Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation

Alroqi, Fayhan; Charbonnier, Louis-Marie; Barış, Safa; Kıykım, Ayça; Chou, Janet; Platt, Craig D.; Algassim, Abdulrahman; Keleş, Sevgi; Saud, Bandar K. Al; Alkuraya, Fowzan S.; Jordan, Michael B.; Geha, Raif S.; Chatila, Talal A.

doi:10.1016/j.jaci.2017.05.022

Cited by 88 publications

(68 citation statements)

References 38 publications

(61 reference statements)

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“…However, in contrast to several documented reports regarding the positive correlation of Th17 and IL‐17 with autoimmune disorders, we found that LRBA‐deficient patients have lower peripheral Th17 cells and IL‐17 than in HCs. Our findings were similar to those by Alroqi et al (), who identified that the expression of the Th17‐associated chemokine receptor CCR6 and IL‐17 was markedly decreased in LRBA‐deficient patients, while TFH cells highly expressed the Th1‐associated chemokine receptor CXCR3 and IFN‐γ, compared with HCs. Interestingly, our results showed that LRBA‐deficient patients have higher IL‐17 and IFN‐γ‐double producing cells (Th1‐like Th17 cells) than those in HCs.…”

Section: Discussionsupporting

confidence: 91%

“…On the other hand, Charbonnier et al (2015) documented that patients with LRBA deficiency exhibit dysregulated circulating T follicular helper (TFH) cells (a phenotype related to several human autoimmune diseases), due to the profound deficiency of CTLA4 expression by Treg cells (Lo et al, 2015). Recently, Alroqi et al (2017) confirmed previous reports and proposed that TFH dysregulation in LRBA deficiency was not due to an intrinsic abnormality in TFH cells; rather, it reflects the failure of LRBA-deficient Treg cells to control TFH cell differentiation as well as suppression of other effector T cells.…”

Section: Discussionmentioning

confidence: 99%

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The imbalance of circulating T helper subsets and regulatory T cells in patients with LRBA deficiency: Correlation with disease severity

Azizi

Mirshafiey

Abolhassani

et al. 2018

Journal Cellular Physiology

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Patients with lipopolysaccharides responsive beige-like anchor protein (LRBA) deficiency suffer from a variety of immunological abnormalities. In the current study, we investigated the role of T helper (Th) cell subsets and regulatory T (Treg) cells and their related cytokines and transcription factors in the immune dysregulation of LRBA deficiency. The study population comprised of 13 LRBA-deficient patients and 13 age- and sex-matched healthy controls (HCs). Th subsets and Treg were examined by flow cytometry. The expression of determinant cytokines (interferon-γ [IFN-γ], interleukin [IL]-17, IL-22, and IL-10), and cell subset-specific transcription factors were evaluated before and after proliferation and activation stimuli. The frequencies of Th1, Th1-like Th17 and Th22 cells along with the expression of T-box transcription factor (TBET) and runt-related transcription factor 1 (RUNX1) were significantly increased in patients with LRBA. Moreover, IFN-γ and IL-22 production in LRBA-deﬁcient CD4 T cells were elevated after lymphocyte stimulation, particularly in patients with enteropathy. However, CD4 CD25 FoxP3 CD127 cells were significantly decreased in LRBA-deficient patients compared with those of HCs, particularly in patients with autoimmunity. There was a negative correlation between the frequencies of CD4 CD25 FoxP3 CD127 cells and Th1-like Th17 cells in LRBA-deficient patients, and an overlapping phenotype of autoimmunity and enteropathy were observed in ~70% of patients. The frequency of Th17 cells was lower in patients with enteropathy, while Th1-like Th17 cells were higher than in those without enteropathy. Our findings demonstrated an imbalance in Th subsets, mainly in Th1-like Th17 and Treg cells and their corresponding cytokines in LRBA deficiency, which might be important in the immunopathogenesis of autoimmunity and enteropathy.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

The imbalance of circulating T helper subsets and regulatory T cells in patients with LRBA deficiency: Correlation with disease severity

