FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2124517141> ?p ?o ?g. }

• W2124517141 endingPage "1096.e8" @default.
• W2124517141 startingPage "1093" @default.
• W2124517141 abstract "InstructionsCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the instructions listed below:1.Review the target audience, learning objectives and author disclosures.2.Complete the pre-test online at www.jacionline.org (click on the Online CME heading).3.Follow the online instructions to read the full version of the article, including the clinical vignette and review components.4.Complete the post-test. At this time, you will have earned 1.00 AMA PRA Category 1 CME CreditTM.5.Approximately 4 weeks later you will receive an online assessment regarding your application of this article to your practice. Once you have completed this assessment, you will be eligible to receive 2 MOC Part II Self-Assessment credits from the American Board of Allergy and Immunology.Date of Original Release: April 2015. Credit may be obtained for these courses until March 31, 2016.Copyright Statement: Copyright © 2015-2016. All rights reserved.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Aaruni Khanolkar, MBBS, PhD, Jeffrey D. Wilks, BS, Lawrence J. Jennings, MD, PhD, Jessica L. Davies, BS, Joshua A. Zollett, BS, Loren L. Lott, BS, Erin R. Fullmer, BS, Nicolas E. Bensen, BS, Katrin M. Carlson-Leuer, PhD, William T. Tse, MD, PhD, and Ramsay L. Fuleihan, MD (authors), and James T. Li, MD, PhD (series editor)Activity Objectives1.To understand the complexities and nuances associated with functional impairments detected in maternally engrafted T cells.2.To become aware of emerging information that seeks to define the mechanistic basis of humoral insufficiency in patients with IL-2 receptor γ mutations.3.To appreciate the integrated cross-disciplinary approach required for the evaluation and management of a patient with a primary immunodeficiency disorder.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: R. L. Fuleihan has received research support from the Jeffrey Modell Foundation, has received payment for lectures from Baxter, and is on the Data Safety Monitoring Board for Sigma-Tau. The rest of the authors have received money for their institutions from the Jeffrey Modell Foundation for being Jeffrey Modell Foundation Diagnostic and Research Centers for Primary Immunodeficiencies. J. T. Li has consulted for Abbott. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the instructions listed below:1.Review the target audience, learning objectives and author disclosures.2.Complete the pre-test online at www.jacionline.org (click on the Online CME heading).3.Follow the online instructions to read the full version of the article, including the clinical vignette and review components.4.Complete the post-test. At this time, you will have earned 1.00 AMA PRA Category 1 CME CreditTM.5.Approximately 4 weeks later you will receive an online assessment regarding your application of this article to your practice. Once you have completed this assessment, you will be eligible to receive 2 MOC Part II Self-Assessment credits from the American Board of Allergy and Immunology. Date of Original Release: April 2015. Credit may be obtained for these courses until March 31, 2016. Copyright Statement: Copyright © 2015-2016. All rights reserved. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Aaruni Khanolkar, MBBS, PhD, Jeffrey D. Wilks, BS, Lawrence J. Jennings, MD, PhD, Jessica L. Davies, BS, Joshua A. Zollett, BS, Loren L. Lott, BS, Erin R. Fullmer, BS, Nicolas E. Bensen, BS, Katrin M. Carlson-Leuer, PhD, William T. Tse, MD, PhD, and Ramsay L. Fuleihan, MD (authors), and James T. Li, MD, PhD (series editor) Activity Objectives1.To understand the complexities and nuances associated with functional impairments detected in maternally engrafted T cells.2.To become aware of emerging information that seeks to define the mechanistic basis of humoral insufficiency in patients with IL-2 receptor γ mutations.3.To appreciate the integrated cross-disciplinary approach required for the evaluation and management of a patient with a primary immunodeficiency disorder. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: R. L. Fuleihan has received research support from the Jeffrey Modell Foundation, has received payment for lectures from Baxter, and is on the Data Safety Monitoring Board for Sigma-Tau. The rest of the authors have received money for their institutions from the Jeffrey Modell Foundation for being Jeffrey Modell Foundation Diagnostic and Research Centers for Primary Immunodeficiencies. J. T. Li has consulted for Abbott. A 6-month-old male infant born to nonconsanguineous parents of western European descent was admitted to our institution in early May 2013 after unresolved watery diarrhea lasting 5 weeks with a frequency of approximately 10 bowel movements per day. He was a full-term infant weighing 8 lbs, 6 oz at birth and delivered by means of cesarean section. He met normal developmental milestones on routine check-up and received routine immunizations, including 2 doses of the pentavalent live rotavirus vaccine, on schedule. The family medical history was unremarkable overall other than the occurrence of gestational diabetes in the mother, which was controlled by diet. The patient has 1 older female sibling who is healthy. His first episode after birth that necessitated hospitalization and treatment with intravenous antibiotics was acute right mastitis at the age of 1.5 months. A second pediatric intensive care unit admission followed 3 months later, which was brought on by an episode of croup, bacterial pneumonia, and acute bilateral otitis media. His third admission to a community hospital occurred because of his intractable diarrhea, which commenced after his second dose of the live rotavirus vaccine administered in the first week of April 2013. A preliminary immunology workup revealed severely decreased serum immunoglobulin levels, which prompted his transfer to our institution. CBC revealed normal lymphocyte numbers, and his initial immunologic workup in our laboratory confirmed his hypogammaglobulinemia (see Table E1 in this article's Online Repository at www.jacionline.org) and also revealed markedly reduced numbers of peripheral blood natural killer (NK) and CD4 T cells (see Table E2 in this article's Online Repository at www.jacionline.org). Peripheral blood B-cell numbers were less affected, although they were still less than normal, whereas the CD8 T-cell numbers were least aberrant (see Table E2). Routine immunophenotyping further demonstrated normal HLA-DR expression on B cells and a markedly increased frequency of HLA-DR–expressing T cells, indicating the presence of activated circulating T cells (see Table E2). CD4 and CD8 T-cell receptor–Vβ analysis revealed polyclonal repertoires for both subsets, with frequencies of the CD8-Vβ5.2, Vβ22 and CD4-Vβ13.1, Vβ22 families that were mildly increased (1.3- to 2-fold above the upper limit of the normal range, data not shown). Overall, this initial analysis revealed a host with poor B-cell function, absence of both endogenous and maternal antibodies, varying degrees of numeric deficiencies of key lymphocyte subsets, and a greater than normal proportion of activated T cells. To minimize the risk of future infections, the patient was started on intravenous immunoglobulin therapy. Further analysis revealed a major discrepancy between peripheral B cells and T cells based on the assessment of memory and naive subsets in these lymphocyte populations (see Fig E1, A, in this article's Online Repository at www.jacionline.org). Specifically, only 3% of the patient's CD19+ cells displayed a memory phenotype based on CD27 coexpression, and this memory subset did not contain any B cells harboring isotype-switched surface B-cell receptors (see Fig E1, A). In contrast, 96% of the CD4+ T cells and 85% of the CD8+ T cells displayed a CD45RO+RA− memory phenotype (see Fig E1, A). Given the low probability of a 6-month-old child harboring such a high frequency of circulating memory T cells, we wanted to determine whether these T cells were of maternal origin.E1Muller S.M. Ege M. Pottharst A. Schulz A.S. Schwarz K. Friedrich W. Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients.Blood. 2001; 98: 1847-1851Crossref PubMed Scopus (176) Google Scholar Fragment analysis of short tandem repeats of the maternal buccal smear, the patient's buccal smears, and peripheral blood leukocytes revealed 16% of total circulating leukocytes in the patient to be of maternal origin (Table I). A similar analysis of T cells and granulocytes purified from the patient's blood established that greater than 98% of the T cells were of maternal origin and that a similar proportion of granulocytes (CD15+ myeloid cells) were of host origin (Table I). Flow cytometric determination of HLA-A2 expression, an HLA allele of paternal origin inherited by the patient, demonstrated its presence on B cells and monocytes but not on T cells circulating in the patient's blood (see Fig E1, B). These findings, coupled with the near absence of endogenous NK cells alluded to the possibility that the patient had X-linked severe combined immunodeficiency (SCID) with maternal T-cell engraftment.E1Muller S.M. Ege M. Pottharst A. Schulz A.S. Schwarz K. Friedrich W. Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients.Blood. 2001; 98: 1847-1851Crossref PubMed Scopus (176) Google Scholar, E2Noguchi M. Yi H. Rosenblatt H.M. Filipovich A.H. Adelstein S. Modi W.S. et al.Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans.Cell. 1993; 73: 147-157Abstract Full Text PDF PubMed Scopus (1147) Google Scholar, E3Buckley R.H. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution.Annu Rev Immunol. 2004; 22: 625-655Crossref PubMed Scopus (415) Google Scholar, E4Shearer W.T. Dunn E. Notarangelo L.D. Dvorak C.C. Puck J.M. Logan B.R. et al.Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience.J Allergy Clin Immunol. 2014; 133: 1092-1098Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar This possibility was further explored by evaluating circulating T cells and B cells in the patient's peripheral blood for the expression of IL-2Rγ and Janus kinase 3 (JAK3; see Fig 1, A). Additionally, this provided a putative explanation for the patient's chronic watery diarrhea because a duodenal biopsy specimen had revealed chronic inflammation of the lamina propria with numerous infiltrating CD3+ T cells, villous blunting, and scattered apoptotic cells within crypts but no immunohistochemical evidence of fungus/yeast, cytomegalovirus, adenovirus, and Giardia species infection (data not shown). A similar microscopic examination of the sigmoid colon and rectal biopsy specimens revealed no specific histopathologic changes (data not shown). Furthermore, a rotavirus antigen rapid test of a fecal specimen analyzed within 24 hours of the patient's admission to our institution also showed negative test results, and the patient also had negative test results on the fecal specimen to detect the presence of ova/parasites, Giardia lamblia, Cryptosporidium species, Clostridium difficile, and other enteropathogenic bacteria.Table IPretransplantation chimerism analysisLocusPatientMotherBuccal smearPurified myeloid cells (CD15+)Total cells in whole bloodPurified T cells (CD3+)Buccal smearD3S135815;1815;1815;181818vWA14;1814;1814;17;1817;1817;18FGA21;2421;2421;242121X and YX;YX;YX;YXXD8S117910;1210;1210;12;1312;1312;13D21S1130;3230;3230;32;32.232;32.232;32.2D18S5113;1613;1613;14;1614;1614;16D5S81811;1211;1211;1211;1211;12D13S3178;118;118;10;118;108;10D7282011119;119;119;11The patient's total blood cells showed mixed chimerism, whereas the CD15+ subset only had alleles corresponding to the patient, and the CD3+ subset only had alleles corresponding to the mother. Open table in a new tab The patient's total blood cells showed mixed chimerism, whereas the CD15+ subset only had alleles corresponding to the patient, and the CD3+ subset only had alleles corresponding to the mother. Collectively, the infiltrating CD3+ T cells most likely represented a graft-versus-host response that potentially contributed to the patient's gastrointestinal symptoms. The likelihood of an immunopathologic cause of the patient's gastrointestinal symptoms was further supported by the gradual resolution of the chronic diarrhea after the initiation of immunosuppressive therapy with cyclosporine, followed by reduced-intensity conditioning (fludarabine, busulfan, and anti-thymocyte globulin) in preparation for a sibling donor stem cell transplant, which was performed in the first week of June 2013. The full version of this article, including a review of relevant issues to be considered, can be found online at www.jacionline.org. If you wish to receive CME or MOC credit for the article, please see the instructions above. SCID represents a heterogeneous group of primary immunodeficiency disorders characterized by the loss of specific lymphocyte subsets induced by genetic mutations that affect key immunoregulatory molecules. Patients with X-linked SCID have mutations in the gene encoding for the common γ-chain (CD132), the signaling subunit of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.E3Buckley R.H. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution.Annu Rev Immunol. 2004; 22: 625-655Crossref PubMed Scopus (415) Google Scholar These cytokines influence a wide variety of immunologic processes ranging from lymphocyte activation, CD4 T-cell subset differentiation, T and NK cell homeostatic proliferation, T follicular helper cell function, and plasma cell differentiation.E3Buckley R.H. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution.Annu Rev Immunol. 2004; 22: 625-655Crossref PubMed Scopus (415) Google Scholar, E5Crotty S. Follicular helper CD4 T cells (TFH).Annu Rev Immunol. 