• Skip to primary navigation
  • Skip to main content

Stanford Alliance for Primary Immunodeficiency

Stanford University

  • SAPI
  • Stanford PI Clinic
  • Patient Support
    • Diagnosis
    • Treatment and Complications
    • School
    • Work
    • Parenting
    • Sibling
    • Lifestyle
    • Mentorship Program
    • PI Resources
      • Immune Deficiency Foundation (IDF)
      • Jeffrey Modell Foundation
      • Painted Turtle Camp
      • Make-A-Wish
      • Baxter IVIG
      • CSL Behring IVIG
  • Kids’ Zone
    • Kids’ Zone
    • Pre-Teen FAQ
    • Teen FAQ
  • PID Research
    • Butte Lab Immunology Research Projects
    • PID Research blog
  • Local Events
  • Donate
You are here: Home / Archives for Research

Research

Dominant-negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes

May 26, 2023 By Manish Butte

iScience. 2023 May 5;26(6):106818. doi: 10.1016/j.isci.2023.106818. eCollection 2023 Jun 16.

ABSTRACT

Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disease characterized by severe and childhood onset organ-specific autoimmunity caused by mutations in the autoimmune regulator (AIRE) gene. More recently, dominant-negative mutations within the PHD1, PHD2, and SAND domains have been associated with an incompletely penetrant milder phenotype with later onset familial clustering, often masquerading as organ-specific autoimmunity. Patients with immunodeficiencies or autoimmunity where genetic analyses revealed heterozygous AIRE mutations were included in the study and the dominant-negative effects of the AIRE mutations were functionally assessed in vitro. We here report additional families with phenotypes ranging from immunodeficiency, enteropathy, and vitiligo to asymptomatic carrier status. APS-1-specific autoantibodies can hint to the presence of these pathogenic AIRE variants although their absence does not rule out their presence. Our findings suggest functional studies of heterozygous AIRE variants and close follow-up of identified individuals and their families.

PMID:37235056 | PMC:PMC10206195 | DOI:10.1016/j.isci.2023.106818

Powered by WPeMatico

Filed Under: Research

T cell immunity following COVID-19 vaccination in adult patients with primary antibody deficiency – a 22-month follow-up

May 26, 2023 By Manish Butte

Front Immunol. 2023 May 9;14:1146500. doi: 10.3389/fimmu.2023.1146500. eCollection 2023.

ABSTRACT

Primary antibody deficiencies, such as common variable immunodeficiency (CVID), are heterogenous disease entities consisting of primary hypogammaglobulinemia and impaired antibody responses to vaccination and natural infection. CVID is the most common primary immunodeficiency in adults, presenting with recurrent bacterial infections, enteropathy, autoimmune disorders, interstitial lung diseases and increased risk of malignancies. Patients with CVID are recommended to be vaccinated against SARS-CoV-2, but there are relatively few studies investigating humoral and cellular responses to immunization. We studied the dynamics of humoral and cell-mediated immunity responses up to 22 months in 28 patients with primary immunodeficiency and three patients with secondary immunodeficiency receiving ChAdOx1, BNT162b2 and mRNA-1273 COVID-19 vaccines. Despite inadequate humoral response to immunization, we demonstrate a robust T cell activation likely protecting from severe COVID-19.

PMID:37234151 | PMC:PMC10206403 | DOI:10.3389/fimmu.2023.1146500

Powered by WPeMatico

Filed Under: Research

Corrigendum: Vulnerability to meningococcal disease in immunodeficiency due to a novel pathogenic missense variant in NFKB1

May 26, 2023 By Manish Butte

Front Immunol. 2023 May 10;14:1212029. doi: 10.3389/fimmu.2023.1212029. eCollection 2023.

ABSTRACT

[This corrects the article DOI: 10.3389/fimmu.2021.767188.].

PMID:37234149 | PMC:PMC10207328 | DOI:10.3389/fimmu.2023.1212029

Powered by WPeMatico

Filed Under: Research

Immune Responses 6 Months After mRNA-1273 COVID-19 Vaccination and the Effect of a Third Vaccination in Patients with Inborn Errors of Immunity

May 25, 2023 By Manish Butte

J Clin Immunol. 2023 May 26. doi: 10.1007/s10875-023-01514-7. Online ahead of print.

ABSTRACT

PURPOSE: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective long-term protection against COVID-19 is therefore of great importance in these patients, but little is known about the decay of the immune response after primary vaccination. We studied the immune responses 6 months after two mRNA-1273 COVID-19 vaccines in 473 IEI patients and subsequently the response to a third mRNA COVID-19 vaccine in 50 patients with common variable immunodeficiency (CVID).

