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J Clin Immunol. 2021 May 19. doi: 10.1007/s10875-021-01050-2. Online ahead of print.

ABSTRACT

PURPOSE: Common variable immunodeficiency disorders (CVID) is characterized by low/absent serum immunoglobulins and susceptibility to bacterial infection. Patients can develop an infections-only phenotype or a complex disease course with inflammatory, autoimmune, and/or malignant complications. We hypothesized that deficient DNA repair mechanisms may be responsible for the antibody deficiency and susceptibility to inflammation and cancer in some patients.

METHODS: Germline variants were identified following targeted sequencing of n = 252 genes related to DNA repair in n = 38 patients. NanoString nCounter PlexSet assay measured gene expression in n = 20 CVID patients and n = 7 controls. DNA damage and apoptosis were assessed by flow cytometry in n = 34 CVID patients and n = 11 controls.

RESULTS: Targeted sequencing supported enrichment of rare genetic variants in genes related to DNA repair pathways with novel and rare likely pathogenic variants identified and an altered gene expression signature that distinguished patients from controls and complex patients from those with an infections-only phenotype. Consistent with this, flow cytometric analyses of lymphocytes following DNA damage revealed a subset of CVID patients whose immune cells have downregulated ATM, impairing the recruitment of other repair factors, delaying repair and promoting apoptosis.

CONCLUSION: These data suggest that germline genetics and altered gene expression predispose a subset of CVID patients to increased sensitivity to DNA damage and reduced DNA repair capacity.

PMID:34009545 | DOI:10.1007/s10875-021-01050-2

Clin Exp Immunol. 2021 May 18. doi: 10.1111/cei.13620. Online ahead of print.

ABSTRACT

Lymphadenopathies can be part of the clinical spectrum of several primary immunodeficiencies, including diseases with immune dysregulation, and autoinflammatory disorders, as the clinical expression of benign polyclonal lymphoproliferation, granulomatous disease, or lymphoid malignancy. Lymphadenopathy poses a significant diagnostic dilemma when it represents the first sign of a disorder of the immune system, leading to a consequently delayed diagnosis. Additionally, the finding of lymphadenopathy in a patient with diagnosed immunodeficiency raises the question of the differential diagnosis between benign lymphoproliferation and malignancies. Lymphadenopathies are evidenced in 15-20% of the patients with common variable immunodeficiency, while in other antibody deficiencies the prevalence is lower. They are also evidenced in different combined immunodeficiency disorders, including Omenn syndrome, which presents in the first months of life. Interestingly, in the activated phosphoinositide 3-kinase delta syndrome, autoimmune lymphoproliferative syndrome, EBV-related lymphoproliferative disorders, and regulatory T cells disorders, lymphadenopathy is one of the leading signs of the entire clinical picture. Among autoinflammatory diseases, the highest prevalence of lymphadenopathies is observed in patients with PFAPA and hyper-IgD syndrome. The mechanisms underlying lymphoproliferation in the different disorders of the immune system are multiple and not completely elucidated. The advances in genetic techniques provide the opportunity of identifying new monogenic disorders, allowing to make genotype-phenotype correlations and to provide adequate follow-up and treatment in the single diseases. In this work, we provide an overview of the most relevant immune disorders associated with lymphadenopathy, focusing on their diagnostic and prognostic implications.

PMID:34008169 | DOI:10.1111/cei.13620

Hum Mutat. 2021 May 18. doi: 10.1002/humu.24220. Online ahead of print.

ABSTRACT

Biobanks with exomes linked to electronic health records (EHRs) enable the study of genetic pleiotropy between rare variants and seemingly disparate diseases. We performed robust clinical phenotyping of rare, putatively deleterious variants (loss-of-function [LoF] and deleterious missense variants) in ERCC6, a gene implicated in inherited retinal disease. We analyzed 213,084 exomes, along with a targeted set of retinal, cardiac, and immune phenotypes from two large-scale EHR-linked biobanks. In the primary analysis, a burden of deleterious variants in ERCC6 was strongly associated with 1) retinal disorders; 2) cardiac and electrocardiogram perturbations; and 3) immunodeficiency and decreased immunoglobulin levels. Meta-analysis of results from the BioMe Biobank and UK Biobank showed significant association of deleterious ERCC6 burden with retinal dystrophy (OR=2.6, 95% CI 1.5-4.6; P=8.7 x 10^-4 ), atypical atrial flutter (OR=3.5, 95% CI 1.9-6.5; P=6.2 x 10^-5 ), arrhythmia (OR=1.5, 95% CI 1.2-2.0; P=2.7 x 10^-3 ), and lymphocyte immunodeficiency (OR=3.8, 95% CI 2.1-6.8; P=5.0 x 10^-6 ). Carriers of ERCC6 LoF variants who lacked a diagnosis of these conditions exhibited increased symptoms, indicating underdiagnosis. These results reveal a unique genetic link among retinal, cardiac, and immune disorders and underscore the value of EHR-linked biobanks in assessing the full clinical profile of carriers of rare variants. This article is protected by copyright. All rights reserved.

