Impaired IgA class switching in APRIL-deficient mice

Castigli, Emanuela; Scott, Sumi; Dedeoğlu, Fatma; Bryce, Paul J.; Jabara, Haifa H.; Bhan, Atul K.; Mizoguchi, Emiko; Geha, Raif S.

doi:10.1073/pnas.0307348101

Cited by 397 publications

(337 citation statements)

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“…One strain of APRIL-deficient mice had lowered IgA serum levels and impaired mucosal IgA responses 21 that were not observed in a second APRIL-deficient strain. 22 Reduced IgA serum levels are also characteristic of TACI-deficient mice, indicating that APRIL might mediate IgA class switch, or survival of switched IgAsecreting cells, through TACI.…”

Section: Introductionmentioning

confidence: 80%

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TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts

Bossen

Cachero

Tardivel

et al. 2008

Blood

257

270

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The cytokine BAFF binds to the receptors TACI, BCMA, and BAFF-R on B cells, whereas APRIL binds to TACI and BCMA only. The signaling properties of soluble trimeric BAFF (BAFF 3-mer) were compared with those of higher-order BAFF oligomers. All forms of BAFF bound BAFF-R and TACI, and elicited BAFF-R-dependent signals in primary B cells. In contrast, signaling through TACI in mature B cells or plasmablasts was only achieved by higher-order BAFF and APRIL oligomers, all of which were also po-tent activators of a multimerization-dependent reporter signaling pathway. These results indicate that, although BAFF-R and TACI can provide B cells with similar signals, only BAFF-R, but not TACI, can respond to soluble BAFF 3-mer, which is the main form of BAFF found in circulation. BAFF 60-mer, an efficient TACI agonist, was also detected in plasma of BAFF transgenic and nontransgenic mice and was more than 100-fold more active than BAFF 3-mer for the activation of multimerization-dependent signals. TACI supported survival of activated B cells and plasmablasts in vitro, providing a rational basis to explain the immunoglobulin deficiency reported in TACI-deficient persons

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Section: Introductionmentioning

confidence: 80%

“…21 IgM production in supernatants of B splenocytes cultured for 6 days was increased 3-and 6-fold in response to cross-linked APRIL and BAFF 60-mer, respectively, an effect that was mainly mediated by TACI ( Figure 4A). In contrast, BAFF 3-mer only induced a modest, BAFF-R-dependent response.…”

Section: Increased Immunoglobulin Production By B Splenocytes and Plamentioning

confidence: 99%

TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts

Bossen

Cachero

Tardivel

et al. 2008

Blood

257

270

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“…These negative association studies include candidate genes such as APRIL, where the corresponding mouse knock out shows impaired IgA class switching [43], and the BAFFR, where the initial study suggested an association with CVID in a German family [44]. The association of unusual PID case presentations in patients carrying the CD45 C77G polymorphism in a heterozygous form is intriguing [45].…”

Section: Negative Association Studies In Igad/cvidmentioning

confidence: 99%

Antibody deficiency diseases

Pan‐Hammarström

Hammarström

2008

Eur J Immunol

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Primary immunodeficiency diseases are rare disorders characterized by quantitative or qualitative defects in cells or components in the immune system, resulting in a high degree of susceptibility to various types of infections. During differentiation, stem cells undergo a series of discrete steps, governed by a large number of different genes. Mutations/deletions in these genes will result in a block in differentiation of the affected cell lineage(s), leading to immunodeficiency. To date, more than 150 different types of disorders have been described. In this review, we will focus on novel findings in antibody deficiency syndromes. IntroductionPrimary immunodeficiency diseases (PID) are disorders characterized by quantitative or qualitative defects in cells or components in the immune system, resulting in a high degree of susceptibility to various types of infections. During differentiation, stem cells undergo a series of discrete steps, governed by a large number of different genes. Mutations/deletions in these genes will result in a block in differentiation of the affected cell lineage(s), leading to immunodeficiency. To date, more than 150 different types of diseases have been described and the genetic basis for most of these defects is known (see [1,2] for recent reviews).Principally, PID can be subdivided into T cell, B cell, combined (T+B), phagocyte and complement defects. The combined immunodeficiencies (SCID) are clinically the most severe and will, if undiagnosed, lead to death of the affected child, usually within the first year of life. Other defects, numerically more prevalent and including common variable immunodeficiency (CVID) and IgA deficiency (IgAD), will result in considerable morbidity, but are rarely associated with mortality.The above defects are all "global", i.e. associated with susceptibility to a variety of different pathogens. However, recently, several PID have been described that are characterized by an increased frequency of infections caused by selected pathogens such as mycobacteria, pneumococci [3] and herpes simplex virus [4,5]. Such "holes-in-the-repertoire" defects (for recent review see [6]) are likely to be common in the population and may, taken together, account for a substantial number of, hitherto largely undiagnosed, patients with PID. Furthermore, a recent observation [7] shows that novel mutations in "classical" genes, i.e. those known to be involved in a given PID, may give rise to a different phenotype, suggesting that the field is getting more complex than previously recognized. In addition, the etiology of several phenotypically similar, albeit in some cases not entirely identical, PID have recently been shown to be caused by mutations in other genes than those originally implicated (examples include hyper-IgM (HIGM, see below), X-linked lymphoproliferative syndrome [8], hyper-IgE [9, 10], Omenn syndrome [11] and X-linked susceptibility to mycobacterial infections [12]. Differences in glycosylation pattern may also account for selected disease phenotypes [13] and...

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“…Interestingly, APRIL is known to increase IgA and IgM but not IgG responses to T cell-dependent antigens (Stein et al, 2002). More specifically, APRIL is known to exclusively influence IgA isotype regulation: IgA production increases in APRIL transgenic mice (Stein et al, 2002), and conversely, IgA class switching recombination is impaired in APRIL-deficient mice (Castigli et al, 2004).…”

Section: Introductionmentioning

confidence: 99%