Microscopic polyangiitis associated with thymic tumor: a case report and review of the literature.

BACKGROUND: Thymic hyperplasia and thymic epithelial tumor (thymoma) have been associated with a variety of autoimmune diseases. Renal involvement has been reported in patients with thymoma. Minimal change disease and membranous nephropathy are frequently observed in glomerular lesions of thymoma patients, but ANCA-associated renal vasculitis is rare. We present a case of thymoma-associated microscopic polyangiitis with positivity for three ANCAs: MPO-ANCA, PR3-ANCA and azurocidin-ANCA. CASE PRESENTATION: An 89-year-old Japanese woman was admitted to our hospital following an episode of general fatigue, nausea, muscle weakness of the lower limbs, and ophthalmoplegia. On urinalysis, proteinuria, hematuria, and cellular casts were observed. Elevated levels of serum creatinine and C-reactive protein were also demonstrated, and MPO-, PR3- and azurocidin-ANCA were detected on serological examination. Renal biopsy showed pauci-immune crescentic glomerulonephritis. We therefore diagnosed rapidly progressive glomerulonephritis due to microscopic polyangiitis. Acetylcholine-receptor antibody was also detected. Chest computed tomography and MRI revealed a lobulated tumor in the anterior mediastinum. We thus also diagnosed myasthenia gravis with thymoma. CONCLUSION: Considering the patient's triple-ANCA positivity, thymic diseases may be associated with the pathogenesis of ANCA-associated vasculitis due to central T-cell tolerance. A further accumulation of cases is needed, because thymectomy does not always induce the remission of thymoma-associated autoimmune diseases.

Ni los anticuerpos antinucleares ni los anticuerpos dirigidos contra antígenos extraíbles del núcleo son lo que solían ser. Un futuro cambio de nomenclatura y recomendaciones para su determinación en práctica clínica habitual / Neither the anti-nuclear antibodies nor the anti-extractable nuclear antigens Are What They Used to Be. A Future Change of Nomenclature

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The relation between histopathological classification and renal outcome, ANCA subtype and treatment regimens in ANCA-associated vasculitis.

OBJECTIVES: ANCA-associated vasculitis (AAV) is associated with an increased risk of death and end stage renal disease (ESRD). The aim of this study was to examine the correlation between a histopathological classification and renal outcome and to describe the interaction with ANCA subtype and initial treatment. METHODS: Eighty-seven patients with AAV from 1999-2010 from two centres in Denmark were included in the study and had a 3 year follow-up. Data was collected retrospectively. The renal biopsies were reclassi ed into one of the following groups: crescentic, sclerotic, focal and mixed. RESULTS: Histopathologic groups were not associated with eGFR at three years. Age and baseline eGFR were independent prognostic for eGFR at three years. More patients in the crescentic group than in the mixed and focal groups developed ESRD (33%, 13% and 5% respectively). Patients reaching ESRD had few- er non-affected glomeruli (14 % vs. 34%, p=0.0014) and lower eGFR at baseline (7 vs. 21.7 ml/min/m(2), p<0.0001). At baseline MPO-ANCA positive patients were older, had more sclerotic glomeruli and had a lower eGFR after three years compared to PR3-ANCA positive patients. PR3-ANCA positive patients receiving plasma exchange (PE) improved eGFR more from baseline to three years than those not receiving PE (36 vs. 20 ml/min/m2, p=0.01). CONCLUSIONS: In our cohort most pa- tients in the crescentic group and fewer in the focal group reached ESRD. Age and baseline eGFR are prognostic of renal function after 3 years, as also in the PR3-ANCA positive subgroup initial treatment with PE.

Long-term outcome of anti-neutrophil cytoplasm antibody-associated glomerulonephritis: evaluation of the international histological classification and other prognostic factors.