PMID:34005834 | DOI:10.1002/humu.24220

Allergy Asthma Clin Immunol. 2021 May 17;17(1):50. doi: 10.1186/s13223-021-00551-4.

ABSTRACT

BACKGROUND: A retrospective review of clinical manifestations and demographic pattern of patients diagnosed as chronic granulomatous disease (CGD) from 7 hospitals in Malaysia. An analysis of the available database would establish clinical characteristics, diagnoses and outcome including microbiologic pattern. Studying the demography allows us to document the occurrence of CGD amongst multiethnic groups and its geographical distribution for Malaysia.

METHODS: Data from the Malaysia Primary Immunodeficiency Network (MyPIN) with cases of CGD diagnosed from 1991 until 2016 were collated and analysed.

RESULTS: Twenty patients were diagnosed as CGD. Males (N = 13, 65%) outnumber females (N = 7, 35%). CGD is commonest amongst the Malays (65%) followed by the Chinese (15.0%), Indians (10.0%) and natives of Borneo (10.0%), reflecting the ethnic composition of the country. The mean age of diagnosis was 3.7 years. There was a positive family history in 40% of the cases. Abscess was the main presenting feature in 16 patients (80%) with one involving the brain. Pneumonia occurred in 10 (50%) and one with complicated bronchiectasis. Catalase-positive bacteria were the most commonly isolated pathogen with Chromobacterium violaceum predominating (N = 5, 25%) with consequent high mortality (N = 4, 80%). All CGD patients with C. violaceum infection displayed CD4 + (T helper cells) lymphopenia.

CONCLUSION: This study has shown CGD occurs in the major ethnic groups of Malaysia. To the best of our knowledge, this is the first and the largest series of chronic granulomatous disease in South East Asia which may be reflective of similar clinical pattern in the region. C. violaceum infection is associated with a higher mortality in CGD patients in Malaysia. All the CGD patients with C. violaceum infection in this patient series displayed CD4 + (T helper) lymphopenia. We recorded rare clinical manifestation of CGD viz. brain abscess and bronchiectasis.

PMID:34001231 | DOI:10.1186/s13223-021-00551-4

Am J Hematol. 2021 May 17. doi: 10.1002/ajh.26242. Online ahead of print.

ABSTRACT

The differential diagnosis of marrow failure (MF) is crucial in the diagnostic work-up, since genetic forms require specific care. We retrospectively studied all patients with single/multi-lineage MF evaluated in a single-center to identify the type and incidence of underlying molecular defects. The diepoxybutane test was used to screen Fanconi Anemia. Other congenital MFs have been searched using Sanger and/or Next Generation Sequencing analysis, depending on the available tools over the years. Between 2009-2019, 97 patients (aged 0-32 years-median 5) with single-lineage (29%) or multilineage (68%) MF were evaluated. Fifty-three (54%) and 28 (29%) were diagnosed with acquired and congenital MF, respectively. The remaining 16 (17%), with trilinear (9) and monolinear (7) MF, were found to have an underlying primary immunodeficiency (PID) and showed clinical and biochemical signs of immune-dysregulation in 10/16 (62%) and in 14/16 (87%) of cases, respectively. Clinical signs were also found in 22/53 (41%) and 8/28 (28%) patients with idiopathic and classical cMF, respectively. Eight out of 16 PIDs patients were successfully transplanted, 4 received immunosuppression, 2 didn’t require treatment, and the remaining 2 died. We show that patients with single/multi-lineage MF may have underlying PIDs in a considerable number of cases and that MF may represent a relevant clinical sign in patients with PIDs, thus widening their clinical phenotype. An accurate immunological work-up should be performed in all patients with MF, and PID-related genes should be considered when screening MF in order to identify disorders that may receive targeted treatments and/or appropriate conditioning regimen before transplant. This article is protected by copyright. All rights reserved.

PMID:34000087 | DOI:10.1002/ajh.26242

Front Pediatr. 2021 Apr 28;9:662645. doi: 10.3389/fped.2021.662645. eCollection 2021.

