Zhuoli Zhang

Polymorphisms in the CD3Z Gene Influence TCRζ Expression in Systemic Lupus Erythematosus Patients and Healthy Controls

TCRζ (CD247) functions as an amplification module in the TCR signaling cascade and is essential for assembly and surface expression of the TCR/CD3 complex. The TCRζ-chain is down-regulated in many chronic infectious and inflammatory diseases, including systemic lupus erythematosus (SLE). It is unclear whether reduced TCRζ expression is a cause or a consequence of chronic inflammatory responses. We have addressed this question by adopting a combined genetic and functional approach. We analyzed TCRζ protein expression using a FACS-based expression index and documented considerable, but longitudinally stable, variation in TCRζ expression in healthy individuals. The variation in TCRζ expression was associated with polymorphisms in the CD3Z 3′-untranslated region (UTR) in SLE patients and healthy controls. Detailed mapping of the 3′-UTR revealed that the minor alleles of two single nucleotide polymorphisms (SNPs) in strong disequilibrium (rs1052230 and rs1052231) were the causal variants associated with low TCRζ expression (p = 0.015). Using allelic imbalance analysis, the minor alleles of these 3′-UTR SNPs were associated with one-third of the level of mRNA compared with the major allele. A family-based association analysis showed that the haplotype carrying the low-expression variants predisposes to SLE (p = 0.033). This suggests that a genetically determined reduction in TCRζ expression has functional consequences manifested by systemic autoimmunity.

Rheumatoid arthritis: a disease of chronic, low-amplitude signals transduced through T cell antigen receptors?

SummaryTechnology has advanced to the stage where it is now possible to identify genes that confer low to moderate risk of developing autoimmune diseases such as rheumatoid arthritis (RA). This has been facilitated by the growing appreciation that these hard to detect genetic signals can only be defined in large cohorts of well characterized patients. In RA, the association between disease susceptibility and genes encoded within the MHC has been known for decades. Recent studies have identified several new candidate genes that provide further insights into the molecular nature of aberrant immune responses in chronic inflammatory diseases. Here, we describe some of these new genes. Based on their known functions we propose that in a subgroup of patients with RA inheritance of allelic variants at distinct loci could lead to dysregulation of adaptive immune responses characterized by chronic, low-amplitude signaling transduced by antigen T cell receptors.ZusammenfassungTechnologische Fortschritte haben es möglich gemacht, Gene, welche mit einem niedrigen bis mäßigem Risiko für die Entwicklung von Autoimmunerkrankungen wie rheumatoide Arthritis (RA) assoziiert sind, zu identifizieren. Dies wurde durch die zunehmende Einsicht ermöglicht, dass diese schwer detektierbaren genetischen Signale nur in großen Kohorten von gut charakterisierten Patienten definiert werden können. Bei der RA ist der Zusammenhang der Krankheitssuszeptibilität und MHC-Genen seit Jahrzehnten bekannt. Aktuelle Studien haben verschiedene neue Kandidatengene, welche weitere Erkenntnisse über die molekulare Natur von gestörten Immun-Antworten bei chronischen entzündlichen Erkrankungen ergeben, identifiziert. In dieser Arbeit beschreiben wir einige dieser neuen Gene. Aufgrund ihrer bekannten Funktionen nehmen wir an, dass in einer Subgruppe von RA-Patienten die Vererbung von allelischen Varianten bei bestimmten Gen-Loci zu einer Dysregulation von adaptiven Immun-Antworten führt, welche durch chronische Signale mit niedriger Amplitude über Antigen T-Zellrezeptoren übertragen werden.