T-cell mitochondrial dysfunction and lymphopenia in DOCK2-deficient patients
To the Editor: Dedicator of cytokinesis 2 (DOCK2) is a guanine nucleotide exchange factor expressed predominantly in hematopoietic cells that activates the Rac GTPases.1,2 Biallelic mutations in DOCK2 cause a combined immunodeficiency with T-cell lymphopenia and impaired T-cell activation.1,3 The me...
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| Veröffentlicht in: | Journal of allergy and clinical immunology 2019-07, Vol.144 (1), p.306-309.e2 |
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| creator | Alosaimi, Mohammed F. Shendi, Hiba Beano, Abdallah Stafstrom, Kelsey El Hawary, Rabab Meshaal, Safa Galal, Nermeen Pai, Sung-Yun El-Marsafy, Aisha Geha, Raif S. Chou, Janet |
| description | To the Editor: Dedicator of cytokinesis 2 (DOCK2) is a guanine nucleotide exchange factor expressed predominantly in hematopoietic cells that activates the Rac GTPases.1,2 Biallelic mutations in DOCK2 cause a combined immunodeficiency with T-cell lymphopenia and impaired T-cell activation.1,3 The mechanisms underlying the T-cell lymphopenia associated with DOCK2 deficiency are incompletely understood. Because of the importance of the Rac GTPases in maintaining mitochondrial homeostasis,4,5 we investigated mitochondrial function in 2 unrelated patients with novel DOCK2 mutations abrogating protein expression. [...]to our DOCK2-deficient patients, CD4+ and CD8+ T cells robustly increased membrane potential after T-cell activation (see Fig E1). [...]chronic antigenic T-cell activation cannot solely explain the defective mitochondrial membrane potential seen in DOCK2-deficient T cells. Because Patient 1 had normal numbers of B cells, we were able to generate an EBV-transformed lymphoblastoid B-cell line (BLCL) from her PBMCs. |
| doi_str_mv | 10.1016/j.jaci.2019.02.020 |
| format | Article |
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Because of the importance of the Rac GTPases in maintaining mitochondrial homeostasis,4,5 we investigated mitochondrial function in 2 unrelated patients with novel DOCK2 mutations abrogating protein expression. [...]to our DOCK2-deficient patients, CD4+ and CD8+ T cells robustly increased membrane potential after T-cell activation (see Fig E1). [...]chronic antigenic T-cell activation cannot solely explain the defective mitochondrial membrane potential seen in DOCK2-deficient T cells. Because Patient 1 had normal numbers of B cells, we were able to generate an EBV-transformed lymphoblastoid B-cell line (BLCL) from her PBMCs.</description><identifier>ISSN: 0091-6749</identifier><identifier>EISSN: 1097-6825</identifier><identifier>DOI: 10.1016/j.jaci.2019.02.020</identifier><identifier>PMID: 30826364</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Activation ; Age ; Antigens ; CD4 antigen ; CD8 antigen ; Cell activation ; Cytokinesis ; Cytomegalovirus ; Defects ; Female ; GTPase-Activating Proteins - deficiency ; GTPase-Activating Proteins - genetics ; Guanine ; Guanine nucleotide exchange factor ; Guanine Nucleotide Exchange Factors - deficiency ; Guanine Nucleotide Exchange Factors - genetics ; Homeostasis ; Humans ; Immunodeficiency ; Immunoglobulins ; Immunologic Deficiency Syndromes - genetics ; Immunologic Deficiency Syndromes - immunology ; Infant ; Infections ; Lymphocytes ; Lymphocytes B ; Lymphocytes T ; Lymphopenia ; Male ; Membrane potential ; Metabolism ; Mitochondria ; Mitochondria - immunology ; Mutation ; Patients ; Protein expression ; Respiration ; T-Lymphocytes - immunology ; Viral infections</subject><ispartof>Journal of allergy and clinical immunology, 2019-07, Vol.144 (1), p.306-309.e2</ispartof><rights>2019 American Academy of Allergy, Asthma & Immunology</rights><rights>2019. 