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Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

ABSTRACT: Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities.We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects.Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK.Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-? and programmed death 1. IFN-? inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations.Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-? functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.

SUBMITTER: Ma CS

PROVIDER: S-EPMC5042203 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

Ma Cindy S CS Wong Natalie N Rao Geetha G Avery Danielle T DT Torpy James J Hambridge Thomas T Bustamante Jacinta J Okada Satoshi S Stoddard Jennifer L JL Deenick Elissa K EK Pelham Simon J SJ Payne Kathryn K Boisson-Dupuis Stéphanie S Puel Anne A Kobayashi Masao M Arkwright Peter D PD Kilic Sara Sebnem SS El Baghdadi Jamila J Nonoyama Shigeaki S Minegishi Yoshiyuki Y Mahdaviani Seyed Alireza SA Mansouri Davood D Bousfiha Aziz A Blincoe Annaliesse K AK French Martyn A MA Hsu Peter P Campbell Dianne E DE Stormon Michael O MO Wong Melanie M Adelstein Stephen S Smart Joanne M JM Fulcher David A DA Cook Matthew C MC Phan Tri Giang TG Stepensky Polina P Boztug Kaan K Kansu Aydan A İkincioğullari Aydan A Baumann Ulrich U Beier Rita R Roscioli Tony T Ziegler John B JB Gray Paul P Picard Capucine C Grimbacher Bodo B Warnatz Klaus K Holland Steven M SM Casanova Jean-Laurent JL Uzel Gulbu G Tangye Stuart G SG

The Journal of allergy and clinical immunology 20150707 4

<h4>Background</h4>Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities.<h4>Objective</h4>We sought to determine the signa ...[more]

PMID: 26162572

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Project description:BackgroundEosinophilia is not an uncommon clinical finding. However, diagnosis of its cause can be a dilemma once common culprits, namely infection, allergy and reactive causes are excluded. Primary immunodeficiency disorders (PID) are among known differentials of eosinophilia. However, the list of PIDs typically reported with eosinophilia is small and the literature lacks an inclusive list of PIDs which have been reported with eosinophilia. This motivated us to review the literature for all PIDs which have been described to have elevated eosinophils as this may contribute to an earlier diagnosis of PID and further the understanding of eosinophilia.MethodsA retrospective PubMed, and Google Scholar search using the terms "eosinophilia" and "every individual PID" as classified by Expert Committee of the International Union of Immunological Societies with the limit of the English language was performed. Results were assessed to capture case(s) which reported eosinophilia in the context of PID conditions. Absolute eosinophil counts (AEC) were retrieved from manuscripts whenever reported.ResultsIn addition to the typical PID conditions described with eosinophilia, we document that MHC class II deficiency, CD3γ deficiency, STAT1 deficiency (AD form), Kostmann disease, cyclic neutropenia, TCRα deficiency, Papillon-Lefevre syndrome, CD40 deficiency, CD40L deficiency, anhidrotic ectodermal dysplasia with immune deficiency, ataxia-telangiectasia, common variable immunodeficiency disorders (CVID), Blau syndrome, CARD9 deficiency, neonatal onset multisystem inflammatory disease or chronic infantile neurologic cutaneous and articular syndrome (NOMID/CINCA), chronic granulomatous disease, MALT1 deficiency and Roifman syndrome have been noted to have elevated eosinophils. Severe eosinophilia (>5.0 × 10(9)/L) was reported in Omenn syndrome, Wiskott Aldrich syndrome, ADA deficiency, autoimmune lymphoproliferative syndrome, immunodysregulation polyendocrinopathy enteropathy X-linked, STAT3 deficiency, DOCK8 deficiency, CD40 deficiency, MHC II deficiency, Kostmann disease, Papillon-Lefevre syndrome, and CVID.ConclusionsThis literature review shows that there is an extensive list of PIDs which have been reported with eosinophilia. This list helps clinicians to consider an extended differential diagnoses when tasked with exclusion of PID as a cause for eosinophilia.

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Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

Publications

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

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