Abnormal CD40 Ligand (CD154) Expression in Human Immunodeficiency Virus-Infected Children

O’Gorman, Maurice R.G.; DuChateau, Brian K.; Paniagua, Mary C.; Hunt, Janelle; Bensen, Nicolas; Yogev, Ram

doi:10.1128/cdli.8.6.1104-1109.2001

Cited by 13 publications

(11 citation statements)

References 37 publications

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“…Although many of these discrepancies may be related to differences in immunologic and virologic status of the patient (29), others may be related to the lability of CD154 expression after CD40 ligation (34) and differences between preformed or induced forms of the protein (21, 35). Most studies that showed reduced induction of CD154 on activated CD4 ϩ T cells of HIV-infected patients used assay conditions that would be more consistent with preformed levels of CD154 (28,30,31), whereas our assay conditions would be more consistent with induced levels of CD154. Furthermore, cell membrane alterations induced by chronic activation in HIV (A.M. and S.M., unpublished observations) and other inflammatory diseases (21) potentially could have impacted CD154-CD40 interactions involved in B cell responses that we and others have reported.…”

Section: Discussionmentioning

confidence: 99%

Perturbations in B cell responsiveness to CD4⁺T cell help in HIV-infected individuals

Moir

Ogwaro

Malaspina

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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T he scope of B cell abnormalities in HIV-infected patients, first described almost 20 years ago (1), has come to define a pervasive paradigm in HIV infection, namely that of immunodeficiency in the setting of virus-driven immune activation. Hallmarks of B cell abnormalities in HIV disease include hypergammaglobulinemia (2-4), increased expression of activation markers (5), increased levels of autoantibodies (6, 7), increased risk of developing B cell lymphomas (8), and decreased responsiveness to in vivo vaccination and ex vivo stimulation (9, 10). The range of defects in B cell responses includes both T cell-dependent and -independent pathways (1, 11, 12), suggesting that along with defects in CD4 ϩ T cell help, HIV infection causes intrinsic B cell defects. Recent studies have shown that the majority of these abnormalities are attributable to ongoing viral replication and are reversible by the suppression of plasma viremia with effective antiretroviral therapy (2, 6, 13-15). In light of similar abnormalities described in the CD4 ϩ and CD8 ϩ T cell compartments of HIV-infected individuals (16-18), there is clear evidence that immune activation brought on by unchecked HIV-1 replication has widespread deleterious effects on the immune system.Insight into the apparent paradox that in vivo B cell hyperactivity translates into poor response to immunogens and ex vivo stimuli has remained elusive for almost two decades. However, with the availability of antiretroviral therapies that can effectively sustain the suppression of virus replication, it has become apparent that B cell hyperactivity and poor responsiveness to stimulation are directly linked to ongoing virus replication by mechanisms that may include cytokine deregulation, loss of memory B cells, and induction of terminal differentiation (15,19,20). However, most studies on B cell function have been based primarily, if not exclusively, on responsiveness of B cells to exogenous surrogates of antigenic stimulation, such as soluble anti-Ig antibodies and trimeric CD40 ligand (CD154), triggers of the B cell receptor (BCR) and CD40, respectively.The initiation of a humoral immune response to T celldependent antigens requires cognate interactions between antigen-specific B cells and activated antigen-specific CD4 ϩ T cells involving both cell-contact interactions and soluble factors. One of the most important contact-mediated interactions between B cells and CD4 ϩ T cells involves CD40 expressed constitutively on B cells and its membrane-bound ligand CD154 expressed on activated CD4 ϩ T cells (21). The expression of CD154 on activated CD4 ϩ T cells is induced after T cell receptor triggering by antigen-presenting cells, likely dendritic cells, and requires key costimulatory interactions between CD80͞CD86 on mature antigen-presenting cells and CD28 on CD4 ϩ T cells (22). These interactions also induce CD4 ϩ T cells to secrete cytokines, which, together with expression of CD154, provide CD4 ϩ T cells with full helper function. T helper (Th) cells can be divided into ...