ABSTRACT

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a crucial immune checkpoint that is constitutively expressed in regulatory T (Treg) cells. Following T-cell activation, CTLA-4 is rapidly mobilized from its intracellular vesicle pool to the cell surface to control the availability of co-stimulatory B7 molecules, thereby maintaining immune homeostasis. Heterozygous mutations in CTLA-4 lead to defects in (i) CTLA-4 ligand binding, (ii) homo-dimerization, (iii) B7-transendocytosis, and (iv) CTLA-4 vesicle trafficking, resulting in an inborn error of immunity with predominant autoimmunity. CTLA-4 vesicle trafficking impairment is also observed in patients with lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency or the differentially expressed in FDCP6 homolog (DEF6) deficiency, caused by biallelic mutations in LRBA and DEF6, respectively. Therefore, patients with CTLA-4 insufficiency, LRBA deficiency, and-most recently reported-DEF6 deficiency present an overlapping clinical phenotype mainly attributed to a defective suppressive activity of Tregs, as all three diseases reduce overall surface expression of CTLA-4. In this paper, we describe the clinical phenotypes of these immune checkpoint defects, their patho-mechanisms, and visually compare them to other immune regulatory disorders (IPEX syndrome, CD27, and CD70 deficiencies) by using the immune deficiency and dysregulation (IDDA version 2.1) “kaleidoscope” score. This illustrates the variability of the degrees and manifestations of immune deficiency and dysregulation. Patients characteristically present with an increased risk of infections, autoimmune cytopenias, multi-organ autoimmunity, and inflammation, which are often severe and life-threatening. Furthermore, these patients suffer an increased risk of developing malignancies, especially Non-Hodgkin’s lymphoma. Successful treatment options include regular administration of soluble CTLA-4-Ig fusion protein, Treg cell-sparing immune suppressants like sirolimus or mycophenolate mofetil, and hematopoietic stem cell transplantation. This mini-review highlights the most relevant biological and clinical features as well as treatment options for CTLA-4 insufficiency and LRBA and DEF6 deficiencies.

PMID:33996698 | PMC:PMC8113415 | DOI:10.3389/fped.2021.662645

Front Pediatr. 2021 Apr 30;9:615724. doi: 10.3389/fped.2021.615724. eCollection 2021.

ABSTRACT

Collective clinical and immunologic findings of defects in the CD27-CD70 axis indicate a primary immunodeficiency associated with terminal B-cell development defect and immune dysregulation leading to autoimmunity, uncontrolled viral infection, and lymphoma. Since the molecular mechanism underlying this entity of primary immunodeficiency has been recently described, more insight regarding the function and profile of immunity is required. Therefore, this study aimed to investigate stimulated antibody production, polyclonal vs. virus-specific T-cell response, and cytokine production of a CD70-deficient patient reported previously with early-onset antibody deficiency suffering from chronic viral infections and B-cell lymphoma. The patient and her family members were subjected to clinical evaluation, immunological assays, and functional analyses. The findings of this study indicate an impaired ability of B cells to produce immunoglobulins, and a poor effector function of T cells was also associated with the severity of clinical phenotype. Reduced proportions of cells expressing the memory marker CD45RO, as well as T-bet and Eomes, were observed in CD70-deficient T cells. The proportion of 2B4⁺ and PD-1⁺ virus-specific CD8⁺ T cells was also reduced in the patient. Although the CD70-mutated individuals presented with early-onset clinical manifestations that were well-controlled by using conventional immunological and anticancer chemotherapies, with better prognosis as compared with CD27-deficient patients, targeted treatment toward specific disturbed immune profile may improve the management and even prevent secondary complications.

PMID:33996677 | PMC:PMC8120026 | DOI:10.3389/fped.2021.615724

J Hepatol. 2021 May 13:S0168-8278(21)00329-9. doi: 10.1016/j.jhep.2021.04.052. Online ahead of print.

ABSTRACT

BACKGROUND AND AIM: There is uncertainty on the risk of dying after coronavirus disease 2019 (Covid-19) in chronic liver disease patients.

PATIENTS AND METHODS: We explored the outcomes of all Covid-19 adult inpatients in France, in 2020. We computed adjusted odds-ratios to measure the associations between chronic liver disease, alcohol use disorders, mechanical ventilation and day-30, in-hospital, mortality.

