Improved transplant survival and long-term disease outcome in children with MHC class II deficiency

Lum, Su Han; Anderson, Claire; McNaughton, Peter; Engelhardt, Karin R.; MacKenzie, B; Watson, H. J. C.; Al‐Mousa, Hamoud; Al‐Herz, Waleed; Al‐Saud, Bandar; Mohammed, Reem; Al-Zahrani, Daifulah; Alghamdi, Hamza Ali; Goronfolah, Loie; Nademi, Zohreh; Habibollah, Sahar; Flinn, Aisling M.; Shillitoe, Benjamin; Owens, Stephen; Williams, Eleri; Emonts, Marieke; Hambleton, Sophie; Abinun, Mario; Flood, Terry; Cant, Andrew J.; Gennery, Andrew R.; Slatter, Mary

doi:10.1182/blood.2019002690

Cited by 24 publications

(26 citation statements)

References 13 publications

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“…Nonspecific background was reduced with Background Sniper (Biocare Medical, Concord, CA, USA) before heat-based antigenretrieval treatment and incubated with primary antibodies. The following primary antibodies were used: rat anti-human FOXP3 (1:100; eBioscience), mouse anti-human AIRE (1:3000; kindly provided by Prof P. Peterson, University of Tartu, Tartu, Estonia), biotin-UEA (Biotinylated Ulex Europaeus Agglutinin I) (1:800; Vector Laboratories) and Claudin-4 (used according to local standards of Pathological Anatomy Unit of Spedali Civili, (16).…”

Section: Histological Analysismentioning

confidence: 99%

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Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency

et al. 2021

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Major Histocompatibility Complex (MHC) class II (MHCII) deficiency (MHCII-D), also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. Abnormal cross-talk with developing T cells due to the absence of MHCII expression likely leads to defects in thymic epithelial cells (TEC). However, the contribution of TEC alterations to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC in this disease. We observed an overall perturbation of thymic structure and function in both MHCII−/− mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, we demonstrated that impairment of lymphostromal cross-talk in the thymus of MHCII−/− mice affects mTEC maturation and promiscuous gene expression and causes defects of central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential benefits of hematopoietic stem cell transplantation in MHCII deficiency.

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Section: Histological Analysismentioning

confidence: 99%

“…Allogeneic hematopoietic stem cell transplantation (HSCT), preferably from an HLA-identical sibling donor, is the treatment of choice, but overall success rate is limited (10,(13)(14)(15). In recent years HSCT survival has improved, but CD4 + T-cell lymphopenia may persist (16).…”

Section: Introductionmentioning

confidence: 99%

Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency

et al. 2021

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“…MHC II deficiency is classified into 4 complementation groups, named by the order of their discovery according to MHC II molecule expression after pairwise fusion of different patient cell lines [ 3 ]. MHC II deficiency is divided into 4 groups, groups A to D, which are CIITA, RFXANK, RFX5, and RFXAP, respectively [ 4 ]. Group B MHC II deficiency is the most common, with more than half of the patients [ 11 ].…”

Section: Literature Reviewmentioning

confidence: 99%

“…Although MHC II deficiency is regarded as less severe than severe combined immunodeficiency (SCID) according to the International Union of Immunological Societies classification criteria, patients usually exhibit clinical manifestations of typical combined immunodeficiency (CID) but not SCID [ 2 , 3 ]. MHC II deficiency is characterized by an early onset of severe and recurrent infections, mainly of the respiratory and gastrointestinal tract, developmental delay, and early death [ 4 ]. Protracted diarrhea and recurrent pneumonia can be observed in almost all patients [ 2 ].…”

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confidence: 99%

“…The RFX complex, which is composed of regulatory factor X-5 (RFX5), RFX-associated protein (RFXAP), and RFXAP-containing ankyrin repeat (RFXANK), binds directly to the promoters of MHC II genes and associates with other pleiotropic factors to form the MHC II enhanceosome [ 9 ]. Subsequently, due to the 4 different transcript factors, MHC II deficiency is divided into 4 groups from group A to D, which are CIITA, RFXANK, RFX5, and RFXAP, respectively [ 4 ].…”

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A Novel RFXANK Mutation in a Chinese Child With MHC II Deficiency: Case Report and Literature Review

Cai

Zhang

Wang

et al. 2020

Open Forum Infectious Diseases

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Major histocompatibility complex (MHC) II deficiency is a rare primary immunodeficiency disorder which is characterized by the deficiency of MHC class II molecules. The disease is caused by transcription factor mutations including class II transactivator (CIITA), regulatory factor X-5 (RFX5), RFX associated protein (RFXAP) and RFXAP containing ankyrin repeat (RFXANK), respectively. Mutations in the RFXANK gene account for more than 70% of all known patients worldwide. Herein, we reported a 10-month-old boy with MHC II deficiency caused by a novel mutation in RFXANK gene (c.337+1G>C) The boy was admitted to the hospital due to pneumonia and diarrhea at four months of age. Genetic analysis revealed a novel homozygous mutation in the RFXANK gene which derived from the c.337+1G>C heterozygous mutations in the RFXANK gene of his parents. The boy died 3 months after the diagnosis. More than 200 cases have been reported; and literature review revealed different mutation rates of four transcription factors in different countries or regions. This is the first case report of MHC II deficiency from East Asia. We also described all gene mutations which causing MHC II deficiency and epidemiology of MHC II deficiency with gene mutations in this paper.

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Clinical, Immunological, and Genetic Findings in Iranian Patients with MHC-II Deficiency: Confirmation of c.162delG RFXANK Founder Mutation in the Iranian Population

et al. 2023

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Purpose: Major histocompatibility complex class II (MHC-II) de ciency is a rare inborn error of immunity (IEI). Impaired antigen presentation to CD4+ T-cells results in combined immunode ciency. Patients typically present with severe respiratory and gastrointestinal tract infections at early ages. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy.Methods: We describe the clinical, immunologic, and genetic features of eighteen unrelated Iranian patients with MHC-II de ciency.Results: Consanguinity was present in all affected families. The median age at the initial presentation was 5.5 months (range seven days to 18 years). The main symptoms included failure to thrive, persistent diarrhea, and pneumonia. Autoimmune and neurologic features were documented in 30% of the patients, respectively.Thirteen patients carried RFXANK gene mutations, two carried RFX5 gene mutations, and three carried a RFXAP gene mutation. Six patients shared the same RFXANK founder mutation (c.162delG); limited to the Iranian population and dated to approximately 1,296 years ago. Four of the patients underwent HSCT; three of them are alive. On the other hand, nine of the fourteen patients who did not undergo HSCT had a poor prognosis and died.Conclusion: MHC-II deficiency is not rare in Iran, with a high rate of consanguinity. It should be considered in the differential diagnosis of combined immunode ciency (CID) at any age. With the limited access to HSCT and its variable results in MHC-II de ciency, implementing genetic counseling and family planning for the affected families are mandatory. We better determined the c.162delG RFXANKheterozygous mutation frequency in the Iranian population.

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Improved transplant survival and long-term disease outcome in children with MHC class II deficiency

Cited by 24 publications

References 13 publications

Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency

Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency

A Novel RFXANK Mutation in a Chinese Child With MHC II Deficiency: Case Report and Literature Review

Clinical, Immunological, and Genetic Findings in Iranian Patients with MHC-II Deficiency: Confirmation of c.162delG RFXANK Founder Mutation in the Iranian Population

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