Immunological features of 22q11 deletion syndrome

Gennery, Andrew R.

doi:10.1097/mop.0000000000000027

Cited by 10 publications

(11 citation statements)

References 26 publications

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“…Most patients with pDGS carry CrkL gene deletions in chromosome 22q11.2. 27 As shown both in Table E1 in this article’s Online Repository at www.jacionline.org and by other groups, lymphocyte phenotyping of patients with pDGS shows variable T-cell depletion with normal NK cell numbers. 28 To date, however, there are no published descriptions of NK cell function in these patients.…”

Section: Resultsmentioning

confidence: 86%

Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome

Zheng

Noroski

Hanson

et al. 2015

Journal of Allergy and Clinical Immunology

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Background DiGeorge syndrome affects more than 3.5 million persons worldwide. Partial DiGeorge syndrome (pDGS), which is characterized by a number of gene deletions in chromosome 22, including the chicken tumor virus number 10 regulator of kinase (Crk)–like (CrkL) gene, is one of the most common genetic disorders in human subjects. To date, the role of natural killer (NK) cells in patients with pDGS remains unclear. Objective We sought to define the effect of pDGS-related Crk haploinsufficiency on NK cell activation and cytotoxic immunological synapse (IS) structure and function. Methods Inducible CrkL-silenced NK cells were used to recapitulate the pDGS, CrkL-haploinsufficient phenotype. Findings were validated by using NK cells from patients with actual pDGS. Ultimately, deficits in the function of NK cells from patients with pDGS were restored by lentiviral transduction of CrkL. Results Silencing of CrkL expression inhibits NK cell function. Specifically, pDGS haploinsufficiency of CrkL inhibits accumulation of activating receptors, polarization of cytolytic machinery and key signaling molecules, and activation of β2-integrin at the IS. Reintroduction of CrkL protein restores NK cell cytotoxicity. Conclusion CrkL haploinsufficiency causes functional NK deficits in patients with pDGS by disrupting both β2-integrin activation and activating receptor accumulation at the IS. Our results suggest that NK cell IS quality can directly affect immune status, providing a potential target for diagnosis and therapeutic manipulation in patients with pDGS and in other patients with functional NK cell deficiencies.

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Section: Resultsmentioning

confidence: 86%

Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome

Zheng

Noroski

Hanson

et al. 2015

Journal of Allergy and Clinical Immunology

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“…Survival in patients with congenital athymia who undergo HSCT is only 41%, with a GVHD incidence of 50% [ 128 ]. A favorable outcome of hematopoietic stem cell transplant for athymia due to 22q11.2del is more likely when an HLA-matched sibling donor is available [ 129 ]. However, because of the persistent failure of thymopoiesis, maturation and regeneration of naïve T cells remain greatly hindered, as T cell development is generally limited to peripheral expansion [ 128 ].…”

Section: Hematopoietic Stem Cell Transplant (Hsct)mentioning

confidence: 99%

Clinical Practice Guidelines for the Immunological Management of Chromosome 22q11.2 Deletion Syndrome and Other Defects in Thymic Development

et al. 2023

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Current practices vary widely regarding the immunological work-up and management of patients affected with defects in thymic development (DTD), which include chromosome 22q11.2 microdeletion syndrome (22q11.2del) and other causes of DiGeorge syndrome (DGS) and coloboma, heart defect, atresia choanae, retardation of growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE) syndrome. Practice variations affect the initial and subsequent assessment of immune function, the terminology used to describe the condition and immune status, the accepted criteria for recommending live vaccines, and how often follow-up is needed based on the degree of immune compromise. The lack of consensus and widely varying practices highlight the need to establish updated immunological clinical practice guidelines. These guideline recommendations provide a comprehensive review for immunologists and other clinicians who manage immune aspects of this group of disorders.

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“…In this condition, the third and fourth pharyngeal arches, and their subsequent structures, including the nasopharynx, thyroid, parathyroid, thymus, and cardiac outflow tract can be maldeveloped, leading to palatal defects, hypothyroidism, hypocalcemia, T-cell immunodeficiency, and conotruncal cardiac defects among characteristic facial features (44)(45)(46). Since the thymus selects for T-cells that recognize foreign antigens and not self-antigens, thymic hypoplasia causes a T-cell deficiency in up to 75% of these children (43), leading to chronic sinopulmonary infections (82). This reduced thymic T-cell maturation is also evidenced by reduced numbers of TRECs, a byproduct of the selection process (44).…”

Section: Q112 Deletion Syndromementioning

confidence: 99%

Congenital Heart Disease: An Immunological Perspective

Singampalli

Jui

Shani

et al. 2021

Front. Cardiovasc. Med.

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Congenital heart disease (CHD) poses a significant global health and economic burden—despite advances in treating CHD reducing the mortality risk, globally CHD accounts for approximately 300,000 deaths yearly. Children with CHD experience both acute and chronic cardiac complications, and though treatment options have improved, some remain extremely invasive. A challenge in addressing these morbidity and mortality risks is that little is known regarding the cause of many CHDs and current evidence suggests a multifactorial etiology. Some studies implicate an immune contribution to CHD development; however, the role of the immune system is not well-understood. Defining the role of the immune and inflammatory responses in CHD therefore holds promise in elucidating mechanisms underlying these disorders and improving upon current diagnostic and treatment options. In this review, we address the current knowledge coinciding CHDs with immune and inflammatory associations, emphasizing conditions where this understanding would provide clinical benefit, and challenges in studying these mechanisms.

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Immunological features of 22q11 deletion syndrome

Cited by 10 publications

References 26 publications

Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome

Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome

Clinical Practice Guidelines for the Immunological Management of Chromosome 22q11.2 Deletion Syndrome and Other Defects in Thymic Development

Congenital Heart Disease: An Immunological Perspective

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