RESULTS: The sample comprised 259,110 patients [median (interquartile range) age 70 (54, 83) years; 52% men], including 15,746 (6.0%) and 10,006 (3.9%) patients with chronic liver disease and alcohol use disorders, respectively. Mortality was 38,203 (15%) patients, including 7,475 (28%) after mechanical ventilation, and 2,941 (19%) with chronic liver disease. The adjusted odds-ratios for mechanical ventilation and day-30 mortality were 1.54 (95% confidence interval, 1.44 – 1.64, P < 0.001) and 1.79 (1.71 - 1.87, P < 0.001); 0.55 (0.47 - 0.64, P < 0.001) and 0.54 (0.48 - 0.61, P < 0.001); 0.64 (0.53 - 0.76; P < 0.001) and 0.71 (0.63- 0.80, P < 0.001); 0.65 (0.52 - 0.81, P < 0.001) and 2.21 (95% CI, 1.94 - 2.51, P < 0.001); 0.34 (0.24 - 0.50; P < 0.001) and 1.38 (1.17 - 1.62, P < 0.001); and 0.82 (0.76 - 0.89; P < 0.001) and 1.11 (1.05 - 1.17; P < 0.001) for chronic liver disease; mild liver disease; compensated cirrhosis; decompensated cirrhosis; primary liver cancer; and alcohol use disorders, respectively. Chronic viral hepatitis; non-viral, non-alcoholic chronic hepatitis; organ, including liver, transplantation, and acquired immunodeficiency syndrome were not associated with Covid-19 death.

CONCLUSION: Chronic liver disease increased the risk Covid-19 death in France in 2020. Therapeutic effort limitation may have contributed to Covid-19 death of patients with a liver-related complication or with alcohol use disorders.

LAY SUMMARY: We studied the outcomes, including mechanical ventilation and day-30 mortality, of all Covid-19 adults (N=259,110) discharged from acute and post-acute care, private and public hospitals, in France in 2020. Patients with mild liver disease; compensated cirrhosis; organ, including liver, transplantation; or acquired immunodepression syndrome were not at risk for Covid-19 mortality. Patients with alcohol use disorders; decompensated cirrhosis; or primary liver cancer were at high, positive, risk for Covid-19 mortality and at low, negative, risk for mechanical ventilation. Our results suggest that a limitation of the therapeutic effort may have contributed to the excess of mortality of patients with a liver-related complication and of patients with alcohol use disorders in France in 2020.

PMID:33992699 | DOI:10.1016/j.jhep.2021.04.052

Front Immunol. 2021 Apr 28;12:670312. doi: 10.3389/fimmu.2021.670312. eCollection 2021.

ABSTRACT

Activated phosphoinositide 3-kinase δ syndrome (APDS) is an autosomal dominant primary immunodeficiency caused by gain-of-function (GOF) mutations in PIK3CD or PIK3R1 genes. The phenotypes of APDS are highly variable, ranging from asymptomatic adults to profound immunodeficiency causing early death in childhood. Herein, we reported two pediatric patients with APDS presented with recurrent lung infections, sinusitis, hematuria, and positive anti-neutrophil cytoplasmic antibody (ANCA), previously diagnosed as granulomatosis with polyangiitis (GPA). Bronchoscopy showed mucosal nodule lymphoid hyperplasia in the entire airway. Many inflammatory cells infiltrated around the airway and in the lung parenchyma, and numbers of CD3⁺ T cells and CD20⁺ B cells were significantly increased, especially CD3+ T cells. Whole exome sequencing showed that they had the E1021K (c.3061 G >A) mutation in the PIK3CD gene. These are the first reported cases of APDS presenting as childhood-onset GPA. Pediatricians should suspect of APDS in the differential diagnosis of children who present with GPA-like symptoms. Additionally, timely and repeated bronchoscopies could contribute to providing an important diagnostic clue for APDS.

PMID:33995405 | PMC:PMC8113859 | DOI:10.3389/fimmu.2021.670312

Front Immunol. 2021 Apr 28;12:654167. doi: 10.3389/fimmu.2021.654167. eCollection 2021.

ABSTRACT

In immunocompromised patients, EBV may elicit B-cell transformation and proliferation. A 5-year-old microcephalic boy was admitted with fever and non-malignant polymorphic T-cell lymphoproliferative disease associated with EBV. A presumptive diagnosis of primary immunodeficiency with inability to control EBV was made and next-generation sequencing led to the identification of a novel ZBTB24 mutation (ICF2-syndrome). This case shows that susceptibility to EBV seems to be particular of ICF-2 as it has not been described in the other types of ICF. It is mandatory to raise the hypothesis of an underlying PID in case of severe EBV infection.

PMID:33995370 | PMC:PMC8113761 | DOI:10.3389/fimmu.2021.654167