Archivum Immunologiae et Therapiae Experimentalis

, Volume 61, Issue 6, pp 427–443 | Cite as

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

  • Josias Brito Frazão
  • Paolo Ruggero Errante
  • Antonio Condino-Neto
Review

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.

Keywords

Toll-like receptors Immunodeficiencies Recurrent infections NF-kappaB IRAK-4 

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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Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2013

Authors and Affiliations

  • Josias Brito Frazão
    • 1
  • Paolo Ruggero Errante
    • 1
  • Antonio Condino-Neto
    • 1
  1. 1.Department of Immunology, Institute of Biomedical SciencesUniversity of São PauloSão PauloBrazil

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