Publications by authors named "Peter Olofsson"

50 Publications

Technical Aspects of Devices and Equipment for Positive Expiratory Pressure With and Without Oscillation.

Respir Care 2021 Feb 9. Epub 2021 Feb 9.

Department of Physiotherapy, Faculty of Medicine and Health, Örebro University, Stockholm, Sweden.

Background: Breathing exercises with positive expiratory pressure (PEP) and oscillating PEP are common treatments for patients with respiratory impairments. There are several trials evaluating the clinical effects of a variety of commercially available and self-made devices. There is a lack of evaluation concerning technical aspects and construction of the devices. The aims of this review were to describe and compare technical aspects of devices and equipment used for PEP and oscillating PEP as a basis for clinical decisions regarding prescriptions.

Methods: In this systematic review, we included trials evaluating different technical aspects of devices and equipment for PEP and oscillating PEP until June 2019. The literature search was performed in PubMed, CINAHL, Cochrane Library, Embase and PEDro.

Results: The literature search resulted in 812 studies, which, after being read by 2 independent reviewers, were reduced to 21 trials that matched the inclusion criteria. The achieved PEP is dependent on the given resistance or achieved expiratory flow through the devices and their separate parts. Oscillation frequency in oscillating PEP devices affects the pressure and oscillation amplitude and flow. For some devices, the device's position also has an impact on the outcome. There are similarities and differences among all of the devices, and the equipment components are not interchangeable without changing the achieved PEP levels.

Conclusions: Many devices are available to provide PEP and oscillating PEP treatment. These devices differ substantially in design as well as in performance. When using PEP devices, it is important to understand how all parts of the devices affect outcomes. An increased understanding of how PEP is produced for the spontaneously breathing patient is important to achieve desired treatment effects.
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http://dx.doi.org/10.4187/respcare.08003DOI Listing
February 2021

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2 complex.

J Leukoc Biol 2020 Oct 11. Epub 2020 Oct 11.

Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden, Sweden.

The formyl peptide receptors FPR1 and FPR2 are abundantly expressed by neutrophils, in which they regulate proinflammatory tissue recruitment of inflammatory cells, the production of reactive oxygen species (ROS), and resolution of inflammatory reactions. The unique dual functionality of the FPRs makes them attractive targets to develop FPR-based therapeutics as novel anti-inflammatory treatments. The small compound RE-04-001 has earlier been identified as an inducer of ROS in differentiated HL60 cells but the precise target and the mechanism of action of the compound was has until now not been elucidated. In this study, we reveal that RE-04-001 specifically targets and activates FPR1, and the concentrations needed to activate the neutrophil NADPH-oxidase was very low (EC ∼1 nM). RE-04-001 was also found to be a neutrophil chemoattractant, but when compared to the prototype FPR1 agonist N-formyl-Met-Leu-Phe (fMLF), the concentrations required were comparably high, suggesting that signaling downstream of the RE-04-001-activated-FPR1 is functionally selective. In addition, the RE-04-001-induced response was strongly biased toward the PLC-PIP -Ca pathway and ERK1/2 activation but away from β-arrestin recruitment. Compared to the peptide agonist fMLF, RE-04-001 is more resistant to inactivation by the MPO-H O -halide system. In summary, this study describes RE-04-001 as a novel small molecule agonist specific for FPR1, which displays a biased signaling profile that leads to a functional selective activating of human neutrophils. RE-04-001 is, therefore, a useful tool, not only for further mechanistic studies of the regulatory role of FPR1 in inflammation in vitro and in vivo, but also for developing FPR1-specific drug therapeutics.
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http://dx.doi.org/10.1002/JLB.2HI0520-317RDOI Listing
October 2020

Self-reactive T cells induce and perpetuate chronic relapsing arthritis.

Arthritis Res Ther 2020 04 28;22(1):95. Epub 2020 Apr 28.

Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

Background: CD4 T cells play a central role during the early stages of rheumatoid arthritis (RA), but to which extent they are required for the perpetuation of the disease is still not fully understood. The aim of the current study was to obtain conclusive evidence that T cells drive chronic relapsing arthritis.

Methods: We used the rat pristane-induced arthritis model, which accurately portrays the chronic relapsing-remitting disease course of RA, to examine the contribution of T cells to chronic arthritis.

Results: Rats subjected to whole-body irradiation and injected with CD4 T cells from lymph nodes of pristane-injected donors developed chronic arthritis that lasted for more than 4 months, whereas T cells from the spleen only induced acute disease. Thymectomy in combination with irradiation enhanced the severity of arthritis, suggesting that sustained lymphopenia promotes T cell-driven chronic inflammation in this model. The ability of T cells to induce chronic arthritis correlated with their expression of Th17-associated transcripts, and while depletion of T cells in rats with chronic PIA led to transient, albeit significant, reduction in disease, neutralization of IL-17 resulted in almost complete and sustained remission.

Conclusion: These findings show that, once activated, self-reactive T cells can sustain inflammatory responses for extended periods of time and suggest that such responses are promoted in the presence of IL-17.
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http://dx.doi.org/10.1186/s13075-020-2104-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187533PMC
April 2020

NOX2 mediates quiescent handling of dead cell remnants in phagocytes.

Redox Biol 2019 09 20;26:101279. Epub 2019 Jul 20.

