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Spectrum of Anti-Neutrophil Cytoplasmic Antibodies In 283 284 INDIAN JOURNAL OF MEDICAL SCIENCES SPECTRUM OF ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODIES IN The role of neutrophils in the pathophysiology The purpose of this study was to determine the PATIENTS WITH PULMONARY TUBERCULOSIS OVERLAPS WITH of TB seems minor as compared to prevalence of various ANCAs, their specificities THAT OF WEGENER’S GRANULOMATOSIS macrophages and remains uncertain but and as it is known that there are some earlier reports have suggested that similarities between TB and ANCA associated VANDANA D. PRADHAN, SURESH S. BADAKERE, KANJAKSHA GHOSH, ARUNA R. PAWAR mycobacterial infections may play a role in the vasculitis (AAV) i.e. pulmonary infiltrate, pathogenesis of autoimmune disorders.3 haemoptysis, systemic symptoms etc. ABSTRACT Prevalence of other autoantibodies such as Anti-neutrophil cytoplasmic antibodies (ANCA) ANA, anti-dsDNA and AHA were also noted in BACKGROUND AND OBJECTIVES: Mycobacterial infections are known to induce the are known to be highly diagnostic for ‘pauci- these patients. development of autoantibodies and a few of these antibodies are also known to be diagnostic markers for some other diseases and it is uncertain whether these immune’ small vessel vasculitis associated autoantibodies play a role in the pathogenesis of autoimmune disorders. This study disorders like Wegener’s granulomatosis (WG), MATERIAL AND METHODS was undertaken to determine the prevalence of autoantibodies like anti-neutrophil Microscopic polyangitiis (MPA) and Churg cytoplasmic antibodies (ANCA), anti-nuclear antibodies (ANA), anti-double stranded Strauss Syndrome (CSS). There are two main In this study 70 consecutive pulmonary TB antibodies (anti-dsDNA) and anti-histone antibodies (AHA)in pulmonary Tuberculosis. ANCA target antigens in these disorders patients along with 100 age and sex matched MATERIALS & METHODS: Seventy consecutive pulmonary TB patients, 30 patients of namely, Myeloperoxidase (MPO) and healthy normal individuals were included. Sera interstitial lung disease and 100 normal individuals were studied. ANCA and ANA were Proteinase3 (PR3), which have diagnostic of all 70 hospitalized patients were collected detected by indirect immunofluorescence test (IIF). Anti-dsDNA and AHA were tested utility, though other cytoplasmic antigens like from a local TB hospital over a period of four by ELISA. RESULTS: ANCA was detected in 30% cases, and of these 52.4% showed Lactoferrin (LF), Cathepsin G (CG), Elastase months. Patients below 18 years of age and perinuclear pattern (p-ANCA), 38.1% cytoplasmic (c-ANCA) and 9.5% showed an and Azurocidin are being investigated as pregnant women were excluded from the study. ‘atypical’ pattern. ANCA specificities by ELISA revealed that, 47.6% had anti- possible targets for antibody mediated tissue All the patients with pulmonary TB had Myeloperoxidase (anti-MPO), 28.6% had anti-Proteinase3 (anti-PR3) and 19.1% had anti-Lactoferrin (anti-LF) antibodies. ANA and AHA were present in 24.3% and 21.4% destruction leading to vasculitis. Indirect pulmonary infiltrate on X ray chest, AFB cases respectively whereas anti-ds DNA antibodies were absent. Normal controls immunofluorescence test (IIF) is a good positivity in sputum or gastric aspirate and all showed 4% and 2% positivity for ANA and ANCA whereas disease control group of screening assay for identifying ANCA positivity of them presented with haemoptysis, 47/70 ILD showed 7% of ANA and ANCA posititivy. CONCLUSION: The presence of while enzyme linked immunosorbent assays also had low grade fever with anorexia. autoantibodies in TB patients could have a multifactorial etiology. Clinically relevant (ELISAs) are used for identifying specificity.4,5 Mantoux test was positive in all. Thirty patients is the presence of anti-PR3 antibodies. This finding along with pulmonary and renal with interstitial lung disease (ILD) were also manifestations could lead to a false diagnosis of Wegener’s granulomatosis or vice It is also found that mycobacterial infections taken as disease controls. In India TB is often versa because these autoantibodies may be present in both diseases. are associated with induction of diagnosed on the basis of interstitial shadow autoantibodies.6 Tuberculosis is also known to on X ray chest coupled with low grade fever, KEY WORDS: Tuberculosis, autoantibodies, anti-neutrophil cytoplasmic antibodies, anti- be associated with vasculitis in a subset of cough, anorexia and raised erythrocyte nuclear antibodies, Indirect immunofluorescence test, Enzyme linked immunosorbent patients. It is not very well known whether that sedimentation rate (ESR). ILD was confirmed assay vasculitis (endarteritis) is also driven by certain by combination of pulmonary function test autoantibodies like ANCA. There is paucity of including DLCo, bronchoscopy and literature in the incidence and patterns of bronchoalveolar lavage (BAL), high resolution Institute of Immunohaematology, Indian Council of Tuberculosis (TB) is an