**6. Pathophysiology of Henoch-Schönlein Purpura (HSP)**

The etiology of HSP as well as its pathogenesis are largely unknown.

#### **6.1. Genetic factors**

Familial clustering of HSP has been described and suggests a genetic background to the disease [121,122]. In several countries and ethnic groups different HLA types have been associated with susceptibility for HSP [123,124]. The different HLA type associations may explain differences in manifestations between different ethnic groups, but, so far, no conclusions could be drawn from these studies to explain the pathogenesis of HSP. Positivity for HLAB35 was found to increase the risk for the development of HSP [125].

A polymorphism in the angiotensinogen gene (M235T) may confer risk for the development of Henoch-Schönlein Nephritis [126,127].

Polymorphisms in the gene for angiotensin 1-converting enzyme (ACE) may be involved in the pathogenesis of HSP or HSN, although data are conflicting. The insertion (I)/deletion (D) genotype of a polymorphism in ACE may confer susceptibility to HSP [126,127]. The DD polymorphism was related to persistent proteinuria in patients with HSP in one study [128], whereas in another study no correlation was found between the prognosis of HSP and the ACE genotype [129].

Variations in the complement C4 protein gene may confer susceptibility to the development of HSP. C4 null isotypes have been described to be prevalent in a significantly higher propor‐ tion of patients with HSP and HSN than controls [130,131,132]. A partial or complete deficiency of C4 could be related to impaired clearance of immune complexes and thus play a role in the pathogenesis of HSP [133]. Complement deficiency is, however, uncommon and transient in patients with HSP [134].

Investigations addressing polymorphisms in genes encoding for proinflammatory cytokines (TNF-α, IL-1b, IL-8, TGF-β and VEGF) have so far not revealed any predisposing factors for HSP [135,136].

Familial mediterranean fever (FMF) is an autoinflammatory disease caused by a mutation in the MEFV gene, which in 7 % of cases is associated with HSP [137]. There is a high prevalence of children with MEFV mutations among HSP patients in countries with relative abundance of FMF [138,139]. The implication this association has on the general pathogenesis of HSP is, if at all, unclear.

#### **6.2. Infectious and non-infectious agents**

HSP is usually preceded by infections, in up to 95 % of cases localized in the upper respiratory tract, and appears in clusters in families [140,141,142]. The incidence of HSP is highest during early childhood and shows distinct seasonal variations with a peak during autumn and winter [6]. Both early childhood and the autumn-winter season are periods with frequent infections. Thus, clinical observations suggest an important role of infections in the etiology and patho‐ genesis of HSP.

Several studies have shown a circumstantial relation of infections with group A streptococci and the development of HSP [143,144,145]. Others found serological evidence for an associa‐ tion with infections with other bacteria such as Bartonella henselae or viruses such as parvo‐ virus B19 and hepatitis C virus [146,147,148].

Non-infectious agents have been found to be associated with the development of HSP especially in adults. These include certain drugs such as angiotensin-converting enzyme inhibitors, angiotensin II-receptor antagonists, antibiotics, and non-steroidal anti-inflamma‐ tory drugs as well as insect bites, vaccinations or food allergies [149].

#### **6.3. IgA1 in HSP**

lium and interstitial tissues. It may be inferred that the mPR3+/CD177+ cells possess greater

"fighting" neutrophils, designed to migrate from blood into tissues and promote pro-inflam‐ matory, microbicidal functions, while mPR3-negative neutrophils are destined to stay in the intra-vascular compartment, and function as anti-inflammatory cells, until they are needed for resolution of inflammation to produce anti-inflammatory mediators or to phagocytose tissue

Our group is the first to demonstrate a lower rate of spontaneous apoptosis and *longer in vitro* survival in neutrophils from AASV patients in remission as compared to neutrophils from

Contrary to our results, Harper et al. showed that neutrophils from AASV patients, especially

Familial clustering of HSP has been described and suggests a genetic background to the disease [121,122]. In several countries and ethnic groups different HLA types have been associated with susceptibility for HSP [123,124]. The different HLA type associations may explain differences in manifestations between different ethnic groups, but, so far, no conclusions could be drawn from these studies to explain the pathogenesis of HSP. Positivity for HLAB35 was

A polymorphism in the angiotensinogen gene (M235T) may confer risk for the development

Polymorphisms in the gene for angiotensin 1-converting enzyme (ACE) may be involved in the pathogenesis of HSP or HSN, although data are conflicting. The insertion (I)/deletion (D) genotype of a polymorphism in ACE may confer susceptibility to HSP [126,127]. The DD polymorphism was related to persistent proteinuria in patients with HSP in one study [128], whereas in another study no correlation was found between the prognosis of HSP and the ACE

Variations in the complement C4 protein gene may confer susceptibility to the development of HSP. C4 null isotypes have been described to be prevalent in a significantly higher propor‐ tion of patients with HSP and HSN than controls [130,131,132]. A partial or complete deficiency of C4 could be related to impaired clearance of immune complexes and thus play a role in the pathogenesis of HSP [133]. Complement deficiency is, however, uncommon and transient in

/CD177+

/CD177–

neutrophils may be the designated

sub-

killing capabilities, including higher NET and ROS production, than the mPR3–

population. In simplistic terms, the mPR3+

14 Updates in the Diagnosis and Treatment of Vasculitis

healthy blood donors [120].