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Section: Discussionmentioning

confidence: 99%

Perturbations in B cell responsiveness to CD4⁺T cell help in HIV-infected individuals

Moir

Ogwaro

Malaspina

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…T-lymphocyte surface ligands that interact with B lymphocytes at several stages of their activation have been found to be abnormally expressed [26,27]. Finally, HIV-1 infection induces a dysregulation of cytokine production, including interleukin (IL)-10 [24] and IL-15 [28], which may promote polyclonal B-lymphocyte activation and increased Ig production.…”

Section: Discussionmentioning

confidence: 99%

Combined antiretroviral therapy reduces hyperimmunoglobulinemia in HIV-1 infected children

Children

2004

Aids

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“…The clinical relevance of CD154 as well as its central role as a regulator of cell-mediated and humoral immunity led to studies that examined whether induction of CD154 is defective in CD4 ϩ T cells from HIV-1 ϩ patients. Although there are reports that HIV-1 infection is accompanied by defective CD154 induction upon T cell activation (13)(14)(15)(16)(17)(18), other studies did not find evidence of this defect (19,20). A common feature of the studies that reported a normal induction of CD154 in CD4 ϩ T cells from HIV-1 ϩ patients is that T cell activation was induced in the absence of CD40 ϩ APC (19,20).…”

Section: T He Interaction Between T Cells and Apcs Is An Event Centramentioning

confidence: 99%

“…After treatment with DNase (Ambion), 0.5 g of RNA was used to generate cDNA using oligo(dT) [12][13][14][15][16][17][18] primers and Superscript III reverse transcriptase (Invitrogen Life Technologies). cDNA was subjected to RT-PCR using the LightCycler SYBR green fluorophore.…”

Section: Cd4mentioning

confidence: 99%

Role of CD40-Dependent Down-Regulation of CD154 in Impaired Induction of CD154 in CD4+ T Cells from HIV-1-Infected Patients

Subauste

Wessendarp

2007

The Journal of Immunology

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CD40-CD154 interaction is pivotal for cell-mediated immunity. There are contradictory reports on whether HIV-1 infection impairs CD154 induction. The interaction between CD40 and CD154 is important not only because it results in activation of APCs but also because it controls CD154 by diminishing expression of this molecule. Compared with healthy controls, CD4+ T cells from HIV-1+ patients had impaired induction of CD154 when T cell activation was mediated by CD40+ APCs. In contrast, T cell activation in the absence of these cells resulted in normal CD154 expression. CD154 induction in HIV-1+ patients and controls were similar upon blockade of CD40-CD154 binding. Defective regulation of CD154 appeared to occur downstream of the control of mRNA levels because up-regulation of CD154 mRNA was not impaired by HIV-1 infection. This work identifies CD40 as a mediator of impaired CD154 induction in HIV-1 infection and explains why this defect was not detected by studies where T cell activation was triggered independently of CD40+ APCs. In addition, dysregulation of CD154 in HIV-1 infection likely contributes to immunodeficiency because diminished expression of CD154 induced by CD40 is of functional relevance, resulting in decreased dendritic cell maturation.

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Abnormal CD40 Ligand (CD154) Expression in Human Immunodeficiency Virus-Infected Children

Cited by 13 publications

References 37 publications

Perturbations in B cell responsiveness to CD4⁺T cell help in HIV-infected individuals

Perturbations in B cell responsiveness to CD4⁺T cell help in HIV-infected individuals

Combined antiretroviral therapy reduces hyperimmunoglobulinemia in HIV-1 infected children

Role of CD40-Dependent Down-Regulation of CD154 in Impaired Induction of CD154 in CD4+ T Cells from HIV-1-Infected Patients

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Abnormal CD40 Ligand (CD154) Expression in Human Immunodeficiency Virus-Infected Children

Cited by 13 publications

References 37 publications

Perturbations in B cell responsiveness to CD4+T cell help in HIV-infected individuals

Perturbations in B cell responsiveness to CD4+T cell help in HIV-infected individuals

Combined antiretroviral therapy reduces hyperimmunoglobulinemia in HIV-1 infected children

Role of CD40-Dependent Down-Regulation of CD154 in Impaired Induction of CD154 in CD4+ T Cells from HIV-1-Infected Patients

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Perturbations in B cell responsiveness to CD4⁺T cell help in HIV-infected individuals

Perturbations in B cell responsiveness to CD4⁺T cell help in HIV-infected individuals