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Allele frequencies of the four most common HLA-DPB1 alleles in newly recruited patients with Wegener's granulomatosis (WG) and controls. Only data from subjects that were not included in the study by Jagiello et al 11 are shown. Alleles (n = 15) with a minor allele frequency ,5.0% were joined into a single category and treated as one allele. The difference in the overall allele distribution between cases and controls is highly significant (n = 136, p = 1.12610 28 ). Allele *0401 was highly significantly over-represented in patients with WG (p = 1.34610 27 , p c = 6.7610 27 ; c = 5), while allele *0301 (p = 2.84610 25 , p c = 1.4610 24 ) and rare alleles (p = 2.37610 26 , p c = 1.2610 25 ) are much more common in the control group. The overall allele distribution difference was even more significant for the antineutrophil cytoplasmic antibody (ANCA)-positive patient group (n = 108; p = 5.88610 210 ), no significant allele distribution difference was found for the ANCA-negative cohort (n = 27; p = 0.84).
Source publication
A genomic region on chromosome 6p21.3, including HLA-DPB1, has been linked to Wegener's granulomatosis (WG). The basis of this association is difficult to evaluate because of the complex haplotype block architecture of this region.
To identify the causative molecular genetic variation(s) using a detailed HapMap based fine-mapping approach.
282 pati...
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Citations
... With respect to susceptibility to MPA and GPA, three genomewide association studies (GWAS) in European populations have been reported thus far (8)(9)(10). In GPA and PR3-AAV, the most striking association was identified in the HLA-DP region, which is consistent with a previously reported association of GPA with HLA-DPB1*04:01 in a German population (11). Additionally, PRTN3 and SERPINA1 genes, encoding PR3 and a1-antitrypsin, respectively, were identified as susceptibility genes (8,10). ...
Background
Disease relapse remains a major problem in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations, HLA-DPB1*04:01 is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association between HLA-DRB1*09:01 and DQB1*03:03 with susceptibility to, and DRB1*13:02 with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association of DQA1*03:02, which is in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, with MPO-AAV susceptibility was reported in a Chinese population. However, an association between these alleles and risk of relapse has not yet been reported. Here, we examined whether HLA-class II is associated with the risk of relapse in MPO-AAV.
Methods
First, the association of HLA-DQA1*03:02 with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reported DRB1*09:01 and DQB1*03:03 were examined in 440 Japanese patients and 779 healthy controls. Next, the association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies on remission induction therapy. Uncorrected P values (Puncorr) were corrected for multiple comparisons in each analysis using the false discovery rate method.
Results
The association of DQA1*03:02 with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: Puncorr=5.8x10⁻⁷, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40–2.16, MPA: Puncorr=1.1x10⁻⁵, OR 1.71, 95%CI 1.34–2.17). DQA1*03:02 was in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers of DRB1*09:01 (Puncorr=0.049, Q=0.42, hazard ratio [HR]:1.87), DQA1*03:02 (Puncorr=0.020, Q=0.22, HR:2.11) and DQB1*03:03 (Puncorr=0.043, Q=0.48, HR:1.91) than in non-carriers in the log-rank test. Conversely, serine carriers at position 13 of HLA-DRβ1 (HLA-DRβ1_13S), including DRB1*13:02 carriers, showed longer relapse-free survival with nominal significance (Puncorr=0.010, Q=0.42, HR:0.31). By combining DQA1*03:02 and HLA-DRβ1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (Puncorr=0.0055, Q=0.033, HR:4.02).
Conclusion
HLA-class II is associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population.
... The following paragraphs will present the main genetic findings in AAV, discussing separately GPA, MPA and EGPA, as these syndromes have been kept distinct in studies and show phenotypic but also genetic differences. Figure 4 reports the main genetic variants associated with AAV and the P values reflecting the strength of their association 63,66,[68][69][70][71][72][73][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92] . A more comprehensive overview of the genetic associations with AAV syndromes can be found in Supplementary Tables 1 and 2. ...
... Regarding GPA, several associations with classical HLA alleles were detected by candidate-gene association studies but only HLA-DPB1*0401 showed a consistent association across different populations. The implication of this allele in GPA susceptibility was first described in a cohort from northern Germany 62 and subsequently replicated in an independent cohort from a different German centre 83 . Furthermore, polymorphisms at the HLA-DPB1 locus showed the strongest signals in the GWASs performed in AAV [70][71][72] . ...
