The immunobiology of Henoch-Schönlein purpura

Henoch-Sch?nlein purpura (HSP) is a common but enigmatic systemic small vessel vasculitis that primarily affects children. Although the etiology of this disease is unknown, there are tantalizing clues on the natural history and immunopathogenesis. This article reviews these clues including aspects of disease-associated pathogens, immune regulation, with a focus on IgA, and finally the immunogenetic background of host. We also present a hypothetical model for the development of HSP and submit that this paradigm will be a generic one for similar vasculopathies.     

Invasive meningococcal disease presenting as Henoch-Schönlein purpura

Henoch-Schönlein purpura (HSP) is an acute systemic form of vasculitis that has been associated with a number of viral and bacterial infections. Described here are the cases of two children with invasive meningococcal disease who presented with clinical and laboratory findings typical of HSP. Meningococcal infection may have been the trigger for the manifestation of HSP in these patients.     

Grading of acute and chronic renal lesions in Henoch-Sch?nlein purpura.

The renal outcome of 34 patients with Henoch-Sch?nlein purpura nephritis was assessed clinically and by grading acute and chronic renal lesions using a system we applied to primary IgA nephropathy. On a median follow-up period of 65 months, hypertension and the serum levels of creatinine and proteinuria at the time of renal biopsy were correlated with renal survival. Acute glomerular lesions including mesangial hypercellularity, endocapillary proliferation, necrosis, cellular crescents, and leukocytes infiltration were observed, respectively, in 41%, 12%, 50%, 29%, and 32% of the cases. Of these, only glomerular necrotizing lesion and cellular crescent were correlated with the renal survival. Chronic renal lesions based on a grading system applied to primary IgA nephropathy and assessing the extent of glomerular sclerosis (glomerular grading), of tubular loss and interstitial fibrosis (tubulointerstitial grading), and of hyaline arteriolosclerosis demonstrated correlation between these lesions, as well as with renal survival. On follow-up, these chronic renal lesions were predictors of subsequent clinical events associated with disease progression, such as impaired renal function, significant proteinuria, and development of hypertension. Despite some limitations related to the relatively small size, this series indicates that distinction of acute and chronic lesions of Henoch-Schonlein purpura nephritis is important for both the prognosis and management of patients.     

Cytokine pattern and endothelium damage markers in Henoch-Schönlein purpura

In a longitudinal cohort study our aim was to evaluate the cytokine pattern of children affected by Henoch-Schonlein purpura (HSP) and to correlate this pattern to vascular endothelium damage and to nephropathy. The following parameters were monitored at the onset of the disease (T0) and after 6 months of follow-up (T1): clinical scores, serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin 2 (IL-2), soluble IL-2 receptor (IL-2sRalpha), fibrinogen, von Willebrand factor antigen (vWf:Ag) and soluble thrombomodulin (TMD) levels. A total of 24 children (9 M, 15 F), affected by HSP, aged between 3-14 years (median 6 years), were enrolled into the study. IL-2 serum levels were significantly increased at the onset of the disease compared to control group and T1. The same pattern was observed for IL-2sRalpha and TNF-alpha. Fibrinogen and vWf:Ag concentrations were significantly higher at the onset of disease than t1 and in control group. TMD levels resulted constantly within the normal range. Concerning the analyzed parameters, no significant difference resulted to be in subjects with and without renal involvement (hematuria and/or proteinuria). Finally, raised serum TNF-alpha concentration, related to vascular endothelium damage as shown by increased vWf:Ag levels, occurred invariably in children affected by HSP both with and without renal involvement.     

Elevated levels of anti-Helicobacter pylori antibodies in Henoch-Schönlein purpura