Department of Medicine 3, Rheumatology and Immunology, Friedrich Alexander-University Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany. Electronic address:

The phagocyte NADPH oxidase (the NOX2 complex) generates superoxide, the precursor to reactive oxygen species (ROS). ROS possess both antimicrobial and immunoregulatory function. Inactivating mutations in alleles of the NOX2 complex cause chronic granulomatous disease (CGD), characterized by an enhanced susceptibility to infections and autoimmune diseases such as Systemic lupus erythematosus (SLE). The latter is characterized by insufficient removal of dead cells, resulting in an autoimmune response against components of the cell's nucleus when non-cleared apoptotic cells lose their membrane integrity and present autoantigenic molecules in an inflammatory context. Here we aimed to shed light on the role of the NOX2 complex in handling of secondary necrotic cells (SNECs) and associated consequences for inflammation and autoimmunity during lupus. We show that individuals with SLE and CGD display accumulation of SNECs in blood monocytes and neutrophils. In a CGD phenotypic mouse strain (Ncf1** mice) build-up of SNECs in Ly6C blood monocytes was connected with a delayed degradation of the phagosomal cargo and accompanied by production of inflammatory mediators. Treatment with HO or activators of ROS-formation reconstituted phagosomal abundance of SNECs to normal levels. Induction of experimental lupus further induced increased antibody-dependent uptake of SNECs into neutrophils. Lupus-primed Ncf1** neutrophils took up more SNECs than wild type neutrophils, whereas SNEC-accumulation in regulatory Ly6C monocytes was lower in Ncf1**mice. We deduce that the inflammatory rerouting of immune-stimulatory necrotic material into inflammatory phagocyte subsets contributes to the connection between low ROS production by the NOX2 complex and SLE.
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http://dx.doi.org/10.1016/j.redox.2019.101279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669319PMC
September 2019

Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949.

Biochem Pharmacol 2019 08 11;166:163-173. Epub 2019 May 11.

Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 17177, Sweden.

Despite the steadily increased numbers of formyl peptide receptor (FPR) ligands identified over the years, few have been characterized in studies using animal disease models and even less have entered clinical trials in human subjects. A small-molecule compound, Act-389949, was however recently tested in a phase I clinical trial and found to be safe and well tolerated in healthy human subjects. The desired anti-inflammatory property of Act-389949 was proposed to be mediated through FPR2, one of the FPRs expressed in neutrophils, but no basic characterization was included in the study. To gain more insights into FPR2 recognition of this first-in-class compound for future utility of the agonist, we have in this study determined the receptor preference and down-stream signaling characteristics induced by Act-389949 in human blood neutrophils isolated from healthy donors. Our data demonstrate that Act-389949 is an agonist for FPR2 that triggers functional/signaling repertoires comparable to what has been earlier described for other FPR2 agonists, including neutrophil chemotaxis, granule mobilization and activation of the NADPH-oxidase. In fact, Act-389949 was found to be as potent as the prototype FPR2 peptide agonist WKYMVM and had the advantage of being resistant to oxidation by MPO-HO-halide derived oxidants, as compared to the sensitive WKYMVM. The down-stream signals generated by Act-389949 include an FPR2-dependent and Gαq-independent transient rise in intracellular Ca and recruitment of β-arrestin. In summary, our data show that Act-389949 serves as an excellent tool-compound for further dissection of FPR2-regulated activities in vitro and in vivo. Potent and stable FPR ligands such as Act-389949 may therefore be used to develop the next generation of FPR signaling regulating anti-inflammatory therapeutics.
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http://dx.doi.org/10.1016/j.bcp.2019.04.030DOI Listing
August 2019

Correlation and cluster analysis of immunomodulatory drugs based on cytokine profiles.

Pharmacol Res 2018 02 25;128:244-251. Epub 2017 Oct 25.

School of Bioscience, University of Skövde, 541 28, Skövde, Sweden. Electronic address:

Drug discovery is a constant struggle to overcome hurdles posed by the complexity of biological systems. One of these hurdles is to find and understand the molecular target and the biological mechanism of action. Although the molecular target has been determined, the true biological effect may be unforeseen also for well-established drugs. Hence, there is a need for novel ways to increase the knowledge of the biological effects of drugs in the developmental process. In this study, we have determined cytokine profiles for 26 non-biological immunomodulatory drugs or drug candidates and used these profiles to cluster the compounds according to their effect in a preclinical ex vivo culture model of arthritis. This allows for prediction of functions and drug target of a novel drug candidate based on profiles obtained in this study. Results from the study showed that the JAK inhibitors tofacitinib and ruxolitinib formed a robust cluster and were found to have a distinct cytokine profile compared to the other drugs. Another robust cluster included the calcineurin inhibitors cyclosporine A and tacrolimus and the protein kinase inhibitors fostamatinib disodium and sotrastaurin acetate, which caused a strong overall inhibition of the cytokine production. The results of this methodology indicate that cytokine profiles can be used to provide a fingerprint-like identification of a drug as a tool to benchmark novel drugs and to improve descriptions of mode of action.
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http://dx.doi.org/10.1016/j.phrs.2017.10.012DOI Listing
February 2018

NADPH oxidases as drug targets and biomarkers in neurodegenerative diseases: What is the evidence?

Free Radic Biol Med 2017 11 12;112:387-396. Epub 2017 Aug 12.

Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland. Electronic address:

Neurodegenerative disease are frequently characterized by microglia activation and/or leukocyte infiltration in the parenchyma of the central nervous system and at the molecular level by increased oxidative modifications of proteins, lipids and nucleic acids. NADPH oxidases (NOX) emerged as a novel promising class of pharmacological targets for the treatment of neurodegeneration due to their role in oxidant generation and presumably in regulating microglia activation. The unique function of NOX is the generation of superoxide anion (O) and hydrogen peroxide (HO). However in the context of neuroinflammation, they present paradoxical features since O/HO generated by NOX and/or secondary reactive oxygen species (ROS) derived from O/HO can either lead to neuronal oxidative damage or resolution of inflammation. The role of NOX