Azizi

Mirshafiey

Abolhassani

et al. 2018

Journal Cellular Physiology

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“…Indeed, different murine models have demonstrated that CTLA-4 deletion led to autoimmune manifestations with increased Tfr cells (in both lymph nodes and blood). 162,[174][175][176] Overall, our findings suggest that immunopathogenic stratification of SS patients could be achieved through quantification of blood Tfh-and Tfr-cell subsets. 37,38 In humans, monogenic defects involving CTLA-4 and its intracellular trafficking regulator lead to a primary immunodeficiency characterized by recurrent infections and autoimmunity (characterized by inflammatory bowel disease, autoimmune endocrinopathies, and cytopenias).…”

Section: Tfr Cells For Clinical Precision Immunologymentioning

confidence: 64%

“…15,16,45,51 A possible explanation may be a Tfr-cell expansion as an attempt to restore immune tolerance. [167][168][169][170][171][172][173][174][175] In these patients, as well as in SS patients, treatment with CTLA-4-Ig (Abatacept) was found to partially restore immune homeostasis. 37,38 These mice developed spontaneous GCs, suggesting that expansion of Tfr cells can occur concomitantly with autoimmunity, as far as Tfr cells are defective in their regulation ability.…”

Section: Tfr Cells For Clinical Precision Immunologymentioning

confidence: 99%

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

Fonseca

Ribeiro

Graça

2019

Immunological Reviews

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Summary Germinal centers (GC) have been known as key anatomic structures in humoral immunity, where isotype switching and affinity maturation occur. As a consequence, elucidation of GC regulation has potential implications for the understanding of autoantibody‐mediated diseases. It is now accepted that different regulatory mechanisms coexist, including the action of a specialized population of Foxp3+ regulatory T cells with unique access to the B‐cell follicle: the T follicular regulatory (Tfr) cells. Tfr cells develop through a multistep process requiring migration through different compartments of lymphoid tissues. This review discusses the ontogeny and physiology of Tfr cells, their distribution within distinct anatomic compartments, and their function. A greater understanding of Tfr biology and GC regulation is likely to lead to better stratification of patients with autoantibody‐mediated diseases, and to the identification of novel therapeutic targets.

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“…Primary immune regulatory disorders associated with monogenic defects of genes involved in immune regulatory pathways have been recently identified in patients with multisystem autoimmunity and immunodeficiency. Organ‐specific autoimmunity such as autoimmune cytopenia (AIC), inflammatory bowel disease, autoimmune endocrinopathy, and arthritis are the presenting features in many of these patients, as well as hyperinflammation and nonmalignant lymphoproliferation . Advances in genetic sequencing have supported an expanding list of genetic defects in immune regulatory pathways leading to primary immune regulatory disorders.…”

Section: Introductionmentioning

confidence: 99%

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case‐based review

Chandrakasan

Chandra

Saldaña

et al. 2019

Pediatric Blood & Cancer

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An array of monogenic immune defects marked by autoimmunity, lymphoproliferation, and hyperinflammation rather than infections have been described. Primary immune regulatory disorders pose a challenge to pediatric hematologists and oncologists. This paper focuses on primary immune regulatory disorders including autoimmune lymphoproliferative syndrome (ALPS) and ALPS‐like syndromes, immunodysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) and IPEX‐like disorders, common variable immunodeficiency (CVID), CVID‐like, and late‐onset combined immunodeficiency (CID) disorders. Hyperinflammatory disorders and those associated with increased susceptibility to lymphoid malignancies are also discussed. Using a case‐based approach, a review of clinical pearls germane to the clinical and laboratory evaluation as well as the treatment of these disorders is provided.

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Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation

Cited by 88 publications

References 38 publications

The imbalance of circulating T helper subsets and regulatory T cells in patients with LRBA deficiency: Correlation with disease severity

The imbalance of circulating T helper subsets and regulatory T cells in patients with LRBA deficiency: Correlation with disease severity

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case‐based review

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