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), that share features of pauci-immune small-vessel vasculitis and the positivity of ANCA targeting proteinase-3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). AAV syndromes are rare, complex diseases and their aetio-pathogenesis is mainly driven by the interaction between environmental and genetic factors. In patients with GPA and MPA, the genetic associations are stronger with ANCA specificity (PR3- versus MPO-ANCA) than with the clinical diagnosis, which, in keeping with the known clinical and prognostic differences between PR3-ANCA-positive and MPO-ANCA-positive patients, supports an ANCA-based re-classification of these disorders. EGPA is also made up of genetically distinct subsets, which can be stratified on ANCA-status (MPO ANCA-positive versus ANCA-negative); these subsets differ in clinical phenotype and possibly in their response to treatment. Interestingly, MPO-ANCA-positive patients with either MPA or EGPA have overlapping genetic determinants, thus strengthening the concept that this EGPA subset is closely related to the other AAV syndromes. The genetics of AAV provides us with essential information to understand its varied phenotype. This Review discusses the main findings of genetic association studies in AAV, their pathogenic implications and their potential effect on classification, management and prognosis.
... Very low-resolution HLA typing through indirect serological assay (complement dependant micro-cytotoxicity) was also done to identify risk HLA alleles [48][49][50]. Candidate gene/loci association approach was mostly carried-out using conventional methods of genotyping including sequence-specific primer (SSP) or sequence-specific oligonucleotide (SSO), PCRbased restriction fragment length polymorphism (RFLP), TaqMan and Sanger sequencing [51][52][53][54][55][56][57][58][59][60]. Such hypothesis driven approach restricted the discovery of novel HLA and non-HLA risk variants, which was subsequently overcomed by the hypothesis free approaches such as genome-wide genotyping (association study) and high-resolution HLA typing through next generation sequencing (NGS). ...
... HLA-DPB1 has been found to be associated with inflammatory granuloma formation in GPA [54,55]. Significant association of HLA were reported for eGFR, creatinine and haemoglobin [51]. ...
... A German study identified rs35242582 (p = 1.60 × 10 -20 ; OR = 1.63) from HLA-DQA1, and rs1049072 (p = 1.40 × 10 -7 ; OR = 1.31) from HLA-DQB1 as significantly associated variants with GPA [53]. A serological study identified the association of predisposing HLA-DQw1 (p = 0.002) among Caucasians [55]. Notably, a slight reduction in classical allele DQB1*03:01 frequency was also observed in German GPA patients [56]. ...
Granulomatosis with polyangiitis (GPA) previously known as Wegener’s granulomatosis (WG) is a rare rheumatic disease affecting subjects of all ages. Prevalence and incidence of this systemic disease greatly varies across different ethnic groups. GPA is the commonest form of ANCA-associated vasculitis (AAV) with PR3 positivity among 85–95% of the cases. Scientific investigations of GPA is warranted because its severity, clinical heterogeneity, fast disease manifestation and end-organ damage. The etiology of GPA is still unknown. Major role of HLA and non-HLA genes with immune functions were identified, however, very limited replication was observed in different ethnic populations. In the present review, we have discussed the updates on the global epidemiology and contribution of HLA and major non-HLA genes/loci in GPA. We have also highlighted the cross disease association of GPA associated genes that may help in better disease management and predictive medicine. We proposed that high-resolution HLA typing and development of genetic risk model would help in early disease diagnosis and understanding the prognosis.
... All these GWAS studies were conducted in populations with European ancestry and have identified more than 20 genes associated with AAV. The findings of GWAS are listed in Tables 1 and 2. In addition, meta-analysis and fine mapping have also been used to identify new gene variations and analyze the effect of the variants (17)(18)(19)(20)(21). ...
... In another study with 150 GPA patients and 100 healthy controls conducted in northern Germany, HLA-DPB1*0401 was identified to be associated with GPA (P = 1.51 × 10 -10 , OR = 3.91), and DPB1*0401/ RXRB03 haplotype frequency was significantly increased in patients with GPA (P = 7.13 × 10 -17 , OR = 6.41) (18). The result was replicated in an independent German cohort with 108 patients with GPA (P = 6.4 × 10 -8 ) (20). HLA-DPB1 was also considered a genetic risk factor for GPA in a cohort of 176 Han Chinese patients with AAV (100 with GPA, 76 with MPA) and 485 healthy controls (P = 1.83 × 10 -5 , OR = 2.57). ...
... RING is a member of the polycomb repressive complex 1 that mediates histone H2A polyubiquitination and monoubiquitination, regulating its gene expression. Three SNPs in the region near RING1 (rs213210, rs213209, and rs213208) were found to be associated with GPA in German patients (20). The HLA-DPB1/ RING1 haplotype is strongly associated with GPA in ANCApositive subjects. ...
