Next Article in Journal
Overall Dietary Quality Relates to Gut Microbiota Diversity and Abundance
Next Article in Special Issue
Targeting Brain Disease in MPSII: Preclinical Evaluation of IDS-Loaded PLGA Nanoparticles
Previous Article in Journal
A Novel Standardized Cannabis sativa L. Extract and Its Constituent Cannabidiol Inhibit Human Polymorphonuclear Leukocyte Functions
Previous Article in Special Issue
The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers
Article Menu
Issue 8 (April-2) cover image

Export Article

Int. J. Mol. Sci. 2019, 20(8), 1834;

B Cells and Antibodies in Kawasaki Disease
United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA
Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14222, USA
Author to whom correspondence should be addressed.
Received: 19 March 2019 / Accepted: 11 April 2019 / Published: 13 April 2019


The etiology of Kawasaki disease (KD), the leading cause of acquired heart disease in children, is currently unknown. Epidemiology supports a relationship of KD to an infectious disease. Several pathological mechanisms are being considered, including a superantigen response, direct invasion by an infectious etiology or an autoimmune phenomenon. Treating affected patients with intravenous immunoglobulin is effective at reducing the rates of coronary aneurysms. However, the role of B cells and antibodies in KD pathogenesis remains unclear. Murine models are not clear on the role for B cells and antibodies in pathogenesis. Studies on rare aneurysm specimens reveal plasma cell infiltrates. Antibodies generated from these aneurysmal plasma cell infiltrates showed cross-reaction to intracellular inclusions in the bronchial epithelium of a number of pathologic specimens from children with KD. These antibodies have not defined an etiology. Notably, a number of autoantibody responses have been reported in children with KD. Recent studies show acute B cell responses are similar in children with KD compared to children with infections, lending further support of an infectious disease cause of KD. Here, we will review and discuss the inconsistencies in the literature in relation to B cell responses, specific antibodies, and a potential role for humoral immunity in KD pathogenesis or diagnosis.
aggresomes; antibodies; B cells; plasmablasts; inclusions; virus-like particles; endothelial

1. Introduction

1.1. Overview

Kawasaki disease (KD), also known as Kawasaki syndrome, is the leading cause of acquired cardiac disease in children [1]. Diagnosis is purely clinical, as there are no adequately specific or sensitive tests available. The ‘classic’ diagnosis involves five days of fever and having four of the five following criteria: Mucous membrane inflammation, rash, hands and feet swelling, conjunctivitis, and a solitary inflamed lymph node mass [2,3,4,5]. If left untreated, roughly one-quarter of the children meeting clinical criteria will go on to have coronary artery inflammation, including aneurysms. Incomplete cases, those which do not fulfill four of five of the classic criteria, have similar risk of coronary aneurysms [6]. Treating affected patients with intravenous immunoglobulin (IVIG) reduces the rates of coronary aneurysms, with a minority seemingly resistant to treatment [2,3,4,7,8,9,10]. Although most aneurysms resolve, some defects are retained. Initial studies done on adults with a history of KD implies there is a greater lifetime risk of cardiac issues and early mortality [11,12,13,14]. To add to the diagnostic confusion, several infectious etiologies have also been independently associated with aneurysms [15]. It remains a frustrating diagnosis because of the unknown etiology, clinical variability, lack of specific testing, and unclear pathogenesis.

1.2. Genetic Background

There appears to be a genetic influence in exhibiting KD. Incidence is higher in some genetic backgrounds and consistently appears in males greater than females within those backgrounds [16]. By age five in the United States, 1 in 1000 African-American children and 1 in 2000 Caucasian children will have been affected [17,18,19]. In general, Asians have a much higher rate of KD, this is especially evident in Japanese children, whose lifetime incidence rate is near 1% [20]. This predisposition holds even for those persons of Japanese heritage raised in foreign lands, such as the United States [16].

1.3. Epidemiology

The etiology of KD is unknown [4,21,22]. However, there is a proposed relation to an infectious agent. Epidemiological evidence for this comes from the fact that there are seasonal peaks of KD during winter and spring months and outbreaks have been described [22,23,24,25,26,27,28]. Siblings have a higher rate of KD than the general population; usually cases are within the first year [29], and can be as high as up to 50% of cases within 10 days of each other [30]. Recent studies show a lower incidence in breastfed infants [31] and KD is rare in both newborns and individuals over five years of age. This implies a maternally derived protective immunity to a ubiquitous infectious agent [32]. This phenomenon is similar to epidemiological findings with human herpesvirus-6 (HHV-6) infections. In fact, HHV-6 is one of several potential etiologies that have been proposed as the cause of KD [11,16]. Other notable infectious agents include other Herpesviridae (Epstein Barr virus, Cytomegalovirus), human coronavirus (New Haven), retroviruses, Parvovirus B19, bocavirus, and bacterial infections such as staphylococci, streptococci, Bartonella, and Yersinia infections. Some of these agents have been independently associated with aneurysm formation [15]. Epstein Barr virus particularly is associated with coronary aneurysms [33]. Several non-infectious agents have also been proposed such as carpet shampoos, mercury and living near bodies of water [11,16]. Additionally, the recent report of tropospheric wind patterns correlating with outbreaks in Japan would not be consistent with many of the viruses that have been proposed [21,34,35]. These reports imply a relationship to an environmental antigen, as either a priming or inciting event.
If a ubiquitous childhood virus is the cause of KD, the mode of entry would likely be a common mode of infection such as fecal–oral or respiratory spread. To note, mild upper respiratory symptoms have been described in up to 35% of cases [36] with rare but more significant pulmonary disease also being reported [37]. Additionally, outbreaks in the United States have been associated with preceding viral illness [38]. Notably, however, concomitant respiratory viruses are only shown in 9% of cases [39], and in the same study that showed 35% with respiratory symptoms, 61% were noted to have gastrointestinal complaints.

1.4. Theories on Pathogenesis

It is possible that there is not one cause of KD, but multiple etiologies that result in similar pathogenesis. This may explain the clinical variability and lack of a definitive agent, however, the low recurrence rate even in high prevalence areas speaks against a large number of causes [40]. A superantigen response was considered by numerous groups [41,42,43,44,45,46]. Certain bacterial infections contain proteins that non-specifically bind effector cell receptors causing a more generalized polyclonal expansion and inflammation, termed a superantigen effect. Polyclonality of T cell receptor usage has been shown in KD [47,48]; however, the reports are variable as to which subset of T cell receptors are expanded [49]. Other studies support a traditional oligoclonal response consistent with an immune response against a specific etiologic agent. Oligoclonal expansion of CD8+ T cells [50] and peripheral IgM+ B cell responses have been demonstrated [5,51], and IGG+ clonality is seen in studies from our own laboratory (unpublished). Numerous other studies have not shown superantigen-associated expansions of cell subsets [50,52,53]. This concept is reviewed extensively elsewhere [45].
In a recent network and pathway analysis, responses were consistent with global activation of the immune response [54]. Although genome wide searches and similar techniques have not been definitive, genes involved with B cell activation, such as CD40 and the B lymphocyte kinase (BLK), have been identified [55,56]. There is a growing body of literature implicating specific B cell responses in the pathogenesis [57]. In this review we will focus on the literature surrounding these recent reports of antibody reactive cellular inclusions and B cell involvement.

2. Consideration of Humoral Immunity

2.1. Treatment

A number of pharmacologic agents have been used during the inflammatory phase of KD. Treatment with IVIG in KD patients can inhibit coronary aneurysm formation, implying a role for antibodies in disease pathogenesis. However, it is unclear how IVIG actually functions in this setting and if specific antibody responses are responsible for pathogenesis. Potential functions of IVIG include: Replacement for deficient specific protective antibody, anti-idiotype response against pathologic antibodies, B cell downregulation, upregulation of regulatory T cells, downregulation of neutrophil function, downregulation of dendritic cell function, and superantigen neutralization. Recent reviews have explored these functions [58,59]. The main treatment modalities used for refractory treatment are steroids, calcineurin inhibitors, and anti-TNF monoclonal antibodies; all of which have broad immunological effects [60,61]. Success with anti-TNF monoclonal antibodies seemingly argues against a significant role of B cells, as this would effectively release a suppressive action of TNF on B cell proliferation. However, calcineurin inhibition would have the opposite effect by limiting T-cell help to B cells [62]. Limited reports of treatment with anti-B cell monoclonal antibodies (anti-CD20) also support a role for B cell activation in KD pathogenesis [63]. Interluekin-1 (IL 1), has long been known to affect B cell activity [64], but it has a very broad array of inflammatory responses [58]. Notably, there is support in the lactobacillus casei mouse model for IL-1 playing a role [65]. Applicable clinical trials are listed in Table 1.

2.2. KD Murine Models

The first KD model system developed depended on intraperitoneal Candida injections in susceptible mouse strains [72]. This is shown to have a superantigen response mechanism. Similarly, mice developed coronary artery inflammation after intraperitoneal injection with Lactobacillus casei cell wall extract. Pathogenesis in this model parallels KD in that younger mice are more predisposed to develop arteritis and there is a favorable response to IVIG treatment. This disease exhibits mostly a T-cell infiltrate in coronary arterial specimens [42]. In fact, in both RAG-1 [73] and TCR-α [74] deficient mice, this arteritis is diminished [75]. Other models depend on immune complex deposition. This was observed after bovine serum albumin injection into rabbits, which exhibited a disease similar to serum sickness [76]. A number of the model systems have granulomatous changes, which have variably been seen in human specimens [77]. Presently, there is not a model system consistent with direct infectious coronary artery invasion nor that exactly replicates the pathologic changes seen in humans [78]. Considering that the cause in humans is unknown, it is unclear if any of these models of arteritis are truly applicable. Although most data from model systems are supportive of superantigen involvement, studies from human peripheral lymphocyte responses are variable and inconsistent [79].

