Advances in our understanding of the pathogenesis of Henoch-Schönlein purpura and the implications for improving its diagnosis.

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Advances in our understanding of the pathogenesis of HenochScho¨nlein purpura and the implications for improving its diagnosis Expert Rev. Clin. Immunol. 9(12), 1223–1238 (2013)

Se Jin Park1,2, Jin-Soon Suh3, Jun Ho Lee4, Jung Won Lee5, Seong Heon Kim6, Kyoung Hee Han7 and Jae Il Shin*2 1 Department of Pediatrics, Ajou University Hospital, Ajou University School of Medicine, Suwon, Korea 2 Department of Pediatrics, Yonsei University College of Medicine, Severance Children’s Hospital, Seoul, Korea 3 Department of Pediatrics, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea Bucheon, Korea 4 Department of Pediatrics, CHA University, CHA Bundang Medical Center, Seongnam, Korea 5 Department of Pediatrics, Hallym University, Kangnam Sacred Heart Hospital, Seoul, Korea 6 Department of Pediatrics, Pusan National University Children’s Hospital, Yangsan, Korea 7 Department of Pediatrics, Jeju National University School of Medicine, Jeju, Korea *Author for correspondence: Tel.: +82 222 282 050 Fax: +82 239 39118 [email protected]

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Henoch-Scho¨nlein purpura (HSP) is a leukocytoclastic vasculitis classically characterized by palpable purpura, arthritis, abdominal pain and renal disease. In this article, we summarize our current understanding of the pathogenesis of HSP and the implications for improving its diagnosis. Although the pathogenesis of HSP is not fully understood yet, exciting new information has emerged in recent years, leading to a better understanding of its pathogenesis. Here, we discuss genetic predisposition, immunoglobulins with a particular emphasis on IgA1, activated complements, cytokines and chemokines, abnormal coagulation and autoantibodies in the underlying pathogenic mechanisms. Finally, diagnostic criteria for HSP developed by institutions such as the American College of Rheumatology and the European League against Rheumatism/Paediatric Rheumatology European Society were proposed to improve early detection and diagnosis. KEYWORDS: cytokines • diagnosis • genetic susceptibility • Henoch-Scho¨nlein purpura • immunoglobulins • pathogenesis • vasculitis

Henoch-Scho¨nlein purpura (HSP) is one of the most common forms of immune complexmediated vasculitis in childhood and mainly affects the small vessels of the skin, gastrointestinal (GI) tract and kidneys [1,2]. The prevalence of HSP varies from 6.1/100,000–20.4/ 100,000 children [3,4]. The pathogenesis of HSP is unclear, but it is considered a complex disease contributed by various genetic and triggering environmental factors [1]. Although the exact etiology of HSP still remains to be answered, the seasonal distribution (winter and spring) and clinical evidence support the hypothesis that an infectious component as part of its etiology, including parvovirus B19, HBV and HCV, adenovirus, Group A b-hemolytic streptococcus, Staphylococcus aureus and Mycoplasma may predispose a child to HSP [5]. It is often preceded by an upper

10.1586/1744666X.2013.850028

respiratory tract infection of 1–3 weeks prior to the onset of symptoms in children [6], whereas toxins and drugs such as insect bites and clarithromycin may be the causative factors for HSP in adults [7]. The disease is usually self-limited in 1–4 weeks; relapses can occur. Herein, several recent papers and articles were reviewed on what we know about the genetic predisposition, aberrant O-linked glycosylation of immunoglobulin A1 molecules, complement activation cytokines and autoantibodies which are related to the pathogenesis of HSP, and the implications for improving the diagnosis of HSP. Genetic predisposition in HSP

Although most HSP patients are sporadic cases, familial clusterings of HSP have been reported [8–10]. Spyridis et al. reported that

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Park, Suh, Lee et al.

HSP was presented simultaneously in monozygotic twin [8]. HSP and/or nephropathy and IgA nephrophathy (IgAN) have been considered related diseases, and several cases have been reported of families where one family member presents with HSP or IgAN and other members also develop HSP and/or nephropathy or IgAN, even after several years [9–12]. To date, however, genome-wide linkage studies of familial cases in order to identify susceptibility genes have not been performed. HSP is an immune-complex mediated disease. Based on the postulation, that major histocompatibility (MHC) genes may be involved in the pathogenesis of the disease, many investigations focused on the association of human leukocyte antigen (HLA) and HSP [12–16]. Among them, HLA-DRB1 was largely investigated [12,13]. HLA-DRB1 polymorphisms were associated with an increased risk of HSP in Turkish children [13]. The same group also showed that HLA-DRB1 alleles were related to the susceptibility of HSP and the severity of the disease [12]. Furthermore, Amoli et al. and Jin et al. reported that HLA-B35 and HLADQA1 were risk factors for the development of nephropathy in HSP patients, respectively [14,15]. Recently, HLA-A and B polymorphisms were reported to be associated with the susceptibility of HSP in Han and Mongolian children [16]. On the other hand, many case-control association studies have been performed to identify candidate genes for the development of HSP or involvement of nephropathy [17–36]. These studies have mainly targeted genes related to inflammatory factors or the renin–angiotensin system (RAS), based on the disease pathogenesis. The RAS is known to have a role in the modulation of vascular tone and structure either directly or via various factors and various proinflammatory reactions such as cell proliferation, matrix production and cytokine activation [17]. The impact of RAS genes on the expression and outcome of HSP has been investigated in several studies [18,19]. Angiotensinconverting enzyme (ACE) and angiotensinogen gene polymorphism were associated with increased risk of HSP in Turkish children [18]. The differences in genotype distribution of the angiotensinogen gene between HSP without nephropathy and HSP with nephropathy were significantly associated with the development of nephropathy in HSP patients [18]. A recent meta-analysis of eight association studies in Asian children reported that ACE insertion/deletion polymorphism was associated with nephropathy in HSP patients [19]. The associations between HSP and genes encoding inflammation-related molecules such as cytokines and adhesion molecules were investigated in many studies [20–34]. In a Spanish study, an interleukin (IL)-18 promoter polymorphism was associated with the risk of HSP [20]. In a Chinese study, transforming growth factor (TGF)-b polymorphism was also associated with the development of HSP [21]. Several studies reported the associations of HSP and the MEFV gene, encoding pyrin, an important active member of the inflammasome [22–24]. It was shown that mutation of the MEFV gene was a risk factor for the development of HSP and also correlated with some clinical presentations such as age at diagnosis, the frequencies 1224

of arthritis and increased C-reactive protein (CRP) levels [22,23]. In addition, a Chinese study reported the association of MEFV gene polymorphism with the development of HSP [24]. Some representative proinflammatory cytokines, such as IL-8, IL-1 receptor antagonist and IL-1b polymorphisms were not associated with the development of HSP, but with severe renal involvements [25–27]. Adhesion molecules are postulated to be involved in the development of vasculitis because of its biological functions such as the recruitment of inflammatory cells at inflammatory foci, its extravasations and the adhesion of platelets to the endothelium [28]. P-selectin promoter polymorphisms were associated with the risk of HSP and the involvement of nephropathy in HSP patients [29]. On the contrary, intercellular adhesion molecule 1 (ICAM-1) polymorphism seemed to be a protective factor against severe GI complications in HSP patients [30]. In addition, a cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) exon polymorphism and an inducible nitric oxide synthase (iNOS) polymorphism were shown to be risk factors for the development of Henoch-Scho¨nlein purpura nephritis (HSPN) [31,32]. Although the associations of HSP and Toll-like receptors (TLRs), important components in innate immunity, were investigated, significant associations were not found [33,34]. Underglycosylation in the IgA1 hinge was recently discovered to be an important risk factor for the development of HSPN as well as IgAN, and this aberrant glycosylation is inherited in both pediatric IgA and HSPN [35]. Based on these findings, a polymorphism of the C1GALT1 gene encoding ß-1,3-galactosyltransferase, which plays an important role in the glycosylation of the IgA1 hinge region, was investigated [36]. Significant differences in the genotype distribution of the C1GALT1 polymorphism were found between HSP patients with nephropathy and without nephropathy [36]. Candidate genes and the involved biological pathways in HSP are summarized in TABLE 1. To date, however, no confirmed genetic loci for HSP were found. Most studies looking to identify the susceptibility genes have encountered problems recruiting patients, resulting in a relatively small number of participants. Further studies including a large number of subjects to find potential pathogenic pathways and refine prognosis are warranted. Immunoglobulins in HSP Immunoglobulin A in HSP