METHODS: In a prospective multicenter study, 473 IEI patients (including X-linked agammaglobulinemia (XLA) (N = 18), combined immunodeficiency (CID) (N = 22), CVID (N = 203), isolated or undefined antibody deficiencies (N = 204), and phagocyte defects (N = 16)), and 179 controls were included and followed up to 6 months after two doses of the mRNA-1273 COVID-19 vaccine. Additionally, samples were collected from 50 CVID patients who received a third vaccine 6 months after primary vaccination through the national vaccination program. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T cell responses were assessed.

RESULTS: At 6 months after vaccination, the geometric mean antibody titers (GMT) declined in both IEI patients and healthy controls, when compared to GMT 28 days after vaccination. The trajectory of this decline did not differ between controls and most IEI cohorts; however, antibody titers in CID, CVID, and isolated antibody deficiency patients more often dropped to below the responder cut-off compared to controls. Specific T cell responses were still detectable in 77% of controls and 68% of IEI patients at 6 months post vaccination. A third mRNA vaccine resulted in an antibody response in only two out of 30 CVID patients that did not seroconvert after two mRNA vaccines.

CONCLUSION: A similar decline in IgG titers and T cell responses was observed in patients with IEI when compared to healthy controls 6 months after mRNA-1273 COVID-19 vaccination. The limited beneficial benefit of a third mRNA COVID-19 vaccine in previous non-responder CVID patients implicates that other protective strategies are needed for these vulnerable patients.

PMID:37231290 | DOI:10.1007/s10875-023-01514-7

Powered by WPeMatico

Filed Under: Research

Piecing together the subtle clues of common variable immunodeficiency

May 25, 2023 By Manish Butte

JAAPA. 2023 Jun 1;36(6):23-26. doi: 10.1097/01.JAA.0000923544.76902.f9.

ABSTRACT

Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder that results in decreased immunity and increased infection risk. This multisystem disorder often presents as recurrent, prolonged respiratory tract infections. Other manifestations include chronic lung disease, systemic granulomatous disease, malignancies, enteropathy, splenomegaly, and autoimmune disease including cytopenias. Diagnosis often is delayed, affecting patient quality of life, morbidity, and mortality. This article reviews the presentation, diagnosis, and management of patients with CVID.

PMID:37229582 | DOI:10.1097/01.JAA.0000923544.76902.f9

Powered by WPeMatico

Filed Under: Research

Deep phenotypic characterization of the retinal dystrophy in patients with RNU4ATAC-associated Roifman syndrome

May 24, 2023 By Manish Butte

Eye (Lond). 2023 May 24. doi: 10.1038/s41433-023-02581-1. Online ahead of print.

ABSTRACT

PURPOSE: To characterize the retinal phenotype in RNU4ATAC-associated Roifman syndrome.

METHODS: Ten patients (including 8 males) with molecularly confirmed Roifman syndrome underwent detailed ophthalmologic evaluation including fundus imaging, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (SD-OCT), and electroretinography (ERG). Six patients had follow-up eye exams. All patients also underwent comprehensive examination for features of extra-retinal Roifman syndrome.

RESULTS: All patients had biallelic RNU4ATAC variants. Nyctalopia was common (7/10). Visual acuity at presentation ranged from 20/20 to 20/200 (Age Range: 5-41 years). Retinal exam revealed features of generalized retinopathy with mid-peripheral pigment epithelial changes. A para or peri-foveal ring of hyper-autofluorescence was the commonest FAF abnormality noted (6/8). The SD-OCT demonstrated relative preservation of the foveal ellipsoid zone in six cases; associated features included cystoid changes (5/10) and posterior staphyloma (3/10). The ERG was abnormal in all patients; nine showed generalized rod-cone dystrophy, whilst one patient with sectoral retinal involvement only had isolated rod dystrophy (20 years old). On follow-up examination (Mean duration: 8.16 years), progressive loss of visual acuity (2/6), mid-peripheral retinal atrophy (3/6) or shortening of ellipsoid zone width (1/6) were observed.

CONCLUSION: This study has characterized the retinal phenotype in RNU4ATAC-associated Roifman syndrome. Retinal involvement is universal, early-onset, and overall, the retinal and FAF features are consistent with rod-cone degeneration that is slowly progressive over time. The sub-foveal retinal ultrastructure is relatively preserved in majority of patients. Phenotypic variability independent of age exists, and more study of allelic- and sex-based determinants of disease severity are necessary.

PMID:37225827 | DOI:10.1038/s41433-023-02581-1

Powered by WPeMatico

Filed Under: Research

COVID-19 Pneumonia with Migratory Pattern in Agammaglobulinemic Patients: A Report of Two Cases and Review of Literature

May 23, 2023 By Manish Butte

Tomography. 2023 Apr 23;9(3):894-900. doi: 10.3390/tomography9030073.

ABSTRACT

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in serum immunoglobulins and early-onset infections. Coronavirus Disease-2019 (COVID-19) pneumonia in immunocompromised patients presents clinical and radiological peculiarities which have not yet been completely understood. Very few cases of agammaglobulinemic patients with COVID-19 have been reported since the beginning of the pandemic in February 2020. We report two cases of migrant COVID-19 pneumonia in XLA patients.

