The TH1 phenotype of follicular helper T cells indicates an IFN-γ–associated immune dysregulation in patients with CD21low common variable immunodeficiency

Unger, Susanne; Seidl, Maximilian; Schouwenburg, Pauline A. van; Rakhmanov, Mirzokhid; Bulashevska, Alla; Frede, Natalie; Grimbacher, Bodo; Pfeiffer, Jens; Schrenk, Klaudia; Muñoz, Luis; Hanitsch, Leif G.; Stumpf, Ina; Kaiser, Fabian; Hausmann, Oliver; Kollert, Florian; Goldacker, Sigune; Burg, Mirjam van der; Keller, Baerbel; Warnatz, Klaus

doi:10.1016/j.jaci.2017.04.041

Cited by 112 publications

(117 citation statements)

References 60 publications

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“…As explained earlier, TFH can be divided into two subsets: the non-efficient helper TFH1 and the efficient helpers TFH2 and TFH17. Interestingly, we (75) and others (77,78,80) highlight a specific increase of the circulating TFH1 only in non-infectious CVID patients. Moreover, CXCR3 + (75) or Tbet + (78) cells were amplified in secondary lymphoid organs of CVID patients, suggesting that the blood observations reflect the GC counterpart.…”

Section: Tfh and Cvidsupporting

confidence: 50%

“…Interestingly, our group (75) and others (76)(77)(78) observed an increase of circulating TFH (memory CXCR5 + CD4 T cells) in CVID patients harboring non-infectious complications. Moreover, TFH expressing PD-1 were present at higher levels in CVID patients with complications (75)(76)(77)(78). Patients classified as smB − based on the EUROClass have <2% of switched memory B cells among circulating CD19 + cells (12).…”

Section: Tfh and Cvidmentioning

confidence: 71%

“…As TFH1 are good IFNγ producers and are increased in patients, one may hypothesize involvement of this cytokine in CVID pathogenesis. Surprisingly, even though two groups observed enhanced IFNγ production by TFH in CVID patients (77,78) (78). Moreover, the impact of IFNγ on CD21 low cell generation and/or on autoreactive B cell activation has not been directly addressed, therefore still awaiting determination.…”

Section: Tfh and Cvidmentioning

confidence: 98%

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Functions of Tfh Cells in Common Variable Immunodeficiency

et al. 2020

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Common variable immunodeficiency is the most common clinical primary immunodeficiency in adults. Its hallmarks are hypogammaglobulinemia and compromised B-cell differentiation into memory or antibody-secreting cells leading to recurrent infections. This disease is heterogeneous, with some patients harboring multiple complications such as lymphoproliferative disorders, autoimmune manifestations, or granulomatous inflammation. The mechanisms leading to these complications remain elusive despite numerous associations found in the literature. For instance, although described as a B cell intrinsic disease, numerous abnormalities have been reported in other immune cell compartments. Here, we tuned our attention to follicular helper T cells, a CD4 + T cell population specialized in B cell help, considering the recent publications showing an involvement of these cells in CVID pathogenesis.

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Section: Tfh and Cvidsupporting

confidence: 50%

Section: Tfh and Cvidmentioning

confidence: 71%

Section: Tfh and Cvidmentioning

confidence: 98%

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Functions of Tfh Cells in Common Variable Immunodeficiency

et al. 2020

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“…The excessive IL-12 production we have seen in our patients seems to be clinically relevant since this was associated with skewing of helper T cells towards a predominantly Th1 phenotype. A recent study in CVID patients showed that skewed Th1 phenotype of follicular helper cells was associated with immune dysregulation and inflammatory complications [32]. We used findings from our study to select a targeted therapy for one of the patients (P16) with several inflammatory complications (granuloma role of IL-12).…”

Section: Discussionmentioning

confidence: 99%

Expanding Clinical Phenotype and Novel Insights into the Pathogenesis of ICOS Deficiency

et al. 2019

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Background Inducible T cell co-stimulator (ICOS) deficiency has been categorized as a combined immunodeficiency often complicated by enteropathies, autoimmunity, lymphoproliferation, and malignancy. We report seven new patients and four novel ICOS mutations resulting in a common variable immunodeficiency (CVID)-like phenotype and show that dysregulated IL-12 release, reduced cytotoxic T lymphocyte-associated protein 4 (CTLA4) expression, and skewing towards a Th1-dominant phenotype are all associated with inflammatory complications in this condition. Methods A combination of whole exome and Sanger sequencing was used to identify novel mutations. Standard clinical and immunological evaluation was performed. FACS and ELISA-based assays were used to study cytokine responses and ICOS/ICOSL/CTLA4 expression following stimulation of whole blood and PBMCs with multiple TLR ligands, anti-CD3, and PHA. Results Four novel ICOS mutations included homozygous c.323_332del, homozygous c.451C>G, and compound heterozygous c.58+1G>A/c.356T>C. The predominant clinical phenotype was that of antibody deficiency associated with inflammatory complications in 4/7 patients. Six out of seven patients were treated with immunoglobulin replacement and one patient died from salmonella sepsis. All patients who were tested showed reduced IL-10 and IL-17 cytokine responses, normal IL-1β, IL6, and TNF release following LPS stimulation and highly elevated IL-12 production in response to combined LPS/IFNγ Hassan Abolhassani and Yasser M. El-Sherbiny contributed equally to this work.

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“…Similarly, several abnormalities in immune cells' counts and function, in different combinations and in association with specific clinical features, have been described in CVID patients. Among these, the reduction of class-switched memory B cells and/or plasmablasts (9,10), the expansion of transitional B cells and/or CD21low B cells (11,12), the reduction of naive T cell and/or Treg cell, and the increase of peripheral blood T FH cells (13,14), are the most remarkable.…”

Section: Introductionmentioning

confidence: 99%