BACKGROUND: Anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis with renal involvement requires treatment with potentially toxic drugs to reduce morbidity and mortality, and there is a major challenge to determine clinical and histological features predictive of renal prognosis. The aim of our study was to evaluate the use of the 2010 international histological classification for ANCA-associated glomerulonephritis (AAGN) as a predictor of renal outcome when used in conjunction with other prognostic factors. METHODS: One hundred and four patients with AAGN treated at our centre were included: 23 were classified as focal, 26 as crescentic, 48 as mixed and 7 as sclerotic. Renal outcomes were based on estimated glomerular filtration rate (eGFR) at 1 and 5 years, and on renal survival. RESULTS: By univariate analysis, patients in the focal class had the best renal outcome, those in the sclerotic class the worst outcome, and those in the mixed and crescentic classes had intermediate renal survival. There was no significant difference in outcome between the mixed and crescentic classes. In multivariate models, histological class did not improve model fit or associate with renal outcome after adjusting for established prognostic factors. Lower percentage of normal glomeruli, greater degree of tubular atrophy (TA), MPO-ANCA positivity, increasing age and lower starting eGFR, all correlated with poorer renal outcomes. CONCLUSIONS: We conclude that, in our cohort of patients, the international histological classification is predictive of renal outcome in AAGN, but did not appear to be additionally informative over other established prognostic factors in multivariate analysis. However, it may be of value to combine the current histological classification with other established parameters, such as TA and percentage normal glomeruli.

Validation of a newly proposed histopathological classification in Japanese patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: A new histopathological classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis was recently proposed. We evaluated the predictive value of this classification for renal outcome in Japanese patients. METHODS: We enrolled 122 patients with ANCA-associated glomerulonephritis diagnosed at several institutions in Japan between January 2000 and March 2010. Twenty patients were excluded because of observation durations of <1 year, and/or because their biopsy specimens contained <10 glomeruli. Renal biopsy specimens were categorized into four classes according to the proposed classification. We evaluated the predictive value of immunohistochemical staining for α-smooth muscle actin (SMA), Wilm's tumor 1 (WT1), CD68, and cytokeratin for end-stage renal disease (ESRD). RESULTS: The study population included 54 men and 48 women. Age, estimated glomerular filtration rate (eGFR), and proteinuria were 66.3 ± 11.3 years, 21.6 ml/min. and 1.10 g/24 h, respectively. Eighty-six patients were positive for myeloperoxidase-ANCA, five were positive for proteinase 3-ANCA, and 11 were negative for both antibodies. Median follow-up time was 41.0 months. Twenty-three patients (22.5%) developed ESRD during the follow-up period. Twelve patients died during follow up; 7/12 patients developed ESRD before death, and 5/12 patients died without ESRD. The incidence of ESRD increased with sequential categories: focal, 2/46 (4.3%); crescentic, 9/32 (28%); mixed, 8/18 (44%); and sclerotic, 4/6 (67%). The focal class had the best renal survival and the sclerotic class had the worst renal survival (p < 0.001). Kaplan-Meier renal survival analysis was similar to that of the new classification system proposal. In the multivariate analysis, the classification system tended to be a prognostic factor for ESRD (p = 0.0686, crescentic, mixed and sclerotic vs. focal, hazard ratio (HR) [95% confidence interval, CI]; 2.99 [0.61-22.7], 5.04 [1.11-36.4] and 9.93 [1.53-85.7], respectively). α-SMA-positivity also tended to be associated with ESRD (p = 0.1074). CONCLUSION: The new histopathological classification was associated with eGFR at 1 year and tended to be associated with ESRD in our Japanese cohort with ANCA-associated glomerulonephritis. α-SMA positivity might be an additional prognostic factor for ESRD.

Re-evaluation of the histopathologic classification of ANCA-associated glomerulonephritis: a study of 121 patients in a single center.

