Alternative titles; symbols
HGNC Approved Gene Symbol: MYD88
Cytogenetic location: 3p22.2 Genomic coordinates (GRCh38): 3:38,138,661-38,143,022 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p22.2 | Immunodeficiency 68 | 612260 | Autosomal recessive | 3 |
| Macroglobulinemia, Waldenstrom, somatic | 153600 | 3 |
MyD88 is a key downstream adaptor for most Toll-like receptors (TLRs) and interleukin-1 receptors (IL1Rs) (summary by Von Bernuth et al., 2008).
The myeloid differentiation (MyD) marker MyD88 was first characterized during a study of the early genetic responses of murine myeloid cells to various differentiation and growth inhibitory stimuli (Lord et al., 1990). Myeloid differentiation primary response genes are activated in M1 myeloleukemic cells in response to interleukin-6 (IL6; 147620), which induces both growth arrest and terminal differentiation. Hardiman et al. (1997) described the cloning of the mouse MyD88 gene. The first exon encodes a complete 'death domain' similar to the intracellular segment of TNF receptor-1 (191190). Zoo-blot analysis demonstrated that it is an evolutionarily conserved gene. Northern blot analysis revealed widespread expression of the gene in many adult mouse tissues, and RT-PCR detected MyD88 mRNA in T- and B-cell lines and differentiating embryonic stem cells. The broad expression pattern demonstrated that mouse Myd88 expression is not restricted to cells of myeloid lineage as was originally believed.
Bonnert et al. (1997) cloned a human MYD88 cDNA that encodes a 296-amino acid polypeptide with a predicted mass of 33 kD. MYD88 shares 81% amino acid identity with murine MyD88. The 150-amino acid C-terminal region has significant homology to the type I interleukin-1 receptor (147810) cytoplasmic domain. Northern blot analysis revealed that human MYD88 is expressed as 2 MYD88 hybridizing 1.6- and 3-kb mRNAs in a variety of tissues and cell lines.
Using immunofluorescence analysis, Kagan and Medzhitov (2006) found that human MYD88 localized to discrete foci scattered throughout the cytosol of transfected mouse embryonic fibroblasts and macrophages.
Bonnert et al. (1997) found that overexpression of MYD88 caused an increase in the level of transcription from the interleukin-8 (146930) promoter.
Muzio et al. (1997) reported that the C-terminal domain of MYD88 has significant sequence similarity to the cytoplasmic domain of IL1RAP (602626). They showed that ectopic expression of MYD88 strongly induced NFKB (e.g., 164011) activity in a concentration-dependent manner. In addition, the C-terminal region of MYD88 acted as a dominant-negative inhibitor of IL1R1 (147810)/IL1RAP-induced NFKB activity. MYD88 formed an immunoprecipitable complex with IL1RAP and with IRAK2 (603304).
Medzhitov et al. (1998) demonstrated that signaling by the human TOLL receptor (see TLR4; 603030) employs an adaptor protein, MyD88, and induces activation of NFKB via the IRAK (IRAK1; 300283) kinase and the TRAF6 (602355) protein. The Toll-mediated signaling cascade using the NFKB pathway is essential for immune responses in adult Drosophila, and a human homolog of the Drosophila Toll protein induces various immune response genes via this pathway. These findings implicate MyD88 as a general adaptor/regulator molecule for the Toll/IL1R family of receptors for innate immunity.
Hayashi et al. (2001) showed that expression of TLR5 (603031) induces NFKB (see 164011) activation and TNFA (191160) production. Pathogen-associated molecular patterns (PAMPs) known to stimulate other TLR family members failed to stimulate TLR5; however, luciferase reporter assays indicated TLR5 activation in gram-positive and -negative bacterial culture supernatants. By fractionation of Listeria culture supernatants followed by SDS-PAGE, Hayashi et al. (2001) identified flagellin as the TLR5 ligand. Flagellin, a principal component of bacterial flagella, is a virulence factor recognized by the innate immune system in plants, insects, and mammals. Expression of flagellin in nonflagellated bacteria resulted in TLR5 activation, and deletion of flagellin from flagellated bacteria abrogated TLR5 activation. Hayashi et al. (2001) demonstrated that injection of flagellin induces the production of IL6 (147620) in wildtype mice, but not in those lacking the MyD88 adaptor protein, required for TLR signaling. Hayashi et al. (2001) concluded that TLR5 is a pattern-recognition receptor and that its PAMP is flagellin, a protein with conserved N and C termini in a broad group of motile pathogens.
Burns et al. (2003) noted that a MYD88 splice variant encodes a protein, MYD88s, lacking the 58-amino acid intermediary domain between the death domain and the C-terminal TIR domain. MYD88s is detected only after continuous stimulation with bacterial products, such as lipopolysaccharide (LPS), or proinflammatory cytokines. Expression of MYD88s blocks LPS- or IL1-induced NFKB activation, even though, like the full-length protein, MYD88s binds both IL1R and IRAK1. By Western blot analysis of a reconstituted MYD88 -/- cell line, Burns et al. (2003) showed that MYD88, but not MYD88s, triggered IRAK1 phosphorylation and NFKB activation in an IRAK4 (606883)-dependent manner. MYD88s did not bind IRAK4 and blocked its recruitment to IL1Rs. Burns et al. (2003) concluded that MYD88s acts as a negative regulator of IL1R/TLR/MYD88 signals, leading to a controlled negative regulation of innate immune responses.
Diebold et al. (2004) confirmed that mouse plasmacytoid dendritic cells (PDCs) expressing B220 (PTPRC; 151460) but not Cd11b (ITGAM; 120980) were resistant to suppression of Ifna (147660) production mediated by influenza virus NS1 protein, suggesting that PDCs use a dsRNA-independent pathway for recognizing influenza. Chloroquine inhibited influenza-induced Ifna production, indicating that recognition of the virus occurs in the endosomal compartment. Ifna production in response to live or inactivated influenza virus or to viral genomic or host ssRNA required the presence of Myd88 and Tlr7 (300365), but not other TLRs.