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Because of the importance of the Rac GTPases in maintaining mitochondrial homeostasis,4,5 we investigated mitochondrial function in 2 unrelated patients with novel DOCK2 mutations abrogating protein expression. [...]to our DOCK2-deficient patients, CD4+ and CD8+ T cells robustly increased membrane potential after T-cell activation (see Fig E1). [...]chronic antigenic T-cell activation cannot solely explain the defective mitochondrial membrane potential seen in DOCK2-deficient T cells. Because Patient 1 had normal numbers of B cells, we were able to generate an EBV-transformed lymphoblastoid B-cell line (BLCL) from her PBMCs.</description><subject>Activation</subject><subject>Age</subject><subject>Antigens</subject><subject>CD4 antigen</subject><subject>CD8 antigen</subject><subject>Cell activation</subject><subject>Cytokinesis</subject><subject>Cytomegalovirus</subject><subject>Defects</subject><subject>Female</subject><subject>GTPase-Activating Proteins - deficiency</subject><subject>GTPase-Activating Proteins - genetics</subject><subject>Guanine</subject><subject>Guanine nucleotide exchange factor</subject><subject>Guanine Nucleotide Exchange Factors - deficiency</subject><subject>Guanine Nucleotide Exchange Factors - genetics</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Immunodeficiency</subject><subject>Immunoglobulins</subject><subject>Immunologic Deficiency Syndromes - genetics</subject><subject>Immunologic Deficiency Syndromes - immunology</subject><subject>Infant</subject><subject>Infections</subject><subject>Lymphocytes</subject><subject>Lymphocytes B</subject><subject>Lymphocytes T</subject><subject>Lymphopenia</subject><subject>Male</subject><subject>Membrane potential</subject><subject>Metabolism</subject><subject>Mitochondria</subject><subject>Mitochondria - immunology</subject><subject>Mutation</subject><subject>Patients</subject><subject>Protein expression</subject><subject>Respiration</subject><subject>T-Lymphocytes - immunology</subject><subject>Viral infections</subject><issn>0091-6749</issn><issn>1097-6825</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UV2L2zAQFOVKk8vdH-hDMfTZuZVkKTKUQsn1PmggL3kXsiw1Mo7kSk4g__5kcj3al4OFZdnZ2WEGoc8Ylhgwv-uWndJuSQDXSyC54AOaY6hXJReEXaE5QI1LvqrqGbpOqYM8U1F_QjMKgnDKqzna7Ept-r44uDHoffBtdKov2nOyR69HF3yhfFv058OwD4PxThXOF_fb9S9StsY67Ywfi0GNU0836KNVfTK3r32Bdg8_d-uncrN9fF7_2JS6YjCWnAoDRjBKWYOVtZxhDpSQRlTKmrquMG5opSpsNWNC4MZYRslqxYkmrGrpAn2_0A7H5mBanV9H1cshuoOKZxmUk_9vvNvL3-EkOceE1CITfH0liOHP0aRRduEYfZYsCWHAOM96MopcUDqGlKKxbx8wyCkA2ckpADkFIIHkgnz05V9tbyd_Hc-AbxeAyQadnIkyTSZq07po9Cjb4N7jfwGBfpb8</recordid><startdate>20190701</startdate><enddate>20190701</enddate><creator>Alosaimi, Mohammed F.</creator><creator>Shendi, Hiba</creator><creator>Beano, Abdallah</creator><creator>Stafstrom, Kelsey</creator><creator>El Hawary, Rabab</creator><creator>Meshaal, Safa</creator><creator>Galal, Nermeen</creator><creator>Pai, Sung-Yun</creator><creator>El-Marsafy, Aisha</creator><creator>Geha, Raif S.</creator><creator>Chou, Janet</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SS</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>5PM</scope></search><sort><creationdate>20190701</creationdate><title>T-cell mitochondrial dysfunction and lymphopenia in DOCK2-deficient patients</title><author>Alosaimi, Mohammed F. ; Shendi, Hiba ; Beano, Abdallah ; Stafstrom, Kelsey ; El Hawary, Rabab ; Meshaal, Safa ; Galal, Nermeen ; Pai, Sung-Yun ; El-Marsafy, Aisha ; Geha, Raif S. ; Chou, Janet</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c450t-638e0e85335b1aff65160322b84afe99411b34a41fc55881bef5327762c254d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Activation</topic><topic>Age</topic><topic>Antigens</topic><topic>CD4 antigen</topic><topic>CD8 antigen</topic><topic>Cell activation</topic><topic>Cytokinesis</topic><topic>Cytomegalovirus</topic><topic>Defects</topic><topic>Female</topic><topic>GTPase-Activating Proteins - deficiency</topic><topic>GTPase-Activating Proteins - genetics</topic><topic>Guanine</topic><topic>Guanine nucleotide exchange factor</topic><topic>Guanine Nucleotide Exchange Factors - deficiency</topic><topic>Guanine Nucleotide Exchange Factors - genetics</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Immunodeficiency</topic><topic>Immunoglobulins</topic><topic>Immunologic