Although the exact pathogenesis of HSP still remains unknown, it is considered to be a small vessel leukocytoclastic vasculitis mediated by an immune complex, which is characterized by the presence of IgA, and it is suggested that unknown antigens stimulate IgA production, activating some pathways that lead to vasculitis [37]. Many serologic studies revealed increased serum levels of IgA in 50% of HSP patients during the acute stage, and circulating IgA-containing immune complexes and cryoglobulins have also been found in HSP patients in the acute stage [37,38]. Davin et al. reported that the number of IgA-secreting cells was Expert Rev. Clin. Immunol. 9(12), (2013)


Advances in our understanding of the pathogenesis of HSP

elevated in HSP but not in other leukocytoclastic vasculitis [37]. Notably, the number of IgA-secreting cells was increased within 2 weeks of onset, and the secreted a (as)-chain gene was considerably expressed compared with the membrane-bound a (am)-chain gene [38]. This study supports evidence for a selective triggering of differentiation of IgA secreting cells. Despite the fact that serum IgA levels are higher in children with HSP or HSPN than in controls, high serum IgA alone seems to not be a prognostic factor for nephritis [39]. However, we previously showed that the serum IgA/C3 ratio may be a useful marker to predict disease activity and histologic severity in HSPN [40]. Aberrant glycosylation of IgA1

IgA exists as a heterogeneous molecule, and there are two subclasses of IgA, each with structural differences: IgA1 and IgA2 [41,42]. IgA1 is the predominant subclass, accounting for 80–90% of serum IgA [41,42]. IgA1 has a hinge region of the heavy chain with five to six O-linked glycosylated sites, while IgA2 does not [41–43]. The hinge region is composed of Nacetylgalactosamine (GalNAc) with a b-1, 3-linked galactose (Gal) attached to it [44]. It was shown that there is an abnormal glycosylation of the hinge region of IgA1 in HSP [45]. These terminal glycans of IgA1 are better recognized by autoantibodies and prone to cause IgA aggregation and thus macromolecular immune complexes [46]. A recent study suggested the presence of galatose-deficient O-glycans at specific sites (T228 and/or S230) in the hinge region of IgA1 in IgAN [47]. Lau et al. reported that the mean levels of galactose-deficient IgA1(Gd-IgA1) detected by the GalNAc-specific lectin from Helix aspersa were higher in children with IgA nephropathy and HSP nephritis, compared to healthy controls and C1q nephropathy [48]. However, the median level of serum Gd-IgA1 in children with HSP without nephritis did not significantly differ from healthy controls [48]. These data suggest an important role of aberrant glycosylation of IgA1 in the pathogenesis of both IgA nephropathy and HSPN. Recently, Krzystof et al. demonstrated that circulating levels of Gd-IgA1 are highly heritable in children with IgAN and HSPN, providing support for another shared pathogenic link between these disorders [35]. Although a high serum Gd-IgA1 level is not sufficient for the development of clinical symptoms, a serum Gd-IgA1 level may constitute a useful tool for screening and stratification of pediatric patients at risk for HSPN or IgAN [35]. Elevated plasma IgE levels & eosinophil activation in HSP

In a study by Davin et al. [49], increased serum IgE levels were more commonly found in patients with HSPN. Thus, they postulated stimulation of IgE-sensitized mast cells by specific antigens in the presence of IgA circulating immune complexes, release of vasoactive substances, increased capillary permeability [49]. Deposition of the IgA immune complexes was well boosted by subsequent increased local capillary permeability [49]. However, He et al. did not find any significant association between IgE level and HSP severity [50], and therefore the www.expert-reviews.com

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pathogenic roles of IgE remain unclear. Mast cells are not usually found in the mesangium, but sometimes interstitial mast cell infiltration is associated with the development of renal interstitial fibrosis in children with HSPN [51]. It has been suggested that eosinophilic activation is involved in the pathogenesis of HSPN [52–54]. Namgoong et al. investigated serum eosinophil cationic protein (ECP) levels in HSP and IgAN, revealing the presence of significantly higher levels of ECP in HSP than in the control group [52]. The HSP group with nephritis also showed higher levels of ECP than the HSP group without nephritis [52]. However, ECP levels in IgAN were not significantly higher than in a control group [52]. Kawasaki et al. also showed higher serum levels of ECP and IL-5 in HSPN than in HSP without nephritis [53]. In a recent study from China, serum levels of ECP were higher only in active HSPN patients [54]. Data from these studies [52–54] suggest that ECP might play a pathogenic role in the development and progression of HSPN. Complements in HSP

Activation of complement has been thought to be an important factor of tissue injury in HSP. Complement components in the skin and glomeruli or breakdown products of complement in the plasma were found in HSP patients [55,56]. C3 and properdin were found in the glomerular deposits of 75–100% of patients with IgAN and HSP [57]. In 1975, Smith et al. reported that sera from HSP patients with nephritis inhibited the erythrocytes coated with antibody and complement (EAC) rosette formation of normal human lymphocytes, and postulated that activated C3 fragments may be present in their circulation [58]. Defective clearance of IgA-containing complexes by complement system has a role in the pathogenesis of IgAN or HSP [59]. For hepatic clearance of soluble immune complexes containing C3b, binding to the erythrocyte complement receptor (CR1) is necessary before they are transported to the liver [60]. Moreover, deficiency of C4 has been suggested as a risk factor for HSPN, which might represent a defective clearance mechanism [15,61]. Additionally, McLean et al. indicated that individuals with the C4 homozygous null phenotype have a predisposition to the development of HSP nephropathy [62]. Kawana et al. reported the deposition of C5, C6, C7, C8, C9 and cytolytically active C5b-9 complex (membrane attack complex (MAC)) in the vascular walls of the papillary dermis and subpapillary dermal plexus of the vessels in HSP patients, suggesting that MAC may be a cause of vascular endothelial cell damage through complement activation [63]. In 2003, the long pentraxin 3 (PTX3), a complement related protein, was detected in the expanded mesangial areas and endothelial cells in renal biopsies, and the potential role of PTX3 in the modulation of glomerular injury in IgAN or HSPN was suggested [64]. However, PTX3 is related to the classical pathway of complement activation [65]. Serum C3 and C3-C9 hemolytic titers were normal or elevated in HSP, although low serum C3 or C4 levels have been 1225

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Table 1. Candidate genes and the involved biological pathways in Henoch-Scho¨nlein purpura. Putative function Antigen presentation

Gene HLA-A and B

Full name Major histocompatibility complex, class I, A and B

Chromosome 6p21.3

HLA-B


Cytokines

Adhesion molecules

Other inflammatory molecules

Renin-angiotensin system

Glycosylation of IgA

HLA-DRB1

Major histocompatibility complex, class II, DR b-1

IL1B

Interleukin-1 b

Affected gene locations †

†

Ref.

