Scholars@Duke
Joseph Linton Roberts

Joseph Linton Roberts

Professor Emeritus of Pediatrics
Pediatrics, Allergy and Immunology
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Selected Publications

Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency.

Conference J Clin Invest · July 2, 2018 Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the ... Full text Link to item Cite

Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature.

Journal Article J Clin Immunol · July 2016 The purpose of this research was to use next generation sequencing to identify mutations in patients with primary immunodeficiency diseases whose pathogenic gene mutations had not been identified. Remarkably, four unrelated patients were found by next gene ... Full text Open Access Link to item Cite

Clinical application of whole-genome sequencing in patients with primary immunodeficiency.

Journal Article J Allergy Clin Immunol · August 2015 This report illustrates the value of whole genome sequencing (WGS) in elucidating the genetic cause of disease in patients with primary immunodeficiency (PID). As sequencing costs decline, we predict that utilization of next generation sequencing (NGS) in ... Full text Link to item Cite

A nonsense mutation in IKBKB causes combined immunodeficiency.

Journal Article Blood · September 25, 2014 Identification of the molecular etiologies of primary immunodeficiencies has led to important insights into the development and function of the immune system. We report here the cause of combined immunodeficiency in 4 patients from 2 different consanguineo ... Full text Link to item Cite

CD45-deficient severe combined immunodeficiency caused by uniparental disomy.

Journal Article Proc Natl Acad Sci U S A · June 26, 2012 Analysis of the molecular etiologies of SCID has led to important insights into the control of immune cell development. Most cases of SCID result from either X-linked or autosomal recessive inheritance of mutations in a known causative gene. However, in so ... Full text Link to item Cite

Genotype, phenotype, and outcomes of nine patients with T-B+NK+ SCID.

Journal Article Pediatr Transplant · November 2011 There are few reports of clinical presentation, genotype, and HCT outcomes for patients with T-B+NK+ SCID. Between 1981 and 2007, eight of 84 patients with SCID who received and/or were followed after HCT at UCSF had the T-B+NK+ phenotype. One additional p ... Full text Link to item Cite

Partial splenectomy but not total splenectomy preserves immunoglobulin M memory B cells in mice.

Journal Article J Pediatr Surg · September 2011 PURPOSE: The mechanism by which partial splenectomy preserves splenic immune function is unknown. Immunoglobulin (Ig) M memory B cells are critical for the immune response against encapsulated bacteria and are reduced in asplenic patients, although it is u ... Full text Open Access Link to item Cite

Thymic output, T-cell diversity, and T-cell function in long-term human SCID chimeras.

Journal Article Blood · August 13, 2009 Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B, and sometimes NK-cell function. Nonablative human leukocyte antigen-identical or rigorously T cell-depleted haploidentical parent ... Full text Link to item Cite

Clinical efficacy and immune regulation with peanut oral immunotherapy.

Journal Article J Allergy Clin Immunol · August 2009 BACKGROUND: Oral immunotherapy (OIT) has been thought to induce clinical desensitization to allergenic foods, but trials coupling the clinical response and immunologic effects of peanut OIT have not been reported. OBJECTIVE: The study objective was to inve ... Full text Link to item Cite

Flexible stereospecific interactions and composition within nucleoprotein complexes assembled on the TCR alpha gene enhancer.

Journal Article J Immunol · August 1, 2009 During thymocyte maturation, enhancers of genes encoding for TCRdelta (Tcrd) and TCRalpha (Tcra), Edelta(8), and Ealpha, work as a developmental switch controlling transition from Tcrd to Tcra activity at the Tcrad locus. Previous experiments revealed that ... Full text Link to item Cite

Unusual clinical and immunologic manifestations of transplacentally acquired maternal T cells in severe combined immunodeficiency.

Journal Article J Allergy Clin Immunol · August 2007 The persistence of transplacentally transferred maternal T cells is common in infants with severe combined immunodeficiency (SCID), occurring in more than half of patients with SCID undergoing transplantation at our institution. These T cells respond poorl ... Full text Link to item Cite

T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex.

