A Role for CD40-CD40 Ligand Interactions in the Generation of Type 1 Cytokine Responses in Human Leprosy

Yamauchi, Paul S.; Bleharski, Joshua R.; Uyemura, Koichi; Kim, Jenny; Sieling, Peter A.; Miller, A. R.; Brightbill, Hans; Schlienger, Katia; Rea, Thomas H.; Modlin, Robert L.

doi:10.4049/jimmunol.165.3.1506

Cited by 48 publications

(34 citation statements)

References 53 publications

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“…In our hands sCD40L alone did not stimulate significant release of IL-12. This is in accordance with findings of Yamauchi et al (29), who demonstrated in the mouse model that IL-12 production may be independent of CD40 ligation. Data provided by Han et al (30) show that CD40-CD40L receptor interactions have a lesser role in T-dependent activation of human monocytes, this pair is active if monocytes are primed by IFN␥, that is in accordance with our findigs.…”

Section: Discussionsupporting

confidence: 82%

The Expression of CD40 on Monocytes of Children with Primary Humoral Immunodeficiencies

2006

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ABSTRACT:The interactions between CD40 and CD40L (CD154) are critical for effective humoral immune response. CD40 signaling facilitates T lymphocyte dependent B cell proliferation and immunoglobulin isotype switch. The objective of our study was to investigate the CD40 and CD40L expression on peripheral blood mononuclear cells (PBMC) of children with symptomatic transient hypogammaglobulinemia (THI), common variable immunodeficiency (CVID) and selective IgA deficiency (SIgAD). Additionally we studied the production of IL-12 and IL-18 by PBMC stimulated with soluble CD40L. CD40 expression was analyzed on B cells and monocytes, CD40L on activated T lymphocytes, using flow cytometry following staining of the cells with appropriate MAb. We found that CD40 expression on B cells and CD40L on activated T cells were essentially similar in the control and patient groups, while the decreased CD40 expression on monocytes was observed in THI and SIgAD patients compared with normal subjects. The most significant decrease of CD40 expression was observed in THI (37% of positive cells) in comparison with control (81% of positive cells). IL-12, but not IL-18, release by PBMC was increased in THI and CVID, but not in SIgAD. In conclusion we suggest that the decreased expression of CD40 on monocytes of children with THI and SIgAD, but not CVID, may be involved in the pathomechanism of these immunodeficiencies. THI is characterized by delay in IgG, and often IgA, synthesis for as long as 40 mo of age, which spontaneously return to normal values at the age of 2-4 y (1). Affected children often suffer from recurrent otitis, upper respiratory tract infections, food intolerance and atopy. According to Walker et al. (2), THI appears to have a similar prevalence to symptomatic SIgAD, the reasons for delayed immunoglobulin synthesis in THI remain unknown (2).SIgAD is the most common primary immunodeficiency. Approximately 60% of subjects with IgA deficiency are asymptomatic. Those with symptoms suffer from recurrent infections of respiratory tract, gastrointestinal disorders, allergy and autoimmune diseases (3). The term CVID is used to describe an incompletely defined syndrome characterized by defective antibody formation, usually accompanied by decreased serum IgG and IgA levels and generally, but not invariably, decreased serum IgM level (1). First symptoms may occur at any time of life, but the most common disease onset is between 1-5 and 16 -25 y of life (4).Many studies attempting to identify the immunologic defects in CVID have been published. Recently identified monogenic defects (ICOS, TACI, BAFF-R and CD19 defects) account for about 10% of cases, but the immunopathogenesis of the majority of CVID cases still remains unexplored (5,6). The variable clinical features and variety of affected immunologic functions suggest involvement of multiple pathogenetic factors.The production of antibodies is regulated by a complex array of cellular and molecular interactions that take place between antigens and cells of the innate and adaptive ...