2011; 29: 621-663Crossref PubMed Scopus (1938) Google Scholar The initial telltale sign of an X-linked SCID disorder in a peripheral blood sample is a significant numeric deficiency of T cells and NK cells because of an inability to transduce signals through the IL-7 (for T cells) and IL-15 (for NK cells) receptors, which facilitate the long-term survival and maintenance of these lymphocyte subsets.E3Buckley R.H. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution.Annu Rev Immunol. 2004; 22: 625-655Crossref PubMed Scopus (415) Google Scholar Because of the high morbidity and mortality associated with these disorders, early diagnosis and timely and appropriate medical interventions are critical elements of successful disease management. Consequently, many states have initiated newborn screening for SCID by evaluating the presence of T-cell receptor rearrangement excision circles in dried blood spots. Our state, Illinois, began newborn screening for SCID in early 2014. The majority of the affected patients require bone marrow or stem cell transplantation, although in certain cases enzyme replacement therapy can resolve the underlying defect, and precision medicine approaches using gene therapy are also being currently evaluated.E6Chan B. Wara D. Bastian J. Hershfield M.S. Bohnsack J. Azen C.G. et al.Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID).Clin Immunol. 2005; 117: 133-143Crossref PubMed Scopus (133) Google Scholar, E7Hacein-Bey-Abina S. Pai S.Y. Gaspar H.B. Armant M. Berry C.C. Blanche S. et al.A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency.N Engl J Med. 2014; 371: 1407-1417Crossref PubMed Scopus (276) Google Scholar, E8Sauer A.V. Di Lorenzo B. Carriglio N. Aiuti A. Progress in gene therapy for primary immunodeficiencies using lentiviral vectors.Curr Opin Allergy Clin Immunol. 2014; 14: 527-534Crossref PubMed Scopus (25) Google Scholar Transplacental transfer of maternal T cells can occur during pregnancy, but these T cells do not engraft because of allograft rejection by the infant's endogenous T cells.E1Muller S.M. Ege M. Pottharst A. Schulz A.S. Schwarz K. Friedrich W. Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients.Blood. 2001; 98: 1847-1851Crossref PubMed Scopus (176) Google Scholar Consequently, when the host T-cell response is developmentally impaired, the chances of maternal T-cell engraftment are improved.E1Muller S.M. Ege M. Pottharst A. Schulz A.S. Schwarz K. Friedrich W. Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients.Blood. 2001; 98: 1847-1851Crossref PubMed Scopus (176) Google Scholar However, the exact mechanism that contributes to long-term persistence of maternally engrafted T cells in haploidentical infants is not well understood, as indicated in published reports describing the coexistence of autologous and maternal T cells in patients with hypomorphic Janus kinase 3 (JAK3) mutations.E9Cattaneo F. Recher M. Masneri S. Baxi S.N. Fiorini C. Antonelli F. et al.Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment.J Allergy Clin Immunol. 2013; 131: 1136-1145Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Another aspect that is poorly understood is the functional impairment of the engrafted maternal T cells. In vivo functional impairment has been described in a previous study in which the majority of the patients with B+ SCID (25/26, including 10/10 patients with confirmed IL-2 receptor γ [IL-2Rγ] chain mutations) had either no or only mild clinical evidence of cutaneous manifestations of graft-versus-host disease (GVHD).E1Muller S.M. Ege M. Pottharst A. Schulz A.S. Schwarz K. Friedrich W. Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients.Blood. 2001; 98: 1847-1851Crossref PubMed Scopus (176) Google Scholar Interestingly, this study also demonstrated that an absent or attenuated alloreactive response in vivo correlated with a preponderance of circulating maternal CD8 T cells (groups 1 and 2 in the study), whereas the circulating maternal T cells in patients with SCID with severe GVHD were predominantly CD4 T cells (group 3).E1Muller S.M. Ege M. Pottharst A. Schulz A.S. Schwarz K. Friedrich W. Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients.Blood. 2001; 98: 1847-1851Crossref PubMed Scopus (176) Google Scholar Furthermore, in vitro stimulation of circulating T cells with phytohemagglutinin (PHA) demonstrated severe attenuation of proliferative responses in group 1 and 2 patients, whereas the proliferative responses were largely preserved in group 3 patients.E1Muller S.M. Ege M. Pottharst A. Schulz A.S. Schwarz K. Friedrich W. Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients.Blood. 