HLA-A 11, B 15 (Mongolian) HLA-A†26, B†35, B52 (Han) HLA-B†07, B†40 (Mongolian)

D, P

[16]

HLA-B†35

N

[14]

DRB1 10,14,17

D

[12]

-511C/T polymorphism

N

[27]

†

2q14

Effect

†

IL1RN

Interleukin-1 receptor antagonist

2q14.2

VNTR polymorphism

N

[26]

IL18

Interleukin-18

11q22.2-q22.3

-137G/C polymorphism (rs187238)

D

[20]

IL8

Interleukin-8

4q13-q21

2767A/G polymorphism in the 3’UTR

N

[25]

TGFB1

Transforming growth factor b-1

19q13.1

-509C/T polymorphism

D

[21]

P-selectin

Selectin P

1q22-q25

-825A/G polymorphism

D,N

[29]

‡

ICAM-1

Intracellular adhesion molecule-1

19p13.3-p13.2

469K/E genotype

P

[30]

CTLA-4

Cytotoxic T-lymphocyte antigen-4

2q33

49A/G polymorphism (rs231775)

N

[31]

NOS2

Nitric oxide synthase 2, inducible

17q11.2-q12

NOS2A promoter CCTTT repeat microsatillate polymorphism

D, N

[32]

MEFV

Mediterranean fever

16q13.3

p.M694V, p.M680I, p. V726A frequency E148Q (G->C) polymorphism (rs3743930)

D, D

[22–24]

ACE

Angiotensin I converting enzyme

17q23.3

Insertion/deletion polymorphism

D, N

[18,19]

AGT

Angiotensinogen

1q42.2

M235T polymorphism

D, N

[18]

C1GALT1

Core 1 synthase, glycoprotein-Nacetylgalactosamine 3-b-galactosyltransferase 1

7p21.3

1365 G/A polymorphism (rs1047763)

N

[36]

†

Variable copy numbers of an 86 base pair tandem repeat. Protection for severe GI complications in HSP patients. D: Development of HSP; HSP: Henoch-Scho¨nlein purpura; N: Development of Nephropathy in HSP patients; P: Protection for HSP. ‡

reported in some patients with HSP [66–68]. Furthermore, serum C1, C4, and C2 titers and CH50 (classical pathway activity) were normal [66]. However, CH50 was low in 39% of patients with HSP in another study [67]. Among alternative pathway activity parameters (serum properdin, properdin convertase, factor B, the ability of serum to support C3-C9 activation with zymosan or cobra venom factor and the lysis of unsensitized rabbit erythrocytes), only the serum levels of properdin and properdin convertase were abnormal in the acute phase of HSP [66,67]. Properdin, which is activated by properdin convertase, might be fixed to C3b or C3b-B, given the known avidity 1226

of properdin for C3b, and then its complex deposited in the affected tissues [66]. The alternative pathway activation of complement, which is activated by aggregates of IgA and IgM, plays a role in the pathogenesis of HSP [69,70]. Some have reported that IgG co-immunoglobulin deposition may induce complement activation [45,71]. Glomerular deposits of components of the lectin pathway, mannose-binding lectin (MBL) and MBL-associated serine protease (MASP) as well as C3b/C3c, C5b-9 and C4-binding protein (C4bp), were detected in eight of 10 patients with HSPN, and it was suggested that complement activation through the Expert Rev. Clin. Immunol. 9(12), (2013)


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Table 2. Changes in cytokines and chemokines in the pathogenesis of Henoch-Scho¨nlein purpura. Cytokines & chemokines

Changes

Effects

Ref.

IL-17

Increase

Vascular inflammation

[86]

IL-1

Increase

Vascular Inflammation

[87–89]

IL-10

Decrease

Anti-inflammation

[90,91]

TGF-b1

Decrease

Anti-inflammation

[90,91]

IL-1b

Increase

Proinflammation

TNF-a

Increase

Proinflammation, stimulation of endothelial fibroblasts or mesangial cells, angiogenesis

[104,105]

IL-2

Increase

Proinflammation

[95,96,99]

IL-6

Increase

Angiogenesis, proliferation and migration of human endothelial cells

IL-8

Increase

Proinflammation

TWEAK

Increase

Regulator of NF-kB

[107]

VEGF

Increase

Angiogenesis

[108]

[97,98,184]

[98,109]

[102,103]

TGF: Transforming growth factor; TWEAK: TNF-like weak inducer of apoptosis.

lectin pathway was also involved in the onset of HSPN [61]. In 16 patients with mesangial IgA1/IgA2 codeposits, mesangial deposits of C3c, C4, factor B, C4-bp, C5b-9, CD59, MBL and MASP-1 were observed, and it was deduced that complement activation through both the alternative and lectin pathways plays a role in patients with HSPN [72]. Particularly, complement activation through the lectin pathway may contribute to the development of advanced glomerular injuries and prolonged urinary abnormalities in patients with HSPN. The lectin pathway is initiated by lectin and ficolins, which have a high affinity for terminal mannose and N-acetylglucosamine moieties on surfaces of various pathogens such as viruses, bacteria and fungi [73,74]. Binding of the MBL/MASP-1 complex to sugar chains in the mesangium leads to activation of C4 and C2 without the C1 component [74,75]. There are three types of serine proteases (MASP-1, MASP-2 and MASP-3) that form complexes with human MBL, which are reported to bind directly to a number of microorganisms through carbohydrates expressed on their surfaces including Haemophilus parainfluenzae [73,76,77]. The lectin pathway could be activated by human IgA1 or IgA2 binding to MBL [78]. It is believed that the frequency of glomerular deposition of MBL/MASP-1 was greater in HSPN than in IgAN possibly because the renal biopsies had been performed in the acute phase [79]. Plasma levels of C3a and C5a provide a sensitive indicator of in vivo complement activation and have been suggested as a monitor of disease progression [80]. The majority of patients with a C4 null allele had low C4 and MBL levels and had not only an increased risk of developing HSP through a defective clearance mechanism of immune complexes but also a risk of developing serious morbidity associated with HSP including HSPN [81]. www.expert-reviews.com

Hypocomplementemia in the acute stage of HSP (low C3: 4– 8%, low C4: 8–17% and low CH50: 3–33%) did not correlate with the severity of HSP or renal involvement [69,82]. Activated complement C3 was associated with subsequent deterioration of renal function in both IgAN and HSP patients [83]. Furthermore, serum soluble C5b-9 concentration and urinary terminal complement complexes significantly increased in active HSP, with severe clinical manifestations [84,85]. Cytokines in HSP

Exciting new information on cytokines in HSP has emerged in recent years, leading to better understanding of the pathogenesis of HSP. Although the pathogenesis is not fully understood yet, several cytokines have been implicated in many studies of the pathogenesis of HSP vasculitis. Th17 cells, a new subset of T helper cells, play a critical role in the development of autoimmune diseases through the production of some cytokines such as IL-6 and IL-17 [86]. IL-17 is a potent inflammatory cytokine that promotes the expression of chemokines and inflammatory cytokines, including IL-1, cell adhesion molecules and other inflammatory factors [87–89]. CD4+CD25+ Treg cells, a subset which consists of 5–10% of peripheral CD4+ T cells, plays a major role in preventing autoimmune and inflammatory diseases by secreting antiinflammatory cytokines such as IL-10 and TGF-b1 [90,91]. Chen et al. recently reported that the frequency of IL-17-producing Th17 cells and the concentration of IL-17 were higher in HSP patients than in healthy controls (p < 0.05), whereas the frequency of CD4+CD25+ Treg cells and the IL-10 concentration were lower in HSP patients than in healthy controls [92]. They suggested that a Th17/Treg imbalance exists in HSP and plays a potent role in the formation 1227