BACKGROUND: The recently published histopathologic classification of antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis might greatly aid in the prognostication of patients at the time of diagnosis. This study aims to re-evaluate the new classification for its prognostic capacity in an independent Chinese series. METHODS: One hundred and twenty-one consecutive patients with ANCA-associated glomerulonephritis, diagnosed in our center from 1997 to 2010, were included in this retrospective study. The renal specimens were reviewed according to the proposed histopathologic classification. The predictive value of the classification for renal outcome and renal response to treatment was analyzed. RESULTS: Thirty-three (27.3%), 24 (19.8%), 53 (43.8%) and 11 (9.1%) patients were classified as focal, mixed, crescentic and sclerotic ANCA-associated glomerulonephritis, respectively. The renal biopsy categories correlated with initial serum creatinine and the renal response to treatment (P < 0.001, P < 0.01, respectively). The probability of progressing to end-stage renal disease (ESRD) increased with ascending categories of focal, mixed, crescentic and sclerotic glomerulonephritis (P < 0.01). The patients with focal, mixed and crescentic ANCA-associated glomerulonephritis were all at decreased risk for developing ESRD compared with the patients with in the sclerotic category (P < 0.05). CONCLUSIONS: The proposed classification system was re-evaluated for the first time in a relatively large and independent series of patients. This system reflects the severity of the initial renal impairment and can predict, at least to some extent, the renal response to treatment. More importantly, it can independently predict renal outcome, in particular development of ESRD.

Nomenclature and classification of vasculitis: lessons learned from granulomatosis with polyangiitis (Wegener's granulomatosis).

Names influence how something is perceived. Diagnostic terms (diagnoses) are the names of diseases that are usually derived either from some distinctive characteristic of the disease or include an eponym recognizing someone who elucidated the disease. No matter how logical and appropriate a name may be, if it is not usable and used it is of no lasting value. This brief commentary focuses on the nomenclature of systemic vasculitides, and uses as a prime example Wegener's granulomatosis, which has been renamed recently 'granulomatosis with polyangiitis', in part because of concerns about the suitability of Friedrich Wegener as the source of an eponym. The most distinctive pathological feature of Wegener's granulomatosis is multi-focal necrotizing inflammation that has long been called granulomatosis. The systemic variant of Wegener's granulomatosis also is characterized by inflammation in many different vessels or different types, i.e. polyangiitis. Thus, granulomatosis with polyangiitis is a very appropriate alternative term for Wegener's granulomatosis. This term also is in accord with the name for a closely related vasculitis, i.e. microscopic polyangiitis. Terms that indicate aetiology and pathogenesis, when known, are useful to include in names for diseases (diagnoses). Anti-neutrophil cytoplasmic autoantibodies specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA) are implicated in the cause of granulomatosis with polyangiitis and thus also should be specified in the diagnosis (e.g. PR3-ANCA-positive granulomatosis with polyangiitis or MPO-ANCA-positive microscopic polyangiitis). As our understanding of the clinical manifestations, pathogenesis and aetiology of vasculitides change over time, the names and approaches for diagnosing these diseases will change accordingly.

[Clinical feature analysis of 190 patients with anti-neutrophil cytoplasmic antibodies associated vasculitis].

