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The Immune Dysregulation of Common Variable Immunodeficiency Disorders.

December 18, 2020 By Manish Butte

The Immune Dysregulation of Common Variable Immunodeficiency Disorders.

Immunol Lett. 2020 Dec 14;:

Authors: Fernando SL, Jang HS, Li J

Abstract
Common variable immunodeficiency (CVID) is established as a heterogeneous collection of disorders of immune dysregulation rather than an infectious complication of antibody deficiency. Approximately 70% of patients have one or more of the non-infectious complications of autoimmunity, enteropathy, polyclonal lymphocytic and malignancy. The CVID-disorders represent a particular challenge as they fall under an umbrella diagnosis governed currently by non-universal diagnostic criteria. The rubric of CVID is shrinking as next generation sequencing is progressively and rapidly identifying the genetic basis for many of its disorders. Although identification of monogenic cause of CVID allows for naming of separate or specific entities, it still provides valuable insight into the immune dysregulation of these disorders along with recognition of a polygenic basis of disease and cellular changes observed in innate and adaptive immune pathways. Cellular abnormalities in the T-cell (reduced regulatory T cells (Tregs) and increased T follicular helper cells), and B-cell compartments (reduced switched memory B-cells and increased peripheral CD21low cells) along with an increase in innate lymphoid cells type 3 promote a milieu for inflammation. Immune dysregulation also results from increased microbial translocation from impaired gastrointestinal barrier function in CVID-patients with loss of Tregs. An understanding of the manifestations and mechanisms of immune dysregulation allows for improved vigilance in screening for the diagnosis, monitoring for complications of disease and the continued development and introduction of targeted therapies for non-infectious phenotypes.

PMID: 33333111 [PubMed – as supplied by publisher]

Granulomatous Liver Disease in Ataxia-Telangiectasia With the Hyper-IgM Phenotype: A Case Report.

December 18, 2020 By Manish Butte

Granulomatous Liver Disease in Ataxia-Telangiectasia With the Hyper-IgM Phenotype: A Case Report.

Front Pediatr. 2020;8:570330

Authors: Szczawińska-Popłonyk A, Ossowska L, Jończyk-Potoczna K

Abstract
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by neurodegeneration, combined immunodeficiency, and oculocutaneous telangiectasia. The hyper-IgM phenotype of A-T, correlating with a class-switch recombination defect, IgG and IgA deficiency, T helper and B cell lymphopenia, immune dysregulation, proinflammatory immune response, autoimmune disease, and a high risk of lymphomagenesis. Progressive liver disease is a hallmark of classical A-T with the hyper-IgM phenotype and manifests as non-alcoholic hepatic steatosis and fibrosis. We report a case of a 17-year-old male A-T patient, in whom a progressive granulomatous liver disease with portal hypertension, has led to massive splenomegaly and hypersplenism, metabolic liver insufficiency, bleeding from esophageal varices and pancytopenia. In this patient, an unusual severe disease course with a highly variable constellation of A-T symptomatology includes granulomatous skin, visceral, and internal organs disease with liver involvement. The liver disease is associated with the hyper-IgM immunophenotype and escalating neurodegeneration, creating a vicious circle of immune deficiency, permanent systemic inflammatory response, and organ-specific immunopathology.

PMID: 33330270 [PubMed]

Preimplantation Genetic Testing for a Chinese Family With X-Linked Lymphoproliferative Syndrome Type 1.

December 18, 2020 By Manish Butte

Preimplantation Genetic Testing for a Chinese Family With X-Linked Lymphoproliferative Syndrome Type 1.

Front Genet. 2020;11:550507

Authors: Chen S, Shi W, Qian Y, Wang L, Zhang J, Li S, Chen Y, Chang C, Fei H, Zhang L, Huang H, Xu C

