Proteinase 3-ANCA Research Articles

High Prevalence of Autoantibodies to hLAMP-2 in Anti–Neutrophil Cytoplasmic Antibody–Associated Vasculitis

The involvement of autoantibodies to human lysosome-associated membrane protein-2 (hLAMP-2) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is controversial because of the absence of confirmatory data subsequent to the initial reports of their high prevalence in this disease. We characterized three assays for anti-hLAMP-2 antibodies: ELISA and Western blotting assays using unglycosylated recombinant hLAMP-2 expressed in Escherichia coli, and an indirect immunofluorescence assay using stably transfected ldlD cells that expressed glycosylated full-length hLAMP-2 on the plasma membrane. The assays detected autoantibodies to hLAMP-2 in human sera reproducibly and with comparable sensitivity and the assays gave the same results in 80.5% of the test panel of 40 selected positive and negative sera. In untreated patients at presentation, the frequencies of autoantibodies to LAMP-2 were 89%, 91%, and 80%, respectively, among three groups of patients with ANCA-associated vasculitis from Vienna, Austria (n=19); Groningen, the Netherlands (n=50) and Cambridge, United Kingdom (n=53). Prevalence of LAMP-2 autoantibodies was similar in both those with myeloperoxidase-ANCA and proteinase 3-ANCA. Furthermore, we detected LAMP-2 autoantibodies in two ANCA-negative patients. LAMP-2 autoantibodies rapidly became undetectable after the initiation of immunosuppressive treatment and frequently became detectable again during clinical relapse. We conclude that when robust assays are used, circulating autoantibodies to hLAMP-2 can be detected in most European patients with ANCA-associated vasculitis. Large-scale prospective studies are now needed to determine whether they are pathogenic or merely an epiphenomenon.

Proteinase 3 Anti-Neutrophil Cytoplasmic Antibody (PR3-ANCA) Positive IgG4-Related Retroperitoneal Fibrosis: Utility of PET-CT with <sup>18</sup>F-Fluorodeoxy Glucose (FDG)

A 55-year-old man showed a serum creatinine level of 1.51 mg/dL, CRP of 0.79 mg/dL, and proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) of 43.9 EU (normal range: below 10). The serum levels and ratios of IgG1, IgG2, IgG3, and IgG4 to total IgG were 1,570 mg/dL (49%), 1,190 mg/dL (37%), 82 mg/dL (3%), and 351 mg/dL (11%), respectively. Positron emission tomography and CT with (18)F-fluorodeoxyglucose (PET-CT) demonstrated retroperitoneal fibrosis. After a diagnosis of IgG4-related retroperitoneal fibrosis with PR3-ANCA was made, oral prednisolone improved serum creatinine and the titer of PR3-ANCA to normal levels, with no abnormal findings on PET-CT.

Pulmonary Capillaritis in Wegener's Granulomatosis Detected Via Transbronchial Lung Biopsy

A 73-year-old woman presented to our hospital with scleritis, cough, and hemoptysis. Chest computed tomography showed a mass lesion, multiple ground-glass opacities, and nodules. Bronchoscopy showed a skip lesion of mucosal erosion with white necrotic substance; however, a biopsy specimen of the erosion yielded no characteristic findings. Transbronchial lung biopsy showed alveolar hemorrhage and capillaritis. Proteinase-3 antineutrophil cytoplasmic antibody was elevated to 62.5 U/mL, and she was diagnosed as having Wegener's granulomatosis. Steroid therapy combined with cyclophosphamide was started; however, hemoptysis was not resolved until plasmapheresis therapy was added. Her general condition initially improved, but respiratory insufficiency worsened with fever on the 30th hospital day. The patient subsequently died on the 41st hospital day, and cytomegalovirus infection was suggested as a possible cause of death.