Kagan and Medzhitov (2006) found that human TIRAP (606252), a TLR adaptor protein, recruited human MYD88 to the plasma membrane of transfected mouse fibroblasts and macrophages. They proposed that TIRAP functions primarily to recruit MYD88 to activated TLR4 to initiate signal transduction.
Chen et al. (2007) found that the acute neutrophilic inflammatory response to cell injury requires the signaling protein Myd88. Analysis of the contribution of Myd88-dependent receptors to this response revealed only a minor reduction in mice doubly deficient in Toll-like receptor-2 (Tlr2; 603028) and Tlr4 (603030) and normal responses in mice lacking Tlr1 (601194), Tlr3 (603029), Tlr6 (605403), Tlr7 (300365), Tlr9 (605474), or Tlr11 (606270) or the IL18 receptor (IL18R; 604494). However, mice lacking IL1R (147810) showed a markedly reduced neutrophilic inflammatory response to dead cells and tissue injury in vivo as well as greatly decreased collateral damage from inflammation. This inflammatory response required IL1-alpha (147760), and IL1R function was required on non-bone-marrow-derived cells. Notably, the acute monocyte response to cell death, which is thought to be important for tissue repair, was much less dependent on the IL1R-Myd88 pathway. Also, this pathway was not required for the neutrophil response to a microbial stimulus. These findings suggested that inhibiting the IL1R-MYD88 pathway in vivo could block the damage from acute inflammation that occurs in response to sterile cell death, and do so in a way that might not compromise tissue repair or host defense against pathogens.
By stimulating human microvascular endothelial cells expressing FADD (602457) with LPS, which activates the TLR4 signaling pathway, Zhande et al. (2007) showed that FADD attenuated JNK (MAPK8; 601158) and PI3K (see 171834) pathway activation in a death domain-dependent manner. Mouse cells lacking Fadd showed hyperactivation of these pathways. Coimmunoprecipitation and immunoblot analyses in human cells revealed that FADD interacted with IRAK1 and MYD88. LPS stimulation increased IRAK1-FADD interaction and recruitment of the complex to activated MYD88. In mouse cells lacking Irak1, Fadd did not associate with Myd88. IRAK1-mediated shuttling of FADD to MYD88 allowed for controlled and limited activation of the TLR4 signaling pathway. Enforced FADD expression inhibited LPS-induced, but not VEGF (VEGFA; 192240)-induced, endothelial cell sprouting. Fadd deficiency in mouse cells led to enhanced proinflammatory cytokine production induced by stimulation of Tlr4 and Tlr2, but not Tlr3, and reconstitution of Fadd reversed the enhanced proinflammatory cytokine production. Zhande et al. (2007) concluded that FADD is a negative regulator of IRAK1/MYD88-dependent responses in innate immune signaling.
Cirl et al. (2008) showed that virulent bacteria, such as uropathogenic E. coli and Brucella melitensis, secreted inhibitory homologs of TIR domain-containing proteins (TCPs). These TCPs promoted intracellular bacterial survival and kidney pathology after instillation of organisms in mouse bladder. Bacterial TCPs impeded TLR signaling through MYD88 and impaired innate host defense. Molecular epidemiologic analysis of clinical isolates from patients with urinary tract infections further supported the proposal that bacterial TCPs represent a class of virulence factors.
Alu RNA accumulation due to DICER1 (606241) deficiency in retinal pigmented epithelium (RPE) is implicated in geographic atrophy, an advanced form of age-related macular degeneration (AMD; see 603075). Using mouse and human RPE cells and mice lacking various genes, Tarallo et al. (2012) showed that a DICER1 deficit or Alu RNA exposure activated the NLRP3 (606416) inflammasome, triggering TLR-independent MYD88 signaling via IL18 (600953) in the RPE. Inhibition of inflammasome components, MYD88, or IL18 prevented RPE degeneration induced by DICER1 loss or Alu RNA exposure. Because RPE in human geographic atrophy contained elevated NLRP3, PYCARD, and IL18, Tarallo et al. (2012) suggested targeting this pathway for prevention and/or treatment of geographic atrophy.
Zhu et al. (2012) showed that the direct, immediate, and disruptive effects of IL1-beta (IL1B; 147720) on endothelial stability in a human in vitro cell model are NF-kappa-B (see 164011)-independent and are instead the result of signaling through the small GTPase ADP-ribosylation factor-6 (ARF6; 600464) and its activator ARF nucleotide-binding site opener (ARNO; 602488). Moreover, Zhu et al. (2012) showed that ARNO binds directly to the adaptor protein MYD88, and thus proposed MYD88-ARNO-ARF6 as a proximal IL1-beta signaling pathway distinct from that mediated by NF-kappa-B. Finally, Zhu et al. (2012) showed that SecinH3 (182115), an inhibitor of ARF guanine nucleotide exchange factors such as ARNO, enhances vascular stability and significantly improves outcomes in animal models of inflammatory arthritis and acute inflammation.
Zhang et al. (2015) used in vivo aging analyses in mice to demonstrate that neutrophil proinflammatory activity correlates positively with their aging while in circulation. The authors found that aged neutrophils represent an overly active subset exhibiting enhanced alpha-M (120980)-beta-2 (600065) integrin activation and neutrophil extracellular trap formation under inflammatory conditions. Zhang et al. (2015) showed that neutrophil aging is driven by the microbiota via Toll-like receptor (TLR4, 603030 and TLR2, 603028)- and MYD88-mediated signaling pathways. Depletion of the microbiota significantly reduced the number of circulating aged neutrophils and dramatically improved the pathogenesis and inflammation-related organ damage in models of sickle cell disease (603903) or endotoxin-induced septic shock. Zhang et al. (2015) concluded that their results identified a role for the microbiota in regulating a disease-promoting neutrophil subset.
