IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens

Maglione, Paul J.; Simchoni, Noa; Black, Samuel J.; Radigan, Lin; Overbey, Jessica; Bagiella, Emilia; Bussel, James B.; Bossuyt, Xavier; Casanova, Jean‐Laurent; Meyts, Isabelle; Cerutti, Andrea; Pïcard, Capucine; Cunningham‐Rundles, Charlotte

doi:10.1182/blood-2014-07-587824

Cited by 60 publications

(38 citation statements)

References 65 publications

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“…IFN-α similarly boosted responses of naïve B cells to TLR9 agonists (5). TLR9 stimulation of human B cells induced IgM+ memory B cells to secrete anti-carbohydrate antibodies of the IgM isotype (6, 7) and other IgM antibodies of broad specificity (8). These human B cells responses thus resemble well-characterized responses of murine innate-like B populations, namely B1 and splenic marginal zone B cells, both of which respond to TLR stimulation with rapid and high-titer antibody secretion (9–11).…”

Section: Introductionmentioning

confidence: 99%

TLR7- and TLR9-Responsive Human B Cells Share Phenotypic and Genetic Characteristics

Simchoni

Cunningham‐Rundles

2015

The Journal of Immunology

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B cells activated by nucleic-acid sensing Toll-like receptor 7 and TLR9 proliferate and secrete immune globulins. Memory B cells are presumably more responsive due to higher TLR expression levels, but selectivity and differential outcomes remain largely unknown. In this study, peripheral blood human B cells were stimulated by TLR7 or TLR9 ligands, with or without IFNα, and compared to activators CD40L plus IL-21, to identify differentially responsive cell populations, defined phenotypically and by BCR characteristics. While all activators induced differentiation and antibody secretion, TLR stimulation expanded IgM+ memory and plasma cell lineage committed populations and favored secretion of IgM, unlike CD40L/IL-21 which drove IgM and IgG more evenly. Patterns of proliferation similarly differed, with CD40L/IL-21 inducing proliferation of most memory and naïve B cells, in contrast to TLRs which induced robust proliferation in a subset of these cells. On deep sequencing of the IgH locus, TLR responsive B cells shared patterns of IgHV and IgHJ usage, clustering apart from CD40L/IL-21 and control conditions. TLR activators, but not CD40L/IL-21, similarly promoted increased sharing of CDR3 sequences. TLR responsive B cells were characterized by more somatic hypermutation, shorter CDR3 segments, and less negative charges. TLR activation also induced long positively charged CDR3 segments, suggestive of autoreactive antibodies. Testing this, culture supernatants from TLR stimulated B cells were found to bind HEp-2 cells, while those from CD40L/IL-21 stimulated cells did not. Human B cells possess selective sensitivity to TLR stimulation, with distinctive phenotypic and genetic signatures.

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Section: Introductionmentioning

confidence: 99%

TLR7- and TLR9-Responsive Human B Cells Share Phenotypic and Genetic Characteristics

Simchoni

Cunningham‐Rundles

2015

The Journal of Immunology

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“…Innate signaling via toll-like receptors (TLR) and MyD88 reverses anergy in some autoreactive B cells, suggesting that environmental factors that lead to infection and inflammation may also alter tolerance (17, 18). B cells deficient in MyD88 demonstrate impaired IgM responses to bacterial Ags, indicating that innate signaling through TLR pathways is critical for early T cell-independent (TI) immune defense (19). TLR-4 stimulation by LPS unlocks alternate signaling pathways to ERK phosphorylation and NF-κB activation independent of conventional BCR-dependent signaling mediators (20) that may be impaired for anergic B cells.…”

Section: Introductionmentioning

confidence: 99%

Reversing Tolerance in Isotype Switch–Competent Anti-Insulin B Lymphocytes

Williams

Bonami

Hulbert

et al. 2015

The Journal of Immunology

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B lymphocytes that escape central tolerance and mature in the periphery are a liability for developing autoimmunity. IgG insulin autoAbs that predict type 1 diabetes and complicate insulin therapies indicate that mechanisms for tolerance to insulin are flawed. To examine peripheral tolerance in anti-insulin B cells, we generated C57BL/6 mice that harbor anti-insulin VDJH-125 site-directed to the native Ig H chain locus (VH125SD). Class switch-competent anti-insulin B cells fail to produce IgG Abs following T cell-dependent (TD) immunization of VH125SD mice with heterologous insulin, and they exhibit markedly impaired proliferation to anti-CD40 plus insulin in vitro. In contrast, co-stimulation with LPS plus insulin drives robust anti-insulin B cell proliferation. Further, VH125SD mice produce both IgM and IgG2a anti-insulin Abs following immunization with a conjugate of insulin to type 1 T cell-independent Brucella abortus ring test Ag (BRT). Anti-insulin B cells undergo clonal expansion in vivo and emerge as IgM+ and IgM− GL7+ Fas+ germinal center (GC) B cells following immunization with insulin-BRT, but not BRT alone. Analysis of Igκ genes in VH125SD mice immunized with insulin-BRT reveals that anti-insulin Vκ from the pre-immune repertoire are selected into GCs. These data demonstrate that class switch-competent anti-insulin B cells remain functionally silent in TD immune responses, yet these B cells are vulnerable to reversal of anergy following combined BCR/TLR engagement that promotes Ag-specific GC responses and Ab production. Environmental factors that lead to infection and inflammation could play a critical yet under-appreciated role in driving loss of tolerance and promoting autoimmune disease.

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“…The frequency and severity of these infections decrease considerably from adolescence onward, even in the absence of preventive measures, suggesting that the MyD88/IRAK-4-dependent TIR pathway becomes redundant once acquired immunity is fully functional and can ensure protection (43). These disorders have a modest impact on IgMdependent B-cell immunity, delaying its maturation (65,66). IRAK-4-and MyD88-deficient patients also display impaired inflammatory responses, such as weak or delayed fever and plasma C-reactive protein (CRP) induction (43).…”

Section: Significancementioning

confidence: 99%

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

Mina

Borghesi

Zhou

et al. 2017

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

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Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1. Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4-or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient's fibroblasts, which responded very poorly to all TLR2/6 (PAM 2 CSK 4 , LTA, FSL-1), TLR1/2 (PAM 3 CSK 4 ), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1β. By contrast, the patient's peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1β. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.IRAK-1 | IRAK-4 | Toll-like receptor | interleukin-1 receptor | primary immunodeficiency

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IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens

Abstract: Key Points Human IRAK-4 and MyD88 deficiencies impair T-independent IgM production, including IgM recognizing bacterial antigens. T-independent IgM impairment by IRAK-4 and MyD88 deficiencies is linked to inadequacy of the IgM+IgD+CD27+ B-cell subset.

Cited by 60 publications

References 65 publications

TLR7- and TLR9-Responsive Human B Cells Share Phenotypic and Genetic Characteristics

TLR7- and TLR9-Responsive Human B Cells Share Phenotypic and Genetic Characteristics

Reversing Tolerance in Isotype Switch–Competent Anti-Insulin B Lymphocytes

Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

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