2.3. Human Pathologic Studies

The lack of robust studies on human pathological studies on cellular infiltrates in KD is likely explained by the necessary reliance on autopsy specimens. A number of studies have noted lymphocytic infiltrates in samples from later timepoints. Limited studies have shown that acute infiltrates develop over time with late fibrosis occurring in the intima and adventia layers. Neutrophils seem to be the predominant initial cell infiltrate [80]. However, in a series of six specimens, neutrophil infiltration was quickly followed by lymphocyte infiltrates, then mixed lymphocyte and plasma cell infiltrates were demonstrated later, near day 19 of illness [81]. In a separate series (8 specimens), early B lymphocyte infiltration after initial neutrophil infiltrate was confirmed [80]. Prominent nodular infiltrates, similar to atherosclerotic plaque formation, have also been described, but these appear to occur at later timepoints (>3 weeks). These infiltrates consisted of T cells, macrophages, B cells and prevalent IgM+ plasma cells, with less frequent IgA+ plasma cells. The authors compare these to similar B cell rich lesions driven by both superantigens and specific infectious antigens [82].
A pathologic study on seven samples from later timepoints (most greater than two weeks after beginning symptoms of KD) revealed fewer IgM+ plasma cells compared to more prevalent IgA+ plasma cells. These were seemingly specific and prominent in seven KD biopsy specimens, however the fourteen control specimens were from autopsies that succumbed generally from non-inflammatory and non-cardiac syndromes. Notably, mature memory and immature B cells (CD20+ cells) were lacking [83]. Due to the late time point of these specimens, this may not be inconsistent with other reports reviewed previously. The lack of CD20+ B cells was theorized to be from early coronary infiltration of CD20+ B cells followed by immediate switching of these B cells to plasma cells [84]. This increase in infiltrative IgA+ plasma cells could not be explained by a generalized increase in peripheral IgA+ cell, as none was shown in acute or convalescent KD [3]. The largest study, relying on electron microscopic studies, suggests that there is an early necrotizing arteritis indicative of an acute viral infection, followed by a vasculitis, then luminal myofibroblast proliferation [77]. Although this study had 32 samples, it only had three within two weeks of disease onset and a number of findings were different than previous studies. Collection and study of these types of rare samples should continue.
Although plasma cell infiltration as outlined above is intriguing, a similar pathological response is seen in a number of inflammatory conditions such as anti- N-methyl D-aspartate receptors (NMDAR) encephalitis [85], primary sclerosing cholangitis, [86] multiple sclerosis, [87] and responses to tumors [88]. Some, such as IgA nephropathy and rheumatoid pericarditis have shown plasma cell infiltration and IgA staining [89]. In KD it is proposed that these plasma cells mature in situ from initial B cell infiltration. Monoclonal B cell infiltrates have been shown in other disorders [90]. Additionally, in situ lymphoid neogenesis is described in numerous inflammatory and infectious disease systems [91,92,93,94] and some oncologic processes [95,96]. Localized inflammation and cellular damage may lead to exposure of previously hidden self-antigens setting off a localized autoimmune cascade [97]. From pure pathological studies, it is unclear if the clonality of the IgA+ plasma cell infiltrates seen in KD represents a global inflammatory response or a specific antibody driven response against an invasive pathogen.

2.4. Activation of Peripheral B Cells and Antibodies

Unfortunately, there have also been few published reports on the peripheral blood dynamics during KD. Reports do show increased IgA immune complexes and levels [9], although immune complexes do not necessarily portend worse prognosis [98]. Peripheral lymphocyte analysis did not indicate an increase in IgA+ cells in acute, subacute and convalescent KD patient samples [3]. In fact, there was actually a relative paucity of IgA+ peripheral B cells from acute KD samples compared to controls. Interestingly, the lack of IgA+ peripheral B cells continued through convalescence. Other studies have shown no changes in acute and convalescent B cell subgroups, but increases in CD69+ natural killer and γδ T cells were observed [99]. Recently, the B cell marker CD 19+ was used to show an increase in both number of B cells and relative percentage in acute KD compared to controls. The percent of ‘activated’ CD86+ B cells was also significantly elevated [100]. There was also a global increase in the ability of B cells to secrete IgM, IgG, and IgA after TLR-9 stimulation, something that has been previously unexplored in the literature. Overall, in the small number of studies relating to the peripheral blood B cell compartment, there is not a consensus as to whether B cells are responsible for enhanced pathogenesis.
Although, total numbers of cells do not show consistent results, clonal expansion within the B cell compartment can be studied. A specific immune response to an agent typically has an initial inherent immune component that leads to antigen presentation to effector cells. Receptors on the effector cell surface (T-cell receptors in T cells and Immunoglobulin (IG), or antibody, in B cells) bind specific targeted areas of the agent, termed epitopes. Specific recognition by T and B lymphocytes leads to stimulation, lymphocyte replication and clonal expansion; what is termed an oligoclonal response. Oligoclonal expansion is shown in peripheral IgM+ B cells in KD [5]. Detailed pathological studies have revealed what are termed oligoclonal plasma cell infiltrates in KD arterial specimens [101], leading to the cloning of antibody J and association with the presence of the spheroid ICIs as previously discussed [102,103].

2.5. Cloning of Antibodies from Plasma Cell Infiltrates

Antibodies J and A were created from non-native pairing of the most prevalent sequences from reported plasma cell infiltrates (3 repeats of heavy chain and duplicates of light chains) [101,104]. On binding bronchial epithelium specimens from children with KD, antibodies J and A identified intracellular inclusions (ICI) [51,57]. In a subsequent study, 26% of the control group, composed primarily of adult patients, had similar inclusion bodies that were bound by antibody J [105]. Although many viruses can reactivate during stress (Herpesviridae family) or are considered ‘slow’ viral infections [106], the failure of numerous attempts to identify a specific infectious agent argues against such a persistent infection [57]. There remains the possibility that this is a difficult to culture virus, such as coronavirus, which had also enjoyed a short-lived consideration as the cause of KD [107].
The study that created antibodies A and J described a total of 44 heavy chain sequences and 61 light chain sequences. Other antibodies expressed, D and L, and showed no binding to ICIs. There was generally a lack of oligoclonal response with just six light chains duplicated and only the J heavy (3 times) and three other heavy chains duplicated. As these antibodies were created with non-native heavy and light chain pairings, they may have non-specific interactions [108]. This is one of the major challenges in the burgeoning bispecific antibody field [109]. Evidence of in situ maturation of antibodies, such as A and J, also does not preclude such an antibody targeting a self-antigen. Notably, two other rare clones (only one transcript each from the 44 sequence reads) showed weak binding to the same spheroid ICIs. One of these weak binding antibodies (antibody E) also bound plasma cells directly and was subsequently shown to bind kappa chains of IG. This highlights the non-specific autoimmune potential of antibodies from these types of pathologic infiltrates, which will be reviewed later.

2.6. Viral-like Inclusions Reported

Electron micrograph evaluation of autopsy samples from three individuals who had KD revealed ICIs and “virus-like particles” (VLPs) [103]. Unfortunately, these three structures all appeared to have different morphologies and variable association with the ICI [110]. RNA contained in KD sample ICIs was further analyzed by using laser-capture micro-dissection and subsequent 454 sequencing. No homologies to known viral RNA sequences were shown. Specifically, of the 411,561 nucleic acid reads done by 454 sequencing, only 1006 did not have significant GenBank homology [105]. This lack of homology to known viral sequences and paucity of unknown sequence is also not supportive of these being VLPs or viral aggregation of an unknown virus. The limitation to only autopsy specimens, lack of similar findings in other pathological reports, lack of VLP correlation to ICI, and lack of genetic specificity in the included RNA argues against these being related to the etiology of KD.

2.7. Common Structures Appear as Intracellular Inclusions (ICIs)

Because the ICIs observed in KD specimens are identified by recombinant antibodies synthesized from pathologic KD specimens, the authors of these studies conclude that these inclusions are of viral origin, and specifically related to the etiological agent of KD [51,105]. However, it is possible that these ICIs could be any number of host-derived functional structures that are typically observed as protein aggregates. Aggresomes, one such structure, are involved in shuttling of misfolded proteins during cellular stress [111]. Aggresomes are frequently observed as large intracellular aggregates of host proteins and are frequently surrounded by a “cage” of intermediate filament proteins. Available evidence suggests KD ICIs and aggresomes are distinct structures since the ICIs observed in the two autopsy specimens lacked a cytokeratin cage [103]. However, cytokeratin cages are not definitive of aggresomes and their presence may depend on the cell type. More frequently, vimentin is used as an intermediate filament marker for aggresomal cages. Because the expression of vimentin varies in bronchiole epithelial cells [112], other common markers of aggresomes could have been studied, such as ubiquitin, HSP70, HSP40, and proteasomal subunits [111]. Unfortunately, none of these markers were tested. In addition, there are several other large intracellular protein aggregates such as stress granules, p-bodies, prion-aggregates, aggresome-like induced structures (ALIS) and autophagosomes [113,114,115,116,117]. It is possible the ICI identified by antibodies A and J are one of these structures; perhaps the manifestation of KD is the improper regulation of one of these processes.
In addition to protein, the ICIs observed in the limited bronchial epithelial samples were also partially composed of RNA. While the RNA could be of viral origin it is important to note that many of the host-derived intracellular protein aggregates previously noted also contain host mRNA [113,114,116,117]. It is reasonable to conclude that if the ICIs observed in KD patients were related to one of these structures, they would positively stain for RNA.