Multiple cerebral infarcts with a few vasculitic lesions in the chronic stage of cerebral amyloid angiopathy‐related inflammation

We report a 75-year-old man with a 3.5-year history of cerebral amyloid angiopathy (CAA)-related inflammation. His initial symptom was headache and sensory aphasia appeared 1 month later. Brain MRI revealed features compatible with meningoencephalitis involving the right frontal, parietal and temporooccipital lobes. A brain biopsy sample from the right parietal lobe showed thickening of the leptomeninges, and granulomatous vasculitis with multinucleated giant cells and vascular Aβ deposits. No vascular lesions were evident by cerebral angiography. Serological examination revealed an elevated level of proteinase 3 anti-neutrophil cytoplasmic autoantibodies (PR3-ANCA). The patient was treated with corticosteroids, but this was only partially and temporarily effective. Autopsy revealed marked leptomeningeal thickening with inflammatory cell infiltrates and hemosiderin deposits, many superficial predominantly small infarcts at various stages in the cerebral cortex and only a few cerebral active vasculitic lesions. Immunohistochemically, CAA showing widespread Aβ-positive blood vessels with double-barrel formations was demonstrated. In conclusion, we consider that, although the association of PR3-ANCA with the pathogenesis of Aβ-associated vasculitis remained unclear, the present case represents a rare example of CAA-related inflammation at the chronic stage.

Rituximab in relapsing or refractory ANCA-associated vasculitis: a case series of 16 patients

Objectives: Cyclophosphamide (CYC) and corticosteroids are generally considered standard induction therapy for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, a subset of patients are refractory or intolerant to this treatment. Rituximab, a chimeric anti-CD20 antibody, has emerged as a second-line therapy, although controlled studies are scarce in patients with relapsing or refractory disease.Methods: We report 16 patients with AAV who received rituximab for refractory or relapsing vasculitis having previously received CYC. The treatment protocols were 375 mg/m2× IV in five patients, 1000 mg × II in six patients, and 500 mg × II in five patients, all in combination with corticosteroids. A majority of patients used other concurrent immunosuppression, most commonly mycophenolate mofetil. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS 2003) at baseline and during follow-up together with C-reactive protein (CRP) and ANCA. Complete remission was defined as a BVAS score of 0 and partial remission as a reduction in BVAS of at least 50%.Results: Twelve patients achieved complete remission, three patients partial remission, and one patient died during follow-up (median of 20 months, range 3–48 months). Six patients relapsed and received rituximab again. Four of these were positive for capture proteinase 3 (PR-3) ANCA but negative with conventional PR-3 ANCA upon retreatment. Seven patients had an adverse event, including two hepatitis B reactivations and one fatal sepsis.Conclusion: Treatment with rituximab in AAV was associated with prolonged remission in a subset of patients otherwise difficult to manage.

Anti-Neutrophil Cytoplasmic Antibodies Stimulate Release of Neutrophil Microparticles

The mechanisms by which anti-neutrophil cytoplasmic antibodies (ANCAs) may contribute to the pathogenesis of ANCA-associated vasculitis are not well understood. In this study, both polyclonal ANCAs isolated from patients and chimeric proteinase 3-ANCA induced the release of neutrophil microparticles from primed neutrophils. These microparticles expressed a variety of markers, including the ANCA autoantigens proteinase 3 and myeloperoxidase. They bound endothelial cells via a CD18-mediated mechanism and induced an increase in endothelial intercellular adhesion molecule-1 expression, production of endothelial reactive oxygen species, and release of endothelial IL-6 and IL-8. Removal of the neutrophil microparticles by filtration or inhibition of reactive oxygen species production with antioxidants abolished microparticle-mediated endothelial activation. In addition, these microparticles promoted the generation of thrombin. In vivo, we detected more neutrophil microparticles in the plasma of children with ANCA-associated vasculitis compared with that in healthy controls or those with inactive vasculitis. Taken together, these results support a role for neutrophil microparticles in the pathogenesis of ANCA-associated vasculitis, potentially providing a target for future therapeutics.