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by the inflammation of small and medium vessels and presence of proteinase 3-ANCA or myeloperoxidase-ANCA in the circulation. AAV comprises three clinical subtypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA). Although the pathogenesis of AAV is still unclear, genetic and environmental factors and the immune system are thought to be involved. Genetic factors have been confirmed to play an important role in AAV. Genome-wide association studies have identified numerous genetic variants in MHC and non-MHC regions associated with AAV. The strongest evidence of MHC association in AAV is human leukocyte antigen (HLA)-DP. A significant association between AAV and genetic variations in non-MHC regions, such as CTLA-4, FCGR2A, PTPN22, SERPINA1, and TLR9 has also been found. Moreover, different clinical subtypes of AAV have distinct genetic backgrounds. GPA is associated with HLA-DP1, MPA with HLA-DQ, and EGPA with HLA-DRB4. These findings could help elucidate the etiology of AAV and develop new biomarkers for diagnosis and targeted therapy. Herein, we briefly summarize the updates on the genetic pathogenesis and biomarkers of AAV.
... It is reported that almost 50% of Japanese patients with microscopic polyangiitis (MPA) have HLA-DRB1 Ã 09:01 allele, which is significantly higher than that of a healthy control group [6]. Significantly high frequencies of DPB1 Ã 04:01 allele, a known risk allele for granulomatosis with polyangiitis (GPA)/proteinase3 (PR3) -ANCA patients [7] have also been documented in European populations. ...
We report two cases of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) that developed after long-term oral administration of minocycline and consider the contribution of human leukocyte antigen (HLA)-DRB 1 * 09: 01 allele to its development. Case 1; A 47-year-old man receiving minocycline for palmoplantar pustulosis for 24 months developed fever, arthralgia, and irregular livedo on the bilateral lower legs. Skin biopsy demonstrated vasculitis, while a blood test showed positivity of myeloperoxidase (MPO)-ANCA. Discontinuation of minocycline and oral administration of prednisolone relieved the symptoms promptly. Case 2; A 53-year-old woman developed reddish-brown livedo reticularis with tenderness on the bilateral lower legs after administration of minocycline to treat palmoplantar pustulosis for 24 months. Although skin biopsy did not demonstrate vasculitis, a blood test showed MPO-ANCA positivity. Cessation of minocycline resulted in rapid improvement of the cutaneous lesions and constitutional symptoms. We diagnosed both cases as having Drug-associated ANCA-associated Vasculitis (DAV) caused by minocycline according to the diagnostic criteria proposed by Cluver et al. Further examination revealed the presence of HLA-DRB1*09:01 allele in both cases. This allele has been implicated in the genetic background of idiopathic microscopic polyangiitis (MPA) in the Japanese population. Our finding suggests a relationship between the development of MPO-ANCA or DAV caused by minocycline and HLA-DRB1*09:01 allele, but will have to confirmed by further studies with larger numbers of patients.
... It has been shown that presence of HLA DRB1*09:01 allele is associated with myeloperoxidase (MPO)-ANCA associated AAV in Japanese population, while HLA DPB1*04:01 allele was associated with PR3-ANCA GPA in European population. 24,25 Among an Indian cohort of GPA patients, those with active disease had higher levels of serum interleukin (IL)-17 and these levels decreased with induction of remission. Regulatory T cell numbers were found to be normal but their function was compromised. ...
The incidence and clinical features of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) have been shown to vary according to geographical areas, with granulomatosis with polyangiitis (GPA) being more common in northern Europe and microscopic polyangiitis (MPA) being more common in Asian countries. The annual incidence of GPA among Asians varies between 0.37/million to 2.1/million population. The prevalence of GPA has been estimated to be 1.94/100 000 in a Chinese population. Polymorphisms in class II major histocompatibility genes and ETS1 proto‐oncogene has been shown in Asian patients with GPA. There is a difference in mean age at onset and proteinase 3 (PR3) or myeloperoxidase (MPO) positivity in GPA patients from different Asian countries. Those from India had mean age of 40 years and those from Japan had mean age of 65 years. Sixty percent of GPA patients from China and Japan were MPO ANCA positive while the majority of patients from India and Korea were PR3 positive. Geographical variation with lower frequency of renal involvement in Indian studies and higher frequency in Chinese patients has also been noted. Treatment outcomes have been similar to those reported from other parts of the world. Remission was achieved in about two‐thirds of patients while relapses were noted in one‐third to half of the patients. Apart from minor differences in the organ systems involved, MPO‐ANCA GPA and PR3‐ANCA GPA had similar rates of remission and relapses.
