Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome

Sjögren’s syndrome is a common autoimmune disease (~0.7% of European Americans) typically presenting as keratoconjunctivitis sicca and xerostomia. In addition to strong association within the HLA region at 6p21 (Pmeta=7.65×10−114), we establish associations with IRF5-TNPO3 (Pmeta=2.73×10−19), STAT4 (Pmeta=6.80×10−15), IL12A (Pmeta =1.17×10−10), FAM167A-BLK (Pmeta=4.97×10−10), DDX6-CXCR5 (Pmeta=1.10×10−8), and TNIP1 (Pmeta=3.30×10−8). Suggestive associations with Pmeta<5×10−5 were observed with 29 regions including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP amongst others. These results highlight the importance of genes involved in both innate and adaptive immunity in Sjögren’s syndrome

El polimorfismo CCR5 delta 32 (rs333) no está asociado con el síndrome de Sjögren o la diabetes tipo 1 en colombianos

Sjögren's syndrome (SS) and Type 1 Diabetes (T1D) are chronic, progressive autoimmune diseases that affect exocrine glands or ?-cells in the islets of Langerhans in the pancreas, respectively. Typical features of both diseases include production of antibodies against self-antigens and T and B cell infiltrates in organ-specific tissues [12] . Migration of pro-inflammatory memory T cells and monocytes into chronically inflamed tissues is driven by Th1-related chemokines and their receptors. This includes CCR5, a seven-transmembrane domain G protein-coupled receptor (GPCR) involved in intracellular signaling [3] . In Sjögren's syndrome, mRNA and receptor expression of CCR5 are significantly upregulated in inflammatory Th1 cells, parotid gland excretory ducts and conjunctival epithelium of SS-affected individuals indicating that it has a significant role in the progression and severity of pSS disease [45] . In Type 1 Diabetes, recruitment of activated CCR5-expressing T cells to the pancreas or kidney can promote renal disease and impairment of insulin production [6]

TurboGFP impairs T cell clustering after CD3/CD28 activation.

<p>T cells were transfected with either the Scr-Vec-GFP(+) or the Scr-Vec-GFP(−) vectors, then activated by plate-bound anti-CD3 and soluble CD28 for 20 hours. A) GFP-expressing T cells exibit impaired clustering after CD3/CD28 activation. B) Normal cluster formation of CD3/CD28-activated T cells in sample transfected with the Scr-Vec-GFP(−) are indicated by black arrows. A representation of 3 independent experiments is shown. C & D) Activated cell clusters were quantified within one representative field of view at 100x for the Scr-Vec-GFP(−) vector and the Scr-Vec-GFP(+) vector transfections to obtain the total number of clusters (C), or the numbers of clusters by size range (<25 μm, 25–50 μm, and >50 μm) (D) where the black bars indicate the Scr-Vec-GFP(−) transfections and the white bars indicate the Scr-Vec-GFP(+) transfections. Mean and SEM are shown.</p

Analysis of CD25 and CD69 surface expression by flow cytometry.

<p>T cells from seven donors were transfected with the vectors Scr-Vec-GFP(−) (black bars) or Scr-Vec-GFP(+) (white bars). Following 20 hours of anti-CD3/anti-CD28 activation, CD4⁺ and CD8⁺ populations were analyzed for CD25⁺ expression and compared by Student's paired t-test in the CD4⁺ (A) and CD8⁺ (B) populations (<i>P</i> = 0.006 and <i>P</i> = 0.04, respectively). Mean Fluorescence Intensity (MFI) for CD25 expression in CD4⁺ (C) and CD8⁺ (D) populations indicate significant differences for CD4⁺ populations (<i>P</i> = 0.02) and CD8⁺ populations (<i>P</i> = 0.003). E–H) CD69 expression analysis indicates no significant differences in either proportion of CD4⁺ or CD8⁺ CD69-expressing cells or in the MFIs. Mean and SEM are shown and <i>P</i>≤0.05 was considered to be significant.</p

X Chromosome Dose and Sex Bias in Autoimmune Diseases:Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome

OBJECTIVE: More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX , 1 in ~1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren’s syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls. METHODS: We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR). RESULTS: We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ~404 SLE women and ~344 SS women. 47,XXX was present in excess among SLE and SS subjects. CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was respectively ~2.5 and ~2.9 times higher than in 46,XX women and ~25 and ~41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity

Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome

Sjögren's syndrome is a common autoimmune disease (affecting ?0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjögren's syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (P meta = 7.65 × 10 -114), we establish associations with IRF5-TNPO3 (P meta = 2.73 × 10 -19), STAT4 (P meta = 6.80 × 10 -15), IL12A (P meta = 1.17 × 10 -10), FAM167A-BLK (P meta = 4.97 × 10 -10), DDX6-CXCR5 (P meta = 1.10 × 10 -8) and TNIP1 (P meta = 3.30 × 10 -8). We also observed suggestive associations (P meta less than 5 × 10 -5) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjögren's syndrome. © 2013 Nature America, Inc. All rights reserved

Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren's syndrome

Sjögren's syndrome is a common autoimmune disease (affecting ∼0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjögren's syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (Pmeta = 7.65 × 10(-114)), we establish associations with IRF5-TNPO3 (Pmeta = 2.73 × 10(-19)), STAT4 (Pmeta = 6.80 × 10(-15)), IL12A (Pmeta = 1.17 × 10(-10)), FAM167A-BLK (Pmeta = 4.97 × 10(-10)), DDX6-CXCR5 (Pmeta = 1.10 × 10(-8)) and TNIP1 (Pmeta = 3.30 × 10(-8)). We also observed suggestive associations (Pmeta < 5 × 10(-5)) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjögren's syndrome.Christopher J Lessard ... Maureen Rischmueller ... et al