Induction by anti-CD40 antibody or soluble CD40 ligand and cytokines of IgG, IgA and IgE production by B cells from patients with X-linked hyper IgM syndrome

Purpose of the Studies. Hyper-IgM immunodeficiency is characterized by recurrent bacterial infections, normal or elevated IgM, and markedly decreased IgG, IgA, and IgE. Previous research suggested that the T cells of these patients are defective in their ability to help B cells make functional antibody. CD40 ligand (CD4OL) is a membrane glycoprotein on activated T helper cells and binds the CD40 molecule expressed on B cells, and induces proliferation and immunoglobulin class switching (in conjunction with IL-4). The gene for the CD4OL has been mapped to position q26.3-q27.1 on chromosome X (same as the Hyper-IgM gene and the area of isotype switching). Several research groups sought to determine if the immunodeficiency in Hyper-IgM patients is due to defective CD4OL. Findings. The five papers listed above document the work of different research groups that simultaneously found abnormalities in the CD4OL gene in a total of 16 patients with X-linked Hyper-IgM syndrome. Different mutations of the CD4OL gene have been discovered, including point mutations, deletions, and nonsense sequences. Mutant version of CD4OL taken from Hyper IgM patients were unable to "help" B cells in vitro. Thus, deficient CD40/CD40L interactions between B and T cells results in severely impaired immunity. Restricted CD40L gene expression to T cells may ultimately allow gene therapy as treatment. Reviewers' Comments. A concise editorial by Jean Marx entitled "Cell Communication Failure Leads to Immune Disorder" describes this landmark research and accompanies the Spriggs article in the February 12th issue of Science (pp. 896-897). This discovery may not only lead to treatment of this disorder, but also modification of other less favorable immune responses.

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THE CD40 LIGAND gp39, IS DEFECTIVE IN ACTIVATED T CELLS FROM PATIENTS WITH X-LINKED HYPER-IgM SYNDROME

PEDIATRICS ◽

10.1542/peds.94.2.280c ◽

1994 ◽

Vol 94 (2) ◽

pp. 280-280

Author(s):

Arden Levy ◽

Andrew Liu

Keyword(s):

T Cells ◽

B Cells ◽

Bacterial Infections ◽

Cd40 Ligand ◽

Research Groups ◽

Activated T Cells ◽

Immune Disorder ◽

Hyper Igm Syndrome ◽

Hyper Igm

Purpose of the Studies. Hyper-IgM immunodeficiency is characterized by recurrent bacterial infections, normal or elevated IgM, and markedly decreased IgG, IgA, and IgE. Previous research suggested that the T cells of these patients are defective in their ability to help B cells make functional antibody. CD40 ligand (CD4OL) is a membrane glycoprotein on activated T helper cells and binds the CD40 molecule expressed on B cells, and induces proliferation and immunoglobulin class switching (in conjunction with IL-4). The gene for the CD4OL has been mapped to position q26.3-q27.1 on chromosome X (same as the Hyper-IgM gene and the area of isotype switching). Several research groups sought to determine if the immunodeficiency in Hyper-IgM patients is due to defective CD4OL. Findings. The five papers listed above document the work of different research groups that simultaneously found abnormalities in the CD4OL gene in a total of 16 patients with X-linked Hyper-IgM syndrome. Different mutations of the CD4OL gene have been discovered, including point mutations, deletions, and nonsense sequences. Mutant version of CD4OL taken from Hyper IgM patients were unable to "help" B cells in vitro. Thus, deficient CD40/CD40L interactions between B and T cells results in severely impaired immunity. Restricted CD40L gene expression to T cells may ultimately allow gene therapy as treatment. Reviewers' Comments. A concise editorial by Jean Marx entitled "Cell Communication Failure Leads to Immune Disorder" describes this landmark research and accompanies the Spriggs article in the February 12th issue of Science (pp. 896-897). This discovery may not only lead to treatment of this disorder, but also modification of other less favorable immune responses.