OBJECTIVE: To explore the clinical features and disease spectrums for ANCA (anti-neutrophil cytoplasmic antibodies)-associated vasculitis (AAV) and to improve its cognition. METHODS: Clinical features of 190 cases of patients with AAV hospitalized from 1998 to 2008 were reviewed retrospectively. According to the result of ANCA test, the patients were divided into two groups, cytoplasmic ANCA (C-ANCA) positive and perinuclear ANCA (P-ANCA) positive. The authors compared the differences of disease spectrums, clinical manifestations and laboratory tests between two groups. The relative mortality factors were also analyzed. RESULTS: The authors studied 92 males and 98 females with an age range of 8 - 89 (59 +/- 18) years old. There were 156 cases aged 40 - 80 years old (82.1%) and 162 patients (85.3%) were of primary AAV including 146 cases of P-ANCA positive and 16 cases of C-ANCA positive. There were 28 patients with secondary AAV including 18 cases of connective tissue disease, 7 cases of propylthiouracil induction, 1 case each of idiopathic thrombocytopenic purpura, lung cancer and endometrial carcinoma. There were 25 cases of P-ANCA positive and 3 cases of C-ANCA positive in secondary AAV. There were 171 cases (90.0%) in P-ANCA group and 19 cases (10.0%) in C-ANCA group. The number of organ involvement was 2.53 in C-ANCA group and 1.92 in P-ANCA group. Gastrointestinal tract, joint, upper respiratory tract and ocular involvement was more in C-ANCA group than in P-ANCA group. Oral and auricular involvement was more in P-ANCA group than in C-ANCA group. The involvement difference was of statistic significance in upper respiratory tract, joint and eye (all P < 0.05). Renal and pulmonary involvement in P-ANCA group was similar to C-ANCA group. There were 3 mortality cases in C-ANCA group and 22 in P-ANCA group. Respiratory failure and multiple organ dysfunctions were relative mortality factors. CONCLUSIONS: AAV is observed in elders with multiple organ involvement. The number of organ involvement in C-ANCA group is more than that in P-ANCA group. P-ANCA positive patients are more than c-ANCA patients. The disease spectrum is different in these two groups. Secondary AAV is more in P-ANCA group than in C-ANCA group. Clinical manifestations, laboratory tests and type of ANCA are helpful for the diagnosis of AAV.

[Distribution of IgG subclass of anti-myeloperoxidase antibodies in sera from patients with propylthiouracil induced vasculitis].

OBJECTIVE: To investigate the distribution of IgG subclass of anti-myeloperoxidase (MPO) antibodies, a kind of antineutrophil cytoplasmic autoantibody (ANCA), in sera from patients with propylthiouracil (PIU)-induced vasculitis. METHODS: Serum samples were collected from 12 patients with PIU-induced MPO ANCA positive vasculitis, both sera of active and remission phases were collected from 10 of which, and only serum of active phase was collected from 2 of which. Anti-MPO IgG subclasses were detected by antigen-specific ELISA. The distribution of anti-MPO IgG subclasses in PIU-induced vasculitis was compared with that in primary vasculitis. RESULTS: Anti-MPO IgG3 subclass was not detected in the sera from both active and remission phases of PIU-induced vasculitis. In the active phase the following anti-MPO IgG subclasses were found: IgG1 (12/12, 100%), IgG2 (1/12, 66.7%), and IgG4 (7/12, 58.3%). In the remission phase, the following anti-MPO IgG subclasses were found: IgG1 (9/10, 90%), IgG2 (4/10, 40%), and IgG4 (2/10, 20%). The titer of anti-MPO IgG4 subclass remained high in the remission phase in primary vasculitis; however, it decreased significantly after the cessation of PIU use in PIU-induced vasculitis. CONCLUSION: The distribution of anti-MPO IgG subclasses in the sera of the patients with PIU-induced vasculitis is different from that of the patients with primary vasculitis. The higher titer pf MPO-ANCA in the sera of the patients with PIU-induced vasculitis may be associated with the repeated PIU stimulation.

Histologic analysis of renal leukocyte infiltration in antineutrophil cytoplasmic antibody-associated vasculitis: importance of monocyte and neutrophil infiltration in tissue damage.

OBJECTIVE: The histopathologic lesions in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been studied extensively, but the exact composition of the cellular infiltrate is unclear. We undertook this study to analyze renal leukocyte infiltration and the cellular distribution within glomeruli and interstitium in 65 renal biopsy samples obtained from patients newly diagnosed as having AAV. METHODS: Renal cellular tissue infiltration was assessed with an immunoperoxidase method. Furthermore, the infiltrating cell types were correlated with clinical and histopathologic data. RESULTS: The predominant interstitial infiltrating cells were T lymphocytes, while monocytes and, to a lesser extent, granulocytes constituted the dominant infiltrating cell types in glomeruli. Interestingly, lymphocyte infiltration was predominantly periglomerular, especially around glomeruli with sclerosis or heavy crescent formation, while interstitial monocyte and neutrophil infiltration was diffusely distributed over the interstitial tissue. A significant correlation was found for the glomerular infiltration of CD68-positive macrophages with the presence of glomerular necrosis as well as with the number of glomeruli with crescents (P < 0.0001 and P = 0.005, respectively). No correlation was found for interstitial fibrosis with the infiltration of any leukocyte subset. Furthermore, a significant correlation was found for the interstitial as well as for the glomerular infiltration of CD68-positive macrophages with serum creatinine concentration at the time of biopsy (P = 0.001 and P = 0.006, respectively). CONCLUSION: These data underscore a major role of monocytes in addition to neutrophils in the tissue damage of AAV.

