Clinical efficacy in the treatment of rheumatoid arthritis with anti‐CD20 (Rituximab)‐mediated B‐cell depletion has garnered interest in the mechanisms by which B cells contribute to autoimmunity. We ...have reported that B‐cell depletion in a murine model of proteoglycan‐induced arthritis (PGIA) leads to an increase in Treg cells that correlate with decreased autoreactivity. Here, we demonstrate that the increase in Treg cells after B‐cell depletion is due to an increase in the differentiation of naïve CD4+ T cells into Treg cells. Since the development of PGIA is dependent on IFN‐γ and B cells are reported to produce IFN‐γ, we hypothesized that B‐cell‐specific IFN‐γ plays a role in the development of PGIA. Accordingly, mice with B‐cell‐specific IFN‐γ deficiency were as resistant to the induction of PGIA as mice that were completely IFN‐γ deficient. Importantly, despite a normal frequency of IFN‐γ‐producing CD4+ T cells, B‐cell‐specific IFN‐γ‐deficient mice exhibited a higher percentage of Treg cells compared with that in WT mice. These data indicate that B‐cell IFN‐γ production inhibits Treg‐cell differentiation and exacerbates arthritis. Thus, we have established that IFN‐γ, specifically derived from B cells, uniquely contributes to the pathogenesis of autoimmunity through prevention of immunoregulatory mechanisms.
During B lymphopoiesis, recombination of the locus encoding the immunoglobulin κ-chain complex (Igk) requires expression of the precursor to the B cell antigen receptor (pre-BCR) and escape from ...signaling via the interleukin 7 receptor (IL-7R). By activating the transcription factor STAT5, IL-7R signaling maintains proliferation and represses Igk germline transcription by unknown mechanisms. We demonstrate that a STAT5 tetramer bound the Igk intronic enhancer (E(κi)), which led to recruitment of the histone methyltransferase Ezh2. Ezh2 marked trimethylation of histone H3 at Lys27 (H3K27me3) throughout the κ-chain joining region (J(κ)) to the κ-chain constant region (C(κ)). In the absence of Ezh2, IL-7 failed to repress Igk germline transcription. H3K27me3 modifications were lost after termination of IL-7R-STAT5 signaling, and the transcription factor E2A bound E(κi), which resulted in acquisition of H3K4me1 and acetylated histone H4 (H4Ac). Genome-wide analyses showed a STAT5 tetrameric binding motif associated with transcriptional repression. Our data demonstrate how IL-7R signaling represses Igk germline transcription and provide a general model for STAT5-mediated epigenetic transcriptional repression.
Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance
. The protein tyrosine ...phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity
. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8
T cell function by enhancing JAK-STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.
Objective
Inducible costimulator (ICOS)–ICOSL interactions are necessary for activation of Teff cells and follicular helper T (Tfh) cells. ICOSL is expressed on B cells, macrophages, and dendritic ...cells and can be induced on nonhematopoietic cells. The aim of this study was to determine whether expression of ICOSL on B cells is necessary for the development of proteoglycan (PG)–induced arthritis (PGIA).
Methods
PGIA was initiated by immunizing wild‐type and ICOSL‐deficient (ICOSL−/−) or B cell–specific ICOSL−/− chimeric BALB/c mice with human PG in adjuvant. The onset and severity of arthritis were monitored over time. CD4+ T cell proliferation and CD4+ T cell cytokine production were measured in vitro after the cells were restimulated with PG. Germinal center (GC) B cells, plasma cells, Tfh cells, and Treg cells were identified by staining with specific antibodies.
Results
Arthritis progression was completely inhibited in both ICOSL−/− mice and B cell–specific ICOSL−/− chimeric mice. Production of the Teff cell–produced cytokines interferon‐γ and interleukin‐17 (IL‐17) and the antiinflammatory cytokine IL‐4 was suppressed. The reduced percentages of GCs and Tfh cells and the decreased production of IL‐21 correlated with a decrease in the anti‐mouse PG antibody response. However, the percentage of plasma cells was not reduced despite a reduction in IgG responses.
Conclusion
These data indicate that the signals provided by ICOSL‐expressing B cells to Teff cells and Tfh cells are necessary for the development of arthritis. Thus, therapeutic blockade of ICOSL−ICOS interactions may be an effective strategy for the treatment of rheumatoid arthritis.