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CD40 LIGAND MUTATIONS IN X-LINKED IMMUNODEFICIENCY WITH HYPER-IgM

PEDIATRICS ◽

10.1542/peds.94.2.280d ◽

1994 ◽

Vol 94 (2) ◽

pp. 280-280

Author(s):

Arden Levy ◽

Andrew Liu

Keyword(s):

T Cells ◽

B Cells ◽

Bacterial Infections ◽

Point Mutations ◽

Cell Communication ◽

Cd40 Ligand ◽

Research Groups ◽

Immune Disorder ◽

Hyper Igm

Purpose of the Studies. Hyper-IgM immunodeficiency is characterized by recurrent bacterial infections, normal or elevated IgM, and markedly decreased IgG, IgA, and IgE. Previous research suggested that the T cells of these patients are defective in their ability to help B cells make functional antibody. CD40 ligand (CD4OL) is a membrane glycoprotein on activated T helper cells and binds the CD40 molecule expressed on B cells, and induces proliferation and immunoglobulin class switching (in conjunction with IL-4). The gene for the CD4OL has been mapped to position q26.3-q27.1 on chromosome X (same as the Hyper-IgM gene and the area of isotype switching). Several research groups sought to determine if the immunodeficiency in Hyper-IgM patients is due to defective CD4OL. Findings. The five papers listed above document the work of different research groups that simultaneously found abnormalities in the CD4OL gene in a total of 16 patients with X-linked Hyper-IgM syndrome. Different mutations of the CD4OL gene have been discovered, including point mutations, deletions, and nonsense sequences. Mutant version of CD4OL taken from Hyper IgM patients were unable to "help" B cells in vitro. Thus, deficient CD40/CD40L interactions between B and T cells results in severely impaired immunity. Restricted CD40L gene expression to T cells may ultimately allow gene therapy as treatment. Reviewers' Comments. A concise editorial by Jean Marx entitled "Cell Communication Failure Leads to Immune Disorder" describes this landmark research and accompanies the Spriggs article in the February 12th issue of Science (pp. 896-897). This discovery may not only lead to treatment of this disorder, but also modification of other less favorable immune responses.

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A novel mutation in CD40 ligand gene in a sporadic patient with hyper-IgM syndrome

Journal of Shanghai University (English Edition) ◽

10.1007/s11741-998-0082-0 ◽

1998 ◽

Vol 2 (2) ◽

pp. 164-169

Author(s):

Jian Sun ◽

Zi Lin ◽

Daming Ying

Keyword(s):

Novel Mutation ◽

Cd40 Ligand ◽

Hyper Igm Syndrome ◽

Hyper Igm

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Epitope‐dependent synergism and antagonism between CD40 antibodies and soluble CD40 ligand for the regulation of CD23 expression and IgE synthesis in human B cells

Allergy ◽

10.1034/j.1398-9995.1999.00092.x ◽

1999 ◽

Vol 54 (6) ◽

pp. 576-583 ◽

Cited By ~ 17

Author(s):

A Challa ◽

JD Pound ◽

J Gordon ◽

RJ Armitage

Keyword(s):

B Cells ◽

Cd40 Ligand ◽

Soluble Cd40 Ligand ◽

Human B Cells ◽

Ige Synthesis ◽

Cd23 Expression ◽

Synergism And Antagonism

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Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand

Blood ◽

10.1182/blood-2011-04-351254 ◽

2011 ◽

Vol 118 (14) ◽

pp. 3811-3817 ◽

Cited By ~ 32

Author(s):

Ashish Jain ◽

Joseph A. Kovacs ◽

David L. Nelson ◽

Stephen A. Migueles ◽

Stefania Pittaluga ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Intracellular Cytokine Staining ◽

Cd40 Ligand ◽

Genetic Alterations ◽

Delayed Type Hypersensitivity ◽

Free Interval ◽

Hyper Igm Syndrome ◽

Hyper Igm ◽

Drug Free

Abstract X-linked hyper IgM syndrome (XHM) is a combined immune deficiency disorder caused by genetic alterations in CD40 ligand. The purpose of this study was to investigate the safety and efficacy of recombinant CD40 ligand (rCD40L) in the treatment of the disease. Three children were administered rCD40L subcutaneously 3 times per week at 0.03 mg/kg for 22 weeks, and after a 12-week drug-free interval, the dose was increased to 0.05 mg/kg for an additional 22 weeks of treatment. Although specific antibody responses to T cell–dependent antigens was lacking, administration of rCD40 resulted in acquisition of the capacity to mount cutaneous delayed type hypersensitivity reactions that disappeared during the drug-free interval as well as the postbiologic follow-up period. With rCD40L treatment, patient T cells developed a new capacity to respond to T-cell mitogens with synthesis of IFN-γ and TNF-α. Intracellular cytokine staining studies showed that both CD4+ and CD8+ T cells participated in this response. Finally, CD40L therapy was associated with changes in lymph node size and architecture based on comparison of biopsies taken before and after therapy. This clinical study showed that rCD40L is capable of improving T cell–immune function in patients with XHM.

