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Detection of Anti-Neutrophil Antibodies in Autoimmune Neutropenia of Infancy

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Detection of Anti-Neutrophil Antibodies in Autoimmune Neutropenia of Infancy IMAJ • VOL 12 • FEBRUARY 2010 ORIGINAL ARTICLES Detection of Anti-Neutrophil Antibodies in Autoimmune Neutropenia of Infancy: A Multicenter Study Ruti Sella BA1*, Lena Flomenblit MSc4, Itamar Goldstein MD3,4** and Chaim Kaplinsky MD2** 1Rappaport Faculty of Medicine, Technion-Israel institute of Technology, Haifa, Israel. 2Department of Pediatric Hematology Oncology, Safra Children's Hospital, 3Cancer Research Center, and 4Hematology Laboratory, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Israel he causes of neutropenias in infancy and childhood ABSTRACT: Background: Autoimmune neutropenia of infancy is caused T are traditionally classified as a) severe chronic, which by neutrophil-specific autoantibodies. Primary AIN is includes congenital syndromes; b) cyclical and idiopathic characterized by neutrophil count < 500 ml and a benign self- neutropenias; c) acquired or secondary, resulting from drugs, limiting course. Detecting specific antibodies against the iatrogenic insults (e.g., radiation), or infections; d) primary polymorphic human neutrophil antigen usually confirms the hematological disorders; and e) immunological diseases, such diagnosis. Current available tests, however, are expensive as autoimmune neutropenia [1]. and inapplicable in many laboratories as they require the Primary autoimmune neutropenia results from periph- use of isolated and fixed granulocytes obtained from donors eral destruction of granulocytes by specific anti-neutrophil pretyped for their distinct HNA alloform. autoantibodies in the patient's blood. The origin of these Objectives: To assess the performance of a modified test to antibodies remains unknown; it is widely accepted, however, identify by FACS-analysis granulocyte-specific antibodies in the sera of neutropenic children. that the mechanism involves molecular mimicry of microbial Methods: We evaluated 120 children with a clinical suspicion antigens. It has also been hypothesized that the antibodies are of AIN, whose sera were analyzed by flow cytometry for the formed as a result of modification of endogenous antigens presence of autoantibodies using the indirect granulocyte due to drug exposure, abnormal human leukocyte antigen immunofluorescence test. In contrast to the traditional tests, expression, or loss of suppressor activity against lymphocyte the sera were tested against randomly selected untyped clones that are self-reactive [2]. neutrophils derived from a batch of 10 anonymous healthy AIN is most often seen in children, with greater prevalence subjects, presumably including the common HNA alloforms. among females (female to male ratio 6:4). Its precise prevalence Control sera samples were from patients with chemotherapy- is unknown, and is usually cited as 1:100,000 in children from induced, familial or congenital neutropenias. To further infancy to 10 years of age [3]. The prevalence may be higher, assure the quality of the new test, we retested six samples however, as many cases remain undiagnosed due to the benign previously tested by the gold standard method. All medical course of the disease [4]. The disease is most prevalent among files were screened and clinical outcomes were recorded. infants aged 5–15 months and is usually characterized by Results: Our method showed specificity of85 %, sensitivity of severe neutropenia with an absolute neutrophil count < 500 ml 62.5%, and a positive predictive value of 91.8%, values quite and only minor intercurrent infections. The remission is spon- similar to those obtained by more traditional methods. taneous and resolution occurs in 95% of patients within 7–24 Conclusions: The new method showed high specificity for months [4]. When the clinical suspicion cannot establish the detection of anti-neutrophil antibodies in the appropriate diagnosis, detection of specific anti-neutrophil autoantibodies clinical setting and could be an effective tool for clinical can verify it, obviating the need for bone marrow aspiration decision making. and biopsy that are sometimes indicated to rule out chronic IMAJ 2010; 12: 91–96 neutropenias of different etiologies [2]. KEY WORDS: autoimmune neutropenia, anti-neutrophil antibodies, Many methods to detect granulocyte-specific autoantibod- human neutrophil antigen, indirect granulocyte ies exist, but accurate information regarding their sensitivity immunofluorescence test and specificity is lacking [5-14]. Nevertheless, AIN is more often diagnosed today as the credibility and accessibility of * This study was performed in partial fulfillment of the MD thesis these tests are gradually improving [15]. requirements of the Rappaport Faculty of Medicine, Technion-Israel