Phelan et al. (2018) used genomewide CRISPR/Cas9 screening and functional proteomics to determine the molecular basis of exceptional clinical responses to ibrutinib in diffuse large B-cell lymphoma (DLBCL; see 605027). Phelan et al. (2018) discovered a novel mode of oncogenic B-cell receptor (BCR) signaling in ibrutinib-responsive cell lines and biopsies, coordinated by a multiprotein supercomplex formed by MYD88, TLR9, and the BCR. The MYD88-TLR9-BCR supercomplex colocalizes with mTOR on endolysosomes, where it drives prosurvival NF-kappa-B (see 164011) and mTOR (601231) signaling. Inhibitors of BCR and mTOR signaling cooperatively decreased the formation and function of the MYD88-TLR9-BCR supercomplex, providing mechanistic insight into their synergistic toxicity for DLBCL cells containing this complex. Presence of these supercomplexes characterized ibrutinib-responsive malignancies and distinguished ibrutinib responders from nonresponders.
Hardiman et al. (1997) described the gene structure of the mouse MyD88 gene. The complete coding sequence spans 5 exons.
Bonnert et al. (1997) found that the human MYD88 gene is encoded by 5 exons.
By interspecific backcross mapping, Hardiman et al. (1997) localized the mouse MyD88 gene to chromosome 9; the human homolog was mapped to 3p22-p21.3 by PCR analysis of a chromosome 3 somatic cell hybrid mapping panel. Bonnert et al. (1997) used fluorescence in situ hybridization to map the human MYD88 gene to 3p22-3p21.3.
Crystal Structure
Lin et al. (2010) reported the crystal structure of the MyD88-IRAK4 (606883)-IRAK2 (603304) death domain complex, which revealed a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4, and 4 IRAK2 death domains. Assembly of this helical signaling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. Formation of these myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. Composite binding sites are required for recruitment of the individual death domains in the complex, which are confirmed by mutagenesis and previously identified signaling mutations. Specificities of myddosome formation are dictated by both molecular complementation and correspondence of surface electrostatics.
Immunodeficiency 68
Von Bernuth et al. (2008) identified 3 different mutations in the MYD88 gene in children with immunodeficiency-68 (IMD68; 612260) that resulted in susceptibility to pyogenic bacterial infections. Four children from 3 kindreds were homozygous for in-frame deletion of glu52 (E52del; 602170.0001). Two sibs were homozygous for a missense mutation (R196C; 602170.0002), and 1 child from another kindred was compound heterozygous for 2 missense mutations (R196C and L93P, 602170.0003). Two sibs who died in infancy were presumably homozygous for the same E52del mutation found in their surviving brother. The mutations were not found in healthy controls, and all affected conserved residues. Fibroblasts from patients representing the 3 combinations of mutant MYD88 alleles showed normal MYD88 mRNA levels. Western blot analysis revealed low MYD88 protein levels with the homozygous E52del mutation and the compound heterozygous L93P/R196C mutation, and normal MYD88 protein levels with the R196C homozygous mutation. Functional analysis confirmed that the mutations resulted in impaired response to most Toll-like receptors and IL1B, with lack of production of IL6, IL8, and gamma-IFN. The findings were consistent with a loss of function. Von Bernuth et al. (2008) concluded that, like IRAK4 deficiency (IMD67; 607676), MYD88 deficiency abolishes most cytokine responses to TLR stimulation. The authors noted that the immunologic phenotype of the 9 children they reported with MYD88 deficiency was similar to that of Myd88-deficient mice, but the infectious phenotype was different. The MYD88-deficient patients were susceptible to Staphylococcus aureus, Pseudomonas aeruginosa, and Streptococcus pneumoniae, but were normally resistant to most other infectious agents. In contrast, Myd88-deficient mice had been shown to be susceptible to almost all pathogens tested.
In affected members of a large consanguineous family with IMD68, Conway et al. (2010) identified a homozygous nonsense mutation in the MYD88 gene (E66X; 602170.0005). Western blot analysis of patient cells showed absence of the MYD88 protein. Detailed immunologic studies showed impaired response to most Toll-like receptor stimuli, with significantly decreased production of TNFA, IL6, and IL1B compared to controls. The phenotype was notable for cutaneous and systemic Pseudomonas infection, as well as pneumococcal meningitis.
In a boy, born of consanguineous Omani parents, with IMD68, Platt et al. (2019) identified a homozygous nonsense mutation in the MYD88 gene (R272X; 602170.0006). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was found in only heterozygous state at a low frequency in the gnomAD database (1.19 x 10(-5)). Patient cells had no detectable wildtype or truncated MYD88 protein. Functional studies of patient fibroblasts showed impaired cytokine response to LPS, certain Toll-like receptors, and IL1B, whereas response to poly(I:C) and TNFA was normal.
Waldenstrom Macroglobulinemia
For a discussion of somatic MYD88 mutation in IgM monoclonal gammopathy of undetermined significance (MGUS) and Waldenstrom macroglobulinemia (153600), see 602170.0004.
Adachi et al. (1998) observed that mice with a targeted disruption of the Myd88 gene were unable to respond to IL1 (e.g., 147760), as determined by defective T-cell proliferation and the production of cytokines. Likewise, Myd88-deficient mice were unable to produce gamma-interferon (IFNG; 147570) and mediate natural killer cell activity in response to IL18 (600953). NFKB activation in response to IL1 or IL18 was also impaired. These results indicated that MYD88 is a critical component in the IL1R and IL18R (604494) signaling cascades. Kawai et al. (1999) extended these studies to show that responses to lipopolysaccharide, mediated by TLR4 and CD14 (158120), were lost or delayed in Myd88-deficient mice, establishing that MYD88 is part of the TLR signaling cascade as well, acting just upstream of IRAK.
Takeuchi et al. (2000) showed that Tlr2 (603028)- and, particularly, Myd88-deficient mice are highly susceptible, in terms of growth in blood and kidney and decreased survival, to infection with Staphylococcus aureus compared to wildtype mice. In vitro, Tlr2-deficient macrophages produced reduced TNF and interleukin-6 (IL6; 147620) in response to S. aureus compared to wildtype or Tlr4-deficient macrophages, whereas Myd88-deficient macrophages produced no detectable TNF or IL6. The authors concluded that TLR2 and MYD88 are critical in the defense against gram-positive bacteria.