... Among AAV, GPA displays a remarkable HLA-DP association (p = 6.2 × 10 −89 ) (41). The HLA-DPB1*0401 allele is closely linked to PR3-ANCA + GPA (p = 1.2 × 10 −22 ) (42,43). Reduced HLA-DP protein expression is observed in GPA patients with the associated HLA-DP allele (44). ...
Anti-neutrophil cytoplasmic autoantibodies (ANCA) targeting proteinase 3 (PR3) and myeloperoxidase expressed by innate immune cells (neutrophils and monocytes) are salient diagnostic and pathogenic features of small vessel vasculitis, comprising granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and eosinophilic GPA. Genetic studies suggest that ANCA-associated vasculitides (AAV) constitute separate diseases, which share common immunological and pathological features, but are otherwise heterogeneous. The successful therapeutic use of anti-CD20 antibodies emphasizes the prominent role of ANCA and possibly other autoantibodies in the pathogenesis of AAV. However, to elucidate causal effects in AAV, a better understanding of the complex interplay leading to the emergence of B lymphocytes that produce pathogenic ANCA remains a challenge. Different scenarios seem possible; e.g., the break of tolerance induced by a shift from non-pathogenic toward pathogenic autoantigen epitopes in inflamed tissue. This review gives a brief overview on current knowledge about genetic and epigenetic factors, barrier dysfunction and chronic non-resolving inflammation, necro-inflammatory auto-amplification of cellular death and inflammation, altered autoantigen presentation, alternative complement pathway activation, alterations within peripheral and inflamed tissue-residing T- and B-cell populations, ectopic lymphoid tissue neoformation, the characterization of PR3-specific T-cells, properties of ANCA, links between autoimmune disease and infection-triggered pathology, and animal models in AAV.
... On the other hand, protective association of DRB1 Ã 13 has been detected for GPA in Germany [4] and in the Netherlands [5]. Subsequently, association of DPB1 Ã 04:01 with GPA has been reported in a moderately powered study in Germany [6]. ...
... Additionally, in the North American study (in which only GPA was studied), the strongest association was observed in the HLA-DP region. Using imputation, the investigators demonstrated that DPB1 Ã 04 is a risk allele group for GPA [8], supporting the results of a previous study in Germany [6]. ...
... With regards to DPB1, the present study suggested the possibility that the DPB1 Ã 04:01 allele may be associated with PR3-AAV in the Japanese population, as in Caucasian populations [6,8]. In contrast, DPB1 Ã 04:01 was protective against MPO-AAV, although this protection was a secondary effect caused by LD with DRB1 Ã 13:02. ...
Among antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), granulomatosis with polyangiitis (GPA) and proteinase 3-ANCA-positive AAV (PR3-AAV) are prevalent in European populations, while microscopic polyangiitis (MPA) and myeloperoxidase-ANCA-positive AAV (MPO-AAV) are predominant in the Japanese. We previously demonstrated association of DRB1*09:01-DQB1*03:03 haplotype, a haplotype common in East Asians but rare in the European populations, with MPA/MPO-AAV, suggesting that a population difference in HLA-class II plays a role in the epidemiology of this disease. To gain further insights, we increased the sample size and performed an extended association study of DRB1 and DPB1 with AAV subsets in 468 Japanese patients with AAV classified according to the European Medicines Agency algorithm (MPA: 285, GPA: 92, eosinophilic GPA [EGPA]: 56, unclassifiable: 35) and 596 healthy controls. Among these patients, 377 were positive for MPO-ANCA and 62 for PR3-ANCA. The significance level was set at α = 3.3x10-4 by applying Bonferroni correction. The association of DRB1*09:01 with MPO-AAV was confirmed (allele model, P = 2.1x10-4, odds ratio [OR] = 1.57). Protective association of DRB1*13:02 was detected against MPO-AAV (allele model, P = 2.3x10-5, OR = 0.42) and MPA (dominant model, P = 2.7x10-4, OR = 0.43). A trend toward increased frequency of DPB1*04:01, the risk allele for GPA in European populations, was observed among Japanese patients with PR3-AAV when conditioned on DRB1*13:02 (Padjusted = 0.0021, ORadjusted = 3.48). In contrast, the frequency of DPB1*04:01 was decreased among Japanese patients with MPO-AAV, and this effect lost significance when conditioned on DRB1*13:02 (Padjusted = 0.16), suggesting that DRB1*13:02 or other allele(s) in linkage disequilibrium may be responsible for the protection. The differential association of DPB1*04:01 with PR3-AAV and MPO-AAV and difference in DPB1*04:01 allele frequencies between populations supported the hypothesis that the HLA-class II population difference may account in part for these epidemiologic characteristics. Furthermore, taken together with our previous observations, the haplotype carrying DRB1*13:02 was suggested to be a shared protective factor against multiple autoimmune diseases.