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and progression of HSP [92]. These results are in accordance with the previous studies, which reported that the proportions of Th17 cells were increased significantly in HSP patients and the elevated IL-17 levels in childhood HSP may contribute to vascular inflammation [93,94]. Although the precise mechanism of an increase in Th17 cells and the IL-17 concentration in HSP patients remains elusive, IL-17 has also been reported to induce vasculitis through endothelial chemokine production, resulting in polymorphonuclear neutrophil accumulation in HSP patients [94]. According to the previous studies, several proinflammatory cytokines, including TNF-a, IL-1b, IL-2, IL-6, IL-8, TGF-b and VEGF, have been reported to be involved in the development of HSP (TABLE 2) [95–99]. They are likely secreted by vascular endothelial cells, thus initiating and propagating the inflammatory response. These proinflammatory cytokines stimulate the production of chemokines by endothelial cells, attract inflammatory cells and induce the expression of cell adhesion molecules on endothelial cells, facilitating their adhesion to the vascular wall [100,101]. In an experiment of in vitro cultured human umbilical venous endothelial cells (HUVEC) induced by the sera of children with active HSP, the levels of IL-8 and TNF-a were significantly higher in the HSP serum group than in the normal serum groups [102,103]. Circulating IgA antiendothelial cell antibodies derived from the acute stage of childhood HSP may bind to endothelial cells and enhance them to produce IL-8 via the MEK/ERK signaling pathway [103]. TNF-a is known to play an important role in the occurrence of HSP and HSPN. TNF-a is a potent proinflammatory cytokine produced by many cell types, including monocytes/macrophages and renal mesangial and epithelial cells in kidneys [104]. It stimulates mitosis of endothelial fibroblasts or mesangial cells and angiogenesis, and induces a transient expression of the endothelial leukocyte adhesion molecule-1, the vascular cell adhesion molecule-1 and a sustained increase in ICAM-1 [105]. Expression of adhesion molecules such as P-selectin and ICAM-2 on endothelium and ICAM-2 and -3 on inflammatory cells is higher during acute than convalescent HSP [106]. TNF-a also facilitates the release of other proinflammatory cytokines, growth factors and chemokines, such as IL-1b, monocyte chemoattractant protein-1 and TGF-b [97]. In addition, TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF family, has been implicated in the pathogenesis of HSP [107]. In the human dermal microvascular endothelial cell line (HMEC-1), serum levels of TWEAK were elevated in patients with HSP in the acute stage and were correlated with the disease severity [107]. Therefore, TWEAK may act as a regulator of nuclear factor-kB (NF-kB) activation and chemokine production in HMEC, promoting leukocyte migration in cutaneous vasculitis [107]. These findings indicate that IL-8, TNF-a and TWEAK may together play important roles in HSP onset. Of note, Topaloglu et al. demonstrated that plasma vascular endothelial growth factror (VEGF) levels were significantly 1228

higher during the acute phase of HSP, compared with levels during the resolution phase and in healthy control subjects [108]. Serum IL-6 levels were also proven to be significantly elevated in patients with HSP during the acute stage [98]. IL-6, which is involved in angiogenesis, triggers the proliferation and migration of human endothelial cells in a dose-dependent manner, specifically associated with the enhancement of VEGF expression and with the upregulated and phosphorylated VEGF receptor-2 through activating extracellular signal-regulated kinase1/2 signaling [109]. Recently, accelerated extracellular matrix breakdown caused by the increased activity of matrix metalloproteinases (MMPs) has also been implicated in HSP [110,111]. HSP patients showed increased levels of serum activity of MMP-2 and MMP-9 in the acute phase compared with their convalescent phase and their control counterparts [110]. Shin et al. demonstrated that MMP-1, MMP-8, MMP-9, MMP-10, MMP-13, MMP-16 and MMP-26 levels were also significantly higher in patients in the acute stage of HSP than in normal controls, suggesting that abnormal levels of MMP and tissue inhibitors of metalloproteinase (TIMPs) activity may have a role in the pathogenesis of HSP [111]. Cytokines in HSPN

As previously mentioned, increased TNF-a can induce changes in renal endothelial and in mesangial cells. TNF-a, together with other proinflammatory cytokines, chemokines and growth factors, may increase the cytotoxic potential of resident glomerular macrophages, which results in extracellular matrix formation in the mesangial regions of the glomeruli [104]. In animal models of nephritis, TNF-a can cause and exacerbate proteinuria [112]. The production of TNF-a in the glomerulus or interstitium might contribute to glomerular barrier injury and subsequently increase glomerular permeability, thus causing proteinuria [112]. TNF-a levels were increased in the plasma and urine of patients with HSPN [97]. There is also an imbalance of Th1/Th2 in children with glomerulonephritis [113]. The levels of IFN-g and IL-12 in the HSP group were lower than those of the control group, whereas the levels of IL-4 were higher than those of the control group [114]. IFN-inducible protein 10, a Th1 chemoattractant, was lower in HSP during the acute phase of the disease, suggesting diminished Th1 function in HSP [115]. The decrease in IL-12 levels was closely associated with reduced number and function of dendritic cells, which, in peripheral blood, indirectly causes the imbalance of Th1/Th2 [114]. These findings suggest that the pathogenetic mechanism of HSPN may involve the Th2 pattern and Th1/Th2 predominance and that the level of proinflammatory cytokines could be responsible for the process of renal lesions. Therefore, the overexpression of proinflammatory cytokines and chemokines in various combinations may play a critical role in the development of and progression to HSPN and can be one of the targets in HSP therapy. Expert Rev. Clin. Immunol. 9(12), (2013)



Endothelial injury & coagulation abnormalities in HSP

Circulating immune complexes (CIC) and hemostatic alterations can cause endothelial injury of vessels in HSP. Plasma levels of von Willebrand factor antigen (vWf:Ag) were elevated and correlated with the clinical severity score and with IgA and CIC levels, as a consequence of immune-mediated endothelial cell damage [116]. Among the adhesion molecules and vWF, only vWF correlated well with the CRP measurement in the active phase of HSP, which is a good marker of disease activity [117]. In a longitudinal cohort study, vWf:Ag concentrations were significantly higher at the onset of the disease than those of the control group [118]. These data suggest that plasma vWF is closely related to vascular inflammation, endothelial damage and activation of the coagulation system. Brendel-Mu¨ller et al. investigated blood coagulation factors in HSP patients and reported that plasma D-dimer concentrations were significantly increased in 15 of the 17 patients and plasma concentrations of thrombin-antithrombin complex (TAT) and prothrombin fragments (PF) 1 and 2 were found to be abnormal in six of 11 patients [119]. Furthermore, fibrinogen, D-dimer, TAT and PF (1+2) levels in patients with HSP during the acute phase were significantly higher than those of the recovery phase and of the control groups [119]. A significant correlation was detected between the severity of disease and D-dimer, TAT, PF (1+2) and vWAg levels [120]. These findings probably indicate local reactions within inflamed blood vessels rather than a systemic activation of coagulation and hyperfibrinolysis. Although not extensively studied in HSP, factor VIII and homocystein levels in a case report of HSP were found to be high [121], suggesting that HSP itself may lead to a prothrombotic state and increases the risk of developing thrombosis in patients who have any risk factors. Markedly decreased factor XIII (fibrin stabilizing factor) activity may result in severe complications such as massive intracerebral hemorrhage and pulmonary hemorrhage, presumably due to a specific degradation of factor XIII by proteolytic enzymes liberated from inflammatory cells, with defective local hemostasis [122]. Factor XIII concentrations and activity might offer a new possibility as a prognostic indicator in HSP patients. In these HSP patients, treatment with factor XIII combined with an antifibrinolytic drug would control life-threatening bleeding. In addition, Culic et al. analyzed platelet aggregation and reported that most patients had abnormal aggregation curves, in which platelets demonstrated a block of release of the endogenous ADP [123]. Autoantibodies in HSP

Vascular deposition of IgA-dominant immune complexes has been thought to be a specific pathologic finding in HSP [124]. IgA is the principal antibody in the respiratory system for defense against microbial agents, and various autoantibodies have been found to be associated with HSP. www.expert-reviews.com