Antineutrophil cytoplasmic antibodies

Antineutrophil cytoplasmic antibodies (ANCA) are predominantly IgG autoantibodies directed against constituents of primary granules of neutrophils and monocytes lysosomes. Although several antigenic targets have been identified, those ANCA directed to proteinase 3 or myeloperoxidase are clinically relevant, whereas the importance of other ANCA remains unknown. Both are strongly associated with small vessel vasculitides, the ANCA-associated vasculitides, which include Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome, and the localised forms of these diseases (eg, pauci-immune necrotising and crescentic glomerulonephritis). ANCA is a useful serological test to assist in diagnosis of small-vessel vasculitides. 85-95% of patients with Wegener's granulomatosis, microscopic polyangiitis, and pauci-immune necrotising and crescentic glomerulonephritis have serum ANCA. ANCA directed to either proteinase 3 or myeloperoxidase are clinically relevant, yet the relevance of other ANCA remains unknown. Besides their diagnostic potential, ANCA might be valuable in disease monitoring. In addition, data seem to confirm the long-disputed pathogenic role of these antibodies. There is increasing evidence that myeloperoxidase-ANCA are directly involved in the pathogenesis of necrotizing vasculitis. This is less clear for proteinase 3-ANCA, markers for Wegener's granulomatosis. With respect to proteinase 3-ANCA, complementary proteinase 3, a peptide translated from the antisense DNA strand of proteinase 3 and homologous to several microbial peptides, may be involved in induction of proteinase 3-antineutrophil cytoplasmic autoantibodies.

DRB1*15 Allele Is a Risk Factor for PR3-ANCA Disease in African Americans

Anti-neutrophil cytoplasmic autoantibody (ANCA) disease rarely occurs in African Americans and risk factors for the disease in this population are unknown. Here, we genotyped MHC class II alleles and found that, among African Americans, those with proteinase 3-ANCA (PR3-ANCA) had 73.3-fold higher odds of having HLA-DRB1*15 alleles than community-based controls (OR 73.3; 95% CI 9.1 to 591). In addition, a disproportionate number of African American patients carried the DRB1*1501 allelic variant of Caucasian descent rather than the DRB1*1503 allelic variant of African descent. Among Caucasians, those with PR3-ANCA had 2.2-fold higher odds of carrying DRB1*1501 than controls (OR 2.2; 95% CI 1.2 to 4.0). A validation study supported by the Vasculitis Clinical Research Consortium confirmed the strong association between the DRB1*15 allele and PR3-ANCA disease, among African Americans. Furthermore, we found that DRB1*1501 protein binds with high affinity to amino acid sequences of sense-PR3, purportedly an antigenic epitope, and to the amino acid sequence complementary to this epitope in vitro. Peptides of sense-PR3 and complementary-PR3 also bound to TNF-α-induced surface expression of DRB1*1501 on peripheral neutrophils. Taken together, these data suggest HLA-DRB1*15 alleles contribute to the pathogenesis of PR3-ANCA disease.

A rare case of malignant-phase hypertension with pulmonary alveolar hemorrhage

Malignant-phase hypertension is characterized clinically by severe accelerating hypertension with neuroretinopathy or papilledema and by evidence of renal damage. A Japanese male in his early thirties presented with hemoptysis and general fatigue. He had a 5-year history of hypertension, but had not received any treatment. His blood pressure was 290/150mmHg and his serum creatinine level was 8.24mg/dL. Chest X-rays and computed tomography scans of the chest revealed a pulmonary alveolar hemorrhage. He was suspected of having vasculitis syndrome or Goodpasture's syndrome, but his renal biopsy specimen showed malignant nephrosclerosis. Myeloperoxidase antineutrophil cytoplasmic antibody (ANCA), proteinase-3 ANCA and antiglomerular basement membrane antibody were negative. He was treated with a calcium antagonist and a β-blocker, followed by an angiotensin-converting enzyme inhibitor. After the administration of the β-blocker, his blood pressure decreased and his renal function gradually improved. This is a rare case of malignant-phase hypertension with pulmonary alveolar hemorrhage; this condition should be considered in the differential diagnosis in order to avoid unnecessary treatment such as immunosuppressive therapy.