institute of Technology, Haifa, Israel. AIN = autoimmune neutropenia of infancy ** These authors contributed equally to this manuscript HNA = human neutrophil antigen 91 ORIGINAL ARTICLES IMAJ • VOL 12 • FEBRUARY 2010 The methods in use today include the granulocyte direct mance our test was comparable to more traditional methods immunofluorescence test, the granulocyte indirect immu- to detect anti-neutrophil antibodies. nofluorescence test, the granulocyte agglutination test, the enzyme-linked immunosorbent assay, and monoclonal anti- body-specific immobilization of granulocyte antigens [16]. PATIENTS AND METHODS In the indirect immunofluorescence test, the patient's serum In this multicenter cohort study conducted during the period is incubated with normal neutrophils and the autoantibodies 2006–2009, we evaluated 120 patients ranging in age from a are later detected using fluorophore-conjugated secondary few days old to 10 years. These patients presented to the emerg- anti-human immunoglobulin antibodies. As summarized at ency room or to the physician's clinic with signs of infection the Second International Granulocyte Serology Workshop, and were later diagnosed as neutropenic (ANC < 1500/µl), the combination of several diagnostic techniques for gran- or were asymptomatic and diagnosed as neutropenic during ulocyte-specific autoantibodies detection, and especially the a routine blood count. In all cases a high clinical suspicion GIFT and GAT, is most beneficial today for the diagnosis of of AIN was the rule. AIN [15,17]. A blood sample for the anti-neutrophil antibodies test In all the aforementioned methods the detection of was obtained together with the initial laboratory evalua- autoantibodies is complex, because the antibodies are pres- tion for children presenting with fever and/or neutropenia; ent in low titers and bind to their target antigens with low therefore, no venepuncture was needed. Serum was separated avidity. Sometimes it is necessary to test a sample time and from 1–2 ml of blood and immediately frozen at -200C. The again before the presence of the autoantibodies in the serum Institutional Ethics Committee at the Sheba Medical Center can be reliably detected [2,8,18]. approved the study. The specificity of the antibodies to their target neutrophil Patients with ANC > 1500/µl at presentation, age older antigens has been extensively investigated. We know today than 10 years, a probable alternative clinical diagnosis, and that in most patients antibodies to the polymorphic human patients who were lost to follow-up or had inadequate data neutrophil antigen system can be found on the Fcγ receptor were excluded. type IIIb (FcRIIIb, CD16b) expressed only on neutrophils Twenty-seven sera samples from patients with chemo- [6]. The gene frequency found in the white population is ~ therapy-induced, familial or congenital neutropenias were 33% for NA1 and ~ 66% for NA2 [19]. The methods cur- gathered and used as controls. In the latter patients no anti- rently available for the detection of autoantibodies necessitate bodies were expected, and hence positive antibody results purified and fixed granulocytes with a known HNA alloform were defined as false positive. as typed by anti-NA1 or NA2-specific monoclonal antibod- In order to verify the results and reassure the quality of ies. Such techniques are both expensive and inapplicable in our method, we reassessed six samples, previously tested in many laboratories. Since previous trials in Israel to establish Germany using a combination of the direct GIFT and GAT a credible and reliable method to detect antibodies using methods. All medical files were later screened and clinical GIIFT/fluorescence-activated cell sorting-based methods outcome recorded. failed, blood samples are still being sent to a laboratory in Germany, where they are tested using the combination of the STATISTICAL ANALYSIS GIFT and GAT, at considerable expense. A more efficient, We used the efficient-score method (corrected for continu- cost-beneficial method is therefore needed. ity), described by Robert Newcombe, for the calculation of Since the clinical significance of identifying the specific our test performance and 95% confidence interval. We used target antigen has not been proven, we used a modified Pearson's chi-square to evaluate the ANC and the time to GIIFT method to detect the presence of autoantibodies. Thus, recovery from neutropenia in patients with different antibody tested sera were reacted against untyped neutrophils obtained test results. P values < 0.05 were considered significant. by premixing 10 blood samples from randomly selected anonymous healthy subjects. Our working hypothesis was DETECTION OF ANTI-NEUTROphIL ANTIBODIES USING THE INDIRECT that by using a donor mix the cells would very likely contain GIFT METHOD neutrophils expressing
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