... An important finding that could be replicated in several patient cohorts, however, was the presence of certain HLA-DPB1 alleles on chromosome 6 (8)(9)(10)(11)(12). The HLA-DPB1 region was found to be significantly associated with PR3-AAV as compared to MPO-AAV patients (while the latter was associated with the HLA-DQ region). ...
... Genotyping DNA was prepared from buffy coats or from whole blood. Seventeen different HLA-DPB1 alleles were determined as previously described (11,23). All material was analyzed in Bochum, Germany, blinded from clinical data. ...
... More specifically, patients with PR3-ANCA positive vasculitis were shown to carry certain tagSNPs in the HLA-DPB1 region on chromosome 6p21 more often than healthy controls and MPO-ANCA positive patients (10,11). We confirmed the HLA-DPB1 allele distribution in AAV patients from two independent cohorts, using a more direct genotyping approach rather than the tagSNP method used in the GWAS (10). ...
Objective:
The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) form a group of small-vessel vasculitides with systemic involvement. Although the etiology of AAVs remains largely unknown, both genetic and environmental factors have been implicated. Recently, certain alleles in the HLA-DPB1 region on chromosome 6 were shown to be associated with proteinase 3 (PR3)-ANCA-positive AAV but not with myeloperoxidase (MPO)-ANCA-positive AAV. The aim of this study was to investigate whether different alleles in the HLA-DPB1 region have clinical and/or prognostic implications in AAV.
Methods:
One hundred seventy-four patients with a diagnosis of AAV were recruited at the Maastricht University Medical Centre between 2000 and 2009. Seventeen different HLA-DPB1 alleles were determined using the restriction fragment length polymorphism technique. A validation cohort of 170 AAV patients from the Vasculitis Centre of Luebeck/Bad Bramstedt was included.
Results:
In the initial cohort, the distribution of HLA-DPB1 alleles was significantly different between PR3-ANCA-positive compared with MPO-ANCA-positive AAV patients, ANCA-negative AAV patients, and healthy controls. Importantly, HLA-DPB1*04:01 was present in 90% of PR3-ANCA-positive AAV patients compared with 63% of MPO-ANCA-positive AAV patients, 58% of ANCA-negative patients, and 63% of healthy controls. Patients homozygous for HLA-DPB1*04:01 had relapses more often compared with heterozygous patients and noncarrier patients. This association persisted after correction for ANCA subtype and diagnosis. In the validation cohort, patients homozygous for HLA-DPB1*04:01 and those heterozygous for HLA-DPB1*04:01 had relapses more often compared with noncarrier patients. When both patient cohorts were merged (n = 344), homozygous patients relapsed most often, followed by heterozygous patients and noncarrier patients.
Conclusion:
Carriage of HLA-DPB1*04:01 in patients with AAV is significantly associated with an increased risk of relapse compared with HLA-DPB1*04:01-negative patients, irrespective of ANCA status or clinical AAV entity.
... Typically, most autoimmune diseases are attributed to a genetic predisposition combined with exposure to an inciting factor. Genotypic associations in GPA include the following: 4,5,6,7,8,9,10 Carrying a defective allele for alpha-1 antitrypsin, possessing certain polymorphisms of CTLA-4 (cytotoxic T-lymphocyte antigen-4) which is involved in T-cell activation, Possessing the PTPN22*620W allele, which is typically associated with a positive ANCA status and is also associated with T-cell activation, Carrying the DPB1*0401 allele, which is also associated with chronic beryllium disease, a granulomatous disease, Exhibiting certain forms of the Fcγ receptor IIIb on the surface of neutrophils and monocytes/macrophages. According to literature, the lungs are affected in 90 percents of patients 11 . ...
Wegener’s granulomatosis is an uncommon autoimmue disease with multi-system involvement, characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tracts and general focal necrotizing vasculitis (Commonly known as Wegener’s triad). The lungs are involved in 72 percents of patients and the clinical and radiographic findings indicate bilateral pulmonary nodules of varying size and definition, cavitated in half of the patients, accompanied by the nodular lesion with rare involvement of the pleura.
We present a case in 4 year old male child presenting with symptoms of recurrent airway disease and chronic sinusitis with detection of lung lesions on further investigations and pathological confirmation by antineutrophil cytoplasmic antibody positivity and based on radiological and clinical suspicion.