Corynebacterium jeikeium pacemaker infection associated with antineutrophil cytoplasmic antibodies: a single positive blood culture could be sufficient for diagnosis

Corynebacterium jeikeium, a member of the non-diphtheria corynebacteria, has been rarely reported as being responsible for cardiovascular-device infection. Here, we report what is believed to be the first case of C. jeikeium pacemaker infection associated with the presence of proteinase-3 antineutrophil cytoplasmic antibodies. The diagnosis was established based on the positivity of a single positive blood culture and led to pacemaker extraction. This observation highlights the difficulty in the diagnosis of cardiac-device infection in the presence of a single positive blood culture with a fastidious microorganism that could be considered as a contaminant. It also underscores the need for device extraction to ensure healing.

耳下腺腫脹を呈したウェゲナー肉芽腫例

A 65-year-old man admitted for a left parotid tumor and high fever unresponsive to peroral antibiotics was found in gallium scintigraphy to have “hot” spots in the left parotid gland and left maxillary sinus. The ineffectiveness of intravenous antibiotics necessitated open biopsy to histologically diagnose the man’s condition. Surgical parotid gland and maxillary sinus specimens showed necrotizing granulomas with giant cells. Elevated proteinase-3 antineutrophil cytoplasmic antibody (PR3-ANCA) comfirmed a clinical diagnosis of Wegener’s granulomatosis. Treatment with prednisolone and cyclophosphamide led to clinical improvement. Major salivary gland involvement is rarely a presenting symptom in Wegener’s granulomatosis and correctly diagnosing this condition may increase morbidity due to disease progression.

Microscopic polyangiitis with renal mass-like lesion : A case report

A 63-year-old man was admitted to our hospital because of persistent fever, weight loss, painful foot, and purpura on his extremities. He had lower extremity peripheral neuropathy, and skin biopsy of the purpura revealed vasculitis. Serum tests for myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA), proteinase 3-ANCA, and ANCA (indirect fluorescent antibody method) were all negative. Computed tomography revealed a 6-cm large, irregularly shaped lesion in the right kidney, while the nasal sinuses and lungs were intact. Based on these findings, a diagnosis of suspected systemic vasculitis associated with renal cell carcinoma was made. Thus, right nephrectomy was performed. However, the pathological findings showed a large infarct with necrotizing vasculitis of the arcuate, interlobular, and perinephric small arteries and a crescent formation in the glomerulus. Based on these findings, he was diagnosed with microscopic polyangiitis. Due to rapidly worsening symptoms of purpura and neuropathy, treatment with a high dose of corticosteroid was initiated on postoperative day 2, which led to improvement of his symptoms. Vasculitis accompanied with a mass-like lesion is occasionally confused with malignancy. The lesion in our patient was considered to have originated by asymptomatic renal infarction. This case suggests that a renal mass-like lesion with vasculitis should be diagnosed with care.

Occult Pulmonary Hemorrhage as a Rare Presentation of Propylthiouracil-Induced Vasculitis

Propylthiouracil, a drug commonly used to treat hyperthyroidism, is known to cause antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis as a rare complication. The wide clinical spectrum of propylthiouracil-induced vasculitis ranges from mild forms with rash and/or arthralgia to severe forms with renal or pulmonary involvement, which can be critical and life-threatening if left unrecognized and untreated. Given its rarity and exceedingly variable clinical presentations, diagnosis may be challenging, and delayed diagnosis is not uncommon without a high index of suspicion, as illustrated by this report of a 17-year-old girl with Graves' disease who developed occult pulmonary hemorrhage as an overlooked rare presentation of ANCA-associated vasculitis after administration of propylthiouracil. Associated clinical features included fever, fatigue, palpable purpura, polyarthritis, and nephritis. Positive findings on chest radiography prompted the bronchoalveolar lavage procedure, which led to the identification of pulmonary hemorrhage. Skin biopsy showed leukocytoclastic vasculitis. Serologic test results were positive for perinuclear ANCA, cytoplasmic ANCA, myeloperoxidase-ANCA, proteinase 3-ANCA, and cryoglobulins but negative for antinuclear antibody, anti-double-stranded DNA, rheumatoid factor, and anti-hepatitis C virus antibody. The symptoms resolved after discontinuation of propylthiouracil and a few months of corticosteroids and azathioprine. This report highlights the necessity for physicians to keep alert for the protean manifestations of propylthiouracil-induced vasculitis.

