Interleukin receptor–associated kinase (IRAK-4) deficiency associated with bacterial infections and failure to sustain antibody responses

Day, Noorbibi K.; Tangsinmankong, Nutthapong; Ochs, Hans D.; Rucker, Rajivi; Pïcard, Capucine; Casanova, Jean‐Laurent; Haraguchi, Soichi; Good, Robert C.

doi:10.1016/j.jpeds.2003.11.025

Cited by 87 publications

(51 citation statements)

References 6 publications

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“…A recent report identified a pediatric patient who has had severe recurring infections since birth and is deficient in IL-1R-associated kinase 4, a downstream mediator of MyD88 signaling. In vaccination studies, this individual demonstrated defective B cell responses similar to our findings in MyD88 KO mice; this patient generated acute TD Ab responses but was unable to generate long-term humoral immunity (47). This finding suggests that MyD88-dependent pathways may be essential for generating long-term Ab responses not only in mice but also in humans.…”

Section: Discussionsupporting

confidence: 74%

MyD88 Is Required for the Formation of Long-Term Humoral Immunity to Virus Infection

Guay

Andreyeva

Garcea

et al. 2007

The Journal of Immunology

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Development of long-term humoral immunity is a major goal of vaccination, but the mechanisms involved in the formation of long-term Ab responses are still being determined. In this study, we identify a previously unknown requirement for MyD88, an adaptor molecule that mediates signals at most TLRs, for the generation of long-term humoral immunity during live virus infection. Polyoma virus-infected MyD88 knockout mice generated strong acute T cell-dependent antiviral IgM and IgG responses and developed germinal centers. Activation-induced cytidine deaminase, an enzyme required for isotype switching and somatic hypermutation, was also induced in germinal center B cells, similar to wild-type mice. However, MyD88 knockout mice failed to develop bone marrow plasma cells and did not maintain long-term serum antiviral Ab responses. The isotype distribution of antiviral IgG responses was also altered; serum IgG2a and IgG2b levels were diminished, whereas IgG1 responses were not affected. The requirement for MyD88 for the formation of long-term humoral immunity to polyoma virus was intrinsic to B cells and was independent of IL-1R and IL-18R, cytokine receptors that also signal through MyD88. Our findings show that MyD88-dependent signaling pathways in B cells are essential for effectively generating long-term Ab responses and implicate a role for TLR in the formation of long-term humoral immunity.

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Section: Discussionsupporting

confidence: 74%

MyD88 Is Required for the Formation of Long-Term Humoral Immunity to Virus Infection

Guay

Andreyeva

Garcea

et al. 2007

The Journal of Immunology

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“…In particular, patients with mutations of IL receptor-associated kinase-4, which is downstream in TLR signaling, have impaired Ab responses to polysaccharide Ags, and ODN2006 does not stimulate PBMC production of IL-6 or IL-10 (46). Intriguingly, for one patient with this defect studied more extensively after multiple vaccinations, Ab production and B cell memory were severely impaired (60). To further investigate the TLR9 pathway, analysis of biologically related TLR7 and TLR8, which like TLR9, sense pathogen-derived DNA and RNA nucleic acid motifs and similarly recruit MyD88 to endosomal vesicular structures, may help to clarify this defect(s) in CVID.…”

Section: Discussionmentioning

confidence: 99%

TLR9 Activation Is Defective in Common Variable Immune Deficiency

Cunningham‐Rundles

Radigan

Knight

et al. 2006

The Journal of Immunology

109

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Common variable immune deficiency (CVID) is a primary immune deficiency characterized by low levels of serum immune globulins, lack of Ab, and reduced numbers of CD27+ memory B cells. Although T, B, and dendritic cell defects have been described, for the great majority, genetic causes have not been identified. In these experiments, we investigated B cell and plasmacytoid dendritic cell activation induced via TLR9, an intracellular recognition receptor that detects DNA-containing CpG motifs from viruses and bacteria. CpG-DNA activates normal B cells by the constitutively expressed TLR9, resulting in cytokine secretion, IgG class switch, immune globulin production, and potentially, the preservation of long-lived memory B cells. We found that CpG-DNA did not up-regulate expression of CD86 on CVID B cells, even when costimulated by the BCR, or induce production of IL-6 or IL-10 as it does for normal B cells. TLR9, found intracytoplasmically and on the surface of oligodeoxynucleotide-activated normal B cells, was deficient in CVID B cells, as was TLR9 mRNA. TLR9 B cell defects were not related to proportions of CD27+ memory B cells. CpG-activated CVID plasmacytoid dendritic cells did not produce IFN-α in normal amounts, even though these cells contained abundant intracytoplasmic TLR9. No mutations or polymorphisms of TLR9 were found. These data show that there are broad TLR9 activation defects in CVID which would prevent CpG-DNA-initiated innate immune responses; these defects may lead to impaired responses of plasmacytoid dendritic cells and loss of B cell function.

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“…All TLRs are believed to generate MyD88-dependent signals, but TLR3 and TLR4 can also provide MyD88-independent signaling via TRIF and Tram [10,11] . IRAK-4 deficiency in humans has been described to result in several defects in the immune responses to pathogens, such as a lack of induction of IFN-␣ and -␤ production in response to viral stimulation of TLR7, 8 and 9 [12] and a defect in generating a sustained antibody response during childhood [13] . Moreover, IRAK-4, as well as MyD88, have been shown to be pivotal in the negative selection of autoreactive B cells, although this defect does not seem to lead to high titers of autoreactive antibodies in these patients, nor do these patients develop autoimmune diseases [14] .…”

Section: Toll-like Receptor Responses In Irak-4-deficient Neutrophilsmentioning

confidence: 99%

Toll-Like Receptor Responses in IRAK-4-Deficient Neutrophils

et al. 2009

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Human neutrophils were found to express all known Toll-like receptors (TLRs) except TLR3 and TLR7. IRAK-4-deficient neutrophils were tested for their responsiveness to various TLR ligands. Essentially all TLR responses in neutrophils, including the induction of reactive oxygen species generation, adhesion, chemotaxis and IL-8 secretion, were found to be dependent on IRAK-4. Surprisingly, the reactivity towards certain established TLR ligands, imiquimod and ODN-CpG, was unaffected by IRAK-4 deficiency, demonstrating their activity is independent of TLR. TLR-4-dependent signaling in neutrophils was totally dependent on IRAK-4 without any major TRIF-mediated contribution. We did not observe any defects in killing capacity of IRAK-4-deficient neutrophils for Staphylococcus aureus, Escherichia coli and Candida albicans, suggesting that microbial killing is primarily TLR independent.

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Interleukin receptor–associated kinase (IRAK-4) deficiency associated with bacterial infections and failure to sustain antibody responses

Cited by 87 publications

References 6 publications

MyD88 Is Required for the Formation of Long-Term Humoral Immunity to Virus Infection

MyD88 Is Required for the Formation of Long-Term Humoral Immunity to Virus Infection

TLR9 Activation Is Defective in Common Variable Immune Deficiency

Toll-Like Receptor Responses in IRAK-4-Deficient Neutrophils

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