The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome

Aruffo, Alejandro; Farrington, Mary; Hollenbaugh, Diane; Li, Xu; Milatovich, Athena; Nonoyama, Shigeaki; Bajorath, Jürgen; Grosmaire, Laura S.; Stenkamp, Ronald E.; Neubauer, Michael; Roberts, Robert L.; Noelle, Randolph J.; Ledbetter, Jeffrey A.; Francke, Uta; Ochs, Hans D.

doi:10.1016/0092-8674(93)90668-g

Cited by 765 publications

(410 citation statements)

References 36 publications

Supporting

Mentioning

388

Contrasting

Unclassified

Order By: Relevance

“…In response to T-dependent antigens, B cells require costimulatory signaling from T H cells expressing CD40L and cytokines, such as IL-4. B cells from individuals with a mutation in CD40L are unable to undergo class switch recombination in response to T-dependent antigens (Aruffo et al, 1993). Signaling through CD40 activates both canonical and non-canonical NF-kB pathways, although it is unclear which is operative in the response to T-dependent antigens.…”

Section: T-cell Responses Mediated By Nf-kbmentioning

confidence: 99%

NF-κB and the immune response

2006

View full text Add to dashboard Cite

Section: T-cell Responses Mediated By Nf-kbmentioning

confidence: 99%

NF-κB and the immune response

2006

View full text Add to dashboard Cite

“…The disease is caused by defective expression of the CD40 ligand (CD40L) on the surface of activated T cells [2][3][4][5]. Interaction of CD40L with CD40 on both B cells and monocyte derived cells is critical for immunoglobulin isotype switching as well as for activation of macrophages and functional differentiation of T cells [6].…”

Section: Introductionmentioning

confidence: 99%

Allogeneic hematopoietic stem cell transplantation for seven children with X‐linked hyper‐IgM syndrome: A single center experience

et al. 2004

Self Cite

View full text Add to dashboard Cite

X-linked hyper-IgM syndrome (XHIM), or hyper-IgM syndrome type 1 (HIGM1), is a rare primary immunodeficiency disorder susceptible to recurrent bacterial infection and opportunistic infection such as Pneumocystis carinii and Cryptosporidium parvum. The longterm outcome is quite poor, and allogeneic hematopoietic stem cell transplantation (HSCT) offers the only cure. Seven patients with XHIM, from age 3 to 19 years (mean 11.3 years), underwent allogeneic HSCT in our institution. Details of pre-and post-transplantation data and transplantation procedure were analyzed retrospectively. The donors were HLA-identical siblings for three patients and HLA-identical unrelated donors for four patients. All but one received conventional conditioning regimen consisting of busulfan and cyclophosphamide and prophylaxis for graft-versus-host disease (GVHD) consisting of cyclosporine and methotrexate. Five out of seven patients are alive and well with normal CD40L expression, and four of these five are free of intravenous immunoglobulin supplementation. The two patients who died had prolonged episodes of severe and recurrent infections and organ damage. We conclude that conventional allogeneic HSCT from HLA matched related or unrelated donors is curative and feasible for XHIM patients, if performed before significant infections and organ damage occur. For the high-risk patients, an alternative approach including nonmyeloablative HSCT may be more feasible. Am.

show abstract

“…Soluble co-stimulatory signals include cytokines, such as IL-2, IL-4, IL-10 and IL-13, whereas the ligand for CD40 (CD40L) appears to be the most important T-cell surface molecule that mediates productive T-B cell interactions resulting in Ig isotype switching and Ig synthesis [5][6][7]. The crucial role of the interactions between CD40, constitutively expressed on B cells, and CD40L was demonstrated in patients with hyper-IgM syndrome, who can make no or minimal levels of IgG, IgA and IgE in vivo, which was shown to be due to mutations in patients' CD40L gene [8][9][10][11]. The membrane-bound form of TNF-a (mTNF-a) is another T-cell surface molecule that provides co-stimulatory signals for B cells, because neutralizing MoAbs specific for mTNF-a strongly inhibited T-cell dependent Ig isotype switching and polyclonal Ig synthesis [12,13].…”

Section: Introductionmentioning

confidence: 99%

IL‐4 Synergizes with IL‐10 and Anti‐CD40 MoAbs to Induce B‐Cell Differentiation in Patients with Common Variable Immunodeficiency

Punnonen¹,

Kainulainen

Ruuskanen

et al. 1997

Scand J Immunol

View full text Add to dashboard Cite

Punnonen J, Kainulainen L, Ruuskanen O, Nikoskelainen J, Arvilommi H. IL-4 Synergizes with IL-10 and Anti-CD40 MoAbs to Induce B-Cell Differentiation in Patients with Common Variable Immunodeficiency. Scand J Immunol 1997;45:203-212 In the present study the phenotype and function of lymphocytes from patients with common variable immunodeficiency (CVI) were studied. Five out of 12 patients had abnormally low proportion of CD4 + T cells, but PBMC of these patients were capable of proliferating in response to polyclonal T-cell mitogens or PPD antigen. The phenotype of patients' B cells, as determined by expression of CD10, CD19 and CD34, was comparable to that of healthy controls. IL-4 and anti-CD40 MoAbs induced moderate B-cell differentiation in PBMC derived from patients with CVI, but the frequencies of Ig-secreting cells were generally at levels spontaneously observed in healthy controls. IL-10 was completely ineffective in inducing IgG-secreting cells in cultures of PBMC derived from patients with CVI even in the presence of anti-CD40 MoAbs, whereas high frequencies of Ig-secreting cells were induced under similar condition in cultures of PBMC derived from healthy controls. Importantly, when IL-4 was added to cultures stimulated with anti-CD40 MoAbs and IL-10, a very strong synergistic effect on the numbers of Ig-secreting cells and the levels of Ig secretion was observed in PBMC from both patients and controls. Moreover, the frequencies of Ig-secreting cells after activation with anti-CD40 MoAbs, IL-4 plus IL-10 in PBMC from some patients were comparable to those observed in PBMC from healthy controls. Taken together, these results indicate that B cells from patients with CVI have impaired capacity to differentiate into Ig-secreting cells in response to IL-10 and anti-CD40 MoAbs, and that this unresponsiveness can be restored by exogenous IL-4 in a proportion of the patients.

show abstract

The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome

Cited by 765 publications

References 36 publications

NF-κB and the immune response

NF-κB and the immune response

Allogeneic hematopoietic stem cell transplantation for seven children with X‐linked hyper‐IgM syndrome: A single center experience

IL‐4 Synergizes with IL‐10 and Anti‐CD40 MoAbs to Induce B‐Cell Differentiation in Patients with Common Variable Immunodeficiency

Contact Info

Product

Resources

About