2001; 98: 1847-1851Crossref PubMed Scopus (176) Google Scholar However, exogenous administration of IL-2 during culture after PHA stimulation impressively boosted the proliferative responses in groups 1 and 2, whereas the amplitude of the proliferative responses remained fairly stable in the third group.E1Muller S.M. Ege M. Pottharst A. Schulz A.S. Schwarz K. Friedrich W. Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients.Blood. 2001; 98: 1847-1851Crossref PubMed Scopus (176) Google Scholar This observation might be explained by the deficit of circulating CD4 T cells (a major source of IL-2) in groups 1 and 2. In a separate study maternally engrafted CD4 and CD8 T cells in a haploidentical patient with hypomorphic JAK3 mutations displayed poor in vivo proliferative capacity based on the absence of Ki67 expression and did not appear to be activated, being HLA-DR−, on direct ex vivo analysis despite a positive past clinical history for eczema and skin rash.E9Cattaneo F. Recher M. Masneri S. Baxi S.N. Fiorini C. Antonelli F. et al.Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment.J Allergy Clin Immunol. 2013; 131: 1136-1145Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Interestingly, however, these maternally engrafted T cells proliferated vigorously in both short- and long-term in vitro cultures.E9Cattaneo F. Recher M. Masneri S. Baxi S.N. Fiorini C. Antonelli F. et al.Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment.J Allergy Clin Immunol. 2013; 131: 1136-1145Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Another poorly understood aspect of the T−B+NK− SCID phenotype is the generalized deficit in humoral immunity, despite having mild to minimal perturbations in circulating B-cell numbers.E10Allenspach E. Rawlings D.J. Scharenberg A.M. X-linked severe combined immunodeficiency.in: Pagon R.A. Adam M.P. Ardinger H.H. Bird T.D. Dolan C.R. Fong C.T. GeneReviews(R). Univeristy of Washington, Seattle1993-2014Google Scholar, E11Kohn L.A. Seet C.S. Scholes J. Codrea F. Chan R. Zaidi-Merchant S. et al.Human lymphoid development in the absence of common gamma-chain receptor signaling.J Immunol. 2014; 192: 5050-5058Crossref PubMed Scopus (12) Google Scholar Although the paucity of isotype-switched memory B cells and plasma cells directed against peptide antigens is understandable given the underlying T-cell deficiency, the pathologic basis for the marked deficiency in serum IgM and dampened IgG responses to vaccines that use T-independent antigens is intriguing. It is tempting to speculate that intrinsic B-cell programming aberrations are part of the pathophysiology of this clinical entity. Related to this line of thought, it is hypothesized that the numeric deficiency of B cells in the setting of IL-2Rγ and JAK3 mutations is prevented as a result of alternative signaling involving thymic stromal lymphopoietin, which engages the IL-7 receptor α (CD127)–thymic stromal lymphopoietin receptor complex, whereas functional fitness of the B-cell population requires IL-4 signaling, which occurs through the IL-2Rγ–JAK3 pathway.E11Kohn L.A. Seet C.S. Scholes J. Codrea F. Chan R. Zaidi-Merchant S. et al.Human lymphoid development in the absence of common gamma-chain receptor signaling.J Immunol. 2014; 192: 5050-5058Crossref PubMed Scopus (12) Google Scholar Recently, it has also been reported that alternate splicing of the IL-2Rγ gene can generate a truncated dimerized soluble isoform of the protein (sγc) that competes for and hampers binding of the membrane-bound IL-2Rγ to IL-2Rβ (CD122) and IL-7 receptor α (CD127).E12Hong C. Luckey M.A. Ligons D.L. Waickman A.T. Park J.Y. Kim G.Y. et al.Activated T cells secrete an alternatively spliced form of common gamma-chain that inhibits cytokine signaling and exacerbates inflammation.Immunity. 2014; 40: 910-923Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Consequently, this can affect T-cell homeostasis and promote differentiation of residual T cells to a TH1 and TH17 phenotype that can promote inflammation and autoimmunity.E12Hong C. Luckey M.A. Ligons D.L. Waickman A.T. Park J.Y. Kim G.Y. et al.Activated T cells secrete an alternatively spliced form of common gamma-chain that inhibits cytokine signaling and exacerbates inflammation.Immunity. 