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Antiphospholipid antibodies, including anticardiolipin antibodies, are a heterogenous group of immunoglobulins of the IgG, IgM and IgA classes directed against a variety of proteinphospholipid antigens [125]. In the coagulation cascade, antiphospholipid antibodies increase endothelial expression of cell-surface adhesion molecules and secrete inflammatory mediators, resulting in platelet adhesion and endothelial injury [126]. b2-glycoprotein I (b2GPI), one of the phospholipid-binding circulating proteins, binds to negatively charged cardiolipin and acts as a cofactor for the binding of anticardiolipin antibodies [127]. Interestingly, Sokol et al. reported a case of a 15-year-old girl with characteristics of HSP and brain infarct who had a transient IgA anti-phosphatidylethanolamine antibody, which might be related to antiphospholipid antibodies [128]. In addition, Abend et al. reported a case of sinovenous thrombosis associated with positive lupus anticoagulant (LA) in a 15-year-old boy with HSP [129]. Shin et al. reported that Korean patients with HSP, exhibited a high incidence of positive LA at the acute stage of disease [130]. Therefore, antiphospholipid syndrome (APS) should be suspected in cases of HSP and antiphospholipid antibodies should be measured to determine whether antithrombotic therapy is necessary [131], because children with HSP and CNS symptoms had a higher percentage of positive antiphospholipid antibodies in serum and cerebrospinal fluid [132]. It is still poorly understood whether the relationship between HSP and APS is coincidental or different manifestations of the same disease. However, there may be more of an association in which HSP-related antibodies induce vasculitis and antiphospholipid antibodies act as an additional hit, thus leading to the formation of thrombosis [129,130,133]. Kawakami et al. suggested that elevated serum IgA anticardiolipin antibody levels at the time of presentation with initial cutaneous manifestations and serum IgA anticardiolipin antibodies might be an indicator of adult HSP activity [134]. Similary, Yang et al. demonstrated a significant association between the IgA anticardiolipin antibody and childhood HSP during the acute stage [135]. Antineutrophil cytoplasmic antibodies (ANCA) comprise a group of antibodies directed against neutrophil cytoplasmic constituents, in particular proteinase-3 and myeloperoxidase [136– 138]. ANCA are associated with systemic vasculitis, including Wegener´s granulomatosis, microscopic polyangitis and ChurgStrauss syndrome. However, the role of ANCA in HSP is controversial. Although some authors reported that ANCA are not involved in the pathogenesis of HSP [137,138], Ozaltin et al. have found that the presence of IgA ANCA may help, in confirming the diagnosis of HSP [136]. Other autoantibodies, including antinuclear antibody and IgA rhematoid factor, are also found in some patients with acute HSP [139,140]. Recently, some studies have revealed that IgA anti-endothelial cell antibodies could directly activate endothelial cells to produce IL-8 through the MEK/ERK signaling pathway [103]. Still further studies are needed to determine the pathogenesis and clinical significance of various autoantibodies in HSP. 1229

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Implications for improving HSP diagnosis

HSP is a disease, commonly diagnosed by clinical context. However, some cases with atypical clinical presentation make it difficult to diagnose HSP. The purpose of this paragraph is to introduce HSP’s clinical diagnostic criteria and its many atypical clinical features, which have been updated several times over various decades. In 1990, the American College of Rheumatology (ACR) proposed classification criteria to identify HSP and distinguish HSP from other forms of systemic vasculitis [141,142]. The ACR criteria for HSP require the presence of any two or more of the following characteristics: age 20 years at disease onset; palpable purpura; acute abdominal pain; and biopsy showing granulocytes in the walls of small arterioles or venules [141]. In 2005, the European League against Rheumatism/Paediatric Rheumatology European Society (EULAR/PRES) endorsed consensus criteria for the development of the classification of childhood vasculitis based on a literature review [143]. The group modified the classification criteria for HSP as follows: palpable purpura (mandatory criterion) must be present with at least one of the following four characteristics: diffuse abdominal pain; any biopsy showing predominant IgA deposition; arthritis or arthralgia (acute, any joint); and renal involvement (any hematuria and/or proteinuria) [143]. The EULAR, the Paediatric Rheumatology International Trials Organization (PRINTO), and PRES promoted a formal statistical validation process with a large-scale, web-based data collection and proposed the 2008 Ankara Consensus for HSP, childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA) [144]. Some differences between the original ACR criteria and the new EULAR/PRINTO/PRES criteria were histopathologic findings. The ACR criteria required histology showing granulocytes in the walls of arterioles or venules; however, the Ankara Consensus committee chose histopathology showing typically leukocytoclastic vasculitis (LCV) with predominant IgA deposit or proliferative glomerulonephritis with predominant IgA deposit for all doubtful cases such as for purpura with atypical characteristics or distribution in children [144]. LCV on histology in HSP is characterized by neutrophilic infiltration and prominent nuclear fragmentation, involving the upper and middle layers of the dermis with IgA deposition on direct immunofluorescence [145,146]. The pathogenesis of abnormally glycosylated IgA in HSP is reflected in the diagnostic criteria. Linskey et al. reported that patients with IgA-positive vasculitis compared with IgA-negative LCV patients were more likely to have a higher percentage of palpable purpura, lower limb predominance of purpura and joint manifestations [147]. On the contrary, pediatricians do not usually perform a skin biopsy of isolated non-thrombocytopenic purpura to differentiate HSP in children from another common cause of vasculitis such as hypersensitivity vasculitis, which therefore might lead to overdiagnosis and unnecessary follow-ups [3]. To 1230

minimize false-negative biopsy results and to maximize the chance of finding IgA deposits, it is recommended that biopsy specimens should be taken from the edge of fresh skin lesions, because IgA deposits disappear over time due to proteolytic effects in the central lesions and by phagocytosis [147–149]. The cutaneous manifestations of HSP are typically nonthrombocytopenic rashes which evolve from erythematous to urticarial and macular wheels to nonblanching palpable purpura with petechiae and ecchymoses [145]. Palpable purpura means elevated purpura with palpable swelling [146]. In the elderly, palpable purpura lesions are not very elevated because of lower elasticity, and ecchymosis is frequently observed because the aging process loosens collagen fibers and elastin fibers in the dermis [146]. Palpable purpura does not appear to be pathognomonic of HSP and indicates the involvement of small vessel vasculitis in the upper dermis [146]. The KAWAKAMI algorithm for primary cutaneous vasculitis may allow us to accurately identify small vessel vasculitis including Churg-Strauss syndrome, microscopic polyangiitis (MPA), c-WG, cryoglobulinemic vasculitis, HSP, cutaneous leukocytoclastic angiitis (CLA) and cutaneous polyarteritis nodosa (CPN) [146]. The KAWAKAMI algorithm suggests that HSP is indicated when IgA deposition in the vessels, in the dermis, is found in patients with palpable purpura on their lower extremities; CLA is indicated if a histopathological exam reveals LCV without IgA deposits in the upper to middle dermis; on the other hand, if necrotizing vasculitis exists in the lower dermis and/or subcutaneous fat, CPN is indicated [146]. When MPA and HSP overlapping syndrome was reported, a combined immunosuppressive therapy needed to be initiated in patients with this rare condition [150–154]. However, the detection of this overlap may not be easy. We suggested that when a patient presents with an atypical presentation of HSP, polyangiitis overlap syndrome should be suspected, considering its fatal outcome in contrast to the benign nature of HSP [155]. Hemorrhagic bullous skin lesions in HSP can occur in childhood, although its occurrence is rarely described [156– 158]. The occurrence of hemorrhagic bullae as one of the clinical features in HSP may be a source of diagnostic dilemma in children, but skin biopsy may be effective to confirm the diagnosis of HSP and to differentiate from other common causes of bullous lesions in childhood, including toxic epidermal necrolysis, erythema multiforme, pemphigus, bullous impetigo, dermatitis herpetiformis and staphylococcal-scalded skin syndrome [157,158]. Some etiology is associated with HSP including infections (bacteria, virus and parasite), medications, vaccination, tumors, a-1-antitrypsin deficiency and Familial Mediterranean fever [145,159,160]. In cases of vasculitis accompanied by fever, secondary causes such as invasive meningococcal disease should be ruled out from those etiologies because it is more important if the immunosuppressant is Expert Rev. Clin. Immunol. 9(12), (2013)



planned for the treatment of vasculitis [161]. Systemic lupus erythematosus (SLE) or Crohn’s disease sometimes mimic HSP [162–164]. GI manifestations of HSP vary from colicky abdominal pain similar to bowel angina to intestinal bleeding [165,166]. About one-fourth of patients had GI symptoms prior to the development of a cutaneous rash [167]. Uncommon GI complications are intussusceptions [168], intestinal infarction [169], bowel perforation [170], perforation of the gallbladder [171] and enteroenteric fistulae [172], which may require surgical intervention and may have a fatal outcome. The numerous reports of scrotal involvement in HSP have appeared with incidences of scrotal complication varying from 2–38% [173–175]. Clinical symptoms are painful, unilateral and sometimes purpuric scrotal edema, bilateral scrotal hematoma, localized testicular pain with palpation and penile edema, which may be often difficult to distinguish from acute testicular torsion [173,176,177]. Besides, scrotal involvement may precede the cutaneous manifestation of HSP [176,177]. Perturbations of the CNS can occur rarely in HSP, and possible neurologic features include headache, altered mentality, seizures, visual disturbance, verbal disability, peripheral neuropathy, facial palsy, encephalopathy, intracranial hemorrhage and Guillain-Barre´ syndrome [178–180]. Pulmonary hemorrhage is a rare and life-threatening complication in HSP. Early bronchoscopy is recommended for diagnosis of pulmonary hemorrhage if hemoptysis, drop-in hemoglobin and chest infiltrates in radiology are present in patients with HSP [181]. Intensive immunotherapy should be initiated using pulse methylprednisolone and cytotoxic drugs such as cyclophosphamide or azathioprine because untreated pulmonary hemorrhage is rapidly fatal [181–183]. Understanding the diagnostic criteria and atypical presentation of HSP will help us correctly diagnose HSP and prevent serious complications. Expert commentary