Skerrett et al. (2004) found that Myd88-deficient mice were highly susceptible to aerosol infection with Pseudomonas aeruginosa, but not to aerosol infection with S. aureus. They concluded that Myd88-dependent signaling is essential for innate immunity to P. aeruginosa and is dispensable for resistance to pulmonary S. aureus infection.
Using nonlethal microbial stimuli on Il12b (161561)-deficient mice, Jankovic et al. (2002) showed that although Th1-type cytokine production was diminished in the absence of Il12b, the pathogen-specific Cd4 (186940)-positive T cells that emerged nevertheless displayed an Ifng-dominated lymphokine profile and failed to default to a Th2 phenotype. In mice lacking both Il12b and Il10 (124092), these Th1 cells were protective. In contrast, in mice lacking Myd88, not only was a normal Th2-type response to Schistosoma mansoni antigens developed, but, in response to Toxoplasma gondii antigens, no Ifng was detected and the mice defaulted to a Th2-type response. Jankovic et al. (2002) proposed that microbial-induced Th1 polarization is determined during the initial encounter of pathogens with pattern recognition receptors (e.g., TLRs) on antigen-presenting cells. They concluded that IL12, however, does not determine Th1 versus Th2 phenotype.
LaRosa et al. (2008) generated bone marrow chimeras in which T cells, but not cells involved in innate immune responses, lacked Myd88. These chimeric mice showed increased susceptibility to T. gondii disease, developing fatal encephalitis within 30 days. They displayed reduced Ifng production, and the increased susceptibility was independent of Il1r and Il18r signaling. LaRosa et al. (2008) proposed that, in addition to innate immunity, MYD88 expression is necessary in T cells for prolonged resistance to pathogens.
Bjorkbacka et al. (2004) examined atherosclerotic lesion development in uninfected Apoe (APOE; 107741) single-null mice and Apoe -/- Myd88 -/- double-null mice, and found that the Myd88-deficient mice showed a marked reduction in early atherosclerosis. Inactivation of the Myd88 pathway led to a reduction in atherosclerosis through a decrease in macrophage recruitment to the artery wall that was associated with reduced chemokine levels. The findings linked elevated serum lipid levels to a proinflammatory signaling cascade that is also engaged by microbial pathogens.
To examine whether Toll-like receptor signaling regulates phagocytosis, Blander and Medzhitov (2004) compared macrophages from wildtype, Myd88 null, and Tlr2-Tlr4 (603030) double-null mice. Myd null and Tlr2-Tlr4 double-null macrophages were unresponsive to inactivated E. coli. Blander and Medzhitov (2004) found that activation of the Toll-like receptor signaling pathway by bacteria, but not apoptotic cells, regulated phagocytosis at multiple steps including internalization and phagosome maturation. Phagocytosis of bacteria was impaired in the absence of Toll-like receptor signaling. Two modes of phagosome maturation were observed, constitutive and inducible; their differential engagement depended on the ability of the cargo to trigger Toll-like receptor signaling.
Fremond et al. (2004) noted that previous investigations had suggested a minor and redundant role for TLR2, TLR4, and TLR6 (605403) in the early host response to Mycobacterium tuberculosis (Mtb) infection, but a more important role in control of chronic infection. Using Myd88 -/- mice, Fremond et al. (2004) investigated the role of MYD88, which most TLRs, except TLR3 (603029), use as an intracellular adaptor, in resistance to Mtb. Macrophages from Myd88 -/- mice had normal upregulation of costimulatory molecules but reduced cytokine production in response to Mtb infection. Myd88 -/- mice succumbed to a low-dose aerosol Mtb infection in approximately 4 weeks, whereas Tnf -/- mice died within 3 weeks, and wildtype mice survived. Death was accompanied by significantly reduced body weight, increased lung weight, and 2 logs higher bacillary burden. Like Tnf -/- mice, Myd88 -/- mice developed massive necrosis and infiltration of inflammatory cells, primarily neutrophils and macrophages, in lungs. Although BCG vaccination failed to elicit a delayed-type hypersensitivity response in Myd88 -/- mice, it did induce antigen-specific Ifng production in splenocytes and also protected the mice from acute Mtb infection. The Myd88 -/- mice could not, however, durably control the infection. Fremond et al. (2004) concluded that the MYD88-mediated signaling pathway is critically involved in the development of innate, but not adaptive, immunity in response to Mtb infection.
Using mice lacking Myd88 or various members of the IL1R/TLR superfamily, Bellocchio et al. (2004) found that the Myd88-dependent pathway was required for resistance to Candida albicans and Aspergillus fumigatus. Myd88 signaling could occur through distinct TLRs depending on the fungal pathogen and the route of infection, and individual TLRs activated specialized antifungal effector functions on neutrophils. Myd88-dependent signaling in dendritic cells was crucial for priming the antifungal Th1 response. Bellocchio et al. (2004) concluded that innate and adaptive immunity to C. albicans and A. fumigatus requires the coordinated action of distinct members of the IL1R/TLR superfamily acting through MYD88.
To evaluate the role of TLRs in B-cell activation and antibody production, Pasare and Medzhitov (2005) transferred purified B cells from wildtype, Myd88-deficient, Tlr4-deficient, and Cd40 (109535)-deficient mice into B cell-deficient mu-MT mice, which have a mutation in the Ighm gene (147020). They found that primary B-cell activation, including induction of IgM, IgG1, and IgG2 responses, but not IgE or, probably, IgA responses, required TLRs in addition to helper T cells. In contrast, Cd40 was required for isotype switching.