IgG from myeloperoxidase-antineutrophil cytoplasmic antibody-positive patients stimulates greater activation of primed neutrophils than IgG from proteinase 3-antineutrophil cytosplasmic antibody-positive patients.

OBJECTIVE: Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) have been reported to be pathologically and clinically different. The aim of this study was to assess whether these differences could be explained by differing abilities of proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA)-positive IgG preparations or myeloperoxidase-ANCA (MPO-ANCA)-positive IgG preparations to activate neutrophils (polymorphonuclear cells [PMN]) in vitro. METHODS: Using Percoll density gradients, PMN were isolated (concentration 2 x 10(6)/ml) and primed with cytochalasin B (1 ng/ml) and tumor necrosis factor alpha (TNFalpha; 2 ng/ml). The PMN were activated with 200 microg/ml of normal IgG or ANCA. Activation was determined by 1) superoxide anion generation as determined by the superoxide dismutase-inhibitable reduction of ferricytochrome c, 2) monitoring fluxes in Ca2+ concentration using Fura 2-AM-loaded PMN, and 3) degranulation using an MPO assay. Surface expression of PR3 and MPO was determined by fluorescence-activated cell sorter analysis. ANCA isotypes were investigated by enzyme-linked immunosorbent assay. RESULTS: Activation of PMN by MPO-ANCA-positive IgG preparations compared with PR3-ANCA-positive IgG preparations resulted in greater generation of superoxide anions (MPO-ANCA-positive IgG preparations 9.13 +/- 0.39 nmoles [mean +/- SEM], PR3-ANCA-positive IgG preparations 6.32 +/- 0.35 nmoles; P < 0.001), Ca2+ fluxes (MPO-ANCA-positive IgG preparations 0.735 +/- 0.10, PR3-ANCA-positive IgG preparations 0.33 +/- 0.098; P < 0.01), and MPO degranulation (MPO-ANCA-positive IgG preparations 251.98 +/- 26.7 ng, PR3-ANCA-positive IgG preparations 145.19 +/- 19.4 ng; P < 0.001). The increased activation seen with MPO-ANCA-positive IgG preparations was not due to increased expression of MPO on the cell surface, because following TNFalpha priming PR3 was expressed on significantly more cells than was MPO (PR3 expression 54.2 +/- 5.18%, MPO 31.6 +/- 3.55%; P < 0.001). IgG1 and IgG4 were the predominant isotypes in both MPO-ANCA-positive IgG preparations and PR3-ANCA. MPO-ANCA contained significantly more IgG1 than did PR3-ANCA, and PR3-ANCA-positive IgG preparations contained significantly more IgG3. CONCLUSION: In vitro MPO-ANCA-positive IgG preparations are more activating than PR3-ANCA-positive IgG preparations. The increased activation cannot be explained by increased MPO expression on the cell surface or greater IgG3 present in MPO-ANCA-positive IgG preparations. Differences in activation of PMN by these antibodies may determine some differences between WG and MPA.

Wegener's granulomatosis.