Abstract
Background: X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency disorder. We performed experiments based on two strategies of preimplantation genetic testing (PGT) for a family with XLP caused by a mutation in SH2D1A (c.191G > A).
Methods: First, a single-cell polymerase chain reaction (PCR) protocol was established using single lymphocytes. A nested PCR experiment was performed with direct sequencing after whole genome amplification of single cells to assess the accuracy of the genetic diagnosis. Embryos obtained after intracytoplasmic sperm injection were biopsied on day 3 and detected using the established single-cell PCR protocol. In the second PGT cycle, targeted next generation sequencing (NGS) was performed and the single nucleotide polymorphism (SNP) markers flanking SH2D1A were selected to determine the disease-carrying haplotype phase in each embryo.
Result: In the first PGT cycle, six embryos were biopsied. Discounting an embryo from a single failed PCR experiment, five embryos were identified, including three unaffected and two hemizygous. After PCR, one normal embryo was transferred when it was developing into an early blastocyst. Although the ultrasound images indicated a viable singleton pregnancy, the implantation was on the cesarean scar. Therefore, an artificial abortion was performed. In the haplotyping cycle, six embryos were identified to have inherited a haplotype without pathogenic mutations. After the embryo implantation process failed twice, a successful singleton pregnancy was established, and subsequently, a healthy female child was born.
Conclusion: Targeted NGS with haplotyping analysis circumvents the laborious process of multiplex PCR and is more likely to ensure diagnostic accuracy. However, when a genetic recombination occurs close to the site of mutation, confirmed identification using selected SNP markers can be challenging.

PMID: 33329693 [PubMed]

Histology of Interstitial Lung Disease in Common Variable Immune Deficiency.

December 18, 2020 By Manish Butte

Histology of Interstitial Lung Disease in Common Variable Immune Deficiency.

Front Immunol. 2020;11:605187

Authors: Dhalla F, Lochlainn DJM, Chapel H, Patel SY

Abstract
Interstitial lung disease (ILD) is an important non-infectious complication in several primary immune deficiencies. In common variable immune deficiency (CVID) it is associated with complex clinical phenotypes and adverse outcomes. The histology of ILD in CVID is heterogeneous and mixed patterns are frequently observed within a single biopsy, including non-necrotising granulomatous inflammation, lymphoid interstitial pneumonitis, lymphoid hyperplasia, follicular bronchiolitis, organizing pneumonia, and interstitial fibrosis; ILD has to be differentiated from lymphoma. The term granulomatous-lymphocytic interstitial lung disease (GLILD), coined to describe the histopathological findings within the lungs of patients with CVID with or without multisystem granulomata, is somewhat controversial as pulmonary granulomata are not always present on histology and the nature of infiltrating lymphocytes is variable. In this mini review we summarize the literature on the histology of CVID-related ILD and discuss some of the factors that may contribute to the inter- and intra- patient variability in the histological patterns reported. Finally, we highlight areas for future development. In particular, there is a need for standardization of histological assessments and reporting, together with a better understanding of the immunopathogenesis of CVID-related ILD to resolve the apparent heterogeneity of ILD in this setting and guide the selection of rational targeted therapies in different patients.

PMID: 33329602 [PubMed – in process]

Case Report: Convalescent Plasma, a Targeted Therapy for Patients with CVID and Severe COVID-19.

December 18, 2020 By Manish Butte

Case Report: Convalescent Plasma, a Targeted Therapy for Patients with CVID and Severe COVID-19.

Front Immunol. 2020;11:596761

Authors: Van Damme KFA, Tavernier S, Van Roy N, De Leeuw E, Declercq J, Bosteels C, Maes B, De Bruyne M, Bogaert D, Bosteels V, Hoste L, Naesens L, Maes P, Grifoni A, Weiskopf D, Sette A, Depuydt P, Van Braeckel E, Haerynck F, Lambrecht BN

Abstract
The disease course of COVID-19 in patients with immunodeficiencies is unclear, as well as the optimal therapeutic strategy. We report a case of a 37-year old male with common variable immunodeficiency disorder and a severe SARS-CoV-2 infection. After administration of convalescent plasma, the patient’s condition improved rapidly. Despite clinical recovery, viral RNA remained detectable up to 60 days after onset of symptoms. We propose that convalescent plasma might be considered as a treatment option in patients with CVID and severe COVID-19. In addition, in patients with immunodeficiencies, a different clinical course is possible, with prolonged viral shedding.

PMID: 33329586 [PubMed – in process]

[Clinical features of children with immunodeficiency and Mycobacterium tuberculosis infection].

December 18, 2020 By Manish Butte

[Clinical features of children with immunodeficiency and Mycobacterium tuberculosis infection].

