Transcriptional landscapes of emerging autoimmunity: transient aberrations in the targeted tissue’s extracellular milieu precede immune responses in Sjögren’s syndromeReport as inadecuate




Transcriptional landscapes of emerging autoimmunity: transient aberrations in the targeted tissue’s extracellular milieu precede immune responses in Sjögren’s syndrome - Download this document for free, or read online. Document in PDF available to download.

Arthritis Research and Therapy

, 15:R174

First Online: 31 October 2013Received: 14 December 2012Accepted: 11 October 2013

Abstract

IntroductionOur understanding of autoimmunity is skewed considerably towards the late stages of overt disease and chronic inflammation. Defining the targeted organ’s role during emergence of autoimmune diseases is, however, critical in order to define their etiology, early and covert disease phases and delineate their molecular basis.

MethodsUsing Sjögren’s syndrome SS as an exemplary rheumatic autoimmune disease and temporal global gene-expression profiling, we systematically mapped the transcriptional landscapes and chronological interrelationships between biological themes involving the salivary glands’ extracellular milieu. The time period studied spans from pre- to subclinical and ultimately to onset of overt disease in a well-defined model of spontaneous SS, the C57BL-6.NOD-Aec1Aec2 strain. In order to answer this aim of great generality, we developed a novel bioinformatics-based approach, which integrates comprehensive data analysis and visualization within interactive networks. The latter are computed by projecting the datasets as a whole on a priori-defined consensus-based knowledge.

ResultsApplying these methodologies revealed extensive susceptibility loci-dependent aberrations in salivary gland homeostasis and integrity preceding onset of overt disease by a considerable amount of time. These alterations coincided with innate immune responses depending predominantly on genes located outside of the SS-predisposing loci Aec1 and Aec2. Following a period of transcriptional stability, networks mapping the onset of overt SS displayed, in addition to natural killer, T- and B-cell-specific gene patterns, significant reversals of focal adhesion, cell-cell junctions and neurotransmitter receptor-associated alterations that had prior characterized progression from pre- to subclinical disease.

ConclusionsThis data-driven methodology advances unbiased assessment of global datasets an allowed comprehensive interpretation of complex alterations in biological states. Its application delineated a major involvement of the targeted organ during the emergence of experimental SS.

AbbreviationsAChAcetylcholine

ADAMTSA disintegrin-like and metalloprotease with thrombospondin motifs

AICDAActivation-induced cytidine deaminase gene

AKTProtein kinase B

AtgAutophagy-related protein

BTLAB7 family member B- and T-lymphocyte attenuator

CapnCalpain

CDH1E-cadherin

Ctla4Cytotoxic T-lymphocyte antigen 4

ESEnrichment score

FBN1Fibrillin

Fgfr1Fibroblast growth factor receptor 1

GABAγ-aminobutyric acid

GlyGlycine

IcamIntercellular adhesion molecule

IcosInducible T-cell costimulator

IFIH1Interferon-induced helicase C domain–containing protein 1

IFNInterferon

Igfr1Insulin-like growth factor receptor 1

IgH-6Immunoglobulin heavy chain, type μ

ILInterleukin

InsrInsulin receptor

IRF3Interferon regulatory factor 3

ITGIntegrin

KLRD1Killer cell lectinlike receptor subfamily D member 1

KLRG1Killer cell lectinlike receptor subfamily G member 1

KLRK1Cytotoxicity-triggering receptor

NKG2-DType II integral membrane protein

LAMLaminin

LFA-1Lymphocyte function–associated antigen 1

Ly96Lymphocyte antigen 96

MadCAM1Vascular addressin cell adhesion molecule 1

MAPK8Mitogen-activated protein kinase 8

METHepatocyte growth factor receptor

MMPMatrix metalloproteinase

MMTVMouse mammary tumor virus integration site family member

mTorCMammalian target of rapamycin complex

NDPNorrie disease

NF-κBκ-light-chain-enhancer of activated B cells

NgfNerve growth factor

PI3KPhosphoinositide 3-kinase

P2XATP-gated channels P2X purinoceptor

p75NTRp75 neurotrophin receptor

SmadSmad family member

Spp1Osteopontin

STATSignal transducer and activator of transcription

TAGSPercentage of gene hits before for positive enrichment score or after for negative enrichment score peak in running enrichment score, which indicates percentage of genes contributing to enrichment score

TgfβTransforming growth factor β

TLRToll-like receptor

TNFTumor necrosis factor

TNFRSFTumor necrosis factor receptor superfamily

TRAILTumor necrosis factor–related apoptosis-inducing ligand

Ulbp1UL16 binding protein 1

VcanVersican

WispWingless-type MMTV Integration site family 1-inducible-signaling pathway protein

WntWingless-type MMTV Integration site family.

Electronic supplementary materialThe online version of this article doi:10.1186-ar4362 contains supplementary material, which is available to authorized users.

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Author: Nicolas Delaleu - Cuong Q Nguyen - Kidane M Tekle - Roland Jonsson - Ammon B Peck

Source: https://link.springer.com/



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