2.8. Anti-Self-Antibody Responses

As reviewed, the similarly cloned antibody E was shown to bind a self-antigen [102]. The autoimmune aspects of KD have recently been reviewed [118]. Self-antigen responses to a variety of targets have actually been well described in KD. These include recent reports of antibody responses to type III collagen, myosin [119], cardiolipin [120], alpha-enolase [121], and anti-endothelial antibodies. Anti-endothelial antibodies are particularly interesting as these are seen in other disorders, such as SLE and renal allograft rejection [122]. Other vasculitides have also been associated with anti-endothelial antibodies. These have been shown to cause upregulation of E-selectin, VCAM-1, ICAM-1 and NFκB [123]. Responses to these antibodies include upregulation of inflammatory cytokines and apoptosis of the endothelial cells.
In KD subjects, a polyclonal antibody response against endothelial cells has been described [124]. Cytokines, such as IFN-γ, IL-1 and TNF, that would be present during generalized inflammation, facilitate a pathological anti-endothelial response of circulating IgG and IgM antibodies associated with acute KD [125,126]. In cell lysis assays, pathogenesis was eliminated by clearing the serum through anti-IgG and anti-IgM sepharose columns supportive of no role of peripheral anti-IgA responses. This does not eliminate the potential role of intra-tissue IgA+ plasma cell development in pathogenesis as has been postulated [83,102]. Other studies support significant IgM mediated cytotoxicity against endothelial cells in KD patients [127]. Prevalent IgM anti-endothelial responses in KD have also been shown without cytokine stimulation [127,128]. In a mouse model system, anti-endothelial antibody responses were replicated, but these did not demonstrate cardiac vascular involvement [129]. The case report of anti-B cell monoclonal antibody success was proposed by the authors to be due to the downregulation of such an anti-endothelial invasive effect [63]. Although intriguing, it remains unknown if these anti-endothelial responses actually contribute to the vasculitis in KD and other vasculitides [123].

2.9. Similar Plasmablast Responses in KD and other Infections

Recent data from our laboratory further supports an infectious disease etiology playing a role in KD. Numerous studies show that after an antigenic challenge, vaccination and natural infections, B cells transitioning to plasma cells, termed plasmablasts (PBs), can be seen in the peripheral blood [130,131]. These can be recognized by surface markers of CD19, downregulation of CD20, and high levels of CD27 and CD38 [3,132]. In comparison to the general circulating B cell population, PBs are enriched for B cells that contain infection-specific antibodies [133,134]. This is variable as some studies show massive and high enrichment of PBs targeting the antigen of interest [135,136], while other studies show polyspecificity of the PB population and limited enrichment [137,138,139,140]. Immunization studies in adults (tetanus [141], influenza [132], and rabies [142]) show PB have more consistent enrichment for specific antibodies, temporally peak 5–10 days after immunization, and are predictive of later sero-immunity [143]. Elevated circulating peripheral PBs are not specific to infections, as they are elevated in a number of autoimmune diseases and their levels correlate to disease flares [144]. Although certain infections, such as dengue virus, may set off exceedingly high PB levels [145], PB quantities tend to be significantly higher in autoimmune conditions than levels achieved during vaccination or post-infection. This excessive circulating PB response corresponds to flaring of the underlying inflammatory disease, and specifically correlates with c-reactive protein (CRP) level in studies on ulcerative colitis [145,146] and IGG4 related disease [147,148].
We postulated that if KD is caused by an infection, we should observe a predictable rise of PBs in the peripheral blood. We collected samples from 18 children with KD and 69 febrile controls presenting to the emergency department. Overall, we saw an increase in IGG+ B cells, but not a cumulative increase in B cells [149]. Notably, we did not observe an increase in circulating IgA+ B cells. The result of this study is consistent with the majority of the literature that shows B cell stimulation and increasing peripheral B cell numbers during KD [4,5,99,100]. Both KD and infectious control children showed comparable elevations of PBs compared to controls [149]. Importantly, the levels did not correlate with CRPs and were not excessive, which are characteristics of PB responses in autoimmunity. Unfortunately, only five children had repeat samples. Of these five, all had PB elevations on one or both timepoints, leaving only 3 of 18 KD samples not having a measurable elevation of their PBs in this study generally limited to one timepoint. We are currently collecting samples over multiple timepoints to more thoroughly explore this phenomenon.
Ongoing studies are exploring heavy and light chain usage in B cells and PBs during KD with next generation sequencing techniques. To specifically target an etiology, we have created monoclonal antibodies with pairing of the heavy and light chains utilizing the 10x Genomics® Single Cell sequencing technology [150]. As an example, from the PB rise of near 11% of circulating B cells seen in subject 24, we created a panel of 946 paired heavy and light chain sequences. From this sample, there are a number of clones with exact sequence repeats (roughly 5%). To assign clonal groups, we analyzed the sequences using CDR3 length and sequences, and compared predicted germline antibody sequences (from IMGT, [151]). Roughly 40% of clones can be assigned to have clonal relationships. Several of the monoclonal antibodies we generated are presented in Table 2. We chose these fifteen antibodies to highlight markers that show somatic hypermutation and clonal expansion. These are highlighted by predicted clonal members, isotype switching, nucleotide substitutions from predicted germlines, and increases in the subgroup replacement to silent nucleotide mutation (R/S) ratios. Elevation of this ratio supports clonal selection of affinity matured antibodies which would correlate with an increase in mutations leading to changes in the amino acids, particularly in the antigen binding complementarity determining regions (CDRs) [152]. Work on identifying the protein targets of these antibodies is ongoing. Because of the characteristics seen in these antibodies, we hypothesize these antibodies target the etiology that caused KD in this child.

3. Discussion

The roll of B cells and plasma cells in KD is controversial (summarized Table 3). Much of the B cell and antibody data reviewed herein show inconsistent, contradictory or unsubstantiated findings. Pathological specimens and model systems are variably supportive or inconsistent with what is known from human studies. Although B cell and plasma cell infiltration in pathology specimens is intriguing, whether they are bystanders activated by a superantigen effect, are responding to a self-antigen revealed by inflammation, or specific against an infectious etiology, is currently unknown. Like the mouse models and attempts at developing new therapeutics, it is hard to be confident in any one approach without knowledge of the etiology. Although published B cell studies relating to KD are somewhat inconsistent, recent data using advanced sequencing techniques show promise for identification of an etiology.
Since KD is a clinical syndrome without a definitive marker of diagnosis, many of the studies may be influenced by “generous” case definitions of the study participants. Most of the studies reviewed do not include detailed clinical information or rigorous case definitions. This is a general problem with the literature in this field; these machinations seem more consistent in clinical trials and epidemiological studies but are rare in bench-science studies. This potential selection bias may be negatively influencing reproducible, definitive findings and conclusions.
This is a rich opportunity for clinical investigators. Rigorous studies are needed on those children who present with KD. If any pulmonary findings are found, bronchial washings should be obtained and stored for potential molecular diagnostics. Other samples, such as peripheral blood mononuclear cells and serum, should be taken and banked for future studies. Thorough autopsy evaluation should be pursued on any subjects who succumb during the acute or convalescent phases of KD. Improved reporting and national registries would go a long way in establishing a representative pool of patients. Studies currently ongoing on peripheral cytokine profiles, B cells and PBs may show a consistent marker to help define who has KD. A correlative diagnostic marker, possibly even antibody derived, would be a highly desirable first step in future studies.

Author Contributions

This manuscript was conceived and the majority of writing done by M.D.H. M.E.L. contributed expertise and writing in sections relating to inclusions and aggresomes.


Relative funding includes a generous grant from the Wildermuth Foundation through the Variety Club of Buffalo.


We would like to thank Meghan McLaughlin for her instructive comments on this manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.


ALISAggresome-like induced structures
BLKB lymphocyte kinase
CDRComplementarity determining regions
CRPC-reactive protein
HHV-6Human herpesviridae-6
ICIIntracellular inclusions
IVIGIntravenous immunoglobulin
KDKawasaki Disease
NMDARN-methyl D-aspartate receptors
R/SReplacement to silent nucleotide mutation
VLPVirus-like particle


