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Toll-Like Receptors’ Pathway Disturbances are Associated with Increased Susceptibility to Infections in Humans

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  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Toll-like receptors (TLRs) sense microbial products and play an important role in innate immunity. Currently, 11 members of TLRs have been identified in humans, with important function in host defense in early steps of the inflammatory response. TLRs are present in the plasma membrane (TLR1, TLR2, TLR4, TLR5, TLR6) and endosome (TLR3, TLR7, TLR8, TLR9) of leukocytes. TLRs and IL-1R are a family of receptors related to the innate immune response that contain an intracellular domain known as the Toll-IL-1R (TIR) domain that recruits the TIR-containing cytosolic adapters MyD88, TRIF, TIRAP and TRAM. The classical pathway results in the activation of both nuclear factor κB and MAPKs via the IRAK complex, with two active kinases (IRAK-1 and IRAK-4) and two non-catalytic subunits (IRAK-2 and IRAK-3/M). The classical pro-inflammatory TLR signaling pathway leads to the synthesis of inflammatory cytokines and chemokines, such as IL-1β, IL-6, IL-8, IL-12 and TNF-α. In humans, genetic defects have been identified that impair signaling of the TLR pathway and this may result in recurrent pyogenic infections, as well as virus and fungi infections. In this review, we discuss the main mechanisms of microbial recognition and the defects involving TLRs.

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Abbreviations

AD:

Autosomal dominant

APCs:

Antigen-presenting cells

BCG:

Bacillus Calmette-Guérin

BTK:

Brutons’s tyrosine kinase

CD62L:

CD62 ligand

CNS:

Central nervous system

CVID:

Common variable immunodeficiency

DCs:

Dendritic cells

dsRNA:

Double-stranded RNA

EDA-ID:

Ectodermal dysplasia with immunodeficiency

HClO:

Hypochlorous acid

HO-1:

Heme oxygenase 1

HSE:

Herpes simplex virus-encephalitis

HSV-1:

Herpes simplex virus type 1

IFN-γ:

Interferon-gamma

IKK:

Inhibitor of NF-κB kinase complex

IL-8:

Interleukin-8

IRAK-4:

IL-1 receptor-associated kinase 4

LPS:

Lipopolysaccharide

LTA:

Lipoteichoic acid

MALP-2:

Macrophage-activating lipopeptide-2

MAPKs:

Mitogen-activated protein kinases

MBL:

Mannose-binding lectin

MyD88:

Myeloid differentiation factor 88

NADPH:

Nicotinamide adenine dinucleotide oxidase

NEMO:

NF-κB essential modulator

NF-κB:

Nuclear factor kappaB

NLRPs:

NOD leucine-rich repeat and pyrin domain containing proteins

NLRs:

Leucine-rich repeat-containing receptors

PAMPs:

Pathogen-associated molecular patterns

PBMCs:

Peripheral blood mononuclear cells

PDC:

Plasmacytoid DCs

PIC:

Poly-riboinosinicribocytidylic acid

PID:

Primary immunodeficiency diseases

PMN:

Polymorphonuclear cells

PRRs:

Pattern-recognition receptors

RIG-I:

Retinoic acid-inducible gene I protein

ssRNA:

Single-stranded RNA

TIR:

Toll-IL-1R domain

TIRAP:

TIR domain-containing adapter protein

TLRs:

Toll-like receptors

TRAM:

TRIF-related adapter molecule

TRIF:

TIR domain-containing adapter-inducing IFN-β

Xid:

X-linked immune deficiency

XLA:

X-linked agammaglobulinemia

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Frazão, J.B., Errante, P.R. & Condino-Neto, A. Toll-Like Receptors’ Pathway Disturbances are Associated with Increased Susceptibility to Infections in Humans. Arch. Immunol. Ther. Exp. 61, 427–443 (2013). https://doi.org/10.1007/s00005-013-0243-0

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