Wegener's granulomatosis (WG) is currently categorized as one of the antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitides distinguished by its predilection to affect the upper and lower respiratory tracts and kidneys clinically and histologically by the presence of necrosis, granulomatous inflammation, and vasculitis. However, small biopsies, especially from the head and neck region, often lack all these diagnostic histologic findings. Other common histologic features of WG include microabscesses and scattered multinucleated giant cells in a highly inflammatory background. Support from distinctive clinical setting or positive cytoplasmic (C)-ANCA testing may help establish the diagnosis of WG in cases lacking all the typical pathologic findings. The histopathologic differential diagnosis of WG includes nonspecific inflammatory conditions, infections, angiocentric lymphomas, collagen vascular diseases, and other forms of angiitis and granulomatosis. The prognosis of WG has dramatically improved from the 18% 5-month survival rate before the era of immunosuppressive therapy to the current remission rate of over 75% with a regimen of cyclophosphamide and glucocorticoids. A significant rate of relapse and profound disease- and/or treatment-related morbidity still occur. The cause of WG remains unknown, but circumstantial evidences suggest the potential roles of ANCA and infection in the pathogenesis.

A comparison of the characteristics of circulating anti-myeloperoxidase autoantibodies in vasculitis with those in non-vasculitic conditions.

Although circulating anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO) are strongly associated with the presence of vasculitis, they have been described in sera from patients with other conditions. High levels of anti-MPO antibodies can also persist in sera from patients with vasculitis despite the achievement of clinical remission. One possible interpretation is that a potentially pathogenic subset of anti-MPO antibodies exists, which is only present in patients with active vasculitis. We therefore compared the characteristics of anti-MPO antibodies in sera from patients with active vasculitis (n = 18) with those present in remission (n = 9) and in a disease control group (n = 10) without clinical evidence of vasculitis. The class, subclass and ability of anti-MPO antibodies from the three groups of patients to recognize three different conformational epitopes were analysed using ELISA-based techniques. The expression of an idiotope, designated 9G4, was also examined. Epitope recognition by anti-MPO antibodies from all patients tested was found to be similar. Sera from patients with active vasculitis showed an over-representation of IgG4 subclass anti-MPO antibodies and a more frequent presence of IgM class anti-MPO antibodies. In disease controls, IgG1 anti-MPO antibodies were predominant. In vitro, neutrophil activation by ANCA has been shown to be dependent on engagement of neutrophil FcgammaRIIa receptors following binding of these autoantibodies to surface-expressed ANCA antigens. We found that active vasculitis may be associated with the presence of circulating anti-MPO antibodies which do not significantly bind this receptor, suggesting that mechanisms other than those dependent on FcgammaRIIa binding should be explored. In addition, the expression of the 9G4 idiotope on anti-MPO antibodies in 60% (12/18) of patients with active vasculitis and 20% (2/10) of disease control patients may indicate a common origin for anti-MPO antibodies in different individuals.

Antineutrophil cytoplasmic antibody subtypes in children and adolescents after ileal pouch-anal anastomosis for ulcerative colitis.

BACKGROUND: Perinuclear antineutrophil cytoplasmic antibodies occur frequently in adult patients with chronic pouchitis after colectomy and ileal pouch-anal anastomosis for ulcerative colitis. The purpose of the study was to determine the prevalence of perinuclear antineutrophil cytoplasmic antibodies and cytoplasmic antineutrophil cytoplasmic antibody in children and adolescents who undergo colectomy and ileal pouch-anal anastomosis for ulcerative colitis and familial adenomatous polyposis. METHODS: Five groups of children and adolescents (age, <20 years) were studied, with the following histories: acute pouchitis and history of ulcerative colitis; chronic pouchitis and history of ulcerative colitis; pouchitis with Crohn's disease features and a history of ulcerative colitis; no pouchitis and a history of ulcerative colitis; and familial adenomatous polyposis, with or without pouchitis. Antineutrophil cytoplasmic antibody levels and titers were detected in postoperative sera by enzyme-linked immunosorbent assay, and positive results were subtyped by indirect immunofluorescence. RESULTS: The frequency of perinuclear antineutrophil cytoplasmic antibodies and cytoplasmic antineutrophil cytoplasmic antibody in patients with a history of ulcerative colitis were 67% and 15%, compared with a 0% presence in patients with familial adenomatous polyposis (p < 0.001). There was no significant correlation between the frequency of perinuclear antineutrophil cytoplasmic antibodies and ulcerative colitis patient subgroups (patients with and without pouchitis, 66% and 75%). Similarly, there was no significant correlation between the frequency of cytoplasmic antineutrophil cytoplasmic antibodies among ulcerative colitis patient subgroups (patients with and without pouchitis, 19% and 8%). The frequency of cytoplasmic antineutrophil cytoplasmic antibody in patients with Crohn's disease features (50%), was increased, but this difference was not significant. CONCLUSIONS: There is a high frequency of perinuclear antineutrophil cytoplasmic antibodies in children and adolescents who undergo ileal pouch-anal anastomosis for ulcerative colitis, whether or not they have pouchitis. The frequency of cytoplasmic antineutrophil cytoplasmic antibody is lower in this patient population. Additional studies will be required to determine whether the presence of cytoplasmic antineutrophil cytoplasmic antibody is associated with the postoperative development of features of Crohn's disease.