In this review, we have outlined and reviewed the pathogenesis of HSP and the implications for improving its diagnosis. In the past 5 years, there has been significant progress in the investigation of the pathogenesis of HSP. Thus, recent data from the study of children with HSP have suggested that disorders in genetics, immunoglobulins, complements, cytokines, coagulation and autoantibodies may predispose to HSP. A better understanding of the pathophysiology and diagnosis of the disease could be achieved by designing prospective international multicenter studies looking at determinants of clinical and histopathological evolution as well as racial and regional differences in HSP. Such studies should be supported by a database available on the web. Making the diagnosis of HSP is sometimes challenging, as presenting symptoms may be atypical, subclinical and non-


Review

diagnostic. If HSP is suspected, a thorough history and physical examination including recent infections, drug exposure and a detailed family history are important. HSP can present first with diffuse abdominal pain and intestinal bleeding and then later palpable purpuric rashes. Although the laboratory evaluation for HSP is non-specific, acute phase reactants such as the erythrocyte sedimentation rate (ESR) and CRP can be increased. Blood urea nitrogen, creatinine and urinalysis will be useful for the evaluation of renal involvement. Typically, imaging is not warranted when there is a high clinical suspicion of HSP, but the gold standard for diagnosis is tissue biopsy, showing predominant IgA deposition, mostly in the arterioles, capillaries and venules of the skin, GI tract or kidneys. Five-year view

In the next few years, next-generation sequencing technologies and larger genome-wide association studies will help to identify additional risk loci of HSP. The genetic polymorphism may play an important role for us to understand the predisposing, protective, and prognostic factors associated with HSP complications. Epidemiologic studies should also be performed to show global variability in incidence, prevalence and outcomes of HSP among different races. Although the past 5 years brought great advancement in revealing HSP pathophysiology, most studies suffered from retrospective, uncontrolled design and small numbers of patients. Thus, prospective, double-blind and placebo-controlled trials are needed in future studies regarding the pathogenesis of and treatment for HSPN in order to establish the most appropriate treatment. These will be substantial efforts to understand the underlying genetic and environmental causes and to apply this knowledge to the development of novel therapies in HSP research. In order to prove treatment efficacy, clinical, pathologic and experimental data should be collected and collaborative, prospective randomized studies should be performed to reach therapeutic decisions. Trials should be designed to determine the efficacy of immunosuppressive drugs, anticoagulation agents, and plasmapheresis. Other biologic treatments such as rituximab can be an optional treatment. Further detailed investigation of HSP pathogenesis and diagnosis is necessary to identify the most appropriate treatment. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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Key issues • To date, no confirmed genetic loci for Henoch-Scho¨nlein purpura (HSP) were found. Genome-wide linkage study of familial cases should be performed to identify susceptibility genes. • Renal involvement is the critical factor determining the long-term outcome of children with HSP. The pathogenesis of Henoch-Scho¨nlein purpura nephritis (HSPN) is related to the deposition of IgA and IgA-containing immune complexes in the glomerular mesangium. • Aberrant glycosylation of IgA1, IgA circulating immune complexes, stimulation of IgE-sensitized mast cells and eosinophils by specific antigens, activation of complement, release of vasoactive substances, increased permeability of capillary, elevated proinflammatory cytokines and chemokines and perivascular deposition of IgA circulating immune complexes are all associated with the pathogenesis of HSP. Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nyu Medical Center on 02/10/15 For personal use only.

• Atypical presentations and severe, varied complications make it difficult to diagnose HSP. • HSP can overlap with other autoimmune diseases or systemic vasculitis such as microscopic polyangiitis. • International collaboration to study epidemiology is necessary to investigate the genetic polymorphism and variants for a better understanding of the predisposing and protective factors in relation to complications in HSP.

Papers of special note have been highlighted as: • of interest •• of considerable interest 1

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•

This is a comprehensive overview of Henoch-Scho¨nlein purpura (HSP) in the genetic susceptibility and pathogenesis, showing the need of multicenter clinical trials concerning the most effective treatment of severe HSP nephritis.

2

3

4

5

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Davin JC, Weening JJ. Henoch-Scho¨nlein purpura nephritis: an update. Eur. J. Pediatr. 160(12), 689–695 (2001). Aalberse J, Dolman K, Ramnath G, Pereira RR, Davin JC. Henoch-Scho¨nlein purpura in children: an epidemiological study among Dutch paediatricians on incidence and diagnostic criteria. Ann. Rheum. Dis. 66(12), 1648–1650 (2007). Gardner-Medwin JM, Dolezalova P, Cummins C, Southwood TR. Incidence of Henoch-Scho¨nlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet 360(9341), 1197–1202 (2002). Weiss PF, Klink AJ. Luan X, Feudtner C. Temporal association of Streptococcus, Staphylococcus, and parainfluenza pediatric hospitalizations and hospitalized cases of Henoch-Scho¨nlein purpura. J. Rheumatol. 37(12), 2587–2594 (2010).

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Motoyama O. Iitaka K. Familial cases of Henoch-Scho¨nlein purpura in eight families. Pediatr. Int. 47(6), 612–615 (2005).

10

Shin JI, Lee JS. Familial clusturing of Henoch-Scho¨nlein purpura or IgA nephropathy: genetic background or environmental triggers? Pediatr. Dermatol. 25(6), 651 (2008).

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••

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74

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Endo M, Ohi H, Ohsawa I, Fujita T, Matsushita M. Complement activation through the lectin pathway in patients with Henoch-Scho¨nlein purpura nephritis. Am. J. Kidney Dis. 35(3), 401–407 (2000).

80

Abou-Ragheb HH, Williams AJ, Brown CB. Milford-Ward A. Plasma levels of the anaphylatoxins C3a and C4a in patients with IgA nephropathy/ Henoch-Scho¨nlein nephritis. Nephron 62(1), 22–26 (1992).

81

Stefansson Thors V, Kolka R, Sigurdardottir SL, Edvardsson VO, Arason G, Haraldsson A. Increased frequency of C4B*Q0 alleles in patients with Henoch-Scho¨nlein purpura. Scand. J. Immunol. 61(3), 274–278 (2005).

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83

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84

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85

Kusunoki Y, Akutsu Y, Itami N et al. Urinary excretion of terminal complement complexes in glomerular disease. Nephron 59(1), 27–32 (1991).

86

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87

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88

Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 14(2), 155–174 (2003).

89

Khoury SJ. Th17 and Treg balance in systemic sclerosis. Clin. Immunol. 139(3), 231–232 (2011).

90

Ziegler SF. FOXP3: not just for regulatory T cells anymore. Eur. J. Immunol. 37(1), 21–23 (2007).



91


92

Dejaco C, Duftner C, Grubeck-Loebenstein B, Schirmer M. Imbalance of regulatory T cells in human autoimmune diseases. Immunology 117(3), 289–300 (2006). Chen O, Zhu XB, Ren H, Wang YB, Sun R. The imbalance of Th17/Treg in Chinese children with Henoch-Scho¨nlein purpura. Int. Immunopharmacol. 16(1), 67–71 (2013).

93

Li YY, Li CR, Wang GB, Yang J, Zu Y. Investigation of the change in CD4(+) T cell subset in children with Henoch-Scho¨nlein purpura. Rheumatol. Int. 32(12), 3785–3792 (2012).

94

Jen HY, Chuang YH, Lin SC, Chiang BL, Yang YH. Increased serum interleukin-17 and peripheral Th17 cells in children with acute Henoch-Scho¨nlein purpura. Pediatr. Allergy Immunol. 22(8), 862–868 (2011).