Hyaluronan, an extracellular matrix glycosaminoglycan with a repeating disaccharide structure, is produced after tissue injury, and impaired clearance results in unremitting inflammation. Jiang et al. (2005) noted that CD44 (107269) is essential for regulating turnover of hyaluronan, but it is not required for expression of chemokines by macrophages after lung injury. Using Tlr-deficient mouse macrophages, they found that hyaluronan fragments stimulated Mip2 (CXCL2; 139110), Mip1a (CCL3; 182283), and Kc (CXCL1; 155730) in a Tlr2- and Tlr4-dependent manner that also required Myd88. Mice deficient in Tlr2, Tlr4, or Myd88 showed impaired transepithelial migration of inflammatory cells, but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell overexpression of high molecular mass hyaluronan protected against acute lung injury and apoptosis, in part, through TLR-dependent basal activation of NFKB. Jiang et al. (2005) concluded that interaction of TLR2 and TLR4 with hyaluronan provides signals that initiate inflammatory responses, maintain epithelial cell integrity, and promote recovery from acute lung injury.
Mice genetically deficient in both Myd88 and Trif (607601) have a complete lack of known Toll-like receptor signaling, thus allowing assessment of Toll-like receptor dependence of antibody responses. Gavin et al. (2006) used these double knockouts to investigate the role of Toll-like receptor signaling in antibody responses to immunization and the augmenting roles of 4 typical adjuvants (alum, Freund complete adjuvant, Freund incomplete adjuvant, and monophosphoryl-lipid A/trehalose dicorynomycolate adjuvant) to that response. Regardless of adjuvant, these mice exhibited robust antibody responses. Gavin et al. (2006) concluded that Toll-like receptor signaling does not account for the action of classical adjuvants and does not fully explain the action of strong adjuvant containing a Toll-like receptor ligand.
Brown et al. (2007) found that Myd88 -/- mice and Ptgs2 -/- mice exhibited a profound inhibition of endothelial proliferation and cellular organization within rectal crypts after injury. The effects of injury in both mutant mouse strains could be rescued by exogenous prostaglandin E2 (PGE2), suggesting that Myd88 signaling is upstream of Ptgs2 and PGE2. In wildtype mice, the combination of injury and Myd88 signaling led to repositioning of a subset of Ptgs2-expressing stromal cells from the mesenchyme surrounding the middle and upper crypts to an area surrounding the crypt base adjacent to colonic epithelial progenitor cells. Brown et al. (2007) concluded that the MYD88 and prostaglandin signaling pathways interact to preserve epithelial proliferation during injury, and that proper cellular mobilization within the crypt niche is critical to repair after injury.
Apc (611731) Min/+ mice spontaneously develop intestinal tumors and, on average, die within 6 months of age. Rakoff-Nahoum and Medzhitov (2007) showed that deletion of Myd88 in Min/+ mice reduced morbidity and mortality, as well as the size and numbers of intestinal polyps, compared with sex- and age-matched controls. They concluded that MYD88-dependent signaling controls the expression of several key modifier genes of intestinal tumorigenesis and that MYD88 has a critical role in both spontaneous and carcinogen-induced tumor development.
Wen et al. (2008) showed that specific pathogen-free NOD mice lacking Myd88, an adaptor for multiple innate immune receptors that recognize microbial stimuli, do not develop type 1 diabetes (222100). The effect is dependent on commensal microbes because germ-free Myd88-negative NOD mice develop robust diabetes, whereas colonization of these germ-free Myd88-negative NOD mice with a defined microbial consortium (representing bacterial phyla normally present in human gut) attenuates type 1 diabetes. Wen et al. (2008) also found that Myd88 deficiency changes the composition of the distal gut microbiota, and that exposure to the microbiota of specific pathogen-free Myd88-negative NOD donors attenuates type 1 diabetes in germ-free NOD recipients. Wen et al. (2008) concluded that, taken together, their findings indicated that interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying type 1 diabetes predisposition.
In 4 children from 3 unrelated families with immunodeficiency-68 (IMD68; 612260), von Bernuth et al. (2008) identified a homozygous in-frame 3-bp (GAG) deletion in exon 1 of the MYD88 gene, resulting in deletion of glu52 (E52del). Two families (families A and E) were consanguineous and of French and Spanish Gypsy origin. The mutation, which affected a conserved residue in the death domain, segregated with the disorder in 2 families from whom additional members were available for study. Functional analysis confirmed that the E52del mutation resulted in a loss of function, and immunoprecipitation studies showed that the mutation abolished the interaction with IRAK4 (606883). All patients shared a history of susceptibility to pyogenic bacterial infections caused by S. aureus, P. aeruginosa, or S. pneumoniae. Several died in infancy.
Picard et al. (2010) identified a homozygous E65del mutation (based on sequence NM_001172567.1, which corresponds to E52del) in the MYD88 gene in a Serbian boy with IMD68.
In 2 sibs, born of Portuguese patents, with immunodeficiency-68 (IMD68; 612260), von Bernuth et al. (2008) identified a homozygous c.586C-T transition in exon 3 of the MYD88 gene, resulting in an arg196-to-cys (R196C) substitution at a conserved residue in the TIR domain. The mutation prevented interaction with IL1R (147810). Von Bernuth et al. (2008) also identified an unrelated, 3-year-old patient from Turkey who was compound heterozygous for the R196C mutation and a c.278T-C transition in exon 1 that resulted in a leu93-to-pro (L93P; 602170.0003) substitution. The L93P mutation occurred in the death domain and abolished the interaction with IRAK4 (606883). Functional analysis confirmed that both mutations resulted in loss of function. All 3 patients shared a history of susceptibility to pyogenic bacterial infections caused by S. aureus, P. aeruginosa, or S. pneumoniae.
This mutation is designated ARG209CYS (R209C) based on a different sequence (NM_001172567.1).
For discussion of the c.278T-C transition in exon 1 of the MYD88 gene, resulting in a leu93-to-pro (L93P) substitution, that was found in compound heterozygous state in a patient with immunodeficiency-68 (IMD68; 612260) by von Bernuth et al. (2008), see 602170.0002.
This mutation is designated LEU106PRO (L106P) based on a different sequence (NM_001172567.1).