A 44‐year‐old woman with cutaneous bullae and extensive skin necrosis

Five weeks before presentation, the patient had experi-enced a cough and mild dyspnea. She was diagnosed withpneumonia, completed a 7-day course of ciprofloxacin anddoxycycline, and her respiratory symptoms resolved.Three weeks before presentation, the patient had reportedfevers, chills, diaphoresis, arthralgias, and myalgias, anddeveloped a small erythematous lesion on her left breast.The lesion subsequently enlarged and became hemor-rhagic. She simultaneously developed additional lesionson her chest, abdomen, arms, and back. The largest ofthese, located on her left arm, was 15 cm in diameter. Allof the lesions were exquisitely tender. She was hospital-ized at an outside hospital for 5 days and given a diagnosisof cocaine-induced vasculitis. Upon discharge, she wasinstructed to abstain from cocaine and was prescribedtrimethoprim/sulfamethoxazole for a possible cellulitis in-volving the skin lesions.Ten days after discharge from the outside hospital, thepatient presented to our institution for pain managementand further evaluation. The rash had progressed since herearlier discharge. She had continued to use cocaine, her-oin, and prescription opioids. She had last smoked co-caine 3 days before presentation and last used intranasalheroin 1 week before admission. She reported acquiringcocaine from a new supplier 2 weeks before her rash hadbegun.

A comparison of antineutrophil cytoplasmic antibody prevalence in patients treated and untreated for hyperthyroidism

We aimed to compare the prevalence of antineutrophil cytoplasmic antibody (ANCA) and its subgroups between on-treatment (with anti-thyroid drugs; propylthiouracil, methimazole) and untreated patients with hyperthyroidism in our unit. Overall 78 consecutive patients were enrolled in the study; 45 patients were on-treatment (female/male 31:14) and 33 were newly diagnosed (female/male 20:13). We have studied ANCA, perinuclear-ANCA (p-ANCA), cytoplasmic-ANCA (c-ANCA), myeloperoxidase-ANCA (mpo-ANCA), and proteinase 3-ANCA (pr3-ANCA) in sera of all the patients. The data about clinical status, laboratory tests, and physical examination and mean duration of treatment in treated group were recorded. There was no statistically significant difference between the two groups for ANCA, c-ANCA, and pr3-ANCA (P=0.13, P=0.07, and P=0.63 respectively). p-ANCA and mpo-ANCA prevalences were significantly higher in on-treatment group than in untreated group (P=0.04 and P=0.01, respectively). The mean duration of treatment was 17 months in on-treatment group. The use of antithyroid drugs (propylthiouracil, methimazole) seems to be correlated with increased prevalence of ANCA. These drugs may especially increase p-ANCA and mpo-ANCA positivity.

New algorithm (KAWAKAMI algorithm) to diagnose primary cutaneous vasculitis

Palpable purpura tends to indicate involvement of small vessel vasculitis in the upper dermis. Livedo racemosa, nodular lesion and skin ulceration are indicative of involvement of small to medium-sized vessel vasculitis in the lower dermis to subcutaneous fat. We set out to establish a new algorithm (KAWAKAMI algorithm) for primary cutaneous vasculitis based on the Chapel Hill Consensus Conference classification and our research results, and apply to the diagnosis. The first step is to measure serum antineutrophil cytoplasmic antibodies (ANCA) levels. If myeloperoxidase-ANCA is positive, Churg-Strauss syndrome or microscopic polyangiitis can be suspected, and if the patient is positive for proteinase 3-ANCA, Wegener's granulomatosis is most likely. Next, if cryoglobulin is positive, cryoglobulinemic vasculitis should be suspected. Third, if direct immunofluorescence of the skin biopsy specimen reveals immunoglobulin A deposition within the affected vessels, Henoch-Schönlein purpura is indicated. Finally, the presence of anti-phosphatidylserine-prothrombin complex antibodies and/or lupus anticoagulant and histopathological necrotizing vasculitis in the upper to middle dermis (leukocytoclastic vasculitis) indicates cutaneous leukocytoclastic angiitis, whereas if necrotizing vasculitis exists in the lower dermis and/or is associated with the subcutaneous fat, cutaneous polyarteritis nodosa is indicated. The KAWAKAMI algorithm may allow us to refine our earlier diagnostic strategies and allow for efficacious treatment of primary cutaneous vasculitis. In cutaneous polyarteritis nodosa, warfarin or clopidogrel therapies should be administrated, and in cases that have associated active inflammatory lesions, corticosteroids or mizoribine (mycophenolate mofetil) therapy should be added. We further propose prophylactic treatment of renal complications in patients with Henoch-Schönlein purpura.