•

95

96

••

97

98

This study demonstrated an increase in peripheral Th17 cells and serum IL-17 levels in children with HSP, suggesting cellular immunity involvement in the pathogenesis of HSP.

regulation focused on IgA, and the immunogenetic background of host, presenting a hypothetic model for the development of HSP. 100

Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood 84(7), 2068–2101 (1994).

101

Rostoker G, Rymer JC, Bagnard G, Petit-Phar M, Griuncelli M, Pilatte Y. Imbalances in serum proinflammatory cytokines and their soluble receptors: a putative role in the progression of idiopathic IgA nephropathy (IgAN) and Henoch-Scho¨nlein purpura nephritis, and a potential target of immunoglobulin therapy? Clin. Exp. Immunol. 114(3), 468–476 (1998).

102

103

Besbas N, Saatci U, Ruacan S et al. The role of cytokines in Henoch-Scho¨nlein purpura. Scand. J. Rheumatol. 26(6), 456–460 (1997). Yang YH, Lai HJ, Huang CM, Wang LC, Lin YT, Chiang BL. Sera from children with active Henoch-Scho¨nlein purpura can enhance the production of interleukin 8 by human umbilical venous endothelial cells. Ann. Rheum. Dis. 63(11), 1511–1513 (2004). This experiment showed the method how to obtain and culture endothelial cells from human umbilical vein, providing support that some activating factors may be present in HSP. Wu TH, Wu SC, Huang TP, Yu CL, Tsai CY. Increased excretion of tumor necrosis factor alpha and interleukin 1 beta in urine from patients with IgA nephropathy and Scho¨nlein-Henoch purpura. Nephron 74(1), 79–88 (1996). Lin CY, Yang YH, Lee CC, Huang CL, Wang LC, Chiang BL. Thrombopoietin and interleukin-6 levels in Henoch-Scho¨nlein purpura. J. Microbiol. Immunol. Infect. 39(6), 476–482 (2006).

99

Yang YH, Chuang YH, Wang LC, Huang HY, Gershwin ME, Chiang BL. The immunobiology of Henoch-Scho¨nlein purpura. Autoimmun. Rev. 7(3), 179–184 (2008).

•

An attractive review regarding disease-associated pathogens, immune


••

104

105

Wu L, Yuan LP, Fei WJ et al. Impact of sera from children with active Henoch-Scho¨nlein purpura on human umbilical venous endothelial cells (HUVECs) and protective effects of methylprednisolone against HUVECs injury. Zhongguo Dang Dai Er Ke Za Zhi 14(1), 59–63 (2012). Yang YH, Huang YH, Lin YL et al. Circulating IgA from acute stage of childhood Henoch-Scho¨nlein purpura can enhance endothelial interleukin (IL)8 production through MEK/ERK signalling pathway. Clin. Exp. Immunol. 144(2), 247–253 (2006). A seminal study demonstrating that IgA antiendothelial cell antibodies may bind to endothelial and enhance IL-8 production via MEK/ERK signaling pathway. Takemura T, Yoshioka K, Murakami K et al. Cellular localization of inflammatory cytokines in human glomerulonephritis. Virchows Arch. 424(5), 459–464 (1994). Gattorno M, Vignola S, Barbano G et al. Tumor necrosis factor induced adhesion molecule serum concentrations in Henoch-Scho¨nlein purpura and pediatric systemic lupus erythematosus. J. Rheumatol. 27(9), 2251–2255 (2000).

106

Gok F, Ugur Y, Ozen S, Dagdeviren A. Pathogenesis-related adhesion molecules in Henoch-Scho¨nlein vasculitis. Rheumatol. Int. 28(4), 313–316 (2008).

107

Chen T, Guo ZP, Li MM et al. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK), an important mediator of endothelial inflammation, is associated with the pathogenesis of Henoch-Scho¨nlein purpura. Clin. Exp. Immunol. 166(1), 64–71 (2011).

108

Topaloglu R, Sungur A, Baskin E, Besbas N, Saatci U, Bakkaloglu A. Vascular endothelial

Review

growth factor in Henoch-Scho¨nlein purpura. J. Rheumatol. 28(10), 2269–2273 (2001). 109

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110

Mahajan N, Bisht D, Dhawan V, Singh S, Minz RW. Transcriptional expression and gelatinolytic activity of matrix metalloproteinases in Henoch-Scho¨nlein purpura. Acta Paediatr. 99(8), 1248–1252 (2010).

111

Shin JI, Song KS, Kim H et al. The gene expression profile of matrix metalloproteinases and their inhibitors in children with Henoch-Scho¨nlein purpura. Br. J. Dermatol. 164(6), 1348–1355 (2011).

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The first study to demonstrate the expression profile of all matrix metalloproteinases and tissue inhibitors of metalloproteinases in children with HSP.

112

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113

Kawasaki Y, Suzuki J, Sakai N et al. Evaluation of T helper-1/-2 balance on the basis of IgG subclasses and serum cytokines in children with glomerulonephritis. Am. J. Kidney Dis. 44(1), 42–49 (2004).

114

Sun DQ, Zhang QY, Dong ZY, Bai F. Levels of IL-12 produced by dendritic cells and changes of TH1/TH2 balance in children with Henoch-Scho¨nlein purpura. Zhongguo Dang Dai Er Ke Za Zhi 8(4), 307–310 (2006).

115

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116

De Mattia D, Penza R, Giordano P et al. von Willebrand factor and factor XIII in children with Henoch-Scho¨nlein purpura. Pediatr. Nephrol. 9(5), 603–605 (1995).

•

An important study that showed the role of von Willebrand factor and factor XIII activity in children with HSP.

117

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118

Del Vecchio GC, Penza R, Altomare M et al. Cytokine pattern and endothelium damage markers in Henoch-Scho¨nlein

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purpura. Immunopharmacol. Immunotoxicol. 30(3), 623–629 (2008).

131

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119

Brendel-Muller K, Hahn A, Schneppenheim R, Santer R. Laboratory signs of activated coagulation are common in Henoch-Scho¨nlein purpura. Pediatr. Nephrol. 16(12), 1084–1088 (2001).

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Yilmaz D, Kavakli K, Ozkayin N. The elevated markers of hypercoagulability in children with Henoch-Scho¨nlein purpura. Pediatr. Hematol. Oncol. 22(1), 41–48 (2005).

Liu A, Zhang H. Detection of antiphospholipid antibody in children with Henoch-Scho¨nlein purpura and central nervous system involvement. Pediatr. Neurol. 47(3), 167–170 (2012).

133

Zhang H, Huang J. Henoch-Scho¨nlein purpura associated with antiphospholipid syndrome. Pediatr. Nephrol. 25(2), 377–378 (2010).

134

Kawakami T, Yamazaki M, Mizoguchi M, Soma Y. High titer of serum antiphospholipid antibody levels in adult Henoch-Scho¨nlein purpura and cutaneous leukocytoclastic angiitis. Arthritis Rheum. 59(4), 561–567 (2008).

121

Topaloglu R, Bayrakci US, Cil B, Orhon D , Bakkaloglu A. Henoch-Scho¨nlein purpura with high factor VIII levels and deep venous thrombosis: an association or coincidence? Rheumatol. Int. 28(9), 935–937 (2008).

122

Imai T, Okada H, Nanba M, Kawada K, Kusaka T, Itoh S. Henoch-Scho¨nlein purpura with intracerebral hemorrhage. Brain Dev. 24(2), 115–117 (2002).

123

Culic S, Jakl R, Metlicic V et al. Platelet function analysis in children with Scho¨nlein-Henoch syndrome. Arch. Med. Res. 32(4), 268–272 (2001).

124

Knight JF. The rheumatic poison: a survey of some published investigations of the immunopathogenesis of Henoch-Schonlein purpura. Pediatr. Nephrol. 4(5), 533–541 (1990).

125

Harris EN, Gharavi AE, Hughes GR. Anti-phospholipid antibodies. Clin. Rheum. Dis. 11(3), 591–609 (1985).

