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

Guay, Heath; Andreyeva, Tatyana; Garcea, Robert L.; Welsh, Raymond M.; Szomolanyi-Tsuda, Eva

doi:10.4049/jimmunol.178.8.5124

Cited by 59 publications

(64 citation statements)

References 47 publications

(51 reference statements)

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“…A minor allele variant for a SNP in the 3′ UTR of MyD88, an intracellular adaptor molecule that signals for most of the TLRs, was found to be associated with a lower antibody response to measles. The role of MyD88 signaling has been implicated in the generation of long-term antibody response to viral infection using a MyD88 knockout mice model [25]. MD2, another molecule that associates intra-cellularly with TLR4, demonstrated decreased IL-10 secretion in the presence of the heterozygous variant.…”

Section: Discussionmentioning

confidence: 99%

Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: Preliminary results

Dhiman

Ovsyannikova

Vierkant

et al. 2008

Vaccine

138

103

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Toll-like receptors (TLRs) represent the critical "bridge" between innate and adaptive immunity to viral pathogens. We hypothesized that single nucleotide polymorphisms (SNPs) that potentially influence the expression/function of TLRs and their associated intracellular signaling molecules contribute to variations in humoral and cellular immunity to measles vaccine. We genotyped 190 randomly selected subjects (12-18 years old), previously vaccinated with two doses of measles, for known SNPs in TLR 2, 3, 4, 5, 6, 7, 8 and 9, and their associated intracellular signaling genes. Specific SNPs in the TLR 2, 3, 4, 5, 6, MyD88 and MD2 genes were associated with measles-specific humoral and cellular immunity. Heterozygous variants for rs3775291 (Phe412Leu) and rs5743305 (−926bp in promoter region) of the TLR3 gene were associated with low antibody and lymphoproliferative responses (p ≤ 0.02) to measles vaccination. Heterozygous variants for rs4986790 (Gly299Asp) and rs4986791 (Ile399Thr) in the TLR4 gene demonstrated higher levels of (p ≤ 0.02) IL-4 secretion. Heterozygous variants for SNPs in TLR5 (rs5744174) and TLR6 (rs5743818) were associated with higher levels of (p ≤ 0.02) IFN-γ secretion. In addition, SNPs in MyD88 and MD2, intracellular molecules that associate with TLRs, also demonstrated associations with variations in antibody and IL-10 production (p ≤ 0.03). Thus, we identified specific SNP associations between TLRs and their associated signaling molecules that have a known role in viral immunity and variations in both humoral and cellular immunity following measles vaccination. These data contribute to understanding the immunogenetic mechanisms underlying variations in the immune response to measles vaccine.

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Section: Discussionmentioning

confidence: 99%

Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: Preliminary results

Dhiman

Ovsyannikova

Vierkant

et al. 2008

Vaccine

138

103

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“…2C and D). A previous study found the phenotype of GC B cells is B220 1 CD19 1 GL7 high [18]. Thus, to further confirm the acceleration of GC formation in MyD88 À/À mice following oral RASV administration, we used GL7 staining.…”

Section: Expansion Of B-cell Compartment Is Accompanied By Cells and mentioning

confidence: 91%

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

Yang

et al. 2011

Eur J Immunol

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The role of TLR signaling in linking the innate and adaptive immune systems has been a controversial issue that remains to be solved. Here, we determined whether MyD88-dependent TLR signals are required for the generation of B-cell responses during chronic Salmonella infection. Oral administration of recombinant attenuated Salmonella enterica serovar Typhimurium vaccine (RASV) strain in MyD88 À/À mice resulted in chronic infection. Infection was accompanied by enlarged germinal centers and hypergammaglobulinemia with anti-double-stranded DNA (dsDNA)-specific Ab in sera, and the deposition of immune complexes in the kidneys, suggesting onset of autoimmunity. CD4 1 T cells expressing PD-1, CXCR5, ICOS, and IL-21 were dramatically increased in chronically infected mice, indicating the expansion of follicular helper T (Tfh)-like cells. Of note, the depletion of CD4 1 T cells completely blocked the generation of polyclonal IgG Ab in sera after oral RASV challenge. Inflammatory myeloid cells expressing CD11b and Gr-1 accumulated in high numbers in the spleen of MyD88 À/À mice. Interestingly, the blockade of PD-1 or ICOS significantly reduced the hypergammaglobulinemia and dsDNA-specific autoantibody production. Overall, these results suggest that Tfh-like cells in chronic bacterial infection trigger autoimmune hypergammaglobulinemia in a PD-1-and ICOSdependent manner.