Journal Article Blood · April 15, 2007 CD3zeta is a subunit of the T-cell antigen receptor (TCR) complex required for its assembly and surface expression that also plays an important role in TCR-mediated signal transduction. We report here a patient with T(-)B(+)NK(+) severe combined immunodefi ... Full text Link to item Cite

Interleukin 7 receptor alpha-chain-mutation severe combined immunodeficiency without lymphopenia: correction with haploidentical T-cell-depleted bone marrow transplantation.

Journal Article Ann Allergy Asthma Immunol · December 2006 BACKGROUND: Severe combined immunodeficiency (SCID) is a rare primary immunodeficiency characterized by abnormal lymphocyte development and lymphopenia. It often presents during the first year of life with recurrent, opportunistic infections, failure to th ... Full text Link to item Cite

Jak3 and the pathogenesis of severe combined immunodeficiency.

Journal Article Mol Immunol · July 2004 The discovery that Jak3 mutations are a significant cause of severe combined immunodeficiency (SCID), a rare inherited defect characterized by lymphopenia, has provided valuable insights into the functions of Jak3 in lymphoid development and function. The ... Full text Link to item Cite

Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation.

Journal Article Blood · March 15, 2004 We found 10 individuals from 7 unrelated families among 170 severe combined immunodeficiency (SCID) patients who exhibited 9 different Janus kinase 3 (JAK3) mutations. These included 3 missense and 2 nonsense mutations, 1 insertion, and 3 deletions. With t ... Full text Link to item Cite

Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases.

Journal Article Mol Cell · November 2001 Janus kinases comprise carboxyterminal kinase, pseudokinase, SH2-like, and N-terminal FERM domains. We identified three patient-derived mutations in the FERM domain of Jak3 and investigated the functional consequences of these mutations. These mutations in ... Full text Link to item Cite

Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.

Journal Article N Engl J Med · February 18, 1999 BACKGROUND: Since 1968 it has been known that bone marrow transplantation can ameliorate severe combined immunodeficiency, but data on the long-term efficacy of this treatment are limited. We prospectively studied immunologic function in 89 consecutive inf ... Full text Link to item Cite

Role of JAK3 in CD40-mediated signaling.

Journal Article Blood · October 1, 1998 CD40 is a member of the tumor necrosis factor receptor family and plays an important role in B-cell survival, growth, differentiation, and isotype switching. Recently, CD40 has been shown to associate with JAK3, a member of the family of Janus Kinases, whi ... Link to item Cite

Developmental regulation of V(D)J recombination at the TCR alpha/delta locus.

Journal Article Immunol Rev · October 1998 The T-cell receptor (TCR) alpha/delta locus includes a large number of V, D, J and C gene segments that are used to produce functional TCR delta and TCR alpha chains expressed by distinct subsets of T lymphocytes. V(D)J recombination events within the locu ... Full text Link to item Cite

Cooperation among multiple transcription factors is required for access to minimal T-cell receptor alpha-enhancer chromatin in vivo.

Journal Article Mol Cell Biol · June 1998 To understand the molecular basis for the dramatic functional synergy between transcription factors that bind to the minimal T-cell receptor alpha enhancer (Ealpha), we analyzed enhancer occupancy in thymocytes of transgenic mice in vivo by genomic footpri ... Full text Link to item Cite

Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency.

Conference J Clin Invest · July 2, 2018 Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the ... Full text Link to item Cite

Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature.

Journal Article J Clin Immunol · July 2016 The purpose of this research was to use next generation sequencing to identify mutations in patients with primary immunodeficiency diseases whose pathogenic gene mutations had not been identified. Remarkably, four unrelated patients were found by next gene ... Full text Open Access Link to item Cite

Clinical application of whole-genome sequencing in patients with primary immunodeficiency.

Journal Article J Allergy Clin Immunol · August 2015 This report illustrates the value of whole genome sequencing (WGS) in elucidating the genetic cause of disease in patients with primary immunodeficiency (PID). As sequencing costs decline, we predict that utilization of next generation sequencing (NGS) in ... Full text Link to item Cite

A nonsense mutation in IKBKB causes combined immunodeficiency.

Journal Article Blood · September 25, 2014 Identification of the molecular etiologies of primary immunodeficiencies has led to important insights into the development and function of the immune system. We report here the cause of combined immunodeficiency in 4 patients from 2 different consanguineo ... Full text Link to item Cite

CD45-deficient severe combined immunodeficiency caused by uniparental disomy.

