Sjögren Syndrome: An A-to-Z Update

Robert I. Fox, MD, PhD; Carla M. Fox, RN


December 03, 2013

In This Article


Three extensive genome-wide screens were discussed at the ACR meeting:

The Oklahoma cohort[29];

The SICCA cohort; and

The Chinese cohort.[30]

For simplicity, the results of the Oklahoma Genome-Wide Association Study (GWAS) will be detailed below, as they were recently published in Nature Genetics.[31] Lessard and colleagues[29] reported HLA-related genotypic data on 1638 patients in a GWAS:

The strongest effect in GWAS was the long known and strong association with HLA allele association -- ancestral haplotype of DRB1*0201, DQB1*0201, and DQA1*0501.

However, the recognition of RFX5, a key transcriptional regulator of the HLA class II loci extended the previous HLA-D association.

In addition to the HLA data from GWAS, additional exciting data were presented in the Sjögren syndrome symposium. Other statistically significant loci that are involved in both innate and adaptive immunity in Sjogren syndromeincluded:

IRF5- RF5: a member of the interferon regulatory factor family, a group of transcription factors with diverse roles, including virus-mediated activation of interferon and modulation of cell growth, differentiation, apoptosis, and immune system activity.

STAT4: STAT4 genes lie next to the STAT1 gene locus, suggesting that the genes arose by gene duplication. STAT proteins have several functional domains, including an N-terminal interaction domain, a central DNA-binding domain, an SH2 domain, and the C-terminal TraN activation domain.

IL12A: 2 chains of the IL-12 receptor form heterodimer after IL-12 binding and activate the receptor-associated Janus kinases, termed JAK2 and TYK2. STAT4 is phosphorylated by these tyrosine kinases, homodimerizes through its SH2 domain, and translocates into nucleus to activate gene transcription.

BLK:B lymphocyte kinase (tyrosine protein kinase)

TNIP1: TNIP1 has been shown to interact with TNFAIP3 and MAPK, which are both rapidly induced by tumor necrosis factor (TNF) and inhibit NF-kappa B activation as well as TNF-mediated apoptosis. Knockout studies of a similar gene in mice suggested that this gene is critical for limiting inflammation by terminating TNF-induced NF-kappa B responses.

CXCR5: also known as Burkitt lymphoma receptor 1 (BLR1). CXCR5 gene is specifically expressed in follicles in lymph nodes. The gene plays an essential role in B-cell migration.

These results highlight the importance of genes that promote innate immunity (type 1 interferon signature) and acquired immunity (HLA-linked recognition of antigen by T cells and B cells) through traditional antigen-presenting pathways.

One interesting observation is that CXCR5, a homing receptor, was not found in GWAS in patients with SLE. This is one of the few examples where SLE and Sjögren syndrome can be differentiated, and it helps explain the relative organ specificity and lymphoproliferative nature of Sjögren syndrome.

Although genetic associations have been noted, most are not located in protein coding regions of the genome. Adrianto and colleagues[32] presented data to suggest that these nonprotein coding RNA sequences may act as distant promoters or perhaps act as "scaffolding" to help direct other proteins in their activity. Other newly identified genetic loci include OAS1, which may promote a splicing change to the p46 variant of an interferon inducible gene.[33]

The increased frequency of non-Hodgkin lymphoma in Sjögren syndrome may be linked to a genetic polymorphism known as A20, which regulates NF-kappa B activity. These exciting results that link mucosa-associated lymphoid tissue (MALT) lymphomas in patients with Sjögren syndrome to other non-Sjögren syndrome patients with MALT lymphoma were recently published.[34]

Finally, the recent report of genome-wide screening in Han Chinese has confirmed the different HLA-DR association and identified new loci termed GFT1. This study also points out different genetic loci and the diversity of factors that can contribute when a disease such as Sjögren syndrome develops in different ancestral and ethnic backgrounds.[30,35]


An important finding by Lessard and colleagues[29] was the influence of RX5 loci that may help explain the very high genetic linkage with HLA-DR. This single nucleotide polymorphism does not correspond to a functional protein and may act as a different promoter or a noncoding RNA.

Given the importance of acquired immune responses (including characteristic autoantibody and T-cell subsets), an entirely new avenue of treatment may be possible.The linkage of innate and acquired immune system may be provided by the NK-like cells.[36]

In particular, a specific protein (NCR3/NKp30) was released by NK-cell degranulation that facilitates crosstalk between NK and dendritic cells to regulate interferon G secretion. This factor may help explain a role for Th17 cells in the Sjögren syndrome gland and provide a novel series of therapeutic targets. Novel microRNAs, including 44 highly expressed candidates, were found in minor salivary gland biopsies of patients with Sjögren syndrome,[37] which may influence transcription of lymphocytes within the salivary gland.

Differences in gene modification such as histone acetylation were also detected in the Sjögren syndrome salivary glands along with associated changes in histone deacetylase 1 (but not acetylase 2).[38] Alterations in salivary gland cytokines (IL-21 and IL-33) were found to be associated with germinal center formation.[39,40] The presence of germinal centers has previously been shown to correlate with disease severity (extraglandular manifestations) and lymphomagenesis.


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