infectious disease ANCA in florid cases of pulmonary spiral CT scan and consecutive three negative Medical Research, 13th floor, K.E.M. Hospital, Parel, caused by Mycobacterium tuberculosis and is tuberculosis. In addition pulmonary infiltration sputum test for acid fast bacilli (AFB) and Mumbai - 400 012. India. a scourge in the developing countries. TB is associated with haemoptysis in pulmonary negative BAL for AFB stain. As HIV infection Correspondence: Dr. S. S. Badakere, Deputy Director, S. G, Institute of also prevalent in the black population of South tuberculosis may be mistaken as Wegener’s is not an uncommon associate of TB in our Immunohaematology, Indian Council of Medical Research, Africa.1 In India, a high prevalence of TB is due granulomatosis in non endemic areas if it is country all the patients were tested for HIV 13th floor, K.E.M. Hospital, Parel, Mumbai - 400 012. E-mail: [email protected] to the low socioeconomic levels and poverty.2 associated with high levels of ANCA positivity. after proper counseling and HIV positive Indian J Med Sci Vol. 58 No. 7, July 2004 Indian J Med Sci Vol. 58 No. 7, July 2004 ANCA IN TUBERCULOSIS 285 286 INDIAN JOURNAL OF MEDICAL SCIENCES patients were excluded. This prospective study at 1:20 dilution of test serum, using HEp-2 Table 1: Demographic characteristics and specificity by ELISA showed presence of anti- was carried out after obtaining the requisite cells obtained from Entero Virus Research autoantibody profile in study groups. MPO antibodies in 10/21 patients (47.6%), Ethics committee permission and informed Centre, Indian Council of Medical Research, Characteristics TB patients ILD patients Normal anti-PR3 antibodies in 6/21 patients (28.6%) consents from patients. Patients’ selection bias Mumbai and cells were maintained in a controls and anti-LF antibodies in 4/21 patients was avoided by selecting cases only after continuous culture and harvested at log phase Number tested 70 30 100 (19.1%). All the sera positive by ELISA were Age in years: diagnosed by clinicians and the blinding was of growth. The results were interpreted in terms Mean + SD 32.8 + 11.6 28.4 + 10.2 30.5 + 12.2 also positive in IIF test and a good correlation achieved as they were unaware of the of titers i.e, test sera showing Range 18 - 63 18 - 58 20 - 55 was found between IIF titers and ELISA values. Sex: laboratory findings. immunofluorescence at its highest dilution. Males 43 18 30 It was seen that out of 11 patients that showed Anti-dsDNAantibodies12 and anti-histone Females 27 12 20 p-ANCA pattern on IIF where the titers varied ANCA were detected using human neutrophils antibodies (AHA) were detected by ELISA.13 M : F Ratio 1.6 : 1 1.5 : 1 1.5 : 1 between 1: 40- 1: 160 , 10 patients had anti- Autoantibodies tested: (PMN) by IIF technique which is considered as ANCA 21 (30%) 2 (7%) 2 (2%) MPO antibodies having ELISA values ranging a ‘gold standard’ for ANCA screening. Briefly, To study the association between TB cases ANA 17 (24.3%) 2 (7%) 4 (4%) between 10-30 u/ml. Of the 8 patients that AHA 15 (21.4%) 0 4 (4%) the method is as follows. PMN were used to and the probability of having ANCA positivity, showed c-ANCA IIF pattern with 1: 40 to 1: 320 * Anti-dsDNA antibodies were absent in these patients prepare a cytospun substrate using Hettich Odd’s ratio (OR) was used. ANCA serology by titer values, 6 patients had anti-PR3 antibodies M: F Ratio – Male : Female ratio Universal 16A cytocentrifuge and some slides IIF and ELISA in TB patients were statistically SD - Standard Deviation where ELISA values varied between 8 to 25 were fixed with 96% ethanol and others with correlated with ILD patients and the normal u/ml. Both the patients that showed ‘atypical’ 0.45% formalin. After reacting with patient’s healthy controls. Statistical significance was Table 2 shows the statistical details of or X-ANCA had anti-LF antibodies. The IIF sera at 1:20 dilution, the slides were probed tested by Pearson’s ‘X2 test’ with Yate’s association between TB and the probability of patterns of ANCA positivity were compared using FITC tagged polyvalent anti-human correction and calculation of the 95% ANCA positivity. ANCA studies revealed a total with that of Wegener’s granulomatosis patients globulin serum and observed under a confidence intervals. A ‘ p value’ less than 0.05 incidence of 30% positivity among TB patients reported in the literature4,5 and from our own fluorescent microscope, Nikon, Optiphot II, was considered statistically significant. studied (21/70). Of these 11 patients (52.4%) cases.18 Japan. Microphotography was also done using showed perinuclear (p-ANCA) an automated photography system, Nikon AFX RESULTS immunofluorescence pattern and 8 patients The overall incidence of ANA was 24.3% II A, Japan. The slides were also examined (38.1%) showed a cytoplasmic (c-ANCA) where 17/70 patients had ANA and AHA were using a Confocal Laser Scanning Microscope, In this study 70 patients of pulmonary pattern and two patients (9.5%) showed an found in 15/70 patients(21.4%).
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