Journal Article Proc Natl Acad Sci U S A · June 26, 2012 Analysis of the molecular etiologies of SCID has led to important insights into the control of immune cell development. Most cases of SCID result from either X-linked or autosomal recessive inheritance of mutations in a known causative gene. However, in so ... Full text Link to item Cite

Genotype, phenotype, and outcomes of nine patients with T-B+NK+ SCID.

Journal Article Pediatr Transplant · November 2011 There are few reports of clinical presentation, genotype, and HCT outcomes for patients with T-B+NK+ SCID. Between 1981 and 2007, eight of 84 patients with SCID who received and/or were followed after HCT at UCSF had the T-B+NK+ phenotype. One additional p ... Full text Link to item Cite

Partial splenectomy but not total splenectomy preserves immunoglobulin M memory B cells in mice.

Journal Article J Pediatr Surg · September 2011 PURPOSE: The mechanism by which partial splenectomy preserves splenic immune function is unknown. Immunoglobulin (Ig) M memory B cells are critical for the immune response against encapsulated bacteria and are reduced in asplenic patients, although it is u ... Full text Open Access Link to item Cite

Thymic output, T-cell diversity, and T-cell function in long-term human SCID chimeras.

Journal Article Blood · August 13, 2009 Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B, and sometimes NK-cell function. Nonablative human leukocyte antigen-identical or rigorously T cell-depleted haploidentical parent ... Full text Link to item Cite

Clinical efficacy and immune regulation with peanut oral immunotherapy.

Journal Article J Allergy Clin Immunol · August 2009 BACKGROUND: Oral immunotherapy (OIT) has been thought to induce clinical desensitization to allergenic foods, but trials coupling the clinical response and immunologic effects of peanut OIT have not been reported. OBJECTIVE: The study objective was to inve ... Full text Link to item Cite

Flexible stereospecific interactions and composition within nucleoprotein complexes assembled on the TCR alpha gene enhancer.

Journal Article J Immunol · August 1, 2009 During thymocyte maturation, enhancers of genes encoding for TCRdelta (Tcrd) and TCRalpha (Tcra), Edelta(8), and Ealpha, work as a developmental switch controlling transition from Tcrd to Tcra activity at the Tcrad locus. Previous experiments revealed that ... Full text Link to item Cite

Unusual clinical and immunologic manifestations of transplacentally acquired maternal T cells in severe combined immunodeficiency.

Journal Article J Allergy Clin Immunol · August 2007 The persistence of transplacentally transferred maternal T cells is common in infants with severe combined immunodeficiency (SCID), occurring in more than half of patients with SCID undergoing transplantation at our institution. These T cells respond poorl ... Full text Link to item Cite

T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex.

Journal Article Blood · April 15, 2007 CD3zeta is a subunit of the T-cell antigen receptor (TCR) complex required for its assembly and surface expression that also plays an important role in TCR-mediated signal transduction. We report here a patient with T(-)B(+)NK(+) severe combined immunodefi ... Full text Link to item Cite

Interleukin 7 receptor alpha-chain-mutation severe combined immunodeficiency without lymphopenia: correction with haploidentical T-cell-depleted bone marrow transplantation.

Journal Article Ann Allergy Asthma Immunol · December 2006 BACKGROUND: Severe combined immunodeficiency (SCID) is a rare primary immunodeficiency characterized by abnormal lymphocyte development and lymphopenia. It often presents during the first year of life with recurrent, opportunistic infections, failure to th ... Full text Link to item Cite

Jak3 and the pathogenesis of severe combined immunodeficiency.

Journal Article Mol Immunol · July 2004 The discovery that Jak3 mutations are a significant cause of severe combined immunodeficiency (SCID), a rare inherited defect characterized by lymphopenia, has provided valuable insights into the functions of Jak3 in lymphoid development and function. The ... Full text Link to item Cite

Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation.

Journal Article Blood · March 15, 2004 We found 10 individuals from 7 unrelated families among 170 severe combined immunodeficiency (SCID) patients who exhibited 9 different Janus kinase 3 (JAK3) mutations. These included 3 missense and 2 nonsense mutations, 1 insertion, and 3 deletions. With t ... Full text Link to item Cite

Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases.