OBJECTIVE: Henoch-Schonlein purpura (HSP) is a systemic vasculitis characterized by IgA-containing deposits in the skin, joints, gastrointestinal mucosa and glomeruli. HSP is much rarer in adults than in children. Among a number of other pathogenic factors, Helicobacter pylori (Hp) has recently been implicated in the gastrointestinal and extra-gastrointestinal manifestations underlying HSP. We aimed at studying the occurrence of Hp infections in 11 adult HSP patients with appearance in our clinical practice in the last 5 years. METHODS: Eleven adult HSP and 20 healthy adult patients were recruited for this study. Anti-Hp IgG and IgA antibodies were assessed in sera of HSP patients with active (n = 5) and remittent disease (n = 6) and healthy controls (n = 20) in the context of clinical symptoms, endoscopic evaluation, as well as routine and immunolaboratory observations. Concurrent Hp infection was confirmed by urease test and histology. RESULTS: Anti-Hp antibodies were present in 10/11 of HSP patients, and 11/20 of healthy controls. However, only 4/11 HSP patients had concurrent Hp infection as confirmed by urease test and/or histology. In the healthy controls the actual Hp infection was detectable in 9/20 cases. Patients in the acute phase had significantly higher levels of anti-Hp IgG compared to healthy controls (86.0 +/- 32.0 versus 25.5 +/- 28.5 U/ml, p < 0.05). In contrast, anti-Hp IgA/IgG ratios were significantly higher in the remitting phase compared to the control group (3.1 +/- 1.8 versus 0.8 +/- 0.5 ratio, p < 0.05). Among other immunolaboratory markers, serum CRP, circulating IgA and serum tumor necrosis factor-alpha levels were significantly increased in acute patients compared to healthy group results (45.3 +/- 22.7 versus 4.8 +/- 3.5 mg/l, p < 0,05); (58.9 +/- 18.2 versus 25.2 +/- 6.4pg/ml, p < 0,05); (5.5 +/- 1.1 versus 2.4 +/- 1.2 g/l; respectively, p < 0.05). CONCLUSIONS: Hp infection may be associated with the development and progression of HSP. IgG antibodies to Hp may be present mostly in acute HSP, while IgA antibodies may be involved in sustaining gastrointestinal symptoms underlying the chronic phase of the disease.     

Anti-myeloperoxidase and anti-lactoferrin antibodies in patients with IgA nephropathy and Henoch-Schönlein purpura

Antineutrophil cytoplasmic antibodies (ANCA) for two antigens, i.e. myeloperoxidase (MPO) and lactoferrin (LF) in sera from 19 IgA nephropathy (IgAN), 3 adult Henoch-Sch?nlein purpura (HSP) and 8 child HSP patients were examined by enzyme-linked immunoabsorbent assay (ELISA) for immunoglobulin isotypes. All of child HSP patients showed negative ANCA. On the other hand, one IgAN patient and two adult HSP patients showed weak positivity for IgA class anti-MPO antibody. There was no patients who showed positivity for IgG and IgM class anti-MPO antibody. In anti-LF antibody, one IgAN and one adult HSP showed positivity in IgG class; 2 IgAN and 2 HSP in IgA class and 2 IgAN and one HSP in IgM class. These results indicate that adult HSP patients have higher prevalence of IgA class anti-MPO antibody and anti-LF antibody than IgAN or child HSP.     

Acute appendicitis in Henoch-Schönlein purpura: a case report

Common complications of Henoch-Schönlein purpura (HSP) that lead to surgical intervention include intussusception, perforation, necrosis, and massive gastrointestinal bleeding. Acute appendicitis is rarely seen as a complication of HSP. A seven-year-old boy was admitted for arthralgia, abdominal pain, hematochezia, melena, and purpuric rash on the lower extremities. On admission day abdominal ultrasonography was normal, but on day 5, he became pyrexial and developed right iliac fossa pain and tenderness with guarding. Ultrasonography showed distended appendix surrounded by hyperechoic inflamed fat. On exploration an acutely inflamed, necrotic appendix was removed and grossly there was an appendiceal perforation in the appendiceal tip. Microscopically some of the small blood vessels in the submucosa showed fibrinoid necrosis with neutrophilic infiltrations. The authors report the case of a child who developed acute perforative appendicitis requiring appendectomy while on treatment for HSP.     

New insights in the pathogenesis of immunoglobulin A vasculitis (Henoch-Schönlein purpura)

Immunoglobulin A vasculitis (IgAV), also referred to as Henoch-Schönlein purpura, is the most common form of childhood vasculitis. The pathogenesis of IgAV is still largely unknown. The disease is characterized by IgA1-immune deposits, complement factors and neutrophil infiltration, which is accompanied with vascular inflammation. Incidence of IgAV is twice as high during fall and winter, suggesting an environmental trigger associated to climate. Symptoms can resolve without intervention, but some patients develop glomerulonephritis with features similar to IgA nephropathy that include hematuria, proteinuria and IgA deposition in the glomerulus. Ultimately, this can lead to end-stage renal disease. In IgA nephropathy immune complexes containing galactose-deficient (Gd-)IgA1 are found and thought to play a role in pathogenesis. Although Gd-IgA1 complexes are also present in patients with IgAV with nephritis, their role in IgAV is disputed. Alternatively, it has been proposed that in IgAV IgA1 antibodies are generated against endothelial cells. We anticipate that such IgA complexes can activate neutrophils via the IgA Fc receptor FcαRI (CD89), thereby inducing neutrophil migration and activation, which ultimately causes tissue damage in IgAV. In this Review, we discuss the putative role of IgA, IgA receptors, neutrophils and other factors such as infections, genetics and the complement system in the pathogenesis of IgA vasculitis.     