PMID:37218933 | DOI:10.3390/tomography9030073

Powered by WPeMatico

Filed Under: Research

A brazilian nationwide multicenter study on deficiency of deaminase-2 (DADA2)

May 22, 2023 By Manish Butte

Adv Rheumatol. 2023 May 22;63(1):23. doi: 10.1186/s42358-023-00303-5.

ABSTRACT

INTRODUCTION: The deficiency of ADA2 (DADA2) is a rare autoinflammatory disease provoked by mutations in the ADA2 gene inherited in a recessive fashion. Up to this moment there is no consensus for the treatment of DADA2 and anti-TNF is the therapy of choice for chronic management whereas bone marrow transplantation is considered for refractory or severe phenotypes. Data from Brazil is scarce and this multicentric study reports 18 patients with DADA2 from Brazil.

PATIENTS AND METHODS: This is a multicentric study proposed by the Center for Rare and Immunological Disorders of the Hospital 9 de Julho – DASA, São Paulo – Brazil. Patients of any age with a confirmed diagnosis of DADA2 were eligible for this project and data on clinical, laboratory, genetics and treatment were collected.

RESULTS: Eighteen patients from 10 different centers are reported here. All patients had disease onset at the pediatric age (median of 5 years) and most of them from the state of São Paulo. Vasculopathy with recurrent stroke was the most common phenotype but atypical phenotypes compatible with ALPS-like and Common Variable Immunodeficiency (CVID) was also found. All patients carried pathogenic mutations in the ADA2 gene. Acute management of vasculitis was not satisfactory with steroids in many patients and all those who used anti-TNF had favorable responses.

CONCLUSION: The low number of patients diagnosed with DADA2 in Brazil reinforces the need for disease awareness for this condition. Moreover, the absence of guidelines for diagnosis and management is also necessary (t).

PMID:37217999 | DOI:10.1186/s42358-023-00303-5

Powered by WPeMatico

Filed Under: Research

Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity

May 22, 2023 By Manish Butte

Front Immunol. 2023 May 5;14:1172004. doi: 10.3389/fimmu.2023.1172004. eCollection 2023.

ABSTRACT

PURPOSE: Though copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI.

METHODS: We performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings.

RESULTS: Of the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one participant with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone.

CONCLUSION: Pairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.

PMID:37215141 | PMC:PMC10196392 | DOI:10.3389/fimmu.2023.1172004

Powered by WPeMatico

Filed Under: Research

Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants

May 21, 2023 By Manish Butte

J Allergy Clin Immunol. 2023 May 19:S0091-6749(23)00605-X. doi: 10.1016/j.jaci.2023.04.020. Online ahead of print.

ABSTRACT

BACKGROUND: Inborn errors affecting components of the T-cell receptor signaling cascade cause combined immunodeficiency with various degrees of severity. Recently, homozygous variants in LCP2 were reported to cause pediatric onset of severe combined immunodeficiency with neutrophil, platelet and T- and B-cell defects.

OBJECTIVE: To unravel the genetic cause of combined immunodeficiency and early onset immune dysregulation in a 26-year-old male who presented since early childhood with specific antibody deficiency, autoimmunity and inflammatory bowel disease.

METHODS: The patient was subjected to whole exome sequencing of genomic DNA and examination of blood neutrophils, platelets, T and B cells. Expression levels of SH2 domain-containing leukocyte protein 76kD (SLP76) and tonic and ligand-induced PI3K signaling were evaluated by flowcytometric detection of phosphorylated S6 in B- and T-cells.

RESULTS: Compound heterozygous missense variants were identified in LCP2, affecting the proline rich repeat domain of SLP76 (p.P190R and p.R204W). The patients’ total B- and T-cell numbers were within the normal range, as was platelet function. However, neutrophil function, numbers of unswitched and class switched memory B cells, and serum IgA were decreased. Moreover, intracellular SLP76 protein levels were reduced in patient CD4+ T, CD8+ T, B-, and NK cells. Tonic and ligand-induced levels of phosphorylated S6, and ligand-induced phospho- PLC-γ1 were decreased in patient CD4+ T, CD8+ T and B cells.

CONCLUSIONS: Biallelic variants in LCP2 impair neutrophil function and T-cell and B-cell antigen-receptor signaling, and can cause combined immunodeficiency with early onset immune dysregulation, even in the absence of platelet defects.

PMID:37211057 | DOI:10.1016/j.jaci.2023.04.020

Powered by WPeMatico

Filed Under: Research

  • « Go to Previous Page
  • Go to page 1
  • Go to page 2
  • Go to page 3
  • Go to page 4
  • Interim pages omitted …
  • Go to page 544
  • Go to Next Page »

Copyright © 2023 · Genesis Framework by StudioPress · WordPress · Log in