Comparison of anti-GBM antibodies in sera with or without ANCA.

An appreciable percentage of patients with serum anti-glomerular basement membrane (anti-GBM) antibodies also have antineutrophil cytoplasmic antibodies (ANCA), against either myeloperoxidase (MPO-ANCA), or proteinase 3 (PR3-ANCA). In sera without ANCA, the anti-GBM antibodies have been shown to react mainly with the noncollagenous domain (NC1) of Type IV collagen, and especially with its alpha 3 chain, alpha 3(IV)NC1. In most sera, the antibodies can be partially blocked by a monoclonal antibody (Mab17) against alpha 3(IV)NC1, suggesting that a limited region is recognized. Although there is evidence that some anti-GBM antibodies that coexist with ANCA react with alpha 3(IV)NC1, extensive analysis of the specificity of such anti-GBM antibodies has not been reported. In the study presented here, sera were analyzed from 332 patients tested both for anti-GBM antibodies and ANCA (MPO or PR3-ANCA) and found to have one or more positive tests. Of the 100 sera with anti-GBM antibodies, 38 also had ANCA-25 with MPO-ANCA (66%), 12 with PR3-ANCA (32%), and one with both (2%). Of the 232 sera with ANCA only, 153 had MPO-ANCA (66%), 75 had PR3-ANCA (32%), and four had both (2%). Sera was also analyzed from 259 other patients who had positive ANCA tests and were not tested for anti-GBM antibodies: 138 had MPO-ANCA (54%), and 121 had PR3-ANCA (46%). The relative frequencies of MPO or PR3-ANCA in patients with coexisting anti-GBM antibodies did not differ significantly from those in all patients with ANCA (P = 0.35). Seventeen sera with anti-GBM antibodies only and 16 sera with anti-GBM antibodies plus ANCA were selected for further studies to compare the specificity of anti-GBM antibodies in sera with or without ANCA. Using enzyme-linked immunosorbent assays (ELISA), all sera in both groups were found to react with the NC1 domain (as a hexamer) of bovine Type IV collagen and with alpha 3 (IV)NC1 monomers. Furthermore, all but six sera also reacted with one or more of the alpha 1, 2, and 4 (IV)NC1 monomers, generally with considerably lower titers. Reactivity to alpha 3(IV)NC1 was partially blocked by Mab17, with comparable degrees of inhibition in both groups. Western blot analysis with the human NC1 domains revealed no differences in reactivity between the two groups. Thus, differences in antigen specificities of anti-GBM antibodies in sera with or without ANCA were not detected. The anti-GBM response in both situations is hypothesized to be driven by the same immunogen, which is probably derived from NC1 domains of endogenous Type IV collagen.

The current status of neutrophil cytoplasmic antibodies.

Several studies in the past 10 years have demonstrated the occurrence of autoantibodies against cytoplasmic constituents in patients with vasculitis and glomerulonephritis. In this review the nomenclature of these antibodies is discussed and assays and clinical associations are summarized. Although the antigens involved are not completely identified, antibodies and T cells reactive with myeloid lysozomal enzymes may both play a significant role in pathogenesis.