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

Henoch-Schönlein 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.     

HLA-DRB1 in Henoch-Schönlein purpura: A susceptibility study from North India

Etiology of Henoch-Schönlein purpura (HSP) a small vessel vasculitis remains elusive. Susceptibility may be conferred by major histocompatibility complex. There are limited reports on the association of human leucocyte antigens (HLA) and HSP. The aim was to investigate the association of HLA-DRB1 (HLA class II antigen) with HSP. Forty three patients, <14 years, who fulfilled the diagnostic criteria of HSP, laid by ‘European League Against Rheumatism’ were enrolled. Fifty four age-matched, healthy controls were included. PCR with 24 sequence specific primers for HLA-DRB1 allotypes was performed. Commercially available HLA-DR tissue typing kit (Inno-train, Kronberg im Taunus, Hesse, Germany) was utilized. The mean age of patients and controls was 8.5 ± 3.2 and 7.6 ± 3.6 years, respectively (p = 0.18). Gastrointestinal and renal involvement was observed in 25 (58.1%) and 14 (32.6%) patients, respectively. A greater frequency of HLA-DRB1*11 was observed in patients (11.6%) as compared to controls (1.9%), however, the results were not significant following Bonferroni correction. No significantly protective HLA genotype was observed. None of the HLA-DRB1 antigen was noted to increase the susceptibility to gastrointestinal or renal involvement. In conclusion, in the first study from India, none of the HLA-DRB*1 genotypes were observed to increase the susceptibility of North Indian children to HSP.     

Genetics of immunoglobulin-A vasculitis (Henoch-Schönlein purpura): An updated review

Immunoglobulin-A vasculitis (IgAV) is classically a childhood small-sized blood vessel vasculitis with predominant involvement of the skin. Gastrointestinal and joint manifestations are common in patients diagnosed with this condition. Nephritis, which is more severe in adults, constitutes the most feared complication of this vasculitis. The molecular bases underlying the origin of IgAV have not been completely elucidated. Nevertheless, several pieces of evidence support the claim that genes play a crucial role in the pathogenesis of this disease. The human leukocyte antigen (HLA) region is, until now, the main genetic factor associated with IgAV pathogenesis. Besides a strong association with HLA class II alleles, specifically HLA-DRB1 alleles, HLA class I alleles also seem to influence on the predisposition of this disease. Other gene polymorphisms located outside the HLA region, including those coding cytokines, chemokines, adhesion molecules as well as those related to T-cells, aberrant glycosylation of IgA1, nitric oxide production, neoangiogenesis, renin-angiotensin system and lipid, Pyrin and homocysteine metabolism, may be implicated not only in the predisposition to IgAV but also in its severity. An update of the current knowledge of the genetic component associated with the pathogenesis of IgAV is detailed in this review.     

Increased frequency of C4B*Q0 alleles in patients with Henoch-Schönlein purpura

Henoch-Schonlein purpura (HSP) is a vasculitis of unknown aetiology, possibly involving immune complexes. The complement system is essential for the clearance of immune complexes. Our aim was to explore the hypothesis that patients with HSP have abnormal complements, contributing to the development of the disease. The study included 56 patients diagnosed with HSP at the Children's Hospital, Iceland between 1984 and 2000, and 98 blood donors as controls. Serum levels of immunoglobulin A, C4A, C4B and mannan-binding lectin were measured and compared between the two groups. C4 null alleles were significantly more common in HSP patients than in controls (P = 0.018) and were carried by 66.1% of the patients compared with 41.2% of the controls. This difference was due to an increased frequency of C4B*Q0 allele in the HSP group (0.25 versus 0.11 in the control group; P = 0.002). The fact that the majority of our patients carried a C4 null allele indicates that children with C4 deficiencies may have an increased risk of developing HSP. This may reflect inadequate complement activity and possibly present an opportunity to identify patients at risk of developing serious morbidity associated with HSP.     