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“…However, evidence of a central role for MyD88 in bone marrow plasma cell formation supports the former. 45 …”

Section: B-cell Neoplasms' Response To Tlr Ligands Proliferationmentioning

confidence: 99%

“…43,44 This mechanism is thought to generate space in the bone marrow niches, which have a finite capacity. However, because MyD88 is necessary to maintain long-lived mouse plasma cells, 45 and we have detected TLRs in normal plasma cells generated in vitro (G.J. et al, unpublished data, August 2006), we hypothesize that direct activation of plasma cells by TLR ligands could contribute to plasma cell-derived Ig secretion in addition to migration and survival.…”

mentioning

confidence: 99%

Toll-like receptors: lessons to learn from normal and malignant human B cells

Chiron

Bekeredjian‐Ding

Pellat‐Deceunynck

et al. 2008

Blood

103

104

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IntroductionThe human immune system is continuously challenged by commensal microflora as well as invasive infectious agents. The decision to mount a rapid and protective immune response to a pathogen is a consequence of the activation of the innate immune system via pattern recognition receptors, such as Toll-like receptors (TLRs), that sense microbial products. 1 TLR polymorphisms have been implicated in increased severity and predisposition to infection and septic shock 2 in both mice and humans. TLRs recognize highly conserved structures of viral (TLR3,7,8,and 9) and bacterial (TLR1,2,4,5,6,7,8,and 9) origin, known as pathogen-associated molecular patterns (PAMPs; Figure 1). TLR2 heterodimerization with TLR1 or TLR6 is triggered by bacterial lipopeptides, whereas TLR3 is activated by double-stranded RNA, TLR4 is activated by lipopolysaccharide (LPS), TLR5 is activated by flagellin, TLR7 and TLR8 are activated by single-stranded RNA (ssRNA), and TLR9 is activated by unmethylated CpG DNA motifs. Moreover, endogenous ligands released during cellular stress or matrix degradation (eg, heat-shock proteins, fibronectin, heparan sulfates) are thought to activate TLRs. 3 Numerous reports have described how TLRs orchestrate the immune response to pathogens in dendritic cells (DCs) and macrophages. 4 Much less is known about the effects of TLR-mediated B-cell activation, although the design of vaccines could benefit from a more detailed understanding of this process.Leukemic B cells often retain the expression of markers specific for their cellular origin (eg, CD5, CD10, CD138). Furthermore, several reports have demonstrated TLR expression and function in neoplastic B cells. Because DCs can be activated and matured upon triggering of TLRs, immunotherapeutic protocols in leukemia have recently included TLR agonists to improve tumor antigen presentation and subsequent T-cell activation. 5 However, recent reports have indicated that leukemic cells could hijack the TLR machinery to their own benefit. A better understanding of the effects of TLR ligands on normal B cells and their leukemic counterparts could therefore help avoid adverse vaccination effects. In this review, we will discuss the role of TLRs in generating the humoral immune response and their dual effects on different leukemic cell types. TLR expression in normal and neoplastic B cells Normal B-cell subsets and modulation of expressionThe TLR expression pattern is specific for each cell type and is summarized in Figure 2 for human B cells. TLRs expression in human B cells is characterized by high expression of TLR1, 6, 7, 9, and 10. 6-8 Low expression of TLR2 allows for the formation of the functional heterodimers TLR1/2 and TLR2/6, which are required to respond to diacylated and triacylated lipoproteins. The inability to be activated by LPS is a hallmark of human B cells because they lack TLR4, in contrast to mouse B cells. However, human B cells are well equipped to recognize nucleic acids given their expression of TLR7 and TLR9. This profile allows them to ...

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

Cited by 59 publications

References 47 publications

Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: Preliminary results

Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine: Preliminary results

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

Toll-like receptors: lessons to learn from normal and malignant human B cells

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