Primary B-Cell Deficiencies Reveal a Link between Human IL-17-Producing CD4 T-Cell Homeostasis and B-Cell Differentiation

Barbosa, Raquel; Silva, Sara P.; Silva, Susana L.; Melo, Alcinda Campos; Pedro, Elisa; Barbosa, Miguel; Pereira-Santos, Maria Conceição; Victorino, Rui M. M.; Sousa, Ana E.

doi:10.1371/journal.pone.0022848

Cited by 65 publications

(88 citation statements)

References 49 publications

(73 reference statements)

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“…Moreover, mRNA levels of IL-17 and RORC2 were much lower in these patients than in healthy controls, although a slight reduction in IL-23R expression has been observed in CVID patients [49]. As IL-17 and possibly T H 17 cells can contribute to germinal center function [50], these findings are consistent with the results of Barbosa et al, who propose that levels of IL-17 and T H 17 cells correlate negatively with the pathological expansion of a B-cell population associated with impaired germinal center function in CVID [48]. In addition, IL-17 is also produced by follicular helper CD4 + T cells.…”

Section: Helper T-cell Defectssupporting

confidence: 85%

“…However, Barbosa et al [15] found no increase in the frequency of T H 17 cells in CVID patients with autoimmune manifestations, even when CVID patients were subdivided based on the type of autoimmune disorder, including organ-specific autoimmunity and autoimmune cytopenias. In contrast, the CD21 low B-cell subset was significantly increased in CVID patients with autoimmunity [15,48]. In conclusion, no obvious association between autoimmune manifestations and frequency of T H 17 cells and their proinflammatory cytokines was observed in CVID patients.…”

Section: Helper T-cell Defectsmentioning

confidence: 69%

“…In contrast, the authors showed a negative correlation between T H 17 cells and expansion of activated nondifferentiated CD21 low B cells. Therefore, the decline in the frequency of circulating T H 17 cells is matched by B-cell disturbances, a representative feature of germinal center disruption [48]. Moreover, the frequency of T H 17 cells correlated negatively with activated CD4 + T cells in patients with CVID, while there was no correlation with naive and memory T-cell balances.…”

Section: Helper T-cell Defectsmentioning

confidence: 92%

“…Barbosa et al [48] were the first authors to report a decline in the frequency of circulating T H 17 cells in CVID patients. No association was demonstrated between the frequency of T H 17 cells and transitional B cells.…”

Section: Helper T-cell Defectsmentioning

confidence: 99%

“…+ T cells and positively with levels of activated CD4 + T cells in CVID patients [48]. Ganjalikhani-Hakemi et al [49] evaluated T H 17 cell-specific gene expression in CVID patients.…”

Section: Helper T-cell Defectsmentioning

confidence: 99%

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T-Cell Abnormalities in Common Variable Immunodeficiency

Azizi

Rezaei

Kiaee

et al. 2016

J Investig Allergol Clin Immunol

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Common variable immunodeficiency (CVID) is the most common clinical primary immunodeficiency. It is characterized by a defect in B-cell differentiation to plasma and memory B cells. Moreover, numerous T-cell abnormalities have been reported and include decreased T-cell count and proliferative response, increased T-cell activation and apoptosis, and abnormalities in cytokine production. The aims of this review are to describe phenotypic and functional defects in T cells in CVID patients and to review the literature with respect to the effects of immunoglobulin replacement on the T-cell component in CVID patients. Key words: Common variable immunodeficiency. T cell. Helper T cells. Regulatory T cells. ResumenLa inmunodeficiencia común variable (CVID) es la inmunodeficiencia primaria más frecuente. Se caracteriza por un defecto en la diferenciación de linfocitos B hacia células plasmáticas y linfocitos B memoria. Se han descrito numerosas alteraciones en los linfocitos T de estos pacientes, tales como disminución en el número de linfocitos T y en sus respuestas proliferativas, aumento en la activación de células T y en la apoptosis, así como alteraciones en la producción de citokinas. El objetivo de esta revisión es describir las alteraciones funcionales y fenotípicas de los linfocitos T en los pacientes con CVID y revisar la bibliografía en relación a los efectos que la administración de inmunoglobulinas produce en los linfocitos T de los pacientes con CVID. Palabras clave: Inmunodeficiencia común variable. Células T. Células T helper. Células T reguladoras.

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Section: Helper T-cell Defectssupporting

confidence: 85%

Section: Helper T-cell Defectsmentioning

confidence: 69%

Section: Helper T-cell Defectsmentioning

confidence: 92%

Section: Helper T-cell Defectsmentioning

confidence: 99%

“…+ T cells and positively with levels of activated CD4 + T cells in CVID patients [48]. Ganjalikhani-Hakemi et al [49] evaluated T H 17 cell-specific gene expression in CVID patients.…”

