Interferon-γ excess leads to pathogenic accumulation of follicular helper T cells and germinal centers.

Overactivity of the germinal center (GC) pathway resulting from accumulation of follicular helper T (Tfh) cells causes autoimmunity, underscoring the need to understand the factors that control Tfh cell homeostasis. Here we have identifed posttranscriptional repression of interferon-γ (Ifng) mRNA as a mechanism to limit Tfh cell formation. By using the sanroque lupus model, we have shown that decreased Ifng mRNA decay caused excessive IFN-γ signaling in T cells and led to accumulation of Tfh cells, spontaneous GC, autoantibody formation, and nephritis. Unlike ICOS and T-bet deficiency that failed to rescue several autoimmune manifestations, interferon-γ receptor (IFN-γR) deficiency prevented lupus development. IFN-γ blockade reduced Tfh cells and autoantibodies, demonstrating that IFN-γ overproduction was required to sustain lupus-associated pathology. Increased IFN-γR signaling caused Bcl-6 overexpression in Tfh cells and their precursors. This link between IFN-γ and aberrant Tfh cell formation provides a rationale for IFN-γ blockade in lupus patients with an overactive Tfh cell-associated pathway.

Heterozygosity for Roquinsan leads to angioimmunoblastic T-cell lymphoma-like tumors in mice.

Angioimmunoblastic T-cell lymphoma (AITL) is the second most common peripheral T-cell lymphoma with unusual clinical and pathologic features and a poor prognosis despite intensive chemotherapy. Recent studies have suggested AITL derives from follicular helper T (T(FH)) cells, but the causative molecular pathways remain largely unknown. Here we show that approximately 50% of mice heterozygous for the "san" allele of Roquin develop tumors accompanied by hypergammaglobulinemia by 6 months of age. Affected lymph nodes displayed the histologic features diagnostic of AITL, except for the presence of expanded FDC networks. Accumulation of T(FH) cells preceded tumor development, and clonal rearrangements in the TCR-ß genes were present in most tumors. Furthermore, T(FH) cells exhibited increased clonality compared with non-T(FH) cells from the same lymph nodes, even in the absence of tumors. Genetic manipulations that prevent T(FH) development, such as deletion of ICOS, CD28, and SAP, partially or completely abrogated tumor development, confirming a T(FH)-derived origin. Roquin(san/+) mice emerge as a useful model to investigate the molecular pathogenesis of AITL and for preclinical testing of therapies aimed at targeting dysregulated T(FH) cells or their consequences.

Social influences on smoking cessation in mid-life: Prospective cohort of UK women.

INTRODUCTION: Decisions to quit smoking are thought to be influenced by social factors such as friends, family and social groups, but there have been few attempts to examine comprehensively the influence of a range of social factors on smoking cessation. In the largest study to date, we examined whether smoking cessation was associated with marital status and the smoking habits of a partner, socio-economic status and social participation. METHODS: In the prospective Million Women Study, 53,650 current smokers in 2001 (mean age 58.3, SD 4.4) reported their smoking status 4 years later; and reported on social factors on both occasions. Logistic regression yielded odds ratios (ORs) and 99% confidence intervals (CIs) for stopping smoking in the next 4 years by marital status, whether their partner smoked, deprivation, education, and participation in social activities. RESULTS: 31% (16,692) of the current smokers at baseline had stopped after 4 years. Smokers who were partnered at baseline were more likely to quit than those who were not partnered (OR 1.13, 99% CI 1.06-1.19). Compared to having a partner who smoked throughout, those who had a non-smoking partner throughout were more likely to quit (OR 2.01, 99% CI 1.86-2.17), and those who had a partner who smoked at baseline but stopped smoking in the next 4 years were even more likely to quit (OR 6.00, 5.41-6.67). There was no association with cessation for education or deprivation. The association with social participation varied by type of activity but was null overall. CONCLUSION: Women who were partnered were most likely to stop smoking if their partner also stopped smoking. There was little evidence of a strong influence of either socio-economic status or social participation on smoking cessation. These results emphasise the importance of a spouse's smoking habits on the likelihood of a smoker successfully quitting smoking.

Identification of a pathogenic variant in TREX1 in early-onset cerebral systemic lupus erythematosus by Whole-exome sequencing.

Objective. Systemic lupus erythematosus (SLE) isa chronic and heterogeneous autoimmune disease. Both twin and sibling studies indicate a strong genetic contribution to lupus, but in the majority of cases the pathogenic variant remains to be identified. The genetic contribution to disease is likely to be greatest in cases with early onset and severe phenotypes. Whole-exome sequencing now offers the possibility of identifying rare alleles responsible for disease in such cases. This study was undertaken to identify genetic causes of SLE using whole-exome sequencing.Methods. We performed whole-exome sequencing in a 4-year-old girl with early-onset SLE and conducted biochemical analysis of the putative defect.Results. Whole-exome sequencing in a 4-year-old girl with cerebral lupus identified a rare, homozygous mutation in the three prime repair exonuclease 1 gene(TREX1) that was predicted to be highly deleterious.The TREX1 R97H mutant protein had a 20-fold reduction in exonuclease activity and was associated with an elevated interferon-alpha signature in the patient.The discovery and characterization of a pathogenic TREX1 variant in our proband has therapeutic implications.The patient is now a candidate for therapy. Conclusion. Our study is the first to demonstrate that whole-exome sequencing can be used to identify rare or novel deleterious variants as genetic causes of SLE and, through a personalized approach, improve therapeutic options.