Ngo et al. (2011) described the dependence of activated B cell-like (ABC) diffuse large B-cell lymphoma (DLBCLs) on MYD88 and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumors. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 (300283) and IRAK4 (606883) are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumors harbored the same amino acid substitution, L265P, in the MYD88 Toll/IL1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt lymphoma (113970), but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal center B cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wildtype MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-kappa-B (see 164011) signaling, JAK kinase (see 147795) activation of STAT3 (102582), and secretion of IL6 (147620), IL10 (124092), and interferon-beta (147640). Hence, Ngo et al. (2011) concluded that the MYD88 signaling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumors bearing oncogenic MYD88 mutations.
Treon et al. (2012) performed whole-genome sequencing of bone marrow lymphoplasmacytic lymphoma (LPL) cells in 30 patients with Waldenstrom macroglobulinemia (153600), with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors. Among the patients with Waldenstrom macroglobulinemia, Treon et al. (2012) identified a somatic mutation, L265P, in samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This T-to-C transition at genomic position 38182641 predicted an amino acid change that triggers IRAK-mediated NF-kappa-B signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenstrom macroglobulinemia and in 3 of 3 patients with non-IgM-secreting lymphoplasmacytic lymphoma (LPL) (91% of all patients with LPL). MYD88 L265P was absent in paired normal-tissue samples from patients with Waldenstrom macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced I-kappa-B-alpha (164008) and NF-kappa-B p65 (164014) phosphorylation, as well as NF-kappa-B nuclear staining, in Waldenstrom macroglobulinemia cells expressing MYD88 L265P. Similar results were obtained when cells expressing MYD88 L265P were incubated with an IRAK1/4 kinase inhibitor. Somatic variants in ARID1A (603024) in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenstrom macroglobulinemia who had wildtype MYD88 had somatic variants in MLL2 (602113). Treon et al. (2012) concluded that MYD88 L265P is a commonly recurring mutation in patients with Waldenstrom macroglobulinemia that can be useful in differentiating Waldenstrom macroglobulinemia and non-IgM LPL from B-cell disorders that have phenotypic overlap.
Landgren and Staudt (2012) used Sanger sequencing to assess the status of MYD88 L265P expression in patients with IgM monoclonal gammopathy of undetermined significance (MGUS) and found expression of this variant in 5 of 9 patients. All of these patients had both clonal plasma cells and clonal lymphocytes in bone marrow (lymphoplasmacytic precursor neoplasm), suggesting to Landgren and Staudt (2012) that this mutation is a precursor to Waldenstrom macroglobulinemia rather than transformation from IgM MGUS to Waldenstrom macroglobulinemia. Treon et al. (2012) commented that, to overcome the limitations of Sanger sequencing, they developed an allele-specific polymerase chain reaction (AS-PCR) assay to detect the MYD88 L265P mutation with a threshold detection limit of 0.1% (approximately 100-fold better than that of Sanger sequencing). They found that 88 of 96 patients with Waldenstrom macroglobulinemia (92%) and 5 of 11 patients with IgM MGUS (45%), as defined by consensus criteria, were positive for MYD88 L265P expression by either conventional or quantitative AS-PCR assays. Treon et al. (2012) concluded that IgM MGUS is heterogeneous and that MYD88 L265P is probably a driver mutation toward Waldenstrom macroglobulinemia.
In affected members of a large consanguineous family with immunodeficiency-68 (IMD68; 612260), Conway et al. (2010) identified a homozygous mutation in exon 1 of the MYD88 gene, resulting in a glu66-to-ter (E66X) substitution. Western blot analysis of patient cells showed absence of the MYD88 protein. Detailed immunologic studies showed impaired response to most Toll-like receptor stimuli, with significantly decreased production of TNFA, IL6, and IL1B compared to controls. The phenotype was notable for cutaneous and systemic Pseudomonas infection as well as for pneumococcal meningitis.
In a boy, born of consanguineous Omani parents, with immunodeficiency-68 (IMD68; 612260), Platt et al. (2019) identified a homozygous c.814C-T transition in the MYD88 gene, resulting in an arg272-to-ter (R272X) substitution in the TIR domain. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was found in only heterozygous state at a low frequency in the gnomAD database (1.19 x 10(-5)). Patient cells had no detectable wildtype or truncated MYD88 protein. Functional studies of patient fibroblasts showed impaired cytokine response to LPS, certain Toll-like receptors, and IL1B, whereas response to poly(I:C) and TNFA was normal.