Deficiency Syndromes - genetics</topic><topic>Immunologic Deficiency Syndromes - immunology</topic><topic>Infant</topic><topic>Infections</topic><topic>Lymphocytes</topic><topic>Lymphocytes B</topic><topic>Lymphocytes T</topic><topic>Lymphopenia</topic><topic>Male</topic><topic>Membrane potential</topic><topic>Metabolism</topic><topic>Mitochondria</topic><topic>Mitochondria - immunology</topic><topic>Mutation</topic><topic>Patients</topic><topic>Protein expression</topic><topic>Respiration</topic><topic>T-Lymphocytes - immunology</topic><topic>Viral infections</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Alosaimi, Mohammed F.</creatorcontrib><creatorcontrib>Shendi, Hiba</creatorcontrib><creatorcontrib>Beano, Abdallah</creatorcontrib><creatorcontrib>Stafstrom, Kelsey</creatorcontrib><creatorcontrib>El Hawary, Rabab</creatorcontrib><creatorcontrib>Meshaal, Safa</creatorcontrib><creatorcontrib>Galal, Nermeen</creatorcontrib><creatorcontrib>Pai, Sung-Yun</creatorcontrib><creatorcontrib>El-Marsafy, Aisha</creatorcontrib><creatorcontrib>Geha, Raif S.</creatorcontrib><creatorcontrib>Chou, Janet</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of allergy and clinical immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Alosaimi, Mohammed F.</au><au>Shendi, Hiba</au><au>Beano, Abdallah</au><au>Stafstrom, Kelsey</au><au>El Hawary, Rabab</au><au>Meshaal, Safa</au><au>Galal, Nermeen</au><au>Pai, Sung-Yun</au><au>El-Marsafy, Aisha</au><au>Geha, Raif S.</au><au>Chou, Janet</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>T-cell mitochondrial dysfunction and lymphopenia in DOCK2-deficient patients</atitle><jtitle>Journal of allergy and clinical immunology</jtitle><addtitle>J Allergy Clin Immunol</addtitle><date>2019-07-01</date><risdate>2019</risdate><volume>144</volume><issue>1</issue><spage>306</spage><epage>309.e2</epage><pages>306-309.e2</pages><issn>0091-6749</issn><eissn>1097-6825</eissn><abstract>To the Editor: Dedicator of cytokinesis 2 (DOCK2) is a guanine nucleotide exchange factor expressed predominantly in hematopoietic cells that activates the Rac GTPases.1,2 Biallelic mutations in DOCK2 cause a combined immunodeficiency with T-cell lymphopenia and impaired T-cell activation.1,3 The mechanisms underlying the T-cell lymphopenia associated with DOCK2 deficiency are incompletely understood. Because of the importance of the Rac GTPases in maintaining mitochondrial homeostasis,4,5 we investigated mitochondrial function in 2 unrelated patients with novel DOCK2 mutations abrogating protein expression. [...]to our DOCK2-deficient patients, CD4+ and CD8+ T cells robustly increased membrane potential after T-cell activation (see Fig E1). [...]chronic antigenic T-cell activation cannot solely explain the defective mitochondrial membrane potential seen in DOCK2-deficient T cells. Because Patient 1 had normal numbers of B cells, we were able to generate an EBV-transformed lymphoblastoid B-cell line (BLCL) from her PBMCs.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>30826364</pmid><doi>10.1016/j.jaci.2019.02.020</doi><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Activation Age Antigens CD4 antigen CD8 antigen Cell activation Cytokinesis Cytomegalovirus Defects Female GTPase-Activating Proteins - deficiency GTPase-Activating Proteins - genetics Guanine Guanine nucleotide exchange factor Guanine Nucleotide Exchange Factors - deficiency Guanine Nucleotide Exchange Factors - genetics Homeostasis Humans Immunodeficiency Immunoglobulins Immunologic Deficiency Syndromes - genetics Immunologic Deficiency Syndromes - immunology Infant Infections Lymphocytes Lymphocytes B Lymphocytes T Lymphopenia Male Membrane potential Metabolism Mitochondria Mitochondria - immunology Mutation Patients Protein expression Respiration T-Lymphocytes - immunology Viral infections |
| title | T-cell mitochondrial dysfunction and lymphopenia in DOCK2-deficient patients |
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