Epitope shift of proteinase-3 anti-neutrophil cytoplasmic antibodies in patients with small vessel vasculitis

Anti-neutrophil cytoplasmic antibodies against proteinase 3 (PR3-ANCA) are used as diagnostic tools for patients with small vessel vasculitis (AASV). We have produced chimeric mouse/human PR3 molecules and investigate changes in reactivity over time and the possible relationship between epitope specificity and clinical course. Thirty-eight PR3-ANCA-positive patients diagnosed between 1990 and 2003 were followed until December 2005. Plasma was collected at each out-patient visit and older samples were retrieved retrospectively. Patients reacted with multiple epitopes at the time of diagnosis. At subsequent relapses 12 patients shifted reactivity, in 11 cases from epitopes located in the C-terminal towards epitopes in the N-terminal. Patients with reactivity against N-terminal parts of PR3 at diagnosis had a significantly lower relapse rate, 30% compared to 78% in the group with predominantly C-terminal reactivity (P = 0.04). The reactivity pattern did not correlate to outcome measured as death, end-stage renal disease or vasculitis activity index score (VDI) at 5 years. Further research is necessary to conclude if this is a general phenomenon.

Clinical and immunological features of drug-induced and infection-induced proteinase 3-antineutrophil cytoplasmic antibodies and myeloperoxidase-antineutrophil cytoplasmic antibodies and vasculitis

Drugs and infections may induce antineutrophil cytoplasmic antibodies (ANCA) and vasculitic manifestations mimicking ANCA-associated vasculitides (AAV) and mechanisms relevant in their pathogenesis. This review summarizes the most recent findings in this field. Drug-induced and infection-induced proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA may be associated with a vasculitis clinically resembling AAV. Mechanisms relevant for the break of tolerance and induction of ANCA (e.g. danger signals, superantigens, neutrophil extracellular traps, protease-activated receptor-2, IL-17 cells) may be shared to some extent between drug-induced and infection-induced ANCA-positive vasculitis and AAV, especially with regard to the potential role of infection in Wegener's granulomatosis. Differences in immunopathology, clinical presentation, and functional aspects of ANCA help to distinguish drug-induced and infection-induced ANCA-positive vasculitis from AAV, and present new avenues for future research in this field. Medications and infections, which induce PR3-ANCA and MPO-ANCA, have to be considered in the differential diagnosis of primary AAV. Moreover, there is clinical and experimental evidence for an association between certain drugs and infections with ANCA-production. Analysis of ANCA-induction in such conditions also sheds new light on our understanding of immune mechanisms relevant in the break of tolerance and ANCA-production in AAV.

Analysis of T-cell receptor usage in myeloperoxidase−antineutrophil cytoplasmic antibody-associated renal vasculitis

