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.     

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.     

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.     

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.     

The level of IgA antibodies to human umbilical vein endothelial cells can be enhanced by TNF-alpha treatment in children with Henoch-Schönlein purpura

Anti‐endothelial cell antibodies (AECA) have been found to play an important role in many vascular disorders. In order to determine the presence of AECA in children with Henoch–Schönlein purpura (HSP), and to elucidate the pathogenic and clinical value of their measurement in this disease, AECA were detected by immunofluorescence staining and a human umbilical vein endothelial cell (HUVEC)‐based enzyme‐linked immunosorbent assay (ELISA) in 20 children with HSP, 10 children with juvenile rheumatoid arthritis (JRA) without vasculitis and 10 normal healthy children. Antibodies against another endothelial cells, human dermal microvascular endothelial cells (HMVEC‐d) were also detected by cell‐based ELISA. In some experiments, we compared the binding activity of antibodies to HUVEC with and without tumour necrosis factor‐α (TNF‐α) or interleukin‐1 (IL‐1) pretreatment. Patients with acute onset of HSP had higher serum levels of IgA antibodies, both against HUVEC and against HMVEC‐d, than healthy controls (P = 0·001, P = 0·008, respectively). Forty‐five per cent of patients had positive IgA AECA to HUVEC, and 35% had positive IgA AECA to HMVEC‐d. The titres of IgA antibodies to HUVEC paralleled the disease activity. After TNF‐α treatment, the values of IgA AECA to HUVEC in HSP patients were significantly increased (P = 0·02). For IgG and IgM AECA, there was no difference between HSP patients and controls (P = 0·51, P = 0·91). Ten JRA children without vasculitis had no detectable IgG, IgM or IgA AECA activity. The results of this study showed that children with HSP had IgA AECA, which were enhanced by TNF‐α treatment. Although the role of these antibodies is not clear, IgA AECA provide another immunological clue for the understanding of 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.     

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.     

Production of chemokines in Kawasaki disease, Henoch-Schönlein purpura and acute febrile illness

We compared the production of three chemokines; interferon-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1) and growth-related oncogene-α (Gro-α) that attracts monocytes or neutrophils, or both, in peripheral blood at acute stage of Kawasaki disease (n=29), Henoch-Schönlein purpura (n=15) and acute febrile illnesses (n=12). The production of the chemokines was assayed by ELISA. The plasma levels of IP-10 were markedly elevated in Kawasaki disease (538.6±336.4 pg/mL) and acute febrile illnesses (417.1±262.2 pg/mL) compared with in Henoch-Schönlein purpura (58.7±95.7 pg/mL) (p<0.05). The MCP-1 levels were elevated in Kawasaki disease (443.0±473.1 pg/mL) and acute febrile illnesses (328.6±261.1 pg/mL) compared with in Henoch-Schönlein purpura (82.9±79.0 pg/mL) (p<0.05). The Gro-α levels were elevated only in acute febrile illnesses (134.3±153.6 pg/mL) compared with in Kawasaki disease (31.8±22.1 pg/mL) or Henoch-Schönlein purpura (29.4±53.3 pg/mL) (p<0.05). According to these results, monocytes may play an important role in Kawasaki disease. In acute febrile illnesses, both monocytes and neutrophils may play an important role. By contrast, Henoch-Schönlein purpura may not be associated with the role of monocytes and neutrophils. Further studies using a larger number of cases are needed.     

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.     

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.     

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.     

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.     

A Case of Elderly-Onset Crescentic Henoch-Schönlein Purpura Nephritis with Hypocomplementemia and Positive MPO-ANCA

Henoch-Schönlein purpura (HSP) is common in childhood and often self-limiting. There have been limited studies on elderly-onset HSP nephritis (HSPN). A 76-yr-old man was transferred to our hospital with a 1-month history of oliguria, abdominal pain, edema and palpable purpura in the legs. Three months ago, he was admitted to another hospital with jaundice, and consequently diagnosed with early common bile duct cancer. The patient underwent a Whipple''s operation. Antibiotics were administrated because of leakage in the suture from the surgery. However, he showed progressive renal failure with edema and purpura in the legs. Laboratory investigations showed serum creatinine 6.4 mg/dL, 24-hr urine protein 8,141 mg/day, myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA) 1:40 and C₃ below 64.89 mg/dL. Renal biopsy showed crescentic glomerulonephritis, as well as mesangial and extracapillary Ig A deposition. We started steroid therapy and hemodialysis, but he progressed to end-stage renal failure and he has been under maintenance hemodialysis. We describe elderly onset HSPN with MPO-ANCA can be crescentic glomerulonephritis rapidly progressed to end stage renal failure.     

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.     

Histamine concentrations in gastric mucosa of patients with Schönlein-Henoch purpura

Inflammation Research -     

Differences in Clinical Manifestations and Outcomes between Adult and Child Patients with Henoch-Sch?nlein Purpura

We aimed to investigate differences in clinical manifestations and outcomes between adult and child patients with Henoch-Schönlein purpura (HSP), and to analyze the factors associated with poor prognosis for HSP nephritis. This retrospective 10-yr study enrolled 160 patients with HSP who visited Severance Hospital. Purpura was mostly detected in lower extremities, but purpura in upper extremities was more frequently observed in adults than children (41.7% vs 19.3%). Children had a greater frequency of arthralgia (55.4% vs 27.1%), while adults had a greater frequency of diarrhea (20% vs 1.6%). Anemia, elevated C-reactive protein, and level of IgA were more frequently observed in adults (25% vs 7.1%, 65.6% vs 38.4%, 26.3% vs 3.5%). Renal involvement in adults was more severe than in children (79.2% vs 30.4%). Chronic renal failure showed a significant difference in outcomes of HSP between adults (10.4%) and children (1.8%) after a follow up period of an average of 27 months. Furthermore, renal insufficiency at diagnosis was significantly related to the progression to chronic renal failure. Our results showed several differences in the clinical features of HSP between adults and children. Adults with HSP had a higher frequency of renal insufficiency and worse renal outcomes than children. Renal insufficiency at diagnosis might be of predictive value for the progression to chronic renal failure in HSP patients.

Graphical Abstract

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