Primary Immune Regulatory Disorders and Targeted Therapies

Kolukisa, Burcu; Barış, Safa

doi:10.4274/tjh.galenos.2021.2020.0724

Cited by 9 publications

(8 citation statements)

References 47 publications

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“…Immunomodulators with targeted therapy rather than conventional IMT provide better disease control and better prevention from infections [26]. Corticosteroids and IVIG are accepted as the first-line treatment for AIC in patients with IEI; however, the relapse rate is higher in those patients [27,28].…”

Section: Discussionmentioning

confidence: 99%

Autoimmune Cytopenias Are Highly Associated with Inborn Errors of Immunity and They May Be the Initial Presentations in Cases without Severe Infections

Taskin,

Topyıldız,

Edeer Karaca

et al. 2023

Int Arch Allergy Immunol

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Introduction: Inborn errors of immunity (IEIs) are inherited disorders that present with increased susceptibility to infections as well as noninfectious complications. Due to the aberrant immune functions of patients with IEI, autoimmune cytopenia (AIC) may be the initial finding, which makes diagnosis a challenge. We aimed to evaluate the clinical course, laboratory findings, and treatment response of AIC in children with IEI. Methods: Data of children with autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenic purpura (ITP) were obtained from a retrospective chart review of IEI patients diagnosed and followed in our center. Demographic and clinical features and therapeutic outcomes were evaluated. Immunologic findings were compared between patients with AIHA, ITP, and Evans syndrome (ES). The patients were also divided into two subgroups based on the presence or absence of immune dysregulation diseases (IDDs), and all data were compared between these two groups. Results: Out of 562 patients with IEI, 6% (n: 34) had AIC which were ITP (23.5%), AIHA (35.5%), and ES (41.2%). AIC was the initial finding in 50% of these 34 patients. Patients with ES had a higher mean percentage of CD8+ T lymphocytes than ITP patients (40.77 ± 20.21% vs. 22.33 ± 12.48%, p = 0.011). Patients with IDDs were more likely to develop ES (p = 0.004), lymphoproliferation (p = 0.005), and resistance to first-line therapy (p = 0.021) than other IEI groups. Conclusion: This study shows that AIC may be the initial finding of IEI, particularly when lymphoproliferation and resistance to first-line therapy co-occur. Therefore, detailed investigation should be offered to all patients to avoid diagnostic delay.

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Section: Discussionmentioning

confidence: 99%

Autoimmune Cytopenias Are Highly Associated with Inborn Errors of Immunity and They May Be the Initial Presentations in Cases without Severe Infections

Taskin,

Topyıldız,

Edeer Karaca

et al. 2023

Int Arch Allergy Immunol

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“…Classically LRBA deficiency and CTLA‐4 insufficiency have been categorized as Tregopathies, characterized by loss of Treg cell function, which is required for normal immune surveillance and tolerance 34,35 . Interestingly, a variable frequency of Tregs has been reported in different disease cohorts, ranging from normal to reduced or increased levels 3,9,11,22 .…”

Section: Discussionmentioning

confidence: 99%

“…Classically LRBA deficiency and CTLA-4 insufficiency have been categorized as Tregopathies, characterized by loss of Treg cell function, which is required for normal immune surveillance and tolerance. 34,35 Interestingly, a variable frequency of Tregs has been reported in different disease cohorts, ranging from normal to reduced or increased levels. 3,9,11,22 Of note, some CTLA-4-insufficient patients have mutations causing normal protein expression but disturbed function, as demonstrated in previous studies of CTLA-4 missense mutations evaluated by transendocytosis or ligand uptake assays.…”

Section: Discussionmentioning

confidence: 99%

Comparing the levels of CTLA‐4‐dependent biological defects in patients with LRBA deficiency and CTLA‐4 insufficiency