**6.1. Genetic factors**

genotype [129].

patients with HSP [134].

debris and other dead neutrophils at the site of inflammation.

those with active disease, have an accelerated rate of apoptosis [106].

**6. Pathophysiology of Henoch-Schönlein Purpura (HSP)**

The etiology of HSP as well as its pathogenesis are largely unknown.

found to increase the risk for the development of HSP [125].

of Henoch-Schönlein Nephritis [126,127].

IgA deposits in HSP are composed of immune-complexes mainly consisting of IgA1 [150].

Serum samples from HSN patients were found to have elevated levels of underglycosylated polymeric IgA1 compared to controls [151]. However, in children with HSP without renal involvement the levels were not higher than those of controls [152]. Underglycosylated polymeric IgA1 has been found to exhibit an inflammatory and proliferative effect on mesan‐ gial cells (see IgA1 in IgAN). Taken together, underglycosylated polymeric IgA1 seems to be involved in the development of HSN, but its role in the pathogenesis of HSP per se remains unclear.

#### **6.4. Mediators of inflammation**

The acute phase of systemic vasculitis is generally characterized by vascular leukocytic infiltration and activation of innate immunity. Elevated levels of inflammatory cytokines are usually detectable in the serum and affected tissues in these diseases.

IL-6, TNF-α, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), IL-8, TGF-β, and VEGF have been found to be up-regulated during the acute stage of HSP [153,154].

T helper cells (Th) are a sub-population of lymphocytes, which have an important role in adaptive immune responses. Dependent on the surrounding cytokine environment naïve Th-cells differentiate into subtypes with different functions [164]. In patients with HSP an elevated number of Th2 and Th17 with increased synthesis of IL-5 and IL-13 have been found together with increased serum levels of IL-4, IL-6, and IL-17A [165]. The differentia‐ tion towards Th2 is stimulated by exposure to IL-4 and towards Th17 by TGF-β com‐ bined with IL-6. By secreting IL-4, Th2 exhibit a stimulatory effect on B cells and promote the generation of plasma cells. Further secretion of IL-5 or IL-13 from Th2 leads to an antibody switch in plasma cells towards the generation of IgA or IgE, respectively. Th17 secrete IL17, which in turn stimulates the expression of pro-inflammatory cytokines such as IL-1, IL-6, and cell adhesion factors and promotes leukocyte migration to the sites of inflammation. Th17 has been implicated in the pathogenesis of autoimmune diseases [164]. An imbalance of Th with Th2 and TH17 predominance, as seen in HSP, could explain elevated serum levels of IgA and IgE, the expression of pro-inflammatory cytokines and

History, Classification and Pathophysiology of Small Vessel Vasculitis

http://dx.doi.org/10.5772/55238

17

leukocyte infiltrations into affected tissues seen in HSP [166,167].

If the pieces of this puzzle are put together potential origins of cardinal symptoms of

disturbed balance between chemo-attractant and counteracting leukotrienes.

Address all correspondence to: mohamed.abdgawad@med.lu.se

The Department of Medicine, Blekinge Hospital, Karlshamn, Sweden

pain [168].

[169,170,171].

**Author details**

Mohamed Abdgawad\*

HSP emerge. Neutrophilic infiltration of the perivascular region may be mediated by TNF-α, TWEAK, IL-8, chemo-attractant leukotrienes, VEGF and/or Th17 and the extravasation and deposition of IgA by IL-6, TNF-α, VEGF, and Th2. The development of HSN could be related to the prevalence of underglycosylated polymeric IgA1, the effect of IL-6, TNF-α, and a

The contact system, which induces liberation of bradykinin or other vasoactive kinins from high-molecular kininogen, has been found to be activated in HSP, which could contribute to the development of clinical features such as inflammation, vasodilatation, edema and

Increased reactive oxygen species, lipid and protein oxidation, and nitric oxide level detectable during the acute phase of HSP are believed to reflect secondary events and vascular damage

Tissue samples of affected skin areas from patients with HSP show epidermal staining with IL-6 [155]. Serum levels of IL-6 were significantly higher in patients with HSP during the acute phase of disease than in controls and also higher in patients with HSN than HSP without renal affection [153]. IL-6 displays a wide variety of pro-inflammatory properties and promotes the secretion of IgA [153,156].

