Functions of Tfh Cells in Common Variable Immunodeficiency

Saos-Patrinos, Corentin Le; Loizon, Séverine; Blanco, Patrick; Viallard, Jean‐François; Duluc, Dorothée

doi:10.3389/fimmu.2020.00006

Cited by 19 publications

(15 citation statements)

References 83 publications

(101 reference statements)

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“…Low (naïve) CD4 T cells are associated with complications and a poor prognosis in CVID[ 71 ]. Recent publications show an involvement of follicular T cells in CVID pathogenesis[ 72 ]. An increase of circulating memory CXCR5 + CD4 T cells in CVID patients with non-infectious complications has been reported[ 73 ].…”

Section: Laboratory Manifestationsmentioning

confidence: 99%

From infections to autoimmunity: Diagnostic challenges in common variable immunodeficiency

Więsik-Szewczyk

Jahnz-Różyk

2020

WJCC

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Common variable immunodeficiency (CVID) is the most common clinically significant primary antibody deficiency diagnosed in adults. The early symptoms are not specific. They include common infections, mainly of the respiratory tract, caused by typical microorganisms, so cases can be missed in primary care. In the majority of patients increased susceptibility to infections coexists with signs or symptoms of autoimmunity, inflammation or polyclonal lymphoproliferation, which can divert diagnosis from immune deficiency. The overall incidence of malignancy is increased in CVID and certain cancers are significantly more common. Lymphomas and gastric carcinoma are the most frequently reported malignancies in CVID, so a high index of suspicion is recommended. Diagnostic delay in CVID is seen worldwide. The main goal of this paper is to increase the awareness about CVID among health care professionals. We aim to present features which can be helpful in CVID diagnosis in order to shorten the “latency” of proper management of CVID patients. We review clinical symptoms, complications and laboratory abnormalities of CVID. Immunoglobulin replacement therapy is regarded as the cornerstone of pharmacological intervention. New modes of Ig application, mainly subcutaneously and via the hyaluronidase-facilitated subcutaneous route, help to adjust therapy to patients’ needs and preferences. Still there remain unmet needs. It remains to be seen whether CVID complications can be avoided by earlier diagnosis, treatment and thorough monitoring in the context of increased risk of malignancy. Development of patient tailored protocols depending on the clinical phenotype and risk factors might be more appropriate. The most important consideration is to diagnose suspected cases and stratify patients in a precise and timely way. Work is needed to define features predictive of unfavorable prognosis.

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Section: Laboratory Manifestationsmentioning

confidence: 99%

From infections to autoimmunity: Diagnostic challenges in common variable immunodeficiency

Więsik-Szewczyk

Jahnz-Różyk

2020

WJCC

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“…CVID is a collection of disorders of humoral dysregulation resulting in low IgG and Ig/IgM levels and antibody-specific responses with recurrent infections (43). Several previous studies have addressed the immunologic components of CVID in the peripheral blood and tissues of the affected patients and it showed that the B cell and Tfh cell profile are able to determine different forms of the disease (11). Our flow cytometry and RNA seq analyses of Tfh cells separated our cohort of CVID patients into two distinct groups, one of which was characterized by a pronounced splenomegaly and lymphadenopathy.…”

Section: Discussionmentioning

confidence: 79%

“…For instance, a reduction in the number and percentage of isotype-switched B cells (4-5) as well as a loss of plasma cells in the bone marrow and mucosal tissues has been reported (9); on the other hand, T follicular helper (Tfh) cells, which drive T cell-dependent humoral immunity in germinal centres (GCs), were shown to underpin CVID development in some patients (10). A predominant Th1 phenotype and altered Tfh function have beed described in patients affected by CVID with various manifestations of immune dysregulation (11). Follicular regulatory T cells (Tfr) safeguard the function of Tfh cells limiting AI and excessive GC reactions.…”

Section: Introductionmentioning

confidence: 99%

Follicular helper T cell signature of replicative exhaustion, apoptosis and senescence in common variable immunodeficiency