  1. Kawasaki, T. Kawasaki disease. Acta Paediatr. 1995, 84, 713–715. [Google Scholar] [CrossRef] [PubMed]
  2. Kuo, H.C.; Lo, M.H.; Hsieh, K.S.; Guo, M.M.; Huang, Y.H. High-dose aspirin is associated with anemia and does not confer benefit to disease outcomes in Kawasaki disease. PLoS ONE 2015, 10, e0144603. [Google Scholar] [CrossRef]
  3. Shingadia, D.; O’Gorman, M.; Rowley, A.H.; Shulman, S.T. Surface and cytoplasmic immunoglobulin expression in circulating B-lymphocytes in acute Kawasaki disease. Pediatr. Res. 2001, 50, 538–543. [Google Scholar] [CrossRef]
  4. Chang, C.J.; Kuo, H.C.; Chang, J.S.; Lee, J.K.; Tsai, F.J.; Khor, C.C.; Chang, L.C.; Chen, S.P.; Ko, T.M.; Liu, Y.M.; et al. Replication and meta-analysis of GWAS identified susceptibility loci in Kawasaki disease confirm the importance of B lymphoid tyrosine kinase (BLK) in disease susceptibility. PLoS ONE 2013, 8, e72037. [Google Scholar] [CrossRef]
  5. Lee, H.H.; Park, I.H.; Shin, J.S.; Kim, D.S. Immunoglobulin V(H) chain gene analysis of peripheral blood IgM-producing B cells in patients with Kawasaki disease. Yonsei Med. J. 2009, 50, 493–504. [Google Scholar] [CrossRef]
  6. Newburger, J.W.; Takahashi, M.; Gerber, M.A.; Gewitz, M.H.; Tani, L.Y.; Burns, J.C.; Shulman, S.T.; Bolger, A.F.; Ferrieri, P.; Baltimore, R.S.; et al. Diagnosis, treatment, and long-term management of Kawasaki disease: A statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 2004, 114, 1708–1733. [Google Scholar] [CrossRef] [PubMed]
  7. Terai, M.; Honda, T.; Yasukawa, K.; Yasukawa, K.; Higashi, K.; Hamada, H.; Kohno, Y. Prognostic impact of vascular leakage in acute Kawasaki disease. Circulation 2003, 108, 325–330. [Google Scholar] [CrossRef]
  8. Jun, H.O.; Yu, J.J.; Kang, S.Y.; Seo, C.D.; Baek, J.S.; Kim, Y.H.; Ko, J.K. Diagnostic characteristics of supplemental laboratory criteria for incomplete Kawasaki disease in children with complete Kawasaki disease. Korean J. Pediatr. 2015, 58, 369–373. [Google Scholar] [CrossRef]
  9. Ohshio, G.; Furukawa, F.; Khine, M.; Yoshioka, H.; Kudo, H.; Hamashima, Y. High levels of IgA-containing circulating immune complex and secretory IgA in Kawasaki disease. Microbiol. Immunol. 1987, 31, 891–898. [Google Scholar] [CrossRef]
  10. Yanagawa, H.; Yashiro, M.; Nakamura, Y.; Sakata, K.; Kawasaki, T. Iv gamma globulin treatment of Kawasaki disease in Japan: Results of a nationwide survey. Acta Paediatr. 1995, 84, 765–768. [Google Scholar] [CrossRef]
  11. Pinna, G.S.; Kafetzis, D.A.; Tselkas, O.I.; Skevaki, C.L. Kawasaki disease: An overview. Curr. Opin. Infect. Dis. 2008, 21, 263–270. [Google Scholar] [CrossRef] [PubMed]
  12. Nakamura, Y.; Yanagawa, H.; Harada, K.; Kato, H.; Kawasaki, T. Mortality among persons with a history of Kawasaki disease in Japan: The fifth look. Arch. Pediatr. Adolesc. Med. 2002, 156, 162–165. [Google Scholar] [CrossRef] [PubMed]
  13. Nakamura, Y.; Aso, E.; Yashiro, M.; Uehara, R.; Watanabe, M.; Tajimi, M.; Oki, I.; Ojima, T.; Yanagawa, T.; Kawasaki, T. Mortality among persons with a history of Kawasaki disease in Japan: Can paediatricians safely discontinue follow-up of children with a history of the disease but without cardiac sequelae? Acta Paediatr. 2005, 94, 429–434. [Google Scholar] [CrossRef] [PubMed]
  14. Gordon, J.B.; Kahn, A.M.; Burns, J.C. When children with Kawasaki disease grow up: Myocardial and vascular complications in adulthood. J. Am. Coll. Cardiol. 2009, 54, 1911–1920. [Google Scholar] [CrossRef] [PubMed][Green Version]
  15. Chrissoheris, M.P.; Donohue, T.J.; Young, R.S.; Ghantous, A. Coronary artery aneurysms. Cardiol. Rev. 2008, 16, 116–123. [Google Scholar] [CrossRef] [PubMed]
  16. Burgner, D.; Harnden, A. Kawasaki disease: What is the epidemiology telling us about the etiology? Int. J. Infect. Dis. 2005, 9, 185–194. [Google Scholar] [CrossRef][Green Version]
  17. Abuhammour, W.M.; Hasan, R.A.; Eljamal, A.; Asmar, B. Kawasaki disease hospitalizations in a predominantly African-American population. Clin. Pediatr. (Phila) 2005, 44, 721–725. [Google Scholar] [CrossRef]
  18. Clark, D.E.; Denby, K.J.; Kaufman, L.M.; Fill, M.M.A.; Piya, B.; Krishnaswami, S.; Fonnesbeck, C.; Halasa, N. Predictors of intravenous immunoglobulin non-response and racial disparities in Kawasaki disease. Pediatr. Infect. Dis. J. 2018, 37, 1227–1234. [Google Scholar] [CrossRef]
  19. Porcalla, A.R.; Sable, C.A.; Patel, K.M.; Martin, G.R.; Singh, N. The epidemiology of Kawasaki disease in an urban hospital: Does African American race protect against coronary artery aneurysms? Pediatr. Cardiol. 2005, 26, 775–781. [Google Scholar] [CrossRef] [PubMed]
  20. Scuccimarri, R. Kawasaki disease. Pediatr. Clin. N. Am. 2012, 59, 425–445. [Google Scholar] [CrossRef]
  21. Rodo, X.; Ballester, J.; Cayan, D.; Melish, M.E.; Nakamura, Y.; Uehara, R.; Burns, J.C. Association of Kawasaki disease with tropospheric wind patterns. Sci. Rep. 2011, 1, 152. [Google Scholar] [CrossRef] [PubMed]
  22. Burns, J.C.; Cayan, D.R.; Tong, G.; Bainto, E.V.; Turner, C.L.; Shike, H.; Kawasaki, T.; Nakamura, Y.; Yashiro, M.; Yanagawa, H. Seasonality and temporal clustering of Kawasaki syndrome. Epidemiology 2005, 16, 220–225. [Google Scholar] [CrossRef]
  23. Kao, A.S.; Getis, A.; Brodine, S.; Burns, J.C. Spatial and temporal clustering of Kawasaki syndrome cases. Pediatr. Infect. Dis. J. 2008, 27, 981–985. [Google Scholar] [CrossRef]
  24. Makino, N.; Nakamura, Y.; Yashiro, M.; Ae, R.; Tsuboi, S.; Aoyama, Y.; Kojo, T.; Uehara, R.; Kotani, K.; Yanagawa, H. Descriptive epidemiology of Kawasaki disease in Japan, 2011–2012: From the results of the 22nd nationwide survey. J. Epidemiol. 2015, 25, 239–245. [Google Scholar] [CrossRef]
  25. Mauro, A.; Fabi, M.; Da Fre, M.; Guastaroba, P.; Corinaldesi, E.; Calabri, G.B.; Giani, T.; Simonini, G.; Rusconi, F.; Cimaz, R. Kawasaki disease: An epidemiological study in central Italy. Pediatr. Rheumatol. Online J. 2016, 14, 22. [Google Scholar] [CrossRef]
  26. Chen, J.J.; Ma, X.J.; Liu, F.; Yan, W.L.; Huang, M.R.; Huang, M.; Huang, G.Y.; Shanghai Kawasaki Disease Research Group. Epidemiologic features of Kawasaki disease in Shanghai from 2008 through 2012. Pediatr. Infect. Dis. J. 2016, 35, 7–12. [Google Scholar] [PubMed]
  27. Chang, A.; Delmerico, A.M.; Hicar, M.D. Spatiotemporal analysis and epidemiology of Kawasaki disease in Western New York: A sixteen year review of cases presenting to a single tertiary care center. Pediatr. Infect. Dis. J. 2018. [Google Scholar] [CrossRef] [PubMed]
  28. Burns, J.C.; Herzog, L.; Fabri, O.; Tremoulet, A.H.; Rodo, X.; Uehara, R.; Burgner, D.; Bainto, E.; Pierce, D.; Tyree, M.; et al. Seasonality of Kawasaki disease: A global perspective. PLoS ONE 2013, 8, e74529. [Google Scholar] [CrossRef]
  29. Dergun, M.; Kao, A.; Hauger, S.B.; Newburger, J.W.; Burns, J.C. Familial occurrence of Kawasaki syndrome in North America. Arch. Pediatr. Adolesc. Med. 2005, 159, 876–881. [Google Scholar] [CrossRef] [PubMed]
  30. Fujita, Y.; Nakamura, Y.; Sakata, K.; Hara, N.; Kobayashi, M.; Nagai, M.; Yanagawa, H.; Kawasaki, T. Kawasaki disease in families. Pediatrics 1989, 84, 666–669. [Google Scholar]
  31. Yorifuji, T.; Tsukahara, H.; Doi, H. Breastfeeding and risk of Kawasaki disease: A nationwide longitudinal survey in Japan. Pediatrics 2016, 137, e20153919. [Google Scholar] [CrossRef] [PubMed]
  32. Newburger, J.W.; Taubert, K.A.; Shulman, S.T.; Rowley, A.H.; Gewitz, M.H.; Takahashi, M.; McCrindle, B.W. Summary and abstracts of the Seventh International Kawasaki Disease Symposium: December 4–7, 2001, Hakone, Japan. Pediatr. Res. 2003, 53, 153–157. [Google Scholar] [PubMed]
  33. Nakagawa, A.; Ito, M.; Iwaki, T.; Yatabe, Y.; Asai, J.; Hayashi, K. Chronic active Epstein-Barr virus infection with giant coronary aneurysms. Am. J. Clin. Pathol. 1996, 105, 733–736. [Google Scholar] [CrossRef] [PubMed]
  34. Manlhiot, C.; O’Shea, S.; Bernknopf, B.; LaBelle, M.; Chahal, N.; Dillenburg, R.F.; Lai, L.S.; Bock, D.; Lew, B.; Masood, S.; et al. Epidemiology of Kawasaki disease in Canada 2004 to 2014: Comparison of surveillance using administrative data vs. periodic medical record review. Can. J. Cardiol. 2018, 34, 303–309. [Google Scholar] [CrossRef]