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Section: Discussionsupporting

confidence: 82%

The Expression of CD40 on Monocytes of Children with Primary Humoral Immunodeficiencies

2006

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“…The recent implication of CD40/CD40L interactions in the generation of type 1 cytokine responses in human leprosy supports this conclusion. 57 Chemoattraction Ligation of CD40 on ECs, SMCs, M⌽, and T lymphocytes triggers expression and release of chemoattractants overexpressed within human atheroma, such as IL-8, MIP-1␣ (M⌽ inflammatory protein), MIP-1␤, RANTES (regulated on activation, normal T cell expressed and secreted), SDF-1 (stromal cell-derived factor 1), and MCP (monocyte chemotactic protein)-1 ( Table 2 and Figure 2A). 58 -62 These chemokines probably attract and direct T lymphocytes and M⌽ to the atheroma, thus sustaining chronic inflammation.…”

Section: T Helper 1 (Th1) Immune Responsementioning

confidence: 99%

CD40 Signaling and Plaque Instability

Schönbeck

Libby

2001

Circulation Research

506

401

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Abstract-Today, multiple lines of evidence support the view of atherosclerosis as a chronic inflammatory disease and implicate components of the immune system in atherogenesis. Recent work has documented overexpression of the potent immune mediator CD40 and its counterpart CD40 ligand (CD40L) in experimental and human atherosclerotic lesions. Notably, interruption of CD40/CD40L interactions not only diminished the formation and progression of mouse atheroma, but also fostered changes in lesion biology and structure, which are associated in humans with "plaque stabilization." In accordance with the hypothesis that CD40 signaling promotes plaque instability, in vitro studies demonstrated that ligation of CD40 on atheroma-associated cell types, namely endothelial cells, smooth muscle cells, and macrophages, mediates functions considered crucial to the process of atherogenesis, such as the expression of cytokines, chemokines, growth factors, matrix metalloproteinases, and procoagulants.

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“…A previously described Th1 clone, D103.5 (19,20), derived from a tuberculoid lesion and specific for M. leprae 10-kDa protein, was used as a positive control. This T cell clone produces IFN-␥ in response to IL-12 (data not shown).…”

Section: Emsamentioning

confidence: 99%

“…These data demonstrate that the inability of lepromatous patients to up-regulate IL-12R␤2 correlates with their ineffective Th response to M. leprae. (11)(12)(13)(14)(15)(16)(17)(18)(19)(20) patients were normalized to yield equivalent CD3-␦ mRNA PCR products. PCR with specific primers was then used to detect IL-12R␤1 and IL-12R␤2 mRNA.…”

Section: Il-12r␤2 Expression Correlates With Ag Responsiveness In T Cmentioning

confidence: 99%

A Role for IL-12 Receptor Expression and Signal Transduction in Host Defense in Leprosy

Kim

Uyemura²,

Dyke

et al. 2001

The Journal of Immunology

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The generation of cell-mediated immunity against intracellular infection involves the production of IL-12, a critical cytokine required for the development of Th1 responses. The biologic activities of IL-12 are mediated through a specific, high affinity IL-12R composed of an IL-12Rβ1/IL-12Rβ2 heterodimer, with the IL-12Rβ2 chain involved in signaling via Stat4. We investigated IL-12R expression and function in human infectious disease, using the clinical/immunologic spectrum of leprosy as a model. T cells from tuberculoid patients, the resistant form of leprosy, are responsive to IL-12; however, T cells from lepromatous patients, the susceptible form of leprosy, do not respond to IL-12. We found that the IL-12Rβ2 was more highly expressed in tuberculoid lesions compared with lepromatous lesions. In contrast, IL-12Rβ1 expression was similar in both tuberculoid and lepromatous lesions. The expression of IL-12Rβ2 on T cells was up-regulated by Mycobacterium leprae in tuberculoid but not in lepromatous patients. Furthermore, IL-12 induced Stat4 phosphorylation and DNA binding in M. leprae-activated T cells from tuberculoid but not from lepromatous patients. Interestingly, IL-12Rβ2 in lepromatous patients could be up-regulated by stimulation with M. tuberculosis. These data suggest that Th response to M. leprae determines IL-12Rβ2 expression and function in host defense in leprosy.

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A Role for CD40-CD40 Ligand Interactions in the Generation of Type 1 Cytokine Responses in Human Leprosy

Cited by 48 publications

References 53 publications

The Expression of CD40 on Monocytes of Children with Primary Humoral Immunodeficiencies

The Expression of CD40 on Monocytes of Children with Primary Humoral Immunodeficiencies

CD40 Signaling and Plaque Instability

A Role for IL-12 Receptor Expression and Signal Transduction in Host Defense in Leprosy

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