2014; 40: 910-923Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Hence it is plausible that even in patients with hypomorphic IL-2Rγ gene mutations, concomitantly generated soluble isoforms of this protein by maternally derived activated T cells might compete with the membrane-bound isoform on B cells for binding to IL-4Rα (CD124), thereby hindering the IL-4–mediating signaling that facilitates and promotes optimal B-cell function. Furthermore, this ability of sγc to compete for binding to receptor complex components that physically engage with the relevant cytokine might also constrain the function of maternally engrafted T cells themselves. Assessment of surface expression of IL-2Rγ on the patient's B cells revealed a reduced frequency and intensity of expression compared with the control sample assessed in parallel (Fig 1, A). In contrast, more than 90% of the patient's circulating B cells expressed JAK3 (Fig 1, A). Interestingly, although the frequency of IL-2Rγ– and JAK3-expressing T cells was not much reduced on the maternally engrafted T cells, the level of expression of these proteins was reduced by approximately 50% (IL-2Rγ) and 80% (JAK3) vis a vis the control T cells (Fig 1, A).E13Puck J.M. Nussbaum R.L. Conley M.E. Carrier detection in X-linked severe combined immunodeficiency based on patterns of X chromosome inactivation.J Clin Invest. 1987; 79: 1395-1400Crossref PubMed Scopus (128) Google Scholar, E14Conley M.E. Lavoie A. Briggs C. Brown P. Guerra C. Puck J.M. Nonrandom X chromosome inactivation in B cells from carriers of X chromosome-linked severe combined immunodeficiency.Proc Natl Acad Sci U S A. 1988; 85: 3090-3094Crossref PubMed Scopus (121) Google Scholar Targeted Sanger sequencing of the patient's DNA extracted from a whole blood sample revealed a novel missense mutation present in the extracellular domain of the IL-2Rγ gene (c. 185G>A [p.Cys62Tyr]).E15BIOBASE Biological Databases (Human Genome Mutation Database-Professional Version). Available at: www.hgmd.org. Accessed February 25. 2015.Google Scholar As mentioned previously, published evidence has suggested impaired functionality of maternally engrafted T cells in SCID patients with IL-2Rγ mutations based on proliferation studies and lack of clinical evidence of GVHD.E1Muller S.M. Ege M. Pottharst A. Schulz A.S. Schwarz K. Friedrich W. Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients.Blood. 2001; 98: 1847-1851Crossref PubMed Scopus (176) Google Scholar, E9Cattaneo F. Recher M. Masneri S. Baxi S.N. Fiorini C. Antonelli F. et al.Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment.J Allergy Clin Immunol. 2013; 131: 1136-1145Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Although our patient displayed clinical and histologic evidence of intestinally localized GVHD, phosflow analysis of his circulating T and B cells exposed to saturating concentrations of recombinant human IL-2 and IL-4 revealed markedly attenuated phosphorylation of signal transducer and activator of transcription (STAT) 5 and STAT6 on the maternally derived engrafted T cells and STAT6 in the patient's own B cells (Fig 1, B). In addition, mitogen-induced in vitro proliferation of the patient's PBMCs was severely attenuated, as was the amplitude of phorbol 12-myristate 13-acetate/ionomycin–induced CD40-ligand and CD69 upregulation on CD4 T cells (Table E3 and Fig E1, C). This could reflect functional exhaustion of circulating alloreactive T cells. Alternatively, these results could suggest intrinsic differences between circulating maternal T cells that are functionally impaired versus tissue-resident maternal memory T cells that are active and inducing immunopathology. Another intriguing observation was the severe reduction in both the frequency and level of expression (<30% of control levels) of the X-linked inhibitor of apoptosis protein in the circulating CD8 and CD4 T cells (Fig 1, C). This observation could also account for the attenuated mitogen-induced proliferation because it could potentially contribute to enhanced activation-induced cell death after stimulation. The patient underwent successful transplantation with stem cells from his HLA-identical older female sibling (Table E4). Posttransplantation chimerism analysis demonstrated more than 98% donor engraftment for total cells, as well as purified T cells (Table II). Longitudinal chimerism analysis on the patient's whole blood sample shows that this level of donor cell engraftment has remained" @default.
• W2124517141 created "2016-06-24" @default.
• W2124517141 creator A5016644579 @default.
• W2124517141 creator A5019200326 @default.
• W2124517141 creator A5021195479 @default.
• W2124517141 creator A5024356276 @default.
• W2124517141 creator A5057495323 @default.
• W2124517141 creator A5067831557 @default.
• W2124517141 creator A5076671247 @default.
• W2124517141 creator A5080947105 @default.
• W2124517141 creator A5081954803 @default.
• W2124517141 creator A5084339424 @default.
• W2124517141 creator A5089887870 @default.
• W2124517141 date "2015-04-01" @default.