  35. Rodo, X.; Curcoll, R.; Robinson, M.; Ballester, J.; Burns, J.C.; Cayan, D.R.; Lipkin, W.I.; Williams, B.L.; Couto-Rodriguez, M.; Nakamura, Y.; et al. Tropospheric winds from northeastern China carry the etiologic agent of Kawasaki disease from its source to Japan. Proc. Natl. Acad. Sci. USA 2014, 111, 7952–7957. [Google Scholar] [CrossRef] [PubMed][Green Version]
  36. Baker, A.L.; Lu, M.; Minich, L.L.; Atz, A.M.; Klein, G.L.; Korsin, R.; Lambert, L.; Li, J.S.; Mason, W.; Radojewski, E.; et al. Associated symptoms in the ten days before diagnosis of Kawasaki disease. J. Pediatr. 2009, 154, 592–595.e2. [Google Scholar] [CrossRef]
  37. Freeman, A.F.; Crawford, S.E.; Finn, L.S.; Lopez-Andreu, J.A.; Ferrando-Monleon, S.; Perez-Tamarit, D.; Cornwall, M.L.; Shulman, S.T.; Rowley, A.H. Inflammatory pulmonary nodules in Kawasaki disease. Pediatr. Pulmonol. 2003, 36, 102–106. [Google Scholar] [CrossRef]
  38. Bell, D.M.; Brink, E.W.; Nitzkin, J.L.; Hall, C.B.; Wulff, H.; Berkowitz, I.D.; Feorino, P.M.; Holman, R.C.; Huntley, C.L.; Meade, R.H., III; et al. Kawasaki syndrome: Description of two outbreaks in the United States. N. Engl. J. Med. 1981, 304, 1568–1575. [Google Scholar] [CrossRef]
  39. Jordan-Villegas, A.; Chang, M.L.; Ramilo, O.; Mejias, A. Concomitant respiratory viral infections in children with Kawasaki disease. Pediatr. Infect. Dis. J. 2010, 29, 770–772. [Google Scholar] [CrossRef]
  40. Rowley, A.H.; Shulman, S.T. The epidemiology and pathogenesis of Kawasaki disease. Front. Pediatr. 2018, 6, 374. [Google Scholar] [CrossRef]
  41. Curtis, N. Kawasaki disease and toxic shock syndrome–At last the etiology is clear? Adv. Exp. Med. Biol. 2004, 549, 191–200. [Google Scholar] [PubMed]
  42. Duong, T.T.; Silverman, E.D.; Bissessar, M.V.; Yeung, R.S. Superantigenic activity is responsible for induction of coronary arteritis in mice: An animal model of Kawasaki disease. Int. Immunol. 2003, 15, 79–89. [Google Scholar] [CrossRef] [PubMed]
  43. Leung, D.Y.; Meissner, H.C.; Fulton, D.R.; Murray, D.L.; Kotzin, B.L.; Schlievert, P.M. Toxic shock syndrome toxin-secreting Staphylococcus aureus in Kawasaki syndrome. Lancet 1993, 342, 1385–1388. [Google Scholar] [CrossRef]
  44. Leung, D.Y.; Sullivan, K.E.; Brown-Whitehorn, T.F.; Fehringer, A.P.; Allen, S.; Finkel, T.H.; Washington, R.L.; Makida, R.; Schlievert, P.M. Association of toxic shock syndrome toxin-secreting and exfoliative toxin-secreting Staphylococcus aureus with Kawasaki syndrome complicated by coronary artery disease. Pediatr. Res. 1997, 42, 268–272. [Google Scholar] [CrossRef]
  45. Matsubara, K.; Fukaya, T. The role of superantigens of group A Streptococcus and Staphylococcus aureus in Kawasaki disease. Curr. Opin. Infect. Dis. 2007, 20, 298–303. [Google Scholar] [CrossRef] [PubMed]
  46. Uchiyama, T.; Kato, H. The pathogenesis of Kawasaki disease and superantigens. Jpn. J. Infect. Dis. 1999, 52, 141–145. [Google Scholar] [PubMed]
  47. Abe, J.; Kotzin, B.L.; Jujo, K.; Melish, M.E.; Glode, M.P.; Kohsaka, T.; Leung, D.Y. 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. USA 1992, 89, 4066–4070. [Google Scholar] [CrossRef] [PubMed]
  48. Abe, J.; Kotzin, B.L.; Meissner, C.; Melish, M.E.; Takahashi, M.; Fulton, D.; Romagne, F.; Malissen, B.; Leung, D.Y. Characterization of T cell repertoire changes in acute Kawasaki disease. J. Exp. Med. 1993, 177, 791–796. [Google Scholar] [CrossRef][Green Version]
  49. Yoshioka, T.; Matsutani, T.; Iwagami, S.; Toyosaki-Maeda, T.; Yutsudo, T.; Tsuruta, Y.; Suzuki, H.; Uemura, S.; Takeuchi, T.; Koike, M.; et al. Polyclonal expansion of TCRBV2- and TCRBV6-bearing T cells in patients with Kawasaki disease. Immunology 1999, 96, 465–472. [Google Scholar] [CrossRef]
  50. Choi, I.H.; Chwae, Y.J.; Shim, W.S.; Kim, D.S.; Kwon, D.H.; Kim, J.D.; Kim, S.J. Clonal expansion of CD8+ T cells in Kawasaki disease. J. Immunol. 1997, 159, 481–486. [Google Scholar]
  51. Rowley, A.H.; Baker, S.C.; Shulman, S.T.; Fox, L.M.; Takahashi, K.; Garcia, F.L.; Crawford, S.E.; Chou, P.; Orenstein, J.M. Cytoplasmic inclusion bodies are detected by synthetic antibody in ciliated bronchial epithelium during acute Kawasaki disease. J. Infect. Dis. 2005, 192, 1757–1766. [Google Scholar] [CrossRef] [PubMed]
  52. Pietra, B.A.; De Inocencio, J.; Giannini, E.H.; Hirsch, R. TCR V beta family repertoire and T cell activation markers in Kawasaki disease. J. Immunol. 1994, 153, 1881–1888. [Google Scholar] [PubMed]
  53. Sakaguchi, M.; Kato, H.; Nishiyori, A.; Sagawa, K.; Itoh, K. Characterization of CD4+ T helper cells in patients with Kawasaki disease (KD): Preferential production of tumour necrosis factor-alpha (TNF-alpha) by V beta 2- or V beta 8- CD4+ T helper cells. Clin. Exp. Immunol. 1995, 99, 276–282. [Google Scholar] [CrossRef] [PubMed]
  54. Lv, Y.W.; Wang, J.; Sun, L.; Zhang, J.M.; Cao, L.; Ding, Y.Y.; Chen, Y.; Dou, J.J.; Huang, J.; Tang, Y.F.; et al. Understanding the pathogenesis of Kawasaki disease by network and pathway analysis. Comput. Math. Methods Med. 2013, 2013, 989307. [Google Scholar] [CrossRef] [PubMed]
  55. Onouchi, Y.; Ozaki, K.; Burns, J.C.; Shimizu, C.; Terai, M.; Hamada, H.; Honda, T.; Suzuki, H.; Suenaga, T.; Takeuchi, T.; et al. A genome-wide association study identifies three new risk loci for Kawasaki disease. Nat. Genet. 2012, 44, 517–521. [Google Scholar] [CrossRef]
  56. Onouchi, Y.; Onoue, S.; Tamari, M.; Wakui, K.; Fukushima, Y.; Yashiro, M.; Nakamura, Y.; Yanagawa, H.; Kishi, F.; Ouchi, K.; et al. CD40 ligand gene and Kawasaki disease. Eur. J. Hum. Genet. 2004, 12, 1062–1068. [Google Scholar] [CrossRef][Green Version]
  57. Rowley, A.H.; Baker, S.C.; Orenstein, J.M.; Shulman, S.T. Searching for the cause of Kawasaki disease—Cytoplasmic inclusion bodies provide new insight. Nat. Rev. Microbiol. 2008, 6, 394–401. [Google Scholar] [CrossRef]
  58. Burns, J.C.; Kone-Paut, I.; Kuijpers, T.; Shimizu, C.; Tremoulet, A.; Arditi, M. Review: Found in translation: International initiatives pursuing interleukin-1 blockade for treatment of acute Kawasaki disease. Arthritis Rheumatol. 2017, 69, 268–276. [Google Scholar] [CrossRef]
  59. Katz, U.; Shoenfeld, Y.; Zandman-Goddard, G. Update on intravenous immunoglobulins (IVIg) mechanisms of action and off- label use in autoimmune diseases. Curr. Pharm. Des. 2011, 17, 3166–3175. [Google Scholar] [CrossRef] [PubMed]
  60. Dominguez, S.R.; Anderson, M.S. Advances in the treatment of Kawasaki disease. Curr. Opin. Pediatr. 2013, 25, 103–109. [Google Scholar] [CrossRef][Green Version]
  61. Tacke, C.E.; Burgner, D.; Kuipers, I.M.; Kuijpers, T.W. Management of acute and refractory Kawasaki disease. Expert Rev. Anti Infect. Ther. 2012, 10, 1203–1215. [Google Scholar] [CrossRef] [PubMed]
  62. Heidt, S.; Roelen, D.L.; Eijsink, C.; Eikmans, M.; van Kooten, C.; Claas, F.H.; Mulder, A. Calcineurin inhibitors affect B cell antibody responses indirectly by interfering with T cell help. Clin. Exp. Immunol. 2010, 159, 199–207. [Google Scholar] [CrossRef][Green Version]
  63. Sauvaget, E.; Bonello, B.; David, M.; Chabrol, B.; Dubus, J.; Bosdure, E. Resistant Kawasaki disease treated with anti-CD20. J. Pediatr. 2012, 160, 875–876. [Google Scholar] [CrossRef] [PubMed]
  64. Lipsky, P.E.; Thompson, P.A.; Rosenwasser, L.J.; Dinarello, C.A. The role of interleukin 1 in human B cell activation: Inhibition of B cell proliferation and the generation of immunoglobulin-secreting cells by an antibody against human leukocytic pyrogen. J. Immunol. 1983, 130, 2708–2714. [Google Scholar]
  65. Lee, Y.; Schulte, D.J.; Shimada, K.; Chen, S.; Crother, T.R.; Chiba, N.; Fishbein, M.C.; Lehman, T.J.; Arditi, M. Interleukin-1beta is crucial for the induction of coronary artery inflammation in a mouse model of Kawasaki disease. Circulation 2012, 125, 1542–1550. [Google Scholar] [CrossRef]
  66. Tremoulet, A.H.; Jain, S.; Jaggi, P.; Jimenez-Fernandez, S.; Pancheri, J.M.; Sun, X.; Kanegaye, J.T.; Kovalchin, J.P.; Printz, B.F.; Ramilo, O.; et al. Infliximab for intensification of primary therapy for Kawasaki disease: A phase 3 randomised, double-blind, placebo-controlled trial. Lancet 2014, 383, 1731–1738. [Google Scholar] [CrossRef]