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Clinical Features and Genetic Analysis of 20 Chinese Patients with X-Linked Hyper-IgM Syndrome

Journal of Immunology Research ◽

10.1155/2014/683160 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 15

Author(s):

Lin-Lin Wang ◽

Wei Zhou ◽

Wei Zhao ◽

Zhi-Qing Tian ◽

Wei-Fan Wang ◽

...

Keyword(s):

Cd40 Ligand ◽

Chinese Patients ◽

Primary Immunodeficiency Diseases ◽

Novel Mutations ◽

Hematopoietic Stem ◽

Molecular Features ◽

School Of Medicine ◽

Hyper Igm Syndrome ◽

Bioinformatics Software ◽

Hyper Igm

X-linked hyper-IgM syndrome (XHIGM) is one type of primary immunodeficiency diseases, resulting from defects in the CD40 ligand/CD40 signaling pathways. We retrospectively analyzed the clinical and molecular features of 20 Chinese patients diagnosed and followed up in hospitals affiliated to Shanghai Jiao Tong University School of Medicine from 1999 to 2013. The median onset age of these patients was 8.5 months (range: 20 days–21 months). Half of them had positive family histories, with a shorter diagnosis lag. The most common symptoms were recurrent sinopulmonary infections (18 patients, 90%), neutropenia (14 patients, 70%), oral ulcer (13 patients, 65%), and protracted diarrhea (13 patients, 65%). Six patients had BCGitis. Six patients received hematopoietic stem cell transplantations and four of them had immune reconstructions and clinical remissions. Eighteen unique mutations inCD40Lgene were identified in these 20 patients from 19 unrelated families, with 12 novel mutations. We compared with reported mutation results and used bioinformatics software to predict the effects of mutations on the target protein. These mutations reflected the heterogeneity ofCD40Lgene and expanded our understanding of XHIGM.

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Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting

Blood ◽

10.1182/blood-2008-10-183632 ◽

2009 ◽

Vol 113 (16) ◽

pp. 3706-3715 ◽

Cited By ~ 44

Author(s):

Nancy S. Longo ◽

Patricia L. Lugar ◽

Sule Yavuz ◽

Wen Zhang ◽

Peter H. L. Krijger ◽

...

Keyword(s):

B Cells ◽

Somatic Hypermutation ◽

Cytidine Deaminase ◽

Cd40 Ligation ◽

Uracil Dna Glycosylase ◽

Hyper Igm Syndrome ◽

Reduced Frequency ◽

Activation Induced Cytidine Deaminase ◽

Hyper Igm ◽

Ig Heavy Chain

Abstract Subjects with X-linked hyper-IgM syndrome (X-HIgM) have a markedly reduced frequency of CD27+ memory B cells, and their Ig genes have a low level of somatic hypermutation (SHM). To analyze the nature of SHM in X-HIgM, we sequenced 209 nonproductive and 926 productive Ig heavy chain genes. In nonproductive rearrangements that were not subjected to selection, as well as productive rearrangements, most of the mutations were within targeted RGYW, WRCY, WA, or TW motifs (R = purine, Y = pyrimidine, and W = A or T). However, there was significantly decreased targeting of the hypermutable G in RGYW motifs. Moreover, the ratio of transitions to transversions was markedly increased compared with normal. Microarray analysis documented that specific genes involved in SHM, including activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG2), were up-regulated in normal germinal center (GC) B cells, but not induced by CD40 ligation. Similar results were obtained from light chain rearrangements. These results indicate that in the absence of CD40-CD154 interactions, there is a marked reduction in SHM and, specifically, mutations of AICDA-targeted G residues in RGYW motifs along with a decrease in transversions normally related to UNG2 activity.

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