Journal Article Mol Cell · November 2001 Janus kinases comprise carboxyterminal kinase, pseudokinase, SH2-like, and N-terminal FERM domains. We identified three patient-derived mutations in the FERM domain of Jak3 and investigated the functional consequences of these mutations. These mutations in ... Full text Link to item Cite

Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency.

Journal Article N Engl J Med · February 18, 1999 BACKGROUND: Since 1968 it has been known that bone marrow transplantation can ameliorate severe combined immunodeficiency, but data on the long-term efficacy of this treatment are limited. We prospectively studied immunologic function in 89 consecutive inf ... Full text Link to item Cite

Role of JAK3 in CD40-mediated signaling.

Journal Article Blood · October 1, 1998 CD40 is a member of the tumor necrosis factor receptor family and plays an important role in B-cell survival, growth, differentiation, and isotype switching. Recently, CD40 has been shown to associate with JAK3, a member of the family of Janus Kinases, whi ... Link to item Cite

Developmental regulation of V(D)J recombination at the TCR alpha/delta locus.

Journal Article Immunol Rev · October 1998 The T-cell receptor (TCR) alpha/delta locus includes a large number of V, D, J and C gene segments that are used to produce functional TCR delta and TCR alpha chains expressed by distinct subsets of T lymphocytes. V(D)J recombination events within the locu ... Full text Link to item Cite

Cooperation among multiple transcription factors is required for access to minimal T-cell receptor alpha-enhancer chromatin in vivo.

Journal Article Mol Cell Biol · June 1998 To understand the molecular basis for the dramatic functional synergy between transcription factors that bind to the minimal T-cell receptor alpha enhancer (Ealpha), we analyzed enhancer occupancy in thymocytes of transgenic mice in vivo by genomic footpri ... Full text Link to item Cite

Role of JAK3 in CD40 mediated signaling

Journal Article FASEB Journal · March 20, 1998 CD40 is a member of the TNF receptor family and plays an important role in B cell survival, growth, differentiation and isotype switching. Recently, CD40 has been shown to associate with JAK3, a member of the Janus Kinase family which are non-receptor prot ... Cite

Regulation of T cell receptor delta gene rearrangement by CBF/PEBP2.

Journal Article J Exp Med · April 7, 1997 We have analyzed transgenic mice carrying versions of a human T cell receptor (TCR)-delta gene minilocus to study the developmental control of VDJ (variable/diversity/joining) recombination. Previous data indicated that a 1.4-kb DNA fragment carrying the T ... Full text Link to item Cite

Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants.

Journal Article J Pediatr · March 1997 OBJECTIVE: To determine the relative frequencies of the different genetic forms of severe combined immunodeficiency (SCID) and whether there are distinctive characteristics of the particular genotypes. STUDY DESIGN: The demographic, genetic, and immunologi ... Full text Link to item Cite

Developmental regulation of VDJ recombination by the core fragment of the T cell receptor alpha enhancer.

Journal Article J Exp Med · January 6, 1997 The role of T cell receptor alpha enhancer (E alpha) cis-acting elements in the developmental regulation of VDJ recombination at the TCR alpha/delta locus was examined in transgenic mice containing variants of a minilocus VDJ recombination substrate. We de ... Full text Link to item Cite

Developmental regulation of alpha beta T cell antigen receptor assembly in immature CD4+CD8+ thymocytes.

Journal Article Bioessays · December 1995 Most lymphocytes of the T cell lineage develop along the CD4/CD8 pathway and express antigen receptors on their surfaces consisting of clonotypic alpha beta chains associated with invariant CD3- gamma delta epsilon components and sigma chains, collectively ... Full text Link to item Cite

Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development.

Journal Article Science · November 3, 1995 Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor gamma chain (gamma c) gene that encodes a shared, essential component of the receptors of interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15. The Janus ... Full text Link to item Cite

TCR alpha-CD3 delta epsilon association is the initial step in alpha beta dimer formation in murine T cells and is limiting in immature CD4+ CD8+ thymocytes.

Journal Article Immunity · April 1995 The present study has examined the molecular events leading to formation of alpha beta dimers in normal murine thymocytes and mature T cells. We demonstrate that TCR assembly proceeds by initial association of TCR alpha with CD3 delta epsilon proteins and ... Full text Link to item Cite

Disruption of intrathymic CD4-Ia interactions on immature CD4+CD8+ thymocytes results in diminished TCR expression on mature CD8+ T cell progeny.