Cytokine Pattern and Endothelium Damage Markers in Henoch-Schönlein Purpura

In a longitudinal cohort study our aim was to evaluate the cytokine pattern of children affected by Henoch-Schönlein purpura (HSP) and to correlate this pattern to vascular endothelium damage and to nephropathy.

The following parameters were monitored at the onset of the disease (T0) and after 6 months of follow-up (T1): clinical scores, serum levels of tumor necrosis factor α (TNF-α), interleukin 2 (IL-2), soluble IL-2 receptor (IL-2sRα), fibrinogen, von Willebrand factor antigen (vWf:Ag) and soluble thrombomodulin (TMD) levels.

A total of 24 children (9 M, 15 F), affected by HSP, aged between 3–14 years (median 6 years), were enrolled into the study.

IL-2 serum levels were significantly increased at the onset of the disease compared to control group and T1. The same pattern was observed for IL-2sRα and TNF-α. Fibrinogen and vWf:Ag concentrations were significantly higher at the onset of disease than t1 and in control group. TMD levels resulted constantly within the normal range.

Concerning the analyzed parameters, no significant difference resulted to be in subjects with and without renal involvement (hematuria and/or proteinuria). Finally, raised serum TNF-α concentration, related to vascular endothelium damage as shown by increased vWf:Ag levels, occurred invariably in children affected by HSP both with and without renal involvement.     

Increased transforming growth factor-beta (TGF-beta)-secreting T cells and IgA anti-cardiolipin antibody levels during acute stage of childhood Henoch-Schönlein purpura

Henoch–Schönlein purpura (HSP) is a small vessel vasculitis characterized by increased serum IgA and IgA‐dominant immune complex deposition in lesions. The involvement of IgA implies a probable role for TGF‐β, a major factor in IgA production, in the pathogenesis of HSP. Among IgA antibodies, serum IgA anti‐cardiolipin antibodies (aCL) have been found in many diseases, including vasculitis. In addition to the clinical presentations and laboratory parameters, we further investigated the roles of IgA aCL and TGF‐β in childhood HSP. Twenty‐six Chinese children with the diagnosis of HSP were enrolled. Blood samples from these patients were collected at both acute and convalescent stages. Intracellular staining of lymphocytes was performed to enumerate type 1 (interferon‐gamma‐secreting), type 2 (IL‐4‐secreting), and type 3 (TGF‐β‐secreting) helper T cells. Serum levels of TGF‐β were detected by ELISA. Serum IgA aCL of 21 of 26 patients at the acute stage, 11 of them at the convalescent stage, were measured by ELISA. The data showed that IgA aCL serum levels were significantly elevated in patients compared with healthy controls (P < 0·001), and those patients at the convalescent stage (P < 0·001). In addition, TGF‐β‐secreting T cells were significantly elevated during the acute stage, and decreased at the convalescent stage. Although more studies are needed, the high prevalence of IgA aCL and increased TGF‐β‐secreting T cells in children with acute HSP revealed some points which should permit a better understanding of the pathogenesis of HSP.     

Polyangitis overlap syndrome: a fatal case combined with adult Henoch-Schönlein purpura and polyarteritis nodosa

Henoch‐Schönlein purpura (HSP) is a rather common disease characterized by systemic hypersensitivity vasculitis in the skin and other visceral organs. It has a favorable prognosis unless it is complicated by severe glomerular disease. We report a distinctive fatal case of systemic vasculitis combined with HSP and polyarteritis nodosa (PN) in a 56‐year‐old man who died of progressive renal failure one month after the onset of the disease. He complained of arthralgia, purpura of both lower extremities, nasal bleeding and tarry stool, and acute renal failure was noted at the time of admission to hospital. A skin biopsy from the purpura lesion exhibited leucocytoclastic vasculitis with IgA deposition, and HSP was considered. However, renal failure progressed rapidly and subsequently was complicated by acute myocardial infarction. Postmortem examination revealed PN type necrotizing vasculitis in the kidneys, heart and mesentery resulting in acute multiple infarctions of these organs. We think the current case was a polyangitis overlap syndrome. It is important to suspect the polyangitis overlap syndrome positively when progressive acute renal failure is seen in a patient with HSP and to begin appropriate therapy immediately.