Zhongguo Dang Dai Er Ke Za Zhi. 2020 Dec;22(12):1300-1305

Authors: Wang WP, Liu QB

Abstract
OBJECTIVE: To study the clinical features of Mycobacterium tuberculosis infection in children with secondary immunodeficiency disease (SID) versus primary immunodeficiency disease (PID).
METHODS: A retrospective analysis was performed on the medical data of children with immunodeficiency and Mycobacterium tuberculosis infection (36 children with SID and 52 with PID) and 108 children with Mycobacterium tuberculosis infection but without immunodeficiency (control group).
RESULTS: The onset age in the PID group was significantly lower than those in the control and SID groups (P < 0.05), and the proportation of males in the PID group was significantly higher than those in the control and SID groups (P < 0.05). Compared with the control group, the SID and PID groups had significantly lower incidence rates of tuberculosis poisoning symptoms (night sweeting, weight loss, fatigue and loss of appetite) and positive rate of PPD test (P < 0.05), as well as a significantly higher incidence rate of the involvement of ≥ 3 pulmonary lobes (P < 0.05). The children with PID tended to have the involvement of multiple organs (P < 0.05). The SID group had a significantly higher incidence rate of miliary shadow on chest CT than the control and PID groups (P < 0.05). The PID group had a significantly lower positive rate of IFN-gamma release assay (IGRA) than the control and SID groups (P < 0.05). Mycobacterium tuberculosis infection manifested as latent tuberculosis infection (36.1%) and active tuberculosis (63.9%) in the SID group. The infection mainly manifested as bacille Calmette-Guérin disease in the PID group (90.4%), among whom 2 children (3.8%) also had tuberculosis.
CONCLUSIONS: Children with immunodeficiency and Mycobacterium tuberculosis infection have atypical clinical symptoms, with a high incidence rate of disseminated infection and low positive rates of PPD and IGRA tests, which may lead to misdiagnosis and missed diagnosis. Children with immunodeficiency should undergo regular tuberculosis screening for early identification and intervention.

PMID: 33328001 [PubMed – in process]

Spectrum of Inborn errors of immunity in a cohort of 90 patients presenting with complications to BCG vaccination in India.

December 17, 2020 By Manish Butte

Spectrum of Inborn errors of immunity in a cohort of 90 patients presenting with complications to BCG vaccination in India.

Scand J Immunol. 2020 Dec 16;:e13010

Authors: Yadav RM, Dalvi A, Gupta M, Bargir UA, Mhatre S, Aluri J, Kulkarni M, Hule G, Kambli P, Setia P, Jodhawat N, Taur P, Desai M, Madkaikar M

Abstract
World Health Organisation recommends the practice of BCG vaccination at birth in countries which have a high incidence of tuberculosis and/or high leprosy burden. The BCG vaccination is considered safe for a competent immune system. However, in children with weakened immune systems cause of which can be primary or secondary, the vaccine may lead to side effects which can be localized or disseminated. In this study, we report a spectrum of Inborn Errors of Immunity (IEI) commonly referred to as primary immunodeficiency disorders (PIDs) diagnosed in a large cohort of patients presenting with complications to BCG vaccination from India. Retrospective data analysis of patients referred to ICMR- National Institute of Immunohematology (ICMR-NIIH) for IEI workup between 2007-2019 was done. IEI were identified in n=52/90 (57.7%) patients presenting with BCG complications. Of these, n=13(14.4%) patients were diagnosed with Severe Combined Immune-deficiency, n=15(16.7%) with Chronic Granulomatous disease, n=19(21.1%) with Inborn errors of IFN-γ immunity, n=4(4.4%) with Combined immunodeficiency and n=1(1.1%) with Leucocyte Adhesion Deficiency type1. Majority of cases with BCGosis (88%) had an underlying IEI. This study strongly highlights the need for evaluation of patients with BCG complications for underlying IEI. While disseminated BCGosis strongly predicts underlying IEI, even localized persistent adenitis may be a warning sign of underlying IEI. It is also strongly recommended to record a family history of previous sibling death prior to administration of this live vaccine and deferring live vaccine till the diagnosis of IEI is ruled out in cases with a positive family history.

PMID: 33325540 [PubMed – as supplied by publisher]

Identification of novel biomarkers and candidate small molecule drugs in rheumatoid arthritis and osteoarthritis based on bioinformatics analysis of high-throughput data.

December 17, 2020 By Manish Butte

Identification of novel biomarkers and candidate small molecule drugs in rheumatoid arthritis and osteoarthritis based on bioinformatics analysis of high-throughput data.