Background:
Gene-agnostic genomic biomarkers were recently developed to identify homologous recombination deficiency (HRD) tumors that are likely to respond to treatment with PARP inhibitors. Two ...machine-learning algorithms that predict HRD status, CHORD, and HRDetect, utilize various HRD-associated features extracted from whole-genome sequencing (WGS) data and show high sensitivity in detecting patients with
BRCA1/2
bi-allelic inactivation in all cancer types. When using only DNA mutation data for the detection of potential causes of HRD, both HRDetect and CHORD find that 30–40% of cases that have been classified as HRD are due to unknown causes. Here, we examined the impact of tumor-specific thresholds and measurement of promoter methylation of
BRCA1
and
RAD51C
on unexplained proportions of HRD cases across various tumor types.
Methods:
We gathered published CHORD and HRDetect probability scores for 828 samples from breast, ovarian, and pancreatic cancer from previous studies, as well as evidence of their biallelic inactivation (by either DNA alterations or promoter methylation) in HR-related genes. ROC curve analysis evaluated the performance of each classifier in specific cancer. Tenfold nested cross-validation was used to find the optimal threshold values of HRDetect and CHORD for classifying HR-deficient samples within each cancer type.
Results:
With the universal threshold, HRDetect has higher sensitivity in the detection of biallelic inactivation in
BRCA1/2
than CHORD and resulted in a higher proportion of unexplained cases. When promoter methylation was excluded, in ovarian carcinoma, the proportion of unexplained cases increased from 26.8 to 48.8% for HRDetect and from 14.7 to 41.2% for CHORD. A similar increase was observed in breast cancer. Applying cancer-type-specific thresholds led to similar sensitivity and specificity for both methods. The cancer-type-specific thresholds for HRDetect reduced the number of unexplained cases from 21 to 12.3% without reducing the 96% sensitivity to known events. For CHORD, unexplained cases were reduced from 10 to 9% while sensitivity increased from 85.3 to 93.9%.
Conclusion:
These results suggest that WGS-based HRD classifiers should be adjusted for tumor types. When applied, only ∼10% of breast, ovarian, and pancreas cancer cases are not explained by known events in our dataset.
IL-17 is the hallmark cytokine for the newly identified subset of Th cells, Th17. Th17 cells are important instigators of inflammation in several models of autoimmune disease; in particular, collagen ...induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE), which were previously characterized as Th1-mediated diseases. Although high levels of IFN-gamma are secreted in CIA and EAE, disease is exacerbated in IFN-gamma- or IFN-gamma receptor-deficient mice due to the ability of IFN-gamma to suppress IL-17 secretion. However, in proteoglycan-induced arthritis (PGIA), severe arthritis is dependent on the production of IFN-gamma. We were therefore interested in determining the role of IL-17 in PGIA. We assessed the progression of arthritis in IL-17-deficient (IL-17-/-) mice and found the onset and severity of arthritis were equivalent in wild-type (WT) and IL-17-/- mice. Despite evidence that IL-17 is involved in neutrophil recruitment, synovial fluid from arthritic joints showed a comparable proportion of Gr1+ neutrophils in WT and IL-17-/- mice. IL-17 is also implicated in bone destruction in autoimmune arthritis, however, histological analysis of the arthritic joints from WT and IL-17-/- mice revealed a similar extent of joint cellularity, cartilage destruction, and bone erosion despite significantly reduced RANKL (receptor activator of NK-kappaB ligand) expression. There were only subtle differences between WT and IL-17-/- mice in proinflammatory cytokine expression, T cell proliferation, and autoantibody production. These data demonstrate that IL-17 is not absolutely required for autoimmune arthritis and that the production of other proinflammatory mediators is sufficient to compensate for the loss of IL-17 in PGIA.
Rheumatoid arthritis is a chronic autoimmune immune disease affecting approximately 1% of the population. There has been a renewed interest in the role of B cells in rheumatoid arthritis based on the ...evidence that B cell depletion therapy is effective in the treatment of disease. This review summarizes the current knowledge of the mechanisms by which B cells contribute to autoimmune arthritis including roles as autoantibody producing cells, antigen-presenting cells, cytokine producing cells, and regulatory cells.
Germinal Center B-cells Hamel, Keith M.; Liarski, Vladimir M.; Clark, Marcus R.