• W2124517141 modified "2023-10-01" @default.
• W2124517141 title "Signaling impairments in maternal T cells engrafted in an infant with a novel IL-2 receptor γ mutation" @default.
• W2124517141 cites W1582006901 @default.
• W2124517141 cites W1846859874 @default.
• W2124517141 cites W1974487340 @default.
• W2124517141 cites W1988484579 @default.
• W2124517141 cites W1990471922 @default.
• W2124517141 cites W2041526774 @default.
• W2124517141 cites W2056318828 @default.
• W2124517141 cites W2075611226 @default.
• W2124517141 cites W2083685529 @default.
• W2124517141 cites W2084549762 @default.
• W2124517141 cites W2134342374 @default.
• W2124517141 cites W2144154769 @default.
• W2124517141 cites W2147766260 @default.
• W2124517141 cites W2149628283 @default.
• W2124517141 cites W2156230193 @default.
• W2124517141 doi "https://doi.org/10.1016/j.jaci.2015.02.012" @default.
• W2124517141 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25843602" @default.
• W2124517141 hasPublicationYear "2015" @default.
• W2124517141 type Work @default.
• W2124517141 sameAs 2124517141 @default.
• W2124517141 citedByCount "6" @default.
• W2124517141 countsByYear W21245171412018 @default.
• W2124517141 countsByYear W21245171412019 @default.
• W2124517141 countsByYear W21245171412020 @default.
• W2124517141 countsByYear W21245171412022 @default.
• W2124517141 countsByYear W21245171412023 @default.
• W2124517141 crossrefType "journal-article" @default.
• W2124517141 hasAuthorship W2124517141A5016644579 @default.
• W2124517141 hasAuthorship W2124517141A5019200326 @default.
• W2124517141 hasAuthorship W2124517141A5021195479 @default.
• W2124517141 hasAuthorship W2124517141A5024356276 @default.
• W2124517141 hasAuthorship W2124517141A5057495323 @default.
• W2124517141 hasAuthorship W2124517141A5067831557 @default.
• W2124517141 hasAuthorship W2124517141A5076671247 @default.
• W2124517141 hasAuthorship W2124517141A5080947105 @default.
• W2124517141 hasAuthorship W2124517141A5081954803 @default.
• W2124517141 hasAuthorship W2124517141A5084339424 @default.
• W2124517141 hasAuthorship W2124517141A5089887870 @default.
• W2124517141 hasConcept C104317684 @default.
• W2124517141 hasConcept C170493617 @default.
• W2124517141 hasConcept C203014093 @default.
• W2124517141 hasConcept C501734568 @default.
• W2124517141 hasConcept C54355233 @default.
• W2124517141 hasConcept C71924100 @default.
• W2124517141 hasConcept C86803240 @default.
• W2124517141 hasConceptScore W2124517141C104317684 @default.
• W2124517141 hasConceptScore W2124517141C170493617 @default.
• W2124517141 hasConceptScore W2124517141C203014093 @default.
• W2124517141 hasConceptScore W2124517141C501734568 @default.
• W2124517141 hasConceptScore W2124517141C54355233 @default.
• W2124517141 hasConceptScore W2124517141C71924100 @default.
• W2124517141 hasConceptScore W2124517141C86803240 @default.
• W2124517141 hasIssue "4" @default.
• W2124517141 hasLocation W21245171411 @default.
• W2124517141 hasOpenAccess W2124517141 @default.
• W2124517141 hasPrimaryLocation W21245171411 @default.
• W2124517141 hasRelatedWork W1506200166 @default.
• W2124517141 hasRelatedWork W1995515455 @default.
• W2124517141 hasRelatedWork W2048182022 @default.
• W2124517141 hasRelatedWork W2080531066 @default.
• W2124517141 hasRelatedWork W2748952813 @default.
• W2124517141 hasRelatedWork W2899084033 @default.
• W2124517141 hasRelatedWork W3031052312 @default.
• W2124517141 hasRelatedWork W3032375762 @default.
• W2124517141 hasRelatedWork W3108674512 @default.
• W2124517141 hasRelatedWork W4206827732 @default.
• W2124517141 hasVolume "135" @default.
• W2124517141 isParatext "false" @default.
• W2124517141 isRetracted "false" @default.
• W2124517141 magId "2124517141" @default.
• W2124517141 workType "article" @default.