Catak

Akcam

Eltan

et al. 2022

Allergy

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Background Lipopolysaccharide‐responsive beige‐like anchor protein (LRBA) deficiency and cytotoxic T‐lymphocyte protein‐4 (CTLA‐4) insufficiency are recently described disorders that present with susceptibility to infections, autoimmunity, and lymphoproliferation. Clinical and immunological comparisons of the diseases with long‐term follow‐up have not been previously reported. We sought to compare the clinical and laboratory manifestations of both diseases and investigate the role of flow cytometry in predicting the genetic defect in patients with LRBA deficiency and CTLA‐4 insufficiency. Methods Patients were evaluated clinically with laboratory assessments for lymphocyte subsets, T follicular helper cells (TFH), LRBA expression, and expression of CD25, FOXP3, and CTLA4 in regulatory T cells (Tregs) at baseline and 16 h post‐stimulation. Results LRBA‐deficient patients (n = 29) showed significantly early age of symptom onset, higher rates of pneumonia, autoimmunity, chronic diarrhea, and failure to thrive compared to CTLA‐4 insufficiency (n = 12). In total, 29 patients received abatacept with favorable responses and the overall survival probability was not different between transplanted versus non‐transplanted patients in LRBA deficiency. Meanwhile, higher probability of survival was observed in CTLA‐4‐insufficient patients (p = 0.04). The T‐cell subsets showed more deviation to memory cells in CTLA‐4‐insufficiency, accompanied by low percentages of Treg and dysregulated cTFH cells response in both diseases. Cumulative numbers of autoimmunities positively correlated with cTFH frequencies. Baseline CTLA‐4 expression was significantly diminished in LRBA deficiency and CTLA‐4 insufficiency, but significant induction in CTLA‐4 was observed after short‐term T‐cell stimulation in LRBA deficiency and controls, while this elevation was less in CTLA‐4 insufficiency, allowing to differentiate this disease from LRBA deficiency with high sensitivity (87.5%) and specificity (90%). Conclusion This cohort provided detailed clinical and laboratory comparisons for LRBA deficiency and CTLA‐4 insufficiency. The flow cytometric approach is useful in predicting the defective gene; thus, targeted sequencing can be conducted to provide rapid diagnosis and treatment for these diseases impacting the CTLA‐4 pathway.

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“…In 2018, the term tregopathies ( 54 ) was first introduced: it referred to a group of IEI with a clinical phenotype later encompassed within PIRD, in which the affected regulatory target is the Treg cell itself. This group initially included mutations in FOXP3 , CD25 , CTLA-4 , LRBA , BACH2 , IL10 , and gain of function (GOF) of STAT3 ( 47 , 55 , 56 ). Since then, the IUIS expert committee (EC) has added new genes to this category, including mutations in FERMT1 , CD122 , DEF6 , and IKAROS GOF ( 47 , 51 ) ( Figure 2 ).…”

Section: Iei and Treg: The New Kid On The Blockmentioning

confidence: 99%

Treg in inborn errors of immunity: gaps, knowns and future perspectives

Kennedy-Batalla,

Acevedo,

Luo

et al. 2024

Front. Immunol.

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Regulatory T cells (Treg) are essential for immune balance, preventing overreactive responses and autoimmunity. Although traditionally characterized as CD4+CD25+CD127lowFoxP3hi, recent research has revealed diverse Treg subsets such as Tr1, Tr1-like, and CD8 Treg. Treg dysfunction leads to severe autoimmune diseases and immune-mediated inflammatory disorders. Inborn errors of immunity (IEI) are a group of disorders that affect correct functioning of the immune system. IEI include Tregopathies caused by genetic mutations affecting Treg development or function. In addition, Treg dysfunction is also observed in other IEIs, whose underlying mechanisms are largely unknown, thus requiring further research. This review provides a comprehensive overview and discussion of Treg in IEI focused on: A) advances and controversies in the evaluation of Treg extended subphenotypes and function; B) current knowledge and gaps in Treg disturbances in Tregopathies and other IEI including Treg subpopulation changes, genotype-phenotype correlation, Treg changes with disease activity, and available therapies, and C) the potential of Treg cell-based therapies for IEI with immune dysregulation. The aim is to improve both the diagnostic and the therapeutic approaches to IEI when there is involvement of Treg. We performed a non-systematic targeted literature review with a knowledgeable selection of current, high-quality original and review articles on Treg and IEI available since 2003 (with 58% of the articles within the last 6 years) in the PubMed database.

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Primary Immune Regulatory Disorders and Targeted Therapies

Cited by 9 publications

References 47 publications

Autoimmune Cytopenias Are Highly Associated with Inborn Errors of Immunity and They May Be the Initial Presentations in Cases without Severe Infections

Autoimmune Cytopenias Are Highly Associated with Inborn Errors of Immunity and They May Be the Initial Presentations in Cases without Severe Infections

Comparing the levels of CTLA‐4‐dependent biological defects in patients with LRBA deficiency and CTLA‐4 insufficiency

Treg in inborn errors of immunity: gaps, knowns and future perspectives

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