Adachi, O., Kawai, T., Takeda, K., Matsumoto, M., Tsutsui, H., Sakagami, M., Nakanishi, K., Akira, S. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9: 143-150, 1998. [PubMed: 9697844] [Full Text: https://doi.org/10.1016/s1074-7613(00)80596-8]
Bellocchio, S., Montagnoli, C., Bozza, S., Gaziano, R., Rossi, G., Mambula, S. S., Vecchi, A., Mantovani, A., Levitz, S. M., Romani, L. The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J. Immun. 172: 3059-3069, 2004. [PubMed: 14978111] [Full Text: https://doi.org/10.4049/jimmunol.172.5.3059]
Bjorkbacka, H., Kunjathoor, V. V., Moore, K. J., Koehn, S., Ordija, C. M., Lee, M. A., Means, T., Halmen, K., Luster, A. D., Golenbock, D. T., Freeman, M. W. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nature Med. 10: 416-421, 2004. [PubMed: 15034566] [Full Text: https://doi.org/10.1038/nm1008]
Blander, J. M., Medzhitov, R. Regulation of phagosome maturation by signals from Toll-like receptors. Science 304: 1014-1018, 2004. [PubMed: 15143282] [Full Text: https://doi.org/10.1126/science.1096158]
Bonnert, T. P., Garka, K. E., Parnet, P., Sonoda, G., Testa, J. R., Sims, J. E. The cloning and characterization of human MyD88: a member of an IL-1 receptor related family. FEBS Lett. 402: 81-84, 1997. [PubMed: 9013863] [Full Text: https://doi.org/10.1016/s0014-5793(96)01506-2]
Brown, S. L., Riehl, T. E., Walker, M. R., Geske, M. J., Doherty, J. M., Stenson, W. F., Stappenbeck, T. S. Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury. J. Clin. Invest. 117: 258-269, 2007. [PubMed: 17200722] [Full Text: https://doi.org/10.1172/JCI29159]
Burns, K., Janssens, S., Brissoni, B., Olivos, N., Beyaert, R., Tschopp, J. Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J. Exp. Med. 197: 263-268, 2003. [PubMed: 12538665] [Full Text: https://doi.org/10.1084/jem.20021790]
Chen, C.-J., Kono, H., Golenbock, D., Reed, G., Akira, G., Rock, K. L. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nature Med. 13: 851-856, 2007. [PubMed: 17572686] [Full Text: https://doi.org/10.1038/nm1603]
Cirl, C., Wieser, A., Yadav, M., Duerr, S., Schubert, S., Fischer, H., Stappert, D., Wantia, N., Rodriguez, N., Wagner, H., Svanborg, C., Miethke, T. Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nature Med. 14: 399-406, 2008. [PubMed: 18327267] [Full Text: https://doi.org/10.1038/nm1734]
Conway, D. H., Dara, J., Bagashev, A., Sullivan, K. E. Myeloid differentiation primary response gene 88 (MyD88) deficiency in a large kindred. (Letter) J. Allergy Clin. Immun. 126: 172-175, 2010. [PubMed: 20538326] [Full Text: https://doi.org/10.1016/j.jaci.2010.04.014]
Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S., Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303: 1529-1531, 2004. [PubMed: 14976261] [Full Text: https://doi.org/10.1126/science.1093616]
Fremond, C. M., Yeremeev, V., Nicolle, D. M., Jacobs, M., Quesniaux, V. F., Ryffel, B. Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88. J. Clin. Invest. 114: 1790-1799, 2004. [PubMed: 15599404] [Full Text: https://doi.org/10.1172/JCI21027]
Gavin, A. L., Hoebe, K., Duong, B., Ota, T., Martin, C., Beutler, B., Nemazee, D. Adjuvant-enhanced antibody responses in the absence of Toll-like receptor signaling. Science 314: 1936-1938, 2006. [PubMed: 17185603] [Full Text: https://doi.org/10.1126/science.1135299]
Hardiman, G., Jenkins, N. A., Copeland, N. G., Gilbert, D. J., Garcia, D. K., Naylor, S. L., Kastelein, R. A., Bazan, J. F. Genetic structure and chromosomal mapping of MyD88. Genomics 45: 332-339, 1997. [PubMed: 9344657] [Full Text: https://doi.org/10.1006/geno.1997.4940]
Hayashi, F., Smith, K. D., Ozinsky, A.,, Hawn, T. R., Yi, E. C., Goodlett, D. R., Eng, J. K., Akira, S., Underhill, D. M., Aderem, A. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410: 1099-1103, 2001. [PubMed: 11323673] [Full Text: https://doi.org/10.1038/35074106]
Jankovic, D., Kullberg, M. C., Hieny, S., Caspar, P., Collazo, C. M., Sher, A. In the absence of IL-12, CD4+ T cell responses to intracellular pathogens fail to default to a Th2 pattern and are host protective in an IL-10-/- setting. Immunity 16: 429-439, 2002. [PubMed: 11911827] [Full Text: https://doi.org/10.1016/s1074-7613(02)00278-9]
Jiang, D., Liang, J., Fan, J., Yu, S., Chen, S., Luo, Y., Prestwich, G. D., Mascarenhas, M. M., Garg, H. G., Quinn, D. A., Homer, R. J., Goldstein, D. R., Bucala, R., Lee, P. J., Medzhitov, R., Noble, P. W. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nature Med. 11: 1173-1179, 2005. [PubMed: 16244651] [Full Text: https://doi.org/10.1038/nm1315]
Kagan, J. C., Medzhitov, R. Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125: 943-955, 2006. [PubMed: 16751103] [Full Text: https://doi.org/10.1016/j.cell.2006.03.047]
Kawai, T., Adachi, O., Ogawa, T., Takeda, K., Akira, S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11: 115-122, 1999. [PubMed: 10435584] [Full Text: https://doi.org/10.1016/s1074-7613(00)80086-2]
Landgren, O., Staudt, L. MYD88 L265P somatic mutation in IgM MGUS. (Letter) New Eng. J. Med. 367: 2255-2256, 2012. [PubMed: 23215570] [Full Text: https://doi.org/10.1056/NEJMc1211959]
LaRosa, D. F., Stumhofer, J. S., Gelman, A. E., Rahman, A. H., Taylor, D. K., Hunter, C. A., Turka, L. A. T cell expression of MyD88 is required for resistance to Toxoplasma gondii. Proc. Nat. Acad. Sci. 105: 3855-3860, 2008. [PubMed: 18308927] [Full Text: https://doi.org/10.1073/pnas.0706663105]