126

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135

Yang YH, Huang MT, Lin SC, Lin YT, Tsai MJ, Chiang BL. Increased transforming growth factor-beta (TGFbeta)-secreting T cells and IgA anti-cardiolipin antibody levels during acute stage of childhood Henoch-Scho¨nlein purpura. Clin. Exp. Immunol. 122(2), 285–290 (2000).

136

Ozaltin F, Bakkaloglu A, Ozen S et al. The significance of IgA class of antineutrophil cytoplasmic antibodies (ANCA) in childhood Henoch-Scho¨nlein purpura. Clin. Rheumatol. 23(5), 426–429 (2004).

137

Sinico RA, Tadros M, Radice A et al. Lack of IgA antineutrophil cytoplasmic antibodies in Henoch-Scho¨ nlein purpura and IgA nephropathy. Clin. Immunol. Immunopathol. 73(1), 19–26 (1994). Robson WL, Leung AK, Woodman RC. The absence of anti-neutrophil cytoplasmic antibodies in patients with Henoch-Scho¨nlein purpura. Pediatr. Nephrol. 8(3), 295–298 (1994).

Henoch-Scho¨nlein purpura. Arthritis Rheum. 33(8), 1114–1121 (1990). •

The first consensus criteria for identifying HSP and from other forms of systemic vasculitis by the American College of Rheumatology.

142

Hunder GG, Arend WP, Bloch DA et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction. Arthritis Rheum. 33(8), 1065–1067 (1990).

143

Ozen S, Ruperto N, Dillon MJ et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann. Rheum. Dis. 65(7), 936–941 (2006).

•

European league Against Rheumatism/ Paediatric Rheumatology European Society (EULAR/PReS) consensus criteria which was widely accepted in children with HSP for the specific and realistic classification.

144

Ozen S, Pistorio A, Iusan SM et al. EULAR/PRINTO/PRES criteria for Henoch-Scho¨nlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann. Rheum. Dis. 69(5), 798–806 (2010).

•

Validated classification criteria for HSP by European league Against Rheumatism/ Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society.

145

Sohagia AB, Gunturu SG, Tong TR, Hertan HI. Henoch-Scho¨nlein purpura-a case report and review of the literature. Gastroenterol. Res. Pract. 2010, 597648 (2010).

146

Kawakami T. New algorithm (KAWAKAMI algorithm) to diagnose primary cutaneous vasculitis. J. Dermatol. 37(2), 113–124 (2010).

147

Linskey KR, Kroshinsky D, Mihm MC Jr, Hoang MP. Immunoglobulin-A–associated small-vessel vasculitis: a 10-year experience at the Massachusetts General Hospital. J. Am. Acad. Dermatol. 66(5), 813–822 (2012).

127

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128

Sokol DK, Mcintyre JA, Short RA et al. Henoch-Scho¨nlein purpura and stroke: antiphosphatidylethanolamine antibody in CSF and serum. Neurology 55(9), 1379–1381 (2000).

138

129

Abend NS, Licht DJ, Spencer CH. Lupus anticoagulant and thrombosis following Henoch-Scho¨nlein purpura. Pediatr. Neurol. 36(5), 345–347 (2007).

139

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Shin JI, Lee JS, Kim HS. Lupus anticoagulant and IgM anti-phospholipid antibodies in Korean children with Henoch-Scho¨nlein purpura. Scand. J. Rheumatol. 38(1), 73–74 (2009).

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148

140

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Davin JC, Weening JJ. Diagnosis of Henoch-Scho¨nlein purpura: renal or skin biopsy?Pediatr. Nephrol. 18(12), 1201–1203 (2003).

•

141

Mills JA, Michel BA, Bloch DA et al. The American College of Rheumatology 1990 criteria for the classification of

This study emphasized the importance of systemic diagnostic use of a cutaneous biopsy.

149

Van Hale HM, Gibson LE, Schroeter AL. Henoch-Scho¨nlein vasculitis: direct

•

A meaningful data showing an association and high incidence of positive lupus anticoagulant in Korean children with HSP.

1236



immunofluorescence study of uninvolved skin. J. Am. Acad. Dermatol. 15(4 Pt 1), 665–670 (1986). 150


151

152

153

154

155

156

157

Nagasaka T, Miyamoto J, Ishibashi M, Chen KR. MPO-ANCA- and IgA-positive systemic vasculitis: a possibly overlapping syndrome of microscopic polyangiitis and Henoch-Scho¨nlein purpura. J. Cutan. Pathol. 36(8), 871–877 (2009).

Microbiol. Infect. Dis. 23(10), 776–779 (2004). 162

163

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158

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159

Chen KR, Carlson JA. Clinical approach to cutaneous vasculitis. Am. J. Clin. Dermatol. 9(2), 71–92 (2008).

160

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161

Tsolia MN, Fretzayas A, Georgouli H et al. Invasive meningococcal disease presenting as Henoch-Scho¨nlein purpura. Eur. J. Clin.


164

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166

•

Al-Attrach I, Al-Shibli A, Al-Riyami L, Al-Salam S. Systemic lupus erythematosus with severe nephritis that mimicked Henoch-Scho¨nlein purpura. Arab. J. Nephrol. Transplant. 4(3), 159–161 (2011). Soylu A, Kavukcu S, Uzuner N, Olgac N, Karaman O, Ozer E. Systemic lupus erythematosus presenting with normocomplementemic urticarial vasculitis in a 4-year-old girl. Pediatr. Int. 43(4), 420–422 (2001). Saulsbury FT, Hart MH. Crohn’s disease presenting with Henoch-Scho¨nlein purpura. J. Pediatr. Gastroenterol. Nutr. 31(2), 173–175 (2000). Cheungpasitporn W, Jirajariyavej T, Howarth CB, Rosen RM. Henoch-Scho¨nlein purpura in an older man presenting as rectal bleeding and IgA mesangioproliferative glomerulonephritis: a case report. J. Med. Case Rep. 5, 364 (2011). Chang WL, Yang YH, Lin YT, Chiang BL. Gastrointestinal manifestations in Henoch-Scho¨nlein purpura: a review of 261 patients. Acta Paediatr. 93(11), 1427–1431 (2004). This study showed the necessity and importance of stool occult blood and imaging evaluations in HSP patients with gastrointestinal manifestations.

Review

172

Gow KW, Murphy JJ, 3rd, Blair GK, Magee JF, Hailey J. Multiple entero-entero fistulae: an unusual complication of Henoch-Scho¨nlein purpura. J. Pediatr. Surg. 31(6), 809–811 (1996).

173

Aaron S, Al-Watban L, Manca D. Scrotal involvement in an adult with Henoch-Scho¨ nlein purpura. Clin. Rheumatol. 32(Suppl. 1), S93–S95 (2013).

174

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175

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177

Ha TS, Lee JS. Scrotal involvement in childhood Henoch-Scho¨nlein purpura. Acta Paediatr. 96(4), 552–555 (2007).

•

An intriguing study revealing scrotal involvement and related factors in male HSP patients.

178

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179

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167

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168

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169

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180

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170

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181

Rajagopala S, Shobha V, Devaraj U, D’souza G, Garg I. Pulmonary hemorrhage in Henoch-Scho¨nlein purpura: case report and systematic review of the english literature. Semin. Arthritis Rheum. 42(4), 391–400 (2013).

171

Hashimoto A, Matsushita R, Iizuka N et al. Henoch-Scho¨nlein purpura complicated by perforation of the gallbladder. Rheumatol. Int. 29(4), 441–443 (2009).

•

This is an comprehensive study on the diffuse alveolar hemorrhage that is a rare complication of HSP, suggesting the treatment protocols.

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Markus HS, Clark JV. Pulmonary haemorrhage in Henoch-Scho¨nlein purpura. Thorax 44(6), 525–526 (1989).

183

Paller AS, Kelly K, Sethi R. Pulmonary hemorrhage: an often fatal complication of

Henoch-Scho¨nlein purpura. Pediatr. Dermatol. 14(4), 299–302 (1997). 184

systemic vasculitis. QJM 87(12), 741–745 (1994).

Bradley JR, Lockwood CM, Thiru S. Endothelial cell activation in patients with


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