Autoimmunity (Chur, Switzerland),
2012-August, 8/1/2012, 2012-Aug, 2012-08-00, 20120801, Letnik:
45, Številka:
5
Journal Article
Recenzirano
Within the B-cell follicle of secondary lymphoid organs, germinal center (GC) reactions produce high affinity antibody-secreting plasma cells (PCs) and memory B-cells necessary for the host's defense ...against invading pathogens. This process of GC formation is reliant on the activation of antigen-specific B-cells by T-cells capable of recognizing epitopes of the same antigenic complex. The unique architecture of secondary lymphoid organs facilitates these initial GC events through the placement of large clonally-diverse B-cell follicles near equally diverse T-cell zones. Antigen-activated B-cells that receive proper differentiation signals at the T-cell border of the B-cell follicle initiate an early GC B-cell transcriptional profile and migrate to follicular dendritic cell (FDC) networks within the B-cell follicle to seed the GC reaction. Peripheral to FDCs, GC B-cells rapidly divide in dark zones of the GC, and undergo somatic hypermutation of their immunoglobulin (Ig) variable domain. Newly formed GC B-cell clones then migrate into the GC light zone where they compete for antigen and secondary signals presented by FDCs and a specialized subset of CD4+ T-cells known as T-follicular helper (TFH) cells. Survival, proliferative and differentiation signals delivered by mature FDCs and TFH cells initiate transcriptional programs that determine if GC B-cells become memory B-cells or terminally differentiated PCs. To prevent oncogenic transformation and/or the escape of autoreactive clones, there are several regulatory mechanisms that restrict GC B-cell proliferation and survival. Here we will detail the recent advances in GC B-cell biology that relate to their generation and fate-determination as well as their pathogenic potential.
The immune system has developed several regulatory mechanisms to maintain homeostasis of adaptive immune responses. T‐cell programmed death (PD)‐1 recognition of B7‐H1 (PD‐L1) expressed on APC and ...non‐lymphoid tissue regulates T‐cell activation. We show that B7‐H1−/− mice exhibit exacerbated proteoglycan (PG)‐induced arthritis and increased Th‐1 CD4+ T‐cell responses. Unexpectedly, the PG‐specific antibody response in B7‐H1−/− mice was diminished. A reduction in the number of peanut agglutinin+ GC coincided with a decrease in CD19+ GL‐7+ CD95+ GC B cells that was a result of increased caspase‐induced apoptosis. The percent of CD38+ CD138+ emerging plasma cells was decreased. B7‐H1−/− mice exhibited an increased frequency of CD4+ PD‐1hi CXCR5hi ICOShi CD62Llo T follicular helper cells that displayed a hyperactive phenotype with increased expression of mRNA transcripts for Bcl6, IL‐21, and the apoptosis‐inducer molecule FasL. In cell transfer of B7‐H1−/− cells into SCID mice, non‐B and non‐T cells were sufficient to normalize the antibody response, T‐cell hyperactivity, and the development of PG‐induced arthritis. These findings indicate that B7‐H1 on non‐B and non‐T cells signals through PD‐1 on T effector cells to prevent excessive activation and reduce autoimmune arthritis. Furthermore, these findings demonstrate a novel role for B7‐H1 expression in promoting B‐cell survival by regulating the activation of T follicular helper cell.
Objectives
To examine receipt of colorectal cancer (CRC) screening according to age and life expectancy (LE) in adults aged 65 and older.
Design
Population‐based survey.
Setting
United States.
...Participants
Community dwelling adults aged 65 and older who participated in the 2008 or 2010 National Health Interview Survey (N = 7,747).
Measurements
Receipt of CRC screening (e.g., colonoscopy within 10 years) was examined according to age and LE (≥10 and <10 years), adjusting for sociodemographic characteristics and survey year. Frequency of CRC screening was also examined according to age and LE at time of screening (e.g., age at colonoscopy rather than at interview). Participants screened when they were aged 75 and older or had less than a 10‐year LE were considered to have received screening inconsistent with guidelines.
Results
Overall, 38.5% of participants had less than a 10‐year LE; 40.2% were aged 75 and older, and 56.3% had received recent CRC screening (90.1% by colonoscopy). CRC screening was higher in 2010 (58.9%) than 2008 (53.7%, P <.001) and was associated with longer LE and younger age, although 51.1% of adults aged 75 and older reported receiving CRC screening, as did 50.9% of adults with less than a 10‐year LE. Based on age and LE at time of screening (rather than at interview), 28.4% of CRC screening of adults aged 65 and older was targeted to those aged 75 and older and those with less than a 10‐year LE. Of adults aged 65 to 75 with a 10‐year LE or more (adults recommended for screening by guidelines), 39.2% had not recently been screened.
Conclusion
Older adults with little chance of benefit because of limited LE commonly undergo CRC screening, whereas many adults aged 65 to 75 with a 10‐year LE or greater are not screened.
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