20007534
25.  Plasma Clusterin Concentrations May Predict Resistance to Intravenous Immunoglobulin in Patients with Kawasaki Disease 
The Scientific World Journal  2013;2013:382523.
Kawasaki disease (KD) is an acute febrile vasculitic syndrome of early childhood often complicated by coronary artery lesion that drastically reduces the quality of life. The study aimed to identify a reliable marker for predicting nonresponsiveness to the first course of intravenous immunoglobulin (IVIG) in KD patients. A total of 63 patients with KD were enrolled in the study (IVIG response, 58; IVIG resistance, 5). Plasma samples were collected before and after IVIG infusion for measurement of biomarkers. Patients' clinical characteristics and laboratory data were also analyzed. A receiver operating characteristic curve was generated to identify a cut-off value for predicting IVIG resistance. Among the biomarkers, the difference in plasma clusterin concentrations before and after IVIG infusion (CLUSTER 12) was significantly related to IVIG resistance (P = 0.040; 95% confidence interval (CI): −25.8% to −6.0%). Using a CLUSTER 12 cut-off value of <8.52 mg/L, the odds ratio for IVIG resistance was 11.467 (95% CI: 1.186 to 110.853). Patients with plasma CLUSTER 12 concentrations >8.52 mg/L had a much higher risk of IVIG resistance than those with CLUSTER 12 concentrations <8.52 mg/L. Plasma clusterin concentration shows promise as a candidate biomarker for predicting IVIG resistance in patients with KD.
doi:10.1155/2013/382523
PMCID: PMC3727184  PMID: 23956692

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