IL-6 displays, besides its various pro-inflammatory effects, even anti-inflammatory effects by inhibiting TNF-α and IL-1 and activating IL-1ra as well as IL-10 [157].

TNF-α is produced by macrophages and T cells in affected skin areas during HSP. Serum levels of TNF-α were higher in patients with HSN than HSP without renal engagement [153].

It stimulates the presentation of adhesion molecules and receptors on leukocytes and endo‐ thelial cells thereby directing inflammatory events. Furthermore, endothelial cells stimulated with TNF-α were shown to bind IgA with higher affinity [155]. These findings suggest, that TNF-α could be involved in the accumulation of granulocytes and endothelial sequestration of IgA as seen in affected tissues in HSP [153].

TWEAK, a member of the TNF superfamily, which binds to specific receptors on endothelial cells, is involved in the regulation of cell growth, angiogenesis, apoptosis, and inflammation.

In vitro evidence suggests that TWEAK may induce cytokine production by human micro‐ vascular endothelial cells via up-regulation of the production of IL-8 and CCL-5 leading to a leucocyte migration into affected vessels [158,159] which are common aspects of the HSP lesion.

Sera and IgA from patients with HSP induce the secretion of IL-8 from endothelial cells invitro [160,161].

IL-8 is a potent chemoattractant for polymorphonuclear neutrophilic granulocytes (PMNs). Levels of leukotriene B4, also a potent chemo-attractant and activator of PMNs, are elevated both in serum and urine in patients with HSN compared to those with HSP.

Furthermore, the levels of leukotriene A4, which counter-balance the effects of leukotriene B4 and inhibit the synthesis of proinflammatory cytokines (e.g. IL-6, IL-8, TNF- α), are decreased in patients with HSN [162].

The role of VEGF in HSP is not clear-cut. Serum levels of VEGF were significantly higher during the acute phase of HSP than during remission. However tissue staining for VEGF showed more intense staining for VEGF in the epidermis and vascular bed during the resolution phase than during the acute phase of HSP [163]. High serum levels of VEGF could influence endothelial permeability, which may enhance capillary leakage and facilitate the extravasation and perivascular deposition of immune complexes. The increased tissue staining during the resolution phase, on the other hand, suggests a possible function of VEGF in the resolution of vascular damage.

T helper cells (Th) are a sub-population of lymphocytes, which have an important role in adaptive immune responses. Dependent on the surrounding cytokine environment naïve Th-cells differentiate into subtypes with different functions [164]. In patients with HSP an elevated number of Th2 and Th17 with increased synthesis of IL-5 and IL-13 have been found together with increased serum levels of IL-4, IL-6, and IL-17A [165]. The differentia‐ tion towards Th2 is stimulated by exposure to IL-4 and towards Th17 by TGF-β com‐ bined with IL-6. By secreting IL-4, Th2 exhibit a stimulatory effect on B cells and promote the generation of plasma cells. Further secretion of IL-5 or IL-13 from Th2 leads to an antibody switch in plasma cells towards the generation of IgA or IgE, respectively. Th17 secrete IL17, which in turn stimulates the expression of pro-inflammatory cytokines such as IL-1, IL-6, and cell adhesion factors and promotes leukocyte migration to the sites of inflammation. Th17 has been implicated in the pathogenesis of autoimmune diseases [164]. An imbalance of Th with Th2 and TH17 predominance, as seen in HSP, could explain elevated serum levels of IgA and IgE, the expression of pro-inflammatory cytokines and leukocyte infiltrations into affected tissues seen in HSP [166,167].

If the pieces of this puzzle are put together potential origins of cardinal symptoms of

HSP emerge. Neutrophilic infiltration of the perivascular region may be mediated by TNF-α, TWEAK, IL-8, chemo-attractant leukotrienes, VEGF and/or Th17 and the extravasation and deposition of IgA by IL-6, TNF-α, VEGF, and Th2. The development of HSN could be related to the prevalence of underglycosylated polymeric IgA1, the effect of IL-6, TNF-α, and a disturbed balance between chemo-attractant and counteracting leukotrienes.

The contact system, which induces liberation of bradykinin or other vasoactive kinins from high-molecular kininogen, has been found to be activated in HSP, which could contribute to the development of clinical features such as inflammation, vasodilatation, edema and pain [168].

Increased reactive oxygen species, lipid and protein oxidation, and nitric oxide level detectable during the acute phase of HSP are believed to reflect secondary events and vascular damage [169,170,171].