  67. Mori, M.; Hara, T.; Kikuchi, M.; Shimizu, H.; Miyamoto, T.; Iwashima, S.; Oonishi, T.; Hashimoto, K.; Kobayashi, N.; Waki, K.; et al. Infliximab versus intravenous immunoglobulin for refractory Kawasaki disease: A phase 3, randomized, open-label, active-controlled, parallel-group, multicenter trial. Sci. Rep. 2018, 8, 1994. [Google Scholar] [CrossRef] [PubMed]
  68. Newburger, J.W.; Takahashi, M.; Beiser, A.S.; Burns, J.C.; Bastian, J.; Chung, K.J.; Colan, S.D.; Duffy, C.E.; Fulton, D.R.; Glode, M.P.; et al. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N. Engl. J. Med. 1991, 324, 1633–1639. [Google Scholar] [CrossRef]
  69. Newburger, J.W.; Sleeper, L.A.; McCrindle, B.W.; Minich, L.L.; Gersony, W.; Vetter, V.L.; Atz, A.M.; Li, J.S.; Takahashi, M.; Baker, A.L.; et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. N. Engl. J. Med. 2007, 356, 663–675. [Google Scholar] [CrossRef] [PubMed]
  70. Kobayashi, T.; Kobayashi, T.; Morikawa, A.; Ikeda, K.; Seki, M.; Shimoyama, S.; Ishii, Y.; Suzuki, T.; Nakajima, K.; Sakamoto, N.; et al. Efficacy of intravenous immunoglobulin combined with prednisolone following resistance to initial intravenous immunoglobulin treatment of acute Kawasaki disease. J. Pediatr. 2013, 163, 521–526. [Google Scholar] [CrossRef]
  71. Kuo, H.C.; Guo, M.M.; Lo, M.H.; Hsieh, K.S.; Huang, Y.H. Effectiveness of intravenous immunoglobulin alone and intravenous immunoglobulin combined with high-dose aspirin in the acute stage of Kawasaki disease: Study protocol for a randomized controlled trial. BMC Pediatr. 2018, 18, 200. [Google Scholar] [CrossRef]
  72. Murata, H. Experimental candida-induced arteritis in mice. Relation to arteritis in the mucocutaneous lymph node syndrome. Microbiol. Immunol. 1979, 23, 825–831. [Google Scholar] [CrossRef] [PubMed]
  73. Schulte, D.J.; Yilmaz, A.; Shimada, K.; Fishbein, M.C.; Lowe, E.L.; Chen, S.; Wong, M.; Doherty, T.M.; Lehman, T.; Crother, T.R.; et al. Involvement of innate and adaptive immunity in a murine model of coronary arteritis mimicking Kawasaki disease. J. Immunol. 2009, 183, 5311–5318. [Google Scholar] [CrossRef]
  74. Chan, W.C.; Duong, T.T.; Yeung, R.S. Presence of IFN-gamma does not indicate its necessity for induction of coronary arteritis in an animal model of Kawasaki disease. J. Immunol. 2004, 173, 3492–3503. [Google Scholar] [CrossRef] [PubMed]
  75. Yeung, R.S. Kawasaki disease: Update on pathogenesis. Curr. Opin. Rheumatol. 2010, 22, 551–560. [Google Scholar] [CrossRef] [PubMed]
  76. Dou, J.; Li, H.; Sun, L.; Yan, W.; Lv, H.; Ding, Y. Histopathological and ultrastructural examinations of rabbit coronary artery vasculitis caused by bovine serum albumin: An animal model of Kawasaki disease. Ultrastruct. Pathol. 2013, 37, 139–145. [Google Scholar] [CrossRef] [PubMed]
  77. Orenstein, J.M.; Shulman, S.T.; Fox, L.M.; Baker, S.C.; Takahashi, M.; Bhatti, T.R.; Russo, P.A.; Mierau, G.W.; de Chadarevian, J.P.; Perlman, E.J.; et al. Three linked vasculopathic processes characterize Kawasaki disease: A light and transmission electron microscopic study. PLoS ONE 2012, 7, e38998. [Google Scholar] [CrossRef] [PubMed]
  78. Orenstein, J.M.; Rowley, A.H. An evaluation of the validity of the animal models of Kawasaki disease vasculopathy. Ultrastruct. Pathol. 2014, 38, 245–247. [Google Scholar] [CrossRef] [PubMed]
  79. De Inocencio, J.; Hirsch, R. Evidence for superantigen mediated process in Kawasaki disease. Arch. Dis. Child. 1995, 73, 275–276. [Google Scholar] [CrossRef] [PubMed]
  80. Takahashi, K.; Oharaseki, T.; Naoe, S.; Wakayama, M.; Yokouchi, Y. Neutrophilic involvement in the damage to coronary arteries in acute stage of Kawasaki disease. Pediatr. Int. 2005, 47, 305–310. [Google Scholar] [CrossRef] [PubMed]
  81. Fujiwara, T.; Fujiwara, H.; Nakano, H. Pathological features of coronary arteries in children with Kawasaki disease in which coronary arterial aneurysm was absent at autopsy. Quantitative analysis. Circulation 1988, 78, 345–350. [Google Scholar] [CrossRef] [PubMed]
  82. Kuijpers, T.W.; Biezeveld, M.; Achterhuis, A.; Kuipers, I.; Lam, J.; Hack, C.E.; Becker, A.E.; van der Wal, A.C. Longstanding obliterative panarteritis in Kawasaki disease: Lack of cyclosporin A effect. Pediatrics 2003, 112, 986–992. [Google Scholar] [CrossRef]
  83. Rowley, A.H.; Eckerley, C.A.; Jack, H.M.; Shulman, S.T.; Baker, S.C. IgA plasma cells in vascular tissue of patients with Kawasaki syndrome. J. Immunol. 1997, 159, 5946–5955. [Google Scholar] [PubMed]
  84. Brown, T.J.; Crawford, S.E.; Cornwall, M.L.; Garcia, F.; Shulman, S.T.; Rowley, A.H. CD8 T lymphocytes and macrophages infiltrate coronary artery aneurysms in acute Kawasaki disease. J. Infect. Dis. 2001, 184, 940–943. [Google Scholar] [CrossRef] [PubMed]
  85. Martinez-Hernandez, E.; Horvath, J.; Shiloh-Malawsky, Y.; Sangha, N.; Martinez-Lage, M.; Dalmau, J. Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. Neurology 2011, 77, 589–593. [Google Scholar] [CrossRef][Green Version]
  86. Takuma, K.; Kamisawa, T.; Igarashi, Y. Autoimmune pancreatitis and IgG4-related sclerosing cholangitis. Curr. Opin. Rheumatol. 2011, 23, 80–87. [Google Scholar] [CrossRef]
  87. Krumbholz, M.; Derfuss, T.; Hohlfeld, R.; Meinl, E. B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat. Rev. Neurol. 2012, 8, 613–623. [Google Scholar] [CrossRef]
  88. Wouters, M.C.A.; Nelson, B.H. Prognostic significance of tumor-infiltrating B cells and plasma cells in human cancer. Clin. Cancer Res. 2018, 24, 6125–6135. [Google Scholar] [CrossRef] [PubMed]
  89. Butman, S.; Espinoza, L.R.; Del Carpio, J.; Osterland, C.K. Rheumatoid pericarditis. Rapid deterioration with evidence of local vasculitis. JAMA 1977, 238, 2394–2396. [Google Scholar] [CrossRef] [PubMed]
  90. Pajor, L.; Lacza, A.; Kereskai, L.; Jakso, P.; Egyed, M.; Ivanyi, J.L.; Radvanyi, G.; Dombi, P.; Pal, K.; Losonczy, H. Increased incidence of monoclonal B-cell infiltrate in chronic myeloproliferative disorders. Mod. Pathol. 2004, 17, 1521–1530. [Google Scholar] [CrossRef] [PubMed][Green Version]
  91. Manzo, A.; Pitzalis, C. Lymphoid tissue reactions in rheumatoid arthritis. Autoimmun. Rev. 2007, 7, 30–34. [Google Scholar] [CrossRef]
  92. Brusselle, G.G.; Demoor, T.; Bracke, K.R.; Brandsma, C.A.; Timens, W. Lymphoid follicles in (very) severe COPD: Beneficial or harmful? Euro. Respir. J. 2009, 34, 219–230. [Google Scholar] [CrossRef]
  93. Brandtzaeg, P.; Carlsen, H.S.; Halstensen, T.S. The B-cell system in inflammatory bowel disease. Adv. Exp. Med. Biol. 2006, 579, 149–167. [Google Scholar]
  94. Thaunat, O.; Nicoletti, A. Lymphoid neogenesis in chronic rejection. Curr. Opin. Organ Transplant. 2008, 13, 16–19. [Google Scholar] [CrossRef]
  95. O’Brien, P.M.; Tsirimonaki, E.; Coomber, D.W.; Millan, D.W.; Davis, J.A.; Campo, M.S. Immunoglobulin genes expressed by B-lymphocytes infiltrating cervical carcinomas show evidence of antigen-driven selection. Cancer Immunol. Immunother. 2001, 50, 523–532. [Google Scholar] [CrossRef]
  96. Simsa, P.; Teillaud, J.L.; Stott, D.I.; Toth, J.; Kotlan, B. Tumor-infiltrating B cell immunoglobulin variable region gene usage in invasive ductal breast carcinoma. Pathol. Oncol. Res. 2005, 11, 92–97. [Google Scholar] [CrossRef][Green Version]
  97. Hjelmstrom, P. Lymphoid neogenesis: De novo formation of lymphoid tissue in chronic inflammation through expression of homing chemokines. J. Leukoc. Biol. 2001, 69, 331–339. [Google Scholar]
  98. Mason, W.H.; Jordan, S.C.; Sakai, R.; Takahashi, M.; Bernstein, B. Circulating immune complexes in Kawasaki syndrome. Pediatr. Infect. Dis. 1985, 4, 48–51. [Google Scholar] [CrossRef]
  99. Ikeda, K.; Yamaguchi, K.; Tanaka, T.; Mizuno, Y.; Hijikata, A.; Ohara, O.; Takada, H.; Kusuhara, K.; Hara, T. Unique activation status of peripheral blood mononuclear cells at acute phase of Kawasaki disease. Clin. Exp. Immunol. 2010, 160, 246–255. [Google Scholar] [CrossRef]
  100. Giordani, L.; Quaranta, M.G.; Marchesi, A.; Straface, E.; Pietraforte, D.; Villani, A.; Malorni, W.; Del Principe, D.; Viora, M. Increased frequency of immunoglobulin (Ig)A-secreting cells following Toll-like receptor (TLR)-9 engagement in patients with Kawasaki disease. Clin. Exp. Immunol. 2011, 163, 346–353. [Google Scholar] [CrossRef]