Section: Helper T-cell Defectsmentioning

confidence: 99%

See 3 more Smart Citations

T-Cell Abnormalities in Common Variable Immunodeficiency

Azizi

Rezaei

Kiaee

et al. 2016

J Investig Allergol Clin Immunol

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Defective formation of IgA memory B cells, Th1 and Th17 cells in symptomatic patients with selective IgA deficiency

et al. 2020

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Objective. Selective IgA deficiency (sIgAD) is the most common primary immunodeficiency in Western countries. Patients can suffer from recurrent infections and autoimmune diseases because of a largely unknown aetiology. To increase insights into the pathophysiology of the disease, we studied memory B and T cells and cytokine concentrations in peripheral blood. Methods. We analysed 30 sIgAD patients (12 children, 18 adults) through detailed phenotyping of peripheral B-cell, CD8 + T-cell and CD4 + Tcell subsets, sequence analysis of IGA and IGG transcripts, in vitro B-cell activation and blood cytokine measurements. Results. All patients had significantly decreased numbers of T-cell-dependent (TD; CD27 + ) and T-cell-independent (TI; CD27 À ) IgA memory B cells and increased CD21 low B-cell numbers. IgM + IgD À memory B cells were decreased in children and normal in adult patients. IGA and IGG transcripts contained normal SHM levels. In sIgAD children, IGA transcripts more frequently used IGA2 than controls (58.5% vs. 25.1%), but not in adult patients. B-cell activation after in vitro stimulation was normal. However, adult sIgAD patients exhibited increased blood levels of TGF-b1, BAFF and APRIL, whereas they had decreased Th1 and Th17 cell numbers. Conclusion. Impaired IgA memory formation in sIgAD patients is not due to a B-cell activation defect. Instead, decreased Th1 and Th17 cell numbers and high blood levels of BAFF, APRIL and TGF-b1 might reflect disturbed regulation of IgA responses in vivo.These insights into B-cell extrinsic immune defects suggest the need for a broader ª immunological focus on genomics and functional analyses to unravel the pathogenesis of sIgAD.

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IL‐17‐producing CD4⁺ T cells contribute to the loss of B‐cell tolerance in experimental autoimmune myasthenia gravis

et al. 2015

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The role of Th17 cells in the pathogenesis of autoantibody-mediated diseases is unclear. Here, we assessed the contribution of Th17 cells to the pathogenesis of experimental autoimmune myasthenia gravis (EAMG), which is induced by repetitive immunizations with Torpedo californica acetylcholine receptor (tAChR). We show that a significant fraction of tAChR-specific CD4+ T cells is producing IL-17. ko and WT mice (n = 15/group) as described in the Materials and methods. The cumulative results of (A) EAMG disease score and (B) the percentage of incidence are shown as mean ± SEM and are pooled from two independent experiments. * = p < 0.05, *** = p < 0.001 (two-tailed Mann-Whitney U test).autoimmunity has been clearly demonstrated, their contribution to autoantibody-mediated diseases has only been indirectly suggested [2,3]. Myasthenia gravis (MG) is a prototypic antibodymediated autoimmune disease caused by binding of antibodies to the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction, which eventually leads to muscle weakness [4,5] Results Less EAMG symptoms in IL-17 ko miceIn order to assess the role of IL-17 in EAMG disease development, we immunized WT and IL-17 ko mice with tAChR in CFA and evaluated disease symptoms. While some animals already developed mild transient signs of EAMG after the 2nd immunization, more severe muscle weakness did not appear until after the 3rd immunization and then only in WT mice. Altogether, muscle fatigability became evident in the majority, i.e. around 75%, of WT mice (Fig. 1A and B) after the 3rd immunization, while most IL-17 ko mice remained symptom-free and mild muscle weakness was detected in only about 25% of the immunized IL-17 ko mice ( Fig. 1A and B). These findings clearly confirm the contribution of IL-17 to EAMG pathogenesis. T cell differentiation in EAMG does not differ between WT and IL-17 ko miceNext, we investigated whether significant numbers of tAChRspecific Th17 cells can be detected in EAMG. At 2 weeks after each immunization, blood was taken from WT mice and stimulated with a tAChR peptide pool containing the immunodominant tAChR 146-162 peptide [20]. Then the resulting tAChR-specific cytokine production was analyzed. In peripheral blood a significant frequency of CD4 + T cells expressing IL-17 after stimulation with the tAChR peptide pool was already identified at two weeks after the first immunization (Supporting Information Fig. 1). While these cells were still observed at later time points, no further increase was detected after the booster immunizations. Confirming earlier reports [21,22], even after three immunizations we were not able to detect a specific expression of CD40L, IFN-γ, or IL-17 after stimulation with murine AChR peptides (Supporting Information Fig. 2).Since the complete absence of IL-17 might have an impact on T-cell priming in our model, we then analyzed in detail the generation of anti tAChR-specific CD4 + T cells in WT in relation to IL-17 ko mice in EAMG.Splenocytes isolated from WT and IL-17 ko mice that had ...

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Primary B-Cell Deficiencies Reveal a Link between Human IL-17-Producing CD4 T-Cell Homeostasis and B-Cell Differentiation

Cited by 65 publications

References 49 publications

T-Cell Abnormalities in Common Variable Immunodeficiency

T-Cell Abnormalities in Common Variable Immunodeficiency

Defective formation of IgA memory B cells, Th1 and Th17 cells in symptomatic patients with selective IgA deficiency

IL‐17‐producing CD4⁺ T cells contribute to the loss of B‐cell tolerance in experimental autoimmune myasthenia gravis

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Primary B-Cell Deficiencies Reveal a Link between Human IL-17-Producing CD4 T-Cell Homeostasis and B-Cell Differentiation

Cited by 65 publications

References 49 publications

T-Cell Abnormalities in Common Variable Immunodeficiency

T-Cell Abnormalities in Common Variable Immunodeficiency

Defective formation of IgA memory B cells, Th1 and Th17 cells in symptomatic patients with selective IgA deficiency

IL‐17‐producing CD4+ T cells contribute to the loss of B‐cell tolerance in experimental autoimmune myasthenia gravis

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IL‐17‐producing CD4⁺ T cells contribute to the loss of B‐cell tolerance in experimental autoimmune myasthenia gravis