Milardi

Gerosa

et al. 2021

Preprint

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Background: Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency. A significant number of CVID patients are affected by various manifestations of immune dysregulation such as autoimmunity. Follicular T cells cells are thought to support the development of CVID by providing inappropriate signals to B cells during the germinal center (GC) response. Objectives: We determined the possible role of follicular helper (Tfh) and follicular regulatory T (Tfr) cells in patients with CVID by phenotypic, molecular, and functional studies. Methods: We analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh cells in the peripheral blood of 27 CVID patients (11 pediatric and 16 adult) displaying autoimmunity as additional phenotype and compared them to 106 (39 pediatric and 67 adult) age-matched healthy controls. We applied Whole Exome Sequencing (WES) and Sanger sequencing to identify mutations that could account for the development of CVID and associate with Tfh alterations. Results: A group of CVID patients (n=9) showed super-physiological frequency of Tfh1 cells and a prominent expression of PD-1 and ICOS, as well as a Tfh RNA signature consistent with highly active, but exhausted and apoptotic cells. Plasmatic CXCL13 levels were elevated in these patients and positively correlated with Tfh1 cell frequency, PD-1 levels, and an elevated frequency of CD21loCD38lo autoreactive B cells. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were ideintified in four patients belonging to this group. Lymphocytes with highly shortened telomeres, and a Tfh signature enriched in genes involved in telomere elongation and response to DNA damage were seen. Histopathological analysis of the spleen in one patient showed reduced amount and size of the GC that, unexpectedly, contained an increased number of Tfh cells. Conclusion: These data point toward a novel pathogenetic mechanism in a group of patients with CVID, whereby alterations in DNA repair and telomere elongation might be involved in GC B cells, and acquisition of a Th1, highly activated but exhausted and apoptotic phenotype by Tfh cells.

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“…Although the ESID criteria require the exclusion of profound T-cell immunodeficiency, and since it is also not clear whether individuals with proven T-cell defects should be considered as CVID affected [ 113 , 114 ], most authors are inclined to favour the theory that abnormalities in T-cell function are common among patients with CVID [ 115 , 116 ]. These abnormalities comprise aberrations in the total numbers, percentages, surface markers, and function of various T-cell subpopulations [ 115 ].…”

Section: Common Variable Immunodeficiencymentioning

confidence: 99%

Primary Humoral Immune Deficiencies: Overlooked Mimickers of Chronic Immune-Mediated Gastrointestinal Diseases in Adults

Malesza

Krela‐Kaźmierczak

et al. 2020

IJMS

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In recent years, the incidence of immune-mediated gastrointestinal disorders, including celiac disease (CeD) and inflammatory bowel disease (IBD), is increasingly growing worldwide. This generates a need to elucidate the conditions that may compromise the diagnosis and treatment of such gastrointestinal disorders. It is well established that primary immunodeficiencies (PIDs) exhibit gastrointestinal manifestations and mimic other diseases, including CeD and IBD. PIDs are often considered pediatric ailments, whereas between 25 and 45% of PIDs are diagnosed in adults. The most common PIDs in adults are the selective immunoglobulin A deficiency (SIgAD) and the common variable immunodeficiency (CVID). A trend to autoimmunity occurs, while gastrointestinal disorders are common in both diseases. Besides, the occurrence of CeD and IBD in SIgAD/CVID patients is significantly higher than in the general population. However, some differences concerning diagnostics and management between enteropathy/colitis in PIDs, as compared to idiopathic forms of CeD/IBD, have been described. There is an ongoing discussion whether CeD and IBD in CVID patients should be considered a true CeD and IBD or just CeD-like and IBD-like diseases. This review addresses the current state of the art of the most common primary immunodeficiencies in adults and co-occurring CeD and IBD.

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Functions of Tfh Cells in Common Variable Immunodeficiency

Cited by 19 publications

References 83 publications

From infections to autoimmunity: Diagnostic challenges in common variable immunodeficiency

From infections to autoimmunity: Diagnostic challenges in common variable immunodeficiency

Follicular helper T cell signature of replicative exhaustion, apoptosis and senescence in common variable immunodeficiency

Primary Humoral Immune Deficiencies: Overlooked Mimickers of Chronic Immune-Mediated Gastrointestinal Diseases in Adults

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