Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM.

Fuleihan, Ramsay; Ramesh, Narayanaswamy; Loh, Richard; Jabara, Haifa H.; Rosen, R S; Chatila, Talal A.; Fu, Shu Man; Stamenkovic, Ivan; Geha, Raif S.

doi:10.1073/pnas.90.6.2170

Cited by 326 publications

(167 citation statements)

References 27 publications

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“…Although agonistic mAbs to CD40 initially suggested its role as an immune cell activator (18,33), the discovery of its key physiological roles in immune responses followed identification of the ligand for CD40 (initially called gp39 or CD40L, now designated CD154) (34)(35)(36). This, in turn, led to elucidation of the critical role for defective CD40 signaling in the human immunodeficiency disease X-linked hyper-IgM syndrome (37)(38)(39)(40). Soon after the appreciation of CD40's important functions in host immune defenses, studies implicated an important contribution of CD40-mediated activation in pathogenic processes, including transplant rejection, autoimmune diseases, and B cell malignancies (reviewed in Refs.…”

Section: Discussionmentioning

confidence: 99%

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Bankert

Oxley

Smith

et al. 2015

The Journal of Immunology

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Blocking the interaction of CD40 with its ligand CD154 is a desirable goal of therapies for preventing and/or ameliorating autoimmune diseases and transplant rejection. CD154-blocking mAbs used in human clinical trials resulted in unanticipated vascular complications, leading to heightened interest in the therapeutic potential of antagonist mAbs specific for human CD40. Abs that do not require physical competition with CD154 to inhibit CD40 signaling have particular therapeutic promise. In this study, we demonstrate that the antagonist anti-human CD40 mAb PG102 fails to trigger CD40-mediated activation, as well as impairs CD154-mediated CD40 activation, via a distinct nonstimulatory CD40 signaling mechanism. PG102 did not induce early CD40-induced signaling events, and it inhibited early kinase and transcription factor activation by CD154 or agonist anti-CD40 mAbs. However, PG102 stimulated normal CD40-mediated TNFR-associated factor (TRAF)2 and TRAF3 degradation. PG102 induced the formation of a CD40 signaling complex that contained decreased amounts of both TRAF2 and TRAF3 and TRAF2-associated signaling proteins. Additionally, PG102-induced CD40 signaling complexes failed to recruit TRAF6 to detergent-insoluble membrane fractions. Fab fragments of PG102, while retaining CD40 binding, did not induce TRAF degradation, nor could they inhibit CD154-stimulated B cell signaling, indicating that CD40 aggregation is required for the signaling inhibition induced by PG102. The antagonistic impact of PG102 on CD40 signaling reveals that the manner of CD40 ligation can determine sharply different outcomes for CD40 signaling and suggests that such information can be used to therapeutically manipulate these outcomes.

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Section: Discussionmentioning

confidence: 99%

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Bankert

Oxley

Smith

et al. 2015

The Journal of Immunology

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“…Patients with the X-linked hyper-IgM syndrome have a mutation at the CD40L gene, and therefore lack functional CD40L [13]. B lymphocytes were stimulated with caps-PS type 19F and cultured with CD4 + T lymphocytes obtained from either a patient with X-linked hyper-IgM syndrome or an allogeneic control.…”

Section: Cd4 + T Lymphocytes Obtained From a Patient With Hyper-igm Smentioning

confidence: 99%

The human antibody response to pneumococcal capsular polysaccharides is dependent on the CD40‐CD40 ligand interaction

et al. 2004

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Protection against infections with Streptococcus pneumoniae is mediated by antibodies against the capsular polysaccharides (caps-PS). Here we show that in in vitro experiments CD4 + T lymphocytes stimulate and CD8 + T lymphocytes inhibit the human anti-caps-PS antibody response. Using antagonistic anti-CD40 and antagonistic anti-CD40 ligand (CD40L) monoclonal antibodies, we showed that the CD4 + T lymphocyte-mediated stimulation is dependent on the CD40-CD40L interaction. The role of CD40L was further illustrated by the observation that CD4 + T lymphocytes obtained from a patient with hyper-IgM syndrome were unable to enhance the immune response to caps-PS. Furthermore, CD4 + T lymphocytes from cord blood, which did not express CD40L in response to stimulation with caps-PS, failed to stimulate the antibody response of adult B lymphocytes to caps-PS. These in vitro findings were confirmed by in vivo experiments in which SCID/SCID mice were reconstituted with human mononuclear cells. Furthermore, we showed that caps-PS induce production of IL-4, IL-6, IL-10, and IFN-+ , and that this enhanced production was inhibited by blocking the CD40-CD40L interaction. This is the first demonstration that the human immune response to caps-PS, which is markedly regulated by T lymphocytes, is dependent on the CD40-CD40L interaction.

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“…The Xlinked hyper-IgM syndromes (HIGM1 and HIGM-3), are due to mutation of the CD40L and CD40 genes, respectively [6,7]. Mice lacking CD40 have less T reg in the spleen and transfer of their splenocytes to athymic nude mice lead to autoimmune diseases [8].…”

Section: Introductionmentioning

confidence: 99%

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

et al. 2005

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CD4 + CD25 + regulatory T cells (T reg) development and homeostasis require IL-2 and costimulation through same TNF-receptor family members. CD40KO mice have reduced number of T reg in peripheral blood, thymus and spleen. Herein we show that naive T reg express low basal level of CD40L that is upregulated upon TCR-triggered mediated activation. Treatment of wt mice with Ab blocking CD40/CD40L interaction results in a fast decrease in T reg number that rapidly recovers upon Ab withdrawal. CFSE-labeled T reg from wt mice injected into CD40KO, but not wild-type (wt) mice, showed reduced survival and proliferation in homeostatic setting. In vitro, dendritic cells from CD40KO mice but not wt mice produce diminished amount of IL-2 upon T reg encounter and are impaired in expanding T reg, a defect corrected by the addition of rIL-2. Accordingly, four daily IL-2 administrations to CD40KO mice normalize T reg number by promoting both their survival and homeostatic proliferation. Such IL-2 effect is transient since T reg number returns to the low constitutive level described in CD40KO mice within 5 days upon IL-2 withdrawal thus suggesting that IL-2 is persistently needed to assure T reg homeostasis.

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Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM.

Cited by 326 publications

References 27 publications

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

The human antibody response to pneumococcal capsular polysaccharides is dependent on the CD40‐CD40 ligand interaction

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

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Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM.

Cited by 326 publications

References 27 publications

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

The human antibody response to pneumococcal capsular polysaccharides is dependent on the CD40‐CD40 ligand interaction

CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell‐produced IL‐2

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CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2