Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses.
B-cell tolerance
Common variable immunodeficiency
autoimmune cytopenias
commensal bacteria
follicular helper T cell
germinal center responses
regulatory T cell
somatic hypermutation
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
08
11
2017
revised:
29
05
2018
accepted:
01
06
2018
pubmed:
24
6
2018
medline:
13
11
2019
entrez:
24
6
2018
Statut:
ppublish
Résumé
The lack of pathogen-protective, isotype-switched antibodies in patients with common variable immunodeficiency (CVID) suggests germinal center (GC) hypoplasia, yet a subset of patients with CVID is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy. We sought to compare the physical characteristics and immunologic output of GC responses in patients with CVID with AIC (CVID+AIC) and without AIC (CVID-AIC). We analyzed GC size and shape in excisional lymph node biopsy specimens from 14 patients with CVID+AIC and 4 patients with CVID-AIC. Using paired peripheral blood samples, we determined how AICs specifically affected B-and T-cell compartments and antibody responses in patients with CVID. We found that patients with CVID+AIC displayed irregularly shaped hyperplastic GCs, whereas GCs were scarce and small in patients with CVID-AIC. GC hyperplasia was also evidenced by an increase in numbers of circulating follicular helper T cells, which correlated with decreased regulatory T-cell frequencies and function. In addition, patients with CVID+AIC had serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than their counterparts with CVID-AIC. Moreover, IgG Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG
Sections du résumé
BACKGROUND
The lack of pathogen-protective, isotype-switched antibodies in patients with common variable immunodeficiency (CVID) suggests germinal center (GC) hypoplasia, yet a subset of patients with CVID is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy.
OBJECTIVE
We sought to compare the physical characteristics and immunologic output of GC responses in patients with CVID with AIC (CVID+AIC) and without AIC (CVID-AIC).
METHODS
We analyzed GC size and shape in excisional lymph node biopsy specimens from 14 patients with CVID+AIC and 4 patients with CVID-AIC. Using paired peripheral blood samples, we determined how AICs specifically affected B-and T-cell compartments and antibody responses in patients with CVID.
RESULTS
We found that patients with CVID+AIC displayed irregularly shaped hyperplastic GCs, whereas GCs were scarce and small in patients with CVID-AIC. GC hyperplasia was also evidenced by an increase in numbers of circulating follicular helper T cells, which correlated with decreased regulatory T-cell frequencies and function. In addition, patients with CVID+AIC had serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than their counterparts with CVID-AIC. Moreover, IgG
CONCLUSIONS
Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG
Identifiants
pubmed: 29935219
pii: S0091-6749(18)30897-2
doi: 10.1016/j.jaci.2018.06.012
pmc: PMC6400323
mid: NIHMS1512237
pii:
doi:
Substances chimiques
Autoantibodies
0
Immunoglobulin G
0
Types de publication
Clinical Trial
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
258-265Subventions
Organisme : NIAID NIH HHS
ID : R01 AI071087
Pays : United States
Organisme : NIAID NIH HHS
ID : K23 AI137183
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI061093
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI082713
Pays : United States
Organisme : NIAID NIH HHS
ID : K23 AI115001
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Références
Immunity. 2011 Jan 28;34(1):108-21
pubmed: 21215658
J Immunol. 2002 Oct 1;169(7):3777-82
pubmed: 12244172
J Clin Invest. 2016 Nov 1;126(11):4289-4302
pubmed: 27701145
J Clin Immunol. 2014 Aug;34(6):615-26
pubmed: 24789743
J Exp Med. 2013 Mar 11;210(3):457-64
pubmed: 23420879
Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):E2567-75
pubmed: 24821781
J Clin Invest. 2013 Oct;123(10):4283-93
pubmed: 24051380
J Exp Med. 1999 Oct 4;190(7):915-22
pubmed: 10510081
J Exp Med. 2017 Jul 3;214(7):1991-2003
pubmed: 28500047
J Allergy Clin Immunol. 2017 Mar;139(3):913-922
pubmed: 27713077
Blood. 2009 Jul 16;114(3):547-54
pubmed: 19478044
J Exp Med. 2016 Jun 27;213(7):1255-65
pubmed: 27298445
Nat Rev Immunol. 2008 Jan;8(1):34-47
pubmed: 18064051
Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13135-40
pubmed: 9789054
Science. 2003 Sep 5;301(5638):1374-7
pubmed: 12920303
J Allergy Clin Immunol. 2009 Aug;124(2):349-56, 356.e1-3
pubmed: 19592080
Blood. 2010 Jun 17;115(24):5026-36
pubmed: 20231422
Annu Rev Immunol. 2012;30:429-57
pubmed: 22224772
Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13451-6
pubmed: 19666505
Clin Immunol. 2015 Jul;159(1):33-6
pubmed: 25939554
Blood. 2002 Mar 1;99(5):1544-51
pubmed: 11861266
Sci Transl Med. 2015 Aug 26;7(302):302ra135
pubmed: 26311730
J Allergy Clin Immunol Pract. 2016 Jan-Feb;4(1):38-59
pubmed: 26563668
J Exp Med. 2014 Sep 22;211(10):2033-45
pubmed: 25225461