ABSTRACT
Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
Subject(s)
Primary Immunodeficiency Diseases/genetics , Whole Genome Sequencing , Actin-Related Protein 2-3 Complex/genetics , Bayes Theorem , Cohort Studies , Female , Genome-Wide Association Study , Humans , Male , Primary Immunodeficiency Diseases/diagnosis , Primary Immunodeficiency Diseases/immunology , Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics , RNA-Binding Proteins/genetics , Regulatory Sequences, Nucleic Acid/genetics , Suppressor of Cytokine Signaling 1 Protein/genetics , Transcription Factors/geneticsABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
An association has been reported between Wiskott-Aldrich syndrome and necrotizing vasculitis and aneurysmal arterial dilatation. We present here the first endovascular repair of descending thoracic aortic aneurysm in a 35-year-old male patient with the classical Wiskott-Aldrich syndrome phenotype. He had a successful endovascular repair with early discharge from hospital with no postoperative complications. His 1-year follow-up computed tomography scan confirmed appropriate stent position, aneurysm sac resolution with no evidence of endoleak, and no further aneurysm formation.
Subject(s)
Aortic Aneurysm, Thoracic/surgery , Blood Vessel Prosthesis Implantation , Endovascular Procedures , Wiskott-Aldrich Syndrome/complications , Adult , Aortic Aneurysm, Thoracic/diagnostic imaging , Aortic Aneurysm, Thoracic/etiology , Aortography/methods , Humans , Male , Tomography, X-Ray Computed , Treatment Outcome , Wiskott-Aldrich Syndrome/geneticsABSTRACT
A proportion of people living with common variable immunodeficiency disorders develop granulomatous-lymphocytic interstitial lung disease (GLILD). We aimed to develop a consensus statement on the definition, diagnosis, and management of GLILD. All UK specialist centers were contacted and relevant physicians were invited to take part in a 3-round online Delphi process. Responses were graded as Strongly Agree, Tend to Agree, Neither Agree nor Disagree, Tend to Disagree, and Strongly Disagree, scored +1, +0.5, 0, -0.5, and -1, respectively. Agreement was defined as greater than or equal to 80% consensus. Scores are reported as mean ± SD. There was 100% agreement (score, 0.92 ± 0.19) for the following definition: "GLILD is a distinct clinico-radio-pathological ILD occurring in patients with [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded." There was consensus that the workup of suspected GLILD requires chest computed tomography (CT) (0.98 ± 0.01), lung function tests (eg, gas transfer, 0.94 ± 0.17), bronchoscopy to exclude infection (0.63 ± 0.50), and lung biopsy (0.58 ± 0.40). There was no consensus on whether expectant management following optimization of immunoglobulin therapy was acceptable: 67% agreed, 25% disagreed, score 0.38 ± 0.59; 90% agreed that when treatment was required, first-line treatment should be with corticosteroids alone (score, 0.55 ± 0.51).
Subject(s)
Common Variable Immunodeficiency , Granuloma , Lung Diseases, Interstitial , Charities , Common Variable Immunodeficiency/diagnosis , Common Variable Immunodeficiency/diagnostic imaging , Common Variable Immunodeficiency/drug therapy , Common Variable Immunodeficiency/pathology , Consensus , Granuloma/diagnosis , Granuloma/diagnostic imaging , Granuloma/drug therapy , Granuloma/pathology , Humans , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/diagnostic imaging , Lung Diseases, Interstitial/drug therapy , Lung Diseases, Interstitial/pathology , Societies, Medical , United KingdomSubject(s)
Allergens/immunology , Exercise , Gliadin/immunology , Immunoglobulin E/immunology , Wheat Hypersensitivity/diagnosis , Wheat Hypersensitivity/immunology , Antigens, Plant , Dermatitis, Atopic/immunology , Humans , Immunoassay , Immunoglobulin E/blood , Predictive Value of Tests , Wheat Hypersensitivity/classificationABSTRACT
BACKGROUND: The presence of anti-smooth muscle autoantibody (SMA) in Autoimmune Hepatitis (AIH) is well established. However, there are no data demonstrating the clinical significance in patients with normal liver function and few showing positive predictive value for AIH when alanine aminotransferase (ALT) is raised. METHODS: We retrospectively established outcomes in a cohort of 251 consecutive patients with positive tubular or glomerular SMA. Patient records were checked for 12years after the positive SMA result to identify development of AIH. RESULTS: Of 202 patients with SMA and ALT <55IU/L, one (0.5%) had a subsequent diagnosis of AIH and this patient probably had abnormal ALT at the time of SMA detection. 22% of 45 patients with raised ALT (>55IU/L) and 23% of 43 patients with persistently raised ALT (>3months duration), had a diagnosis of AIH on follow up. Of 10 patients with AIH, 80% were diagnosed within three months of the positive SMA. CONCLUSIONS: Progression to AIH in patients with normal liver function and positive SMA-T/G is rare but patients with positive SMA and raised ALT (>55IU/L) should be referred to secondary care for investigation. Positive predictive value of SMA with raised ALT for AIH was 22%.
Subject(s)
Autoantibodies/blood , Hepatitis, Autoimmune/blood , Muscle, Smooth/immunology , Aged , Autoantibodies/immunology , Biomarkers/blood , Female , Hepatitis, Autoimmune/diagnosis , Hepatitis, Autoimmune/immunology , Humans , Liver/immunology , Liver/physiopathology , Male , Middle Aged , Retrospective StudiesABSTRACT
We describe a case of oral hairy leukoplakia that presented with an atypical appearance in a patient on long-term anticonvulsant treatment with an aromatic antiepileptic, lamotrigine. Recent medical history was also significant for recurrent respiratory tract infections requiring treatment with oral antibiotics. Immunologic investigations revealed inverted CD4/CD8 ratio, mild hypogammaglobulinemia, and poor specific antibody titers. Combined immune deficiency caused by long-term treatment with lamotrigine was suspected after other known factors and conditions (including retroviral infection) leading to acquired immune deficiency were excluded. Withdrawal of lamotrigine resulted in complete resolution of oral hairy leukoplakia. There was no significant improvement in immunoglobulin levels. The effect of lamotrigine and other aromatic antiepileptics on the immune system should be considered in a patient presenting with otherwise unexplained oral hairy leukoplakia.