Evidence for the association of unexplained pulmonary hypertension in children with the major histocompatibility complex.

Barst, Robyn J.; Flaster, Edith; Menon, A.; Fotino, M; Morse, Jane H.

doi:10.1161/01.cir.85.1.249

Cited by 44 publications

(28 citation statements)

References 36 publications

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“…However, there are observations suggesting that PPH may have an inflammatory component, which include the following: 1) in the lungs of patients an abnormal production of several cytokines, including RANTES, was demonstrated [10]; 2) PPH is known to associate with conditions that have significant immune deregulation, such as autoimmune diseases (systemic lupus erythematosus, scleroderma, rheumatoid arthritis, dermatomyositis, mixed connective tissue disease) or human immunodeficiency virus (HIV) infection; 3) in a significant percentage of PPH patients, including those without any associated diseases, antinuclear antibodies and/or the Raynauld phenomenon are found [11]; and 4) an increased frequency of HLA class II antigens DR3 [12] and DQ7 [11] have been reported among PPH patients, further suggesting that immune deregulation plays a role in the pathogenesis of the disorder.…”

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confidence: 99%

Fatal primary pulmonary hypertension in a 30‐yr-old female with APECED syndrome

Korniszewski

Kurzyna²,

Stolarski³

et al. 2003

Eur Respir J

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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the autoimmune regulator (AIRE) gene, which has a central function in maintaining immunological tolerance. A number of conditions with proven or likely autoimmune pathogenesis occur in APECED: hypoparathyroidism, adrenocortical insufficency, candidiasis, hypogonadism, type 1 diabetes, hypothyroidism, hypophysitis, hepatitis, malabsorption, nail dystrophy, enamel hypoplasia and keratopathy. It is not clear which factors are responsible for variation in clinical picture of APECED, but human leukocyte antigen (HLA) genotype may be important.The authors report the first description of a case of primary pulmonary hypertension (PPH) in patient with APECED, caused by R257X mutation in AIRE. The HLA genotype of the patient (DRB1*01/DRB1*11, DQB1*0301/DQB1*0501) has been previously reported as a predisposing factor to PPH.The findings from this study, provided that other similar cases are reported, suggest that immune deregulation plays a role in the pathogenesis of primary pulmonary hypertension. Autoimmune polyglandular syndrome type I, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; OMIM 240300), is an autosomal recessive disorder caused by mutations causing loss of function of the autoimmune regulator (AIRE) protein [1]. The AIRE protein is a transcriptional regulator expressed mainly in the thymus and plays a central role in the development and maintenance of immunological tolerance by promoting the ectopic expression of peripheral tissue-restricted antigens in medullary epithelial cells of the thymus [2]. The lack of AIRE results in a number of manifestations with proven or likely autoimmune pathogenesis, of which the most common are hypoparathyroidism, primary adrenocortical insufficency and candidiasis, whereas hypogonadism, insulin-dependent diabetes mellitus, hypothyroidism, hypophysitis, hepatitis, malabsorption, nail dystrophy, enamel hypoplasia and keratopathy, occur less frequently [3]. It is not clear which factors are responsible for the variation in the clinical picture of APECED. The human leukocyte antigen (HLA) genotype may be important, since it was observed that autoimmune conditions in the APECED cohort showed HLA associations that were similar to those found in non-APECED patients with respective autoimmune disorders [4].Primary pulmonary hypertension (PPH) is a disorder characterised by lesions of pulmonary arterioles, which increase vascular resistance and lead to elevated pulmonary arterial pressure. The pathogenesis of PPH is not clear but recently it has been put in a novel perspective by the demonstration of mutations in BMPR-II (bone morphogenic protein receptor II) in a proportion of patients [5][6][7]. BMPR-II is a ubiquitously expressed receptor for a group of growth factors belonging to the transforming growth factor beta superfamily [7,8]. Conversely, since the majority of mutations in BMPR-II were found in familial cases of PPH, it is not cl...

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confidence: 99%

Fatal primary pulmonary hypertension in a 30‐yr-old female with APECED syndrome

Korniszewski

Kurzyna²,

Stolarski³

et al. 2003

Eur Respir J

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“…In accordance with this hypothesis, HLA analyses had been done in patients with primary pulmonary hypertension, and it was reported that certain types of HLA antigens or HLA alleles, such as HLA-B35, -DR3, -DR6, -DR52, -DQ2 and -DQ7, were associated with the disease in Caucasoid populations. [14][15][16][17][18] On the other hand, we reported significant associations of CTEPH with HLA-DPB1*0202 and B*5201 in the Japanese. 19 These observations suggest that HLA-linked gene(s) may control the susceptibility to CTEPH.…”

Section: Introductionmentioning

confidence: 51%

“…19 In addition, we showed that the CTEPH patients carrying HLA-B*5201 or HLA-DPB1*0202 had a low prevalence of DVT. 19 On the other hand, earlier HLA studies in Caucasoid populations showed that some HLA alleles were associated with pulmonary arterial hypertension, but the results were not consistent with each other, [14][15][16][17][18] implying that the observed associations with HLA were specific to the investigated ethnic groups because the complexity of HLA region depends on the nature of ethnic groups. 11 It is also possible that these reports might be false-positive findings owing to the type I error in the statistical analyses, because none of the earlier studies was concerned about multiple testing.…”

Section: Discussionmentioning

confidence: 83%

HLA-DPB1 and NFKBIL1 may confer the susceptibility to chronic thromboembolic pulmonary hypertension in the absence of deep vein thrombosis

et al. 2009

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Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by pulmonary hypertension caused by thromboembolism of the pulmonary artery. Etiology of CTEPH may be heterogeneous and is largely unknown, but genetic factors are considered to be involved in the etiology. It has been reported that deep vein thrombosis (DVT) and/or coagulation factor variants are predisposing factors to CTEPH. However, more than half of the CTEPH patients, especially the Japanese, do not have prior DVT or coagulation abnormality, suggesting that there should be other risk factors for CTEPH. Moreover, there are several reports on the association between CTEPH and human leukocyte antigen (HLA). To further clarify the HLA-linked gene(s) controlling the susceptibility to CTEPH, 160 patients (99 without DVT and 61 with DVT) and 380 healthy controls were analyzed for polymorphisms in 15 microsatellite markers and 5 genes in the HLA region. We found a strong association of HLA markers with the DVT-negative CTEPH, DPB1*0202 (odds ratio (OR)¼5.07, 95% confidence interval (CI)¼2.52-10.19, P¼0.00000075, corrected P-value (Pc)¼0.00014), IKBL-p*03 (OR¼2.33, 95% CI¼1.49-3.66, P¼0.00017, Pc¼0.033) and B*5201 (OR¼2.47, 95% CI¼1.56-3.90, P¼0.000086, Pc¼0.016), whereas no significant association was observed for the DVT-positive CTEPH. The comparison of clinical characteristics of patients stratified by the presence of susceptibility genes implied that the DPB1 gene controlled the severity of the vascular lesion, whereas the IKBL gene (NFKBIL1) was associated with a relatively mild phenotype.

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“…6 Antinuclear antibody positivity has not been found in children with PAH but was observed in 4 of 16 (25%) mothers of children with IPAH. 7 …”

Section: Genetic and Cellular Characteristicsmentioning

confidence: 99%