Lin, S.-C., Lo, Y.-C., Wu, H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465: 885-890, 2010. [PubMed: 20485341] [Full Text: https://doi.org/10.1038/nature09121]
Lord, K. A., Hoffman-Liebermann, B., Liebermann, D. A. Complexity of the immediate early response of myeloid cells to terminal differentiation and growth arrest includes ICAM-1, Jun-B and histone variants. Oncogene 5: 387-396, 1990. [PubMed: 1690380]
Medzhitov, R., Preston-Hurlburt, P., Kopp, E., Stadien, A., Chen, C., Ghosh, S., Janeway, C. A., Jr. MyD88 is an adaptor protein in the hToll/Il-1 receptor family signaling pathways. Molec. Cell 2: 253-258, 1998. [PubMed: 9734363] [Full Text: https://doi.org/10.1016/s1097-2765(00)80136-7]
Muzio, M., Ni, J., Feng, P., Dixit, V. M. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278: 1612-1615, 1997. [PubMed: 9374458] [Full Text: https://doi.org/10.1126/science.278.5343.1612]
Ngo, V. N., Young, R. M., Schmitz, R., Jhavar, S., Xiao, W., Lim, K.-H., Kohlhammer, H., Xu, W., Yang, Y., Zhao, H., Shaffer, A. L., Romesser, P., and 19 others. Oncogenically active MYD88 mutations in human lymphoma. Nature 470: 115-119, 2011. [PubMed: 21179087] [Full Text: https://doi.org/10.1038/nature09671]
Pasare, C., Medzhitov, R. Control of B-cell responses by Toll-like receptors. Nature 438: 364-368, 2005. [PubMed: 16292312] [Full Text: https://doi.org/10.1038/nature04267]
Phelan, J. D., Young, R. M., Webster, D. E., Roulland, S., Wright, G. W., Kasbekar, M., Shaffer, A. L., III, Ceribelli, M., Wang, J. Q., Schmitz, R., Nakagawa, M., Bachy, E., and 28 others. A multiprotein supercomplex controlling oncogenic signalling in lymphoma. Nature 560: 387-391, 2018. [PubMed: 29925955] [Full Text: https://doi.org/10.1038/s41586-018-0290-0]
Picard, C., von Bernuth, H., Ghandil, P., Chrabieh, M., Levy, O., Arkwright, P. D., McDonald, D., Geha, R. S., Takada, H., Krause, J. C., Creech, C. B., Ku, C.-L. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 89: 403-425, 2010. [PubMed: 21057262] [Full Text: https://doi.org/10.1097/MD.0b013e3181fd8ec3]
Platt, C. D., Zaman, F., Wallace, J. G., Seleman, M., Chou, J., Al Sukaiti, N., Geha, R. S. A novel truncating mutation in MYD88 in a patient with BCG adenitis, neutropenia and delayed umbilical cord separation. Clin. Immun. 207: 40-42, 2019. [PubMed: 31301515] [Full Text: https://doi.org/10.1016/j.clim.2019.07.004]
Rakoff-Nahoum, S., Medzhitov, R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317: 124-127, 2007. [PubMed: 17615359] [Full Text: https://doi.org/10.1126/science.1140488]
Skerrett, S. J., Liggitt, H. D., Hajjar, A. M., Wilson, C. B. Cutting edge: myeloid differentiation factor 88 is essential for pulmonary host defense against Pseudomonas aeruginosa but not Staphylococcus aureus. J. Immun. 172: 3377-3381, 2004. [PubMed: 15004134] [Full Text: https://doi.org/10.4049/jimmunol.172.6.3377]
Takeuchi, O., Hoshino, K., Akira, S. Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J. Immun. 165: 5392-5396, 2000. [PubMed: 11067888] [Full Text: https://doi.org/10.4049/jimmunol.165.10.5392]
Tarallo, V., Hirano, Y., Gelfand, B. D., Dridi, S., Kerur, N., Kim, Y., Cho, W. G., Kaneko, H., Fowler, B. J., Bogdanovich, S., Albuquerque, R. J. C., Hauswirth, W. W., and 17 others. DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 149: 847-859, 2012. [PubMed: 22541070] [Full Text: https://doi.org/10.1016/j.cell.2012.03.036]
Treon, S. P., Xu, L., Hunter, Z. R. Reply to Landgren and Staudt. (Letter) New Eng. J. Med. 367: 2256-2257, 2012.
Treon, S. P., Xu, L., Yang, G., Zhou, Y., Liu, X., Cao, Y., Sheehy, P., Manning, R. J., Patterson, C. J., Tripsas, C., Arcaini, L., Pinkus, G. S., Rodig, S. J., Sohani, A. R., Harris, N. L., Laramie, J. M., Skifter, D. A., Lincoln, S. E., Hunter, Z. R. MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia. New Eng. J. Med. 367: 826-833, 2012. [PubMed: 22931316] [Full Text: https://doi.org/10.1056/NEJMoa1200710]
von Bernuth, H., Picard, C., Jin, Z., Pankla, R., Xiao, H., Ku, C.-L., Chrabieh, M., Ben Mustapha, I., Ghandil, P., Camcioglu, Y., Vasconcelos, J., Sirvent, N., and 26 others. Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321: 691-696, 2008. [PubMed: 18669862] [Full Text: https://doi.org/10.1126/science.1158298]
Wen, L., Ley, R. E., Volchkov, P. Y., Stranges, P. B., Avanesyan, L., Stonebraker, A. C., Hu, C., Wong, F. S., Szot, G. L., Bluestone, J. A., Gordon, J. I., Chervonsky, A. V. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455: 1109-1113, 2008. [PubMed: 18806780] [Full Text: https://doi.org/10.1038/nature07336]
Zhande, R., Dauphinee, S. M., Thomas, J. A., Yamamoto, M., Akira, S., Karsan, A. FADD negatively regulates lipopolysaccharide signaling by impairing interleukin-1 receptor-associated kinase 1-MyD88 interaction. Molec. Cell. Biol. 27: 7394-7404, 2007. [PubMed: 17785432] [Full Text: https://doi.org/10.1128/MCB.00600-07]
Zhang, D., Chen, G., Manwani, D., Mortha, A., Xu, C., Faith, J. J., Burk, R. D., Kunisaki, Y., Jang, J.-E., Scheiermann, C., Merad, M., Frenette, P. S. Neutrophil ageing is regulated by the microbiome. Nature 525: 528-532, 2015. [PubMed: 26374999] [Full Text: https://doi.org/10.1038/nature15367]
Zhu, W., London, N. R., Gibson, C. C., Davis, C. T., Tong, Z., Sorenson, L. K., Shi, D. S., Guo, J., Smith, M. C. P., Grossmann, A. H., Thomas, K. R., Li, D. Y. Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability. Nature 492: 252-255, 2012. [PubMed: 23143332] [Full Text: https://doi.org/10.1038/nature11603]