The Importance of Toll-Like Receptor 2 Polymorphisms in Severe Infections

Texereau, J.; Chiche, Jean‐Daniel; Taylor, William R.; Choukroun, G.; Comba, Béatrice; Mira, Jean‐Paul

doi:10.1086/431990

Cited by 152 publications

(135 citation statements)

References 48 publications

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“…267 Furthermore, the coupling of these pattern recognition receptors to downstream adaptor molecules also appear to be distinct as shown by disparities in clinical outcomes in humans with IRAK-4 deficiency versus the susceptibility to pathogens in knockout mice. 268 It is also important to note that significant polymorphisms in TLRs exist which have been shown to be associated with altered innate immune responses [269][270][271] and, by extension, would therefore also be expected to have pronounced effects on the shaping of adaptive immune responses. In practical terms, these considerations emphasize the necessity of examining human innate immune responses (preferably using primary cells ex vivo, with a sufficiently large sample size to account for heterogeneities in responses), even in preliminary studies aimed at screening for immunopotentiatory activities.…”

Section: Discussionmentioning

confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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Section: Discussionmentioning

confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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“…TLR2 reacts with PAMPs found in both Gram-positive and Gram-negative bacteria, and TLR2-deficient mice are much more susceptible to infections than their wild-type counterparts (16). TLR11, the most recently identified member of TLR family, has been found to be capable of preventing urinary tract infections (10,17).…”

Section: Toll-like Receptorsmentioning

confidence: 99%

Aspects of Immune Dysfunction in End-stage Renal Disease

Kato

Chmielewski

Honda

et al. 2008

Clinical Journal of the American Society of Nephrology

907

716

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End-stage renal disease (ESRD) is associated with significantly increased morbidity and mortality resulting from cardiovascular disease (CVD) and infections, accounting for 50% and 20%, respectively, of the total mortality in ESRD patients. It is possible that these two complications are linked to alterations in the immune system in ESRD, as uremia is associated with a state of immune dysfunction characterized by immunodepression that contributes to the high prevalence of infections among these patients, as well as by immunoactivation resulting in inflammation that may contribute to CVD. This review describes disorders of the innate and adaptive immune systems in ESRD, underlining the specific role of ESRD-associated disturbances of Toll-like receptors. Finally, based on the emerging links between the alterations of immune system, CVD, and infections in ESRD patients, it emphasizes the potential role of the immune dysfunction in ESRD as an underlying cause for the high mortality in this patient population and the need for more studies in this area.

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“…To date, several studies have demonstrated that some naturally occurring TLR variants enhance the risk of severe infections in humans, mice, and most recently, domestic cattle (23)(24)(25)(26). In addition to the emerging molecular and population-based casecontrol data, bovine health-related quantitative trait loci (QTL) have been localized to genomic regions either proximal to or directly overlapping one or more TLR loci, and at least two healthrelated QTL are proximal to PGLYRP1 (25)(26)(27)(28)(29)(30)(31).…”

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confidence: 99%

Diversity and evolution of 11 innate immune genes in Bos taurus taurus and Bos taurus indicus cattle

Seabury

Seabury²,

Decker³

et al. 2009

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

100

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The Toll-like receptor (TLR) and peptidoglycan recognition protein 1 (PGLYRP1) genes play key roles in the innate immune systems of mammals. While the TLRs recognize a variety of invading pathogens and induce innate immune responses, PGLYRP1 is directly microbicidal. We used custom allele-specific assays to genotype and validate 220 diallelic variants, including 54 nonsynonymous SNPs in 11 bovine innate immune genes (TLR1-TLR10, PGLYRP1) for 37 cattle breeds. Bayesian haplotype reconstructions and median joining networks revealed haplotype sharing between Bos taurus taurus and Bos taurus indicus breeds at every locus, and we were unable to differentiate between the specialized B. t. taurus beef and dairy breeds, despite an average polymorphism density of one locus per 219 bp. Ninety-nine tagSNPs and one tag insertion-deletion polymorphism were sufficient to predict 100% of the variation at all 11 innate immune loci in both subspecies and their hybrids, whereas 58 tagSNPs captured 100% of the variation at 172 loci in B. t. taurus. PolyPhen and SIFT analyses of nonsynonymous SNPs encoding amino acid replacements indicated that the majority of these substitutions were benign, but up to 31% were expected to potentially impact protein function. Several diversitybased tests provided support for strong purifying selection acting on TLR10 in B. t. taurus cattle. These results will broadly impact efforts related to bovine translational genomics.peptidoglycan recognition protein | bovine translational genomics | bovine Toll-like receptors | single nucleotide polymorphism

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The Importance of Toll-Like Receptor 2 Polymorphisms in Severe Infections

Cited by 152 publications

References 48 publications

Potential adjuvantic properties of innate immune stimuli

Potential adjuvantic properties of innate immune stimuli

Aspects of Immune Dysfunction in End-stage Renal Disease

Diversity and evolution of 11 innate immune genes in Bos taurus taurus and Bos taurus indicus cattle

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