Journal Article Cell Immunol · March 1995 Cell surface TCR expression by developing thymocytes is actively regulated during ontogeny. Whereas most immature CD4+CD8+ thymocytes express low levels of TCR alpha beta, mature CD4+ and CD8+ thymocytes express significantly higher levels of surface TCR. ... Full text Link to item Cite

TCRα-CD3δε{lunate} association is the initial step in αβ dimer formation in murine T cells and is limiting in immature CD4+CD8+ thymocytes

Journal Article Immunity · 1995 The present study has examined the molecular events leading to formation of αβ dimers in normal murine thymocytes and mature T cells. We demonstrate that TCR assembly proceeds by initial association of TCRα with CD3δε{lunate} proteins and by association of ... Cite

Developmental regulation of alpha beta T cell antigen receptor expression results from differential stability of nascent TCR alpha proteins within the endoplasmic reticulum of immature and mature T cells.

Journal Article EMBO J · October 3, 1994 Featured Publication The alpha beta T cell antigen receptor (TCR) that is expressed on most T lymphocytes is a multisubunit transmembrane complex composed of at least six different proteins (alpha, beta, gamma, delta, epsilon and zeta) that are assembled in the endoplasmic ret ... Full text Link to item Cite

Stoichiometry of the T cell antigen receptor (TCR) complex: each TCR/CD3 complex contains one TCR alpha, one TCR beta, and two CD3 epsilon chains.

Journal Article J Exp Med · August 1, 1994 The stoichiometry of the subunits that comprise the T cell antigen receptor (TCR) complex is not completely known. In particular, it is uncertain whether TCR alpha and TCR beta proteins are present in the TCR complex as one or multiple heterodimeric pairs. ... Full text Link to item Cite

Involvement of multiple factors in the clonal deletion of self-reactive T cells.

Journal Article Cell Immunol · October 15, 1993 Self-tolerance is primarily induced by the elimination of potentially self-reactive T cells during early development of the T cell repertoire. In the mouse, endogenous mouse mammary tumor viruses (MMTV), including minor lymphocyte-stimulating antigens and ... Full text Link to item Cite

Haploidentical bone marrow stem cell transplantation in human severe combined immunodeficiency.

Journal Article Semin Hematol · October 1993 From May 1992 to March 1993, 50 infants with severe combined immunodeficiency (SCID) were given bone marrow transplants at Duke University Medical Center. None received chemotherapy for conditioning or for graft-versus-host disease (GVHD) prophylaxis. Fort ... Link to item Cite

Haploidentical bone marrow stem cell transplantation in human severe combined immunodeficiency

Journal Article Seminars in Hematology · January 1, 1993 From May 1992 to March 1993, 50 infants with severe combined immunodeficiency (SCID) were given bone marrow transplants at Duke University Medical Center. None received chemotherapy for conditioning or for graft- versus-host disease (GVHD) prophylaxis. For ... Cite

Expression of Mls determinants in mice exhibiting the severe combined immunodeficiency (scid) mutation or X-linked immunodeficiency (xid) defect.

Journal Article J Immunol · September 1, 1992 While Ig+ B cells appear to be the principal cell type expressing immunogenic minor lymphocyte stimulatory (Mls) determinants, both T cells and B cells are capable of mediating deletion of developing Mls-reactive thymocytes. In addition, levels of mouse ma ... Link to item Cite

Clonal deletion and clonal anergy in the thymus induced by cellular elements with different radiation sensitivities.

Journal Article J Exp Med · March 1, 1990 The present study demonstrates that immune tolerance can be achieved in the thymus both by clonal deletion and by clonal inactivation, but that the two tolerant states are induced by cellular elements with different radiation sensitivities. TCR engagement ... Full text Link to item Cite

Modified MHC restriction of donor-origin T cells in humans with severe combined immunodeficiency transplanted with haploidentical bone marrow stem cells.

Journal Article J Immunol · September 1, 1989 The choice of class II MHC determinants that serve as self-recognition elements for murine CD4+ T cells is thought to be determined by the environment in which T cells mature rather than their genotype. Patients with severe combined immunodeficiency (SCID) ... Link to item Cite