  101. Rowley, A.H.; Shulman, S.T.; Spike, B.T.; Mask, C.A.; Baker, S.C. Oligoclonal IgA response in the vascular wall in acute Kawasaki disease. J. Immunol. 2001, 166, 1334–1343. [Google Scholar] [CrossRef]
  102. Rowley, A.H.; Baker, S.C.; Shulman, S.T.; Garcia, F.L.; Guzman-Cottrill, J.A.; Chou, P.; Terai, M.; Kawasaki, T.; Kalelkar, M.B.; Crawford, S.E. Detection of antigen in bronchial epithelium and macrophages in acute Kawasaki disease by use of synthetic antibody. J. Infect. Dis. 2004, 190, 856–865. [Google Scholar] [CrossRef]
  103. Rowley, A.H.; Baker, S.C.; Shulman, S.T.; Rand, K.H.; Tretiakova, M.S.; Perlman, E.J.; Garcia, F.L.; Tajuddin, N.F.; Fox, L.M.; Huang, J.H.; et al. Ultrastructural, immunofluorescence, and RNA evidence support the hypothesis of a “new” virus associated with Kawasaki disease. J. Infect. Dis. 2011, 203, 1021–1030. [Google Scholar] [CrossRef]
  104. Rowley, A.H.; Shulman, S.T.; Garcia, F.L.; Guzman-Cottrill, J.A.; Miura, M.; Lee, H.L.; Baker, S.C. Cloning the arterial IgA antibody response during acute Kawasaki disease. J. Immunol. 2005, 175, 8386–8391. [Google Scholar] [CrossRef]
  105. Rowley, A.H.; Baker, S.C.; Shulman, S.T.; Garcia, F.L.; Fox, L.M.; Kos, I.M.; Crawford, S.E.; Russo, P.A.; Hammadeh, R.; Takahashi, K.; et al. RNA-containing cytoplasmic inclusion bodies in ciliated bronchial epithelium months to years after acute Kawasaki disease. PLoS ONE 2008, 3, e1582. [Google Scholar] [CrossRef]
  106. Geme, J.W., Jr. A biological perspective of slow virus infection and chronic disease. West. J. Med. 1978, 128, 382–389. [Google Scholar] [PubMed]
  107. Shimizu, C.; Shike, H.; Baker, S.C.; Garcia, F.; van der Hoek, L.; Kuijpers, T.W.; Reed, S.L.; Rowley, A.H.; Shulman, S.T.; Talbot, H.K.; et al. Human coronavirus NL63 is not detected in the respiratory tracts of children with acute Kawasaki disease. J. Infect. Dis. 2005, 192, 1767–1771. [Google Scholar] [CrossRef]
  108. Klein, C.; Sustmann, C.; Thomas, M.; Stubenrauch, K.; Croasdale, R.; Schanzer, J.; Brinkmann, U.; Kettenberger, H.; Regula, J.T.; Schaefer, W. Progress in overcoming the chain association issue in bispecific heterodimeric IgG antibodies. MAbs 2012, 4, 653–663. [Google Scholar] [CrossRef] [PubMed][Green Version]
  109. Schaefer, W.; Regula, J.T.; Bahner, M.; Schanzer, J.; Croasdale, R.; Durr, H.; Gassner, C.; Georges, G.; Kettenberger, H.; Imhof-Jung, S.; et al. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. Proc. Natl. Acad. Sci. USA 2011, 108, 11187–11192. [Google Scholar] [CrossRef][Green Version]
  110. Rowley, A.H. Kawasaki disease: Novel insights into etiology and genetic susceptibility. Annu. Rev. Med. 2011, 62, 69–77. [Google Scholar] [CrossRef]
  111. Kopito, R.R. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 2000, 10, 524–530. [Google Scholar] [CrossRef]
  112. Alonso, L.M.; Cortes, A.; Barrutia, M.G.; Romo, T.; Varas, A.; Zapata, A.G. Bronchial epithelium associated to lymphoid tissue does not selectively express vimentin. Histol. Histopathol. 1997, 12, 931–935. [Google Scholar]
  113. Thomas, M.G.; Loschi, M.; Desbats, M.A.; Boccaccio, G.L. RNA granules: The good, the bad and the ugly. Cell. Signal. 2011, 23, 324–334. [Google Scholar] [CrossRef]
  114. Goggin, K.; Beaudoin, S.; Grenier, C.; Brown, A.A.; Roucou, X. Prion protein aggresomes are poly(A)+ ribonucleoprotein complexes that induce a PKR-mediated deficient cell stress response. Biochim. Biophys. Acta 2008, 1783, 479–491. [Google Scholar] [CrossRef][Green Version]
  115. Lelouard, H.; Ferrand, V.; Marguet, D.; Bania, J.; Camosseto, V.; David, A.; Gatti, E.; Pierre, P. Dendritic cell aggresome-like induced structures are dedicated areas for ubiquitination and storage of newly synthesized defective proteins. J. Cell Biol. 2004, 164, 667–675. [Google Scholar] [CrossRef][Green Version]
  116. Fujiwara, Y.; Furuta, A.; Kikuchi, H.; Aizawa, S.; Hatanaka, Y.; Konya, C.; Uchida, K.; Yoshimura, A.; Tamai, Y.; Wada, K.; et al. Discovery of a novel type of autophagy targeting RNA. Autophagy 2013, 9, 403–409. [Google Scholar] [CrossRef][Green Version]
  117. Beaudoin, S.; Goggin, K.; Bissonnette, C.; Grenier, C.; Roucou, X. Aggresomes do not represent a general cellular response to protein misfolding in mammalian cells. BMC Cell Biol. 2008, 9, 59. [Google Scholar] [CrossRef]
  118. Sakurai, Y. Autoimmune aspects of Kawasaki disease. J. Investig. Allergol. Clin. Immunol. 2018, 29. [Google Scholar] [CrossRef]
  119. Cunningham, M.W.; Meissner, H.C.; Heuser, J.S.; Pietra, B.A.; Kurahara, D.K.; Leung, D.Y. Anti-human cardiac myosin autoantibodies in Kawasaki syndrome. J. Immunol. 1999, 163, 1060–1605. [Google Scholar]
  120. Gupta, M.; Johann-Liang, R.; Bussel, J.B.; Gersony, W.M.; Lehman, T.J. Elevated IgA and IgM anticardiolipin antibodies in acute Kawasaki disease. Cardiology 2002, 97, 180–182. [Google Scholar] [CrossRef] [PubMed]
  121. Chun, J.K.; Lee, T.J.; Choi, K.M.; Lee, K.H.; Kim, D.S. Elevated anti-alpha-enolase antibody levels in Kawasaki disease. Scand. J. Rheumatol. 2008, 37, 48–52. [Google Scholar] [CrossRef]
  122. Cines, D.B.; Lyss, A.P.; Reeber, M.; Bina, M.; DeHoratius, R.J. Presence of complement-fixing anti-endothelial cell antibodies in systemic lupus erythematosus. J. Clin. Investig. 1984, 73, 611–625. [Google Scholar] [CrossRef]
  123. Savage, C.O.; Williams, J.M. Anti endothelial cell antibodies in vasculitis. J. Am. Soc. Nephrol. 2007, 18, 2424–2426. [Google Scholar] [CrossRef]
  124. Barron, K.S. Kawasaki disease in children. Curr. Opin. Rheumatol. 1998, 10, 29–37. [Google Scholar] [CrossRef] [PubMed]
  125. Leung, D.Y.; Collins, T.; Lapierre, L.A.; Geha, R.S.; Pober, J.S. Immunoglobulin M antibodies present in the acute phase of Kawasaki syndrome lyse cultured vascular endothelial cells stimulated by gamma interferon. J. Clin. Investig. 1986, 77, 1428–1435. [Google Scholar] [CrossRef] [PubMed]
  126. Leung, D.Y.; Geha, R.S.; Newburger, J.W.; Burns, J.C.; Fiers, W.; Lapierre, L.A.; Pober, J.S. Two monokines, interleukin 1 and tumor necrosis factor, render cultured vascular endothelial cells susceptible to lysis by antibodies circulating during Kawasaki syndrome. J. Exp. Med. 1986, 164, 1958–1972. [Google Scholar] [CrossRef][Green Version]
  127. Fujieda, M.; Oishi, N.; Kurashige, T. Antibodies to endothelial cells in Kawasaki disease lyse endothelial cells without cytokine pretreatment. Clin. Exp. Immunol. 1997, 107, 120–126. [Google Scholar] [CrossRef][Green Version]
  128. Kaneko, K.; Savage, C.O.; Pottinger, B.E.; Shah, V.; Pearson, J.D.; Dillon, M.J. Antiendothelial cell antibodies can be cytotoxic to endothelial cells without cytokine pre-stimulation and correlate with ELISA antibody measurement in Kawasaki disease. Clin. Exp. Immunol. 1994, 98, 264–269. [Google Scholar] [CrossRef]
  129. Grunebaum, E.; Blank, M.; Cohen, S.; Afek, A.; Kopolovic, J.; Meroni, P.L.; Youinou, P.; Shoenfeld, Y. The role of anti-endothelial cell antibodies in Kawasaki disease - in vitro and in vivo studies. Clin. Exp. Immunol. 2002, 130, 233–240. [Google Scholar] [CrossRef][Green Version]
  130. Van Zelm, M.C.; van der Burg, M.; van Dongen, J.J. Homeostatic and maturation-associated proliferation in the peripheral B-cell compartment. Cell Cycle 2007, 6, 2890–2895. [Google Scholar] [CrossRef]
  131. Nutt, S.L.; Hodgkin, P.D.; Tarlinton, D.M.; Corcoran, L.M. The generation of antibody-secreting plasma cells. Nat. Rev. Immunol. 2015, 15, 160–171. [Google Scholar] [CrossRef]
  132. Wrammert, J.; Smith, K.; Miller, J.; Langley, W.A.; Kokko, K.; Larsen, C.; Zheng, N.Y.; Mays, I.; Garman, L.; Helms, C.; et al. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature 2008, 453, 667–671. [Google Scholar] [CrossRef]
  133. Balakrishnan, T.; Bela-Ong, D.B.; Toh, Y.X.; Flamand, M.; Devi, S.; Koh, M.B.; Hibberd, M.L.; Ooi, E.E.; Low, J.G.; Leo, Y.S.; et al. Dengue virus activates polyreactive, natural IgG B cells after primary and secondary infection. PLoS ONE 2011, 6, e29430. [Google Scholar] [CrossRef] [PubMed]