Bacterial superantigens produced by Staphylococcus aureus may be associated with the onset of proteinase-3 antineutrophil cytoplasmic antibody (PR3-ANCA)-associated vasculitis, including Wegener's granulomatosis. We investigated T-cell subsets to assess the superantigens present in patients with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis. Peripheral-blood mononuclear cells (PBMC) obtained from 40 normal controls and ten patients with MPO-ANCA-associated vasculitis were stained with fluorescence-labeled monoclonal antibodies against T-cell markers, including 17 variable regions of T-cell receptor beta-chains (TCR-Vbeta) and were then analyzed using flow cytometry. Among PBMCs, the percentage of CD3(+) cells from patients with MPO-ANCA-associated vasculitis was significantly lower than that from normal controls, but there were no differences between the two groups in the percentage of CD19(+) cells or CD16(+) cells. Although there were no differences regarding the overall percentage of CD4(+) cells between the two groups, the percentage of CD4(+)CD45RO(+) cells in patients with MPO-ANCA-associated vasculitis was significantly higher than that in normal controls, and percentages of CD4(+)CD45RO(+)HLA-DR(+) and CD4(+)CD45RO(+)CD62L(low) cells in patients with MPO-ANCA-associated vasculitis were also significantly increased. There was no significant difference between the two groups in terms of the usage of the 17 different TCR-Vbeta regions. There was no difference in bacterial superantigens between controls and MPO-ANCA-associated vasculitis patients because of the absence of specific usage of TCR-Vbeta regions. Given the elevated levels of memory T cells, conventional antigens rather than superantigens may be associated with the pathogenesis of MPO-ANCA-associated vasculitis.

Light chain proximal tubulopathy

CASE PRESENTATION A 55-year-old Caucasian woman presented to her primary care physician with complaints of progressive fatigue for several months, dyspnea with minimal exertion, loss of appetite, 15-pound weight loss, and recurrent low-grade fevers. Past medical history was significant only for migraine headaches. The patient was taking no prescription or over-the-counter medications. There was no history of environmental toxin exposure, recent travel, smoking, excess alcohol consumption, or use of illicit drugs. She was empirically treated with a course of esomeprazole and amoxicillin. The patient returned 2 weeks later and reported no improvement in her symptoms. Laboratory studies revealed anemia, thrombocytopenia, hypercalcemia, and acute renal failure. The patient was admitted for further evaluation. Upon admission, physical examination revealed a well nourished but pale female in no acute distress. Her blood pressure was 156/70mmHg, pulse 96bpm, temperature 98.6F, respiratory rate 20breaths/min, and pulse oximetry 100% on room air. Cardiac and pulmonary examinations were unremarkable. Abdominal examination revealed splenomegaly with a palpable liver edge 1–2cm below the right costal margin. Laboratory testing (Table 1) was notable for a hemoglobin of 6.1g/dl (normal range, 11.0–15.0g/dl), platelet count 112K/mm 3 (nl 150–400K/mm 3 ), creatinine 3.7mg/dl, BUN 34mg/dl, and calcium 12.4mg/dl (nl 8.5–10.1mg/dl). Liver function tests, coagulation studies, and parathyroid hormone levels were normal. Urinalysis revealed 1+ protein, 1+ glucose, and trace blood. Negative serologies included anti-glomerular basement membrane antibody, proteinase-3 anti-neutrophil cytoplasmic antibodies, and myeloperoxidase anti-neutrophil cytoplasmic antibodies. Serum complement levels were mildly elevated with C3 179.0mg/dl (nl 75–135mg/dl) and C4 41.9mg/dl (nl 9–36mg/dl). Serum protein electrophoresis with immunofixation showed no monoclonal protein. A bone marrow biopsy revealed normocellular marrow with no evidence of lymphoma or a plasma cell dyscrasia. A non-contrast computed tomography scan of the chest, abdomen, and pelvis was notable for splenomegaly (18 × 15 × 10cm) with a hypodense area measuring 7 × 7 × 4cm and mild hepatomegaly. The kidneys measured 11.7 and 12cm in length by ultrasound, without evidence of obstruction. A skeletal survey showed no abnormalities. The patient was treated with hydration and a single dose of pamidronate. At the time of discharge 6 days later, her creatinine had fallen to 1.9mg/dl, and her calcium had normalized. The patient was seen in nephrologic consultation 1 week after discharge, at which time her creatinine had declined to 1.5mg/dl. Computed tomography scan was repeated with contrast and revealed a 19 × 16 × 10cm spleen with an ill-defined 11 × 11 × 13cm mass with areas of probable necrosis. In light of the absence of a clear indication for splenectomy, a renal biopsy was performed to determine the cause of the patient's persistent renal dysfunction.