Biosci Rep. 2020 Dec 23;40(12):

Authors: Zuo B, Zhu J, Xiao F, Wang C, Shen Y, Chen X

Abstract
BACKGROUND: Rheumatoid arthritis (RA) and osteoarthritis (OA) are two major types of joint diseases. The present study aimed to identify hub genes involved in the pathogenesis and further explore the potential treatment targets of RA and OA.
METHODS: The gene expression profile of GSE12021 was downloaded from Gene Expression Omnibus (GEO). Total 31 samples (12 RA, 10 OA and 9 NC samples) were used. The differentially expressed genes (DEGs) in RA versus NC, OA versus NC and RA versus OA groups were screened using limma package. We also verified the DEGs in GSE55235 and GSE100786. Functional annotation and protein-protein interaction (PPI) network construction of OA- and RA-specific DEGs were performed. Finally, the candidate small molecules as potential drugs to treat RA and OA were predicted in CMap database.
RESULTS: 165 up-regulated and 163 down-regulated DEGs between RA and NC samples, 73 up-regulated and 293 down-regulated DEGs between OA and NC samples, 92 up-regulated and 98 down-regulated DEGs between RA and OA samples were identified. Immune response and TNF signaling pathway were significantly enriched pathways for RA- and OA-specific DEGs, respectively. The hub genes were mainly associated with ‘Primary immunodeficiency’ (RA vs. NC group), ‘Ribosome’ (OA vs. NC group), and ‘Chemokine signaling pathway’ (RA vs. OA group). Arecoline and Cefamandole were the most promising small molecule to reverse the RA and OA gene expression.
CONCLUSION: Our findings suggest new insights into the underlying pathogenesis of RA and OA, which may improve the diagnosis and treatment of these intractable chronic diseases.

PMID: 33325525 [PubMed – in process]

Managing Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders: e-GLILDnet International Clinicians Survey.

December 17, 2020 By Manish Butte

Managing Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders: e-GLILDnet International Clinicians Survey.

Front Immunol. 2020;11:606333

Authors: van de Ven AAJM, Alfaro TM, Robinson A, Baumann U, Bergeron A, Burns SO, Condliffe AM, Fevang B, Gennery AR, Haerynck F, Jacob J, Jolles S, Malphettes M, Meignin V, Milota T, van Montfrans J, Prasse A, Quinti I, Renzoni E, Stolz D, Warnatz K, Hurst JR

Abstract
Background: Granulomatous-lymphocytic interstitial lung disease (GLILD) is a rare, potentially severe pulmonary complication of common variable immunodeficiency disorders (CVID). Informative clinical trials and consensus on management are lacking.
Aims: The European GLILD network (e-GLILDnet) aims to describe how GLILD is currently managed in clinical practice and to determine the main uncertainties and unmet needs regarding diagnosis, treatment and follow-up.
Methods: The e-GLILDnet collaborators developed and conducted an online survey facilitated by the European Society for Immunodeficiencies (ESID) and the European Respiratory Society (ERS) between February-April 2020. Results were analyzed using SPSS.
Results: One hundred and sixty-one responses from adult and pediatric pulmonologists and immunologists from 47 countries were analyzed. Respondents treated a median of 27 (interquartile range, IQR 82-maximum 500) CVID patients, of which a median of 5 (IQR 8-max 200) had GLILD. Most respondents experienced difficulties in establishing the diagnosis of GLILD and only 31 (19%) had access to a standardized protocol. There was little uniformity in diagnostic or therapeutic interventions. Fewer than 40% of respondents saw a definite need for biopsy in all cases or performed bronchoalveolar lavage for diagnostics. Sixty-six percent used glucocorticosteroids for remission-induction and 47% for maintenance therapy; azathioprine, rituximab and mycophenolate mofetil were the most frequently prescribed steroid-sparing agents. Pulmonary function tests were the preferred modality for monitoring patients during follow-up.
Conclusions: These data demonstrate an urgent need for clinical studies to provide more evidence for an international consensus regarding management of GLILD. These studies will need to address optimal procedures for definite diagnosis and a better understanding of the pathogenesis of GLILD in order to provide individualized treatment options. Non-availability of well-established standardized protocols risks endangering patients.

PMID: 33324422 [PubMed – in process]

A novel NEMO/IKBKG mutation identified in a primary immunodeficiency disorder with recurrent atypical mycobacterial infections.

December 16, 2020 By Manish Butte

A novel NEMO/IKBKG mutation identified in a primary immunodeficiency disorder with recurrent atypical mycobacterial infections.

JAAD Case Rep. 2021 Jan;7:33-35

Authors: Kolitz E, Chamseddin B, Son R, Vandergriff T, Hsu AP, Holland S, Wang RC

PMID: 33318999 [PubMed]