  134. Lee, F.E.; Falsey, A.R.; Halliley, J.L.; Sanz, I.; Walsh, E.E. Circulating antibody-secreting cells during acute respiratory syncytial virus infection in adults. J. Infect. Dis. 2010, 202, 1659–1666. [Google Scholar] [CrossRef]
  135. Garcia, M.; Iglesias, A.; Landoni, V.I.; Bellomo, C.; Bruno, A.; Cordoba, M.T.; Balboa, L.; Fernandez, G.C.; Sasiain, M.D.; Martinez, V.P.; et al. Massive plasmablast response elicited in the acute phase of hantavirus pulmonary syndrome. Immunology 2017, 151, 122–135. [Google Scholar] [CrossRef] [PubMed]
  136. Wrammert, J.; Onlamoon, N.; Akondy, R.S.; Perng, G.C.; Polsrila, K.; Chandele, A.; Kwissa, M.; Pulendran, B.; Wilson, P.C.; Wittawatmongkol, O.; et al. Rapid and massive virus-specific plasmablast responses during acute dengue virus infection in humans. J. Virol. 2012, 86, 2911–2918. [Google Scholar] [CrossRef] [PubMed]
  137. Di Niro, R.; Lee, S.J.; Vander Heiden, J.A.; Elsner, R.A.; Trivedi, N.; Bannock, J.M.; Gupta, N.T.; Kleinstein, S.H.; Vigneault, F.; Gilbert, T.J.; et al. Salmonella infection drives promiscuous B cell activation followed by extrafollicular affinity maturation. Immunity 2015, 43, 120–131. [Google Scholar] [CrossRef] [PubMed]
  138. Kauffman, R.C.; Bhuiyan, T.R.; Nakajima, R.; Mayo-Smith, L.M.; Rashu, R.; Hoq, M.R.; Chowdhury, F.; Khan, A.I.; Rahman, A.; Bhaumik, S.K. Single-cell analysis of the plasmablast response to vibrio cholerae demonstrates expansion of cross-reactive memory B cells. MBio 2016, 7. [Google Scholar] [CrossRef] [PubMed]
  139. Liao, H.X.; Chen, X.; Munshaw, S.; Zhang, R.; Marshall, D.J.; Vandergrift, N.; Whitesides, J.F.; Lu, X.; Yu, J.S.; Hwang, K.K.; et al. Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated. J. Exp. Med. 2011, 208, 2237–2249. [Google Scholar] [CrossRef] [PubMed]
  140. Liao, H.; Yu, Y.; Li, S.; Yue, Y.; Tao, C.; Su, K.; Zhang, Z. Circulating plasmablasts from chronically human immunodeficiency virus-infected individuals predominantly produce polyreactive/autoreactive antibodies. Front. Immunol. 2017, 8, 1691. [Google Scholar] [CrossRef]
  141. Odendahl, M.; Mei, H.; Hoyer, B.F.; Jacobi, A.M.; Hansen, A.; Muehlinghaus, G.; Berek, C.; Hiepe, F.; Manz, R.; Radbruch, A.; et al. Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. Blood 2005, 105, 1614–1621. [Google Scholar] [CrossRef] [PubMed][Green Version]
  142. Blanchard-Rohner, G.; Pulickal, A.S.; Jol-van der Zijde, C.M.; Snape, M.D.; Pollard, A.J. Appearance of peripheral blood plasma cells and memory B cells in a primary and secondary immune response in humans. Blood 2009, 114, 4998–5002. [Google Scholar] [CrossRef][Green Version]
  143. Fink, K. Origin and function of circulating plasmablasts during acute viral infections. Front. Immunol. 2012, 3, 78. [Google Scholar] [CrossRef] [PubMed]
  144. Rivas, J.R.; Ireland, S.J.; Chkheidze, R.; Rounds, W.H.; Lim, J.; Johnson, J.; Ramirez, D.M.; Ligocki, A.J.; Chen, D.; Guzman, A.A.; et al. Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients. Acta Neuropathol. 2017, 133, 43–60. [Google Scholar] [CrossRef]
  145. Tarlton, N.J.; Green, C.M.; Lazarus, N.H.; Rott, L.; Wong, A.P.; Abramson, O.N.; Bremer, M.; Butcher, E.C.; Abramson, T. Plasmablast frequency and trafficking receptor expression are altered in pediatric ulcerative colitis. Inflamm. Bowel Dis. 2012, 18, 2381–2391. [Google Scholar] [CrossRef]
  146. Hosomi, S.; Oshitani, N.; Kamata, N.; Sogawa, M.; Okazaki, H.; Tanigawa, T.; Yamagami, H.; Watanabe, K.; Tominaga, K.; Watanabe, T.; et al. Increased numbers of immature plasma cells in peripheral blood specifically overexpress chemokine receptor CXCR3 and CXCR4 in patients with ulcerative colitis. Clin. Exp. Immunol. 2011, 163, 215–224. [Google Scholar] [CrossRef]
  147. Mattoo, H.; Mahajan, V.S.; Della-Torre, E.; Sekigami, Y.; Carruthers, M.; Wallace, Z.S.; Deshpande, V.; Stone, J.H.; Pillai, S. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J. Allergy Clin. Immunol. 2014, 134, 679–687. [Google Scholar] [CrossRef][Green Version]
  148. Wallace, Z.S.; Mattoo, H.; Carruthers, M.; Mahajan, V.S.; Della Torre, E.; Lee, H.; Kulikova, M.; Deshpande, V.; Pillai, S.; Stone, J.H. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann. Rheum. Dis. 2015, 74, 190–195. [Google Scholar] [CrossRef]
  149. Martin, M.; Wrotniak, B.H.; Hicar, M. Suppressed plasmablast responses in febrile infants, including children with Kawasaki disease. PLoS ONE 2018, 13, e0193539. [Google Scholar] [CrossRef]
  150. Ledergor, G.; Weiner, A.; Zada, M.; Wang, S.-Y.; Cohen, Y.C.; Gatt, M.E.; Snir, N.; Magen, H.; Koren-Michowitz, M.; Herzog-Tzarfati, K.; et al. Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma. Nat. Med. 2018, 24, 1867–1876. [Google Scholar] [CrossRef] [PubMed]
  151. Brochet, X.; Lefranc, M.P.; Giudicelli, V. IMGT/V-QUEST: The highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis. Nucleic Acids Res. 2008, 36, W503–W508. [Google Scholar] [CrossRef] [PubMed]
  152. Shlomchik, M.J.; Marshak-Rothstein, A.; Wolfowicz, C.B.; Rothstein, T.L.; Weigert, M.G. The role of clonal selection and somatic mutation in autoimmunity. Nature 1987, 328, 805–811. [Google Scholar] [CrossRef] [PubMed]
Table 1. Advanced clinical trials for treatments to prevent coronary aneurysms in Kawasaki Disease.
Table 1. Advanced clinical trials for treatments to prevent coronary aneurysms in Kawasaki Disease.
DrugClinical TrialsPhaseStatusClosure DateResults Summary or Comments
InfliximabNCT022980623completedSeptember, 2015
InfliximabNCT007604353resultedOctober, 2012Improved defervescence, well tolerated, variable z- score reduction [66].
InfliximabNCT015963353resultedOctober, 2014Improved defervescence, well tolerated [67].
3recruitingSeptember, 2020
EtanerceptNCT008417892Active, not recruitingAugust, 2018
AnakinraNCT021798532recruitingDecember, 2020
2RecruitingApril, 2019
IVIG dosesNCT000005203CompletedNovember, 1989Single dose of IVIG is better than splitting doses [68].
IVIG + pulsed steroidsNCT001320803CompletedMarch, 2005No difference, refractory lower number than expected [69].
IVIG 1 g or 2 gNCT024399963CompletedSeptember, 2016
IVIG + 5 days prednisoloneNCT032005613RecruitingDecember, 2020Proposal published [70].
IVIG without AspirinNCT02951234naRecruitingAugust, 2019Proposal published [71].
Na- not applicable; z- score- standard deviations from the mean.
Table 2. Putative anti-Kawasaki disease etiology antibodies.
Table 2. Putative anti-Kawasaki disease etiology antibodies.
Monoclonal Antibody ClonesClonal MembersExact ReplicantsIG IsotypesVH ^ CDR3 LengthNucleotide Substitutions (%)VH R/S * CDR1VH R/S * CDR2VL & CDR3 lengthNucleotide substitutions (%)VL R/S * CDR1VL R/S * CDR2
24-0244M; G11993.82/05995.03/00
24-675 G1 1893.54.319.5997.09/05
24-3774 G1 1492.38.06.0996.29.00.5
24-4392 M; G21191.54.02.01194.42/02/
24-441/65915 M; G11193.131.030.0997.66.518/0
24-5955 M; G1,21593.09.513/0995.62.70
24-8158 M; G11595.45.59.01097.749/0
24-8934 G1 1291.72.32.41094.419/08
24-9083 M; G1,32096.54.02.599852
^ VH- heavy chain variable region, & VL light chain variable region, * Replacement to silent nucleotide mutation ratios (R/S).
Table 3. Possible ways humoral immunity plays a role in KD.
Table 3. Possible ways humoral immunity plays a role in KD.
Possible ImportanceContrary Findings and Considerations
Efficacy of IVIGTheoretically can provide antibodies to specific etiologyFunction in KD theoretical, many different potential functions of IVIG
Treatment with anti-CD20 antibodyDirectly downregulates IG productionLimited reports and no prospective trials
Response to IL-1 inhibitorsDownregulates IG production, mouse models support IL-1 roleMany other broad affects
Coronary plasma cell infiltratesSeen on coronary path specimens, theorized direct response to infectious agentPlasma cell infiltrates also seen in autoimmune disorders
Anti-self antibodiesCan cause apoptosis of endothelial cellsLater finding, not universally seen; unclear if part of etiology or response to tissue damage
Plasmablast (PB) levelLevel similar to infection, may be set off by etiology of KDNumber of coinfections and IVIG may make defining specificity difficult
PB timingSimilar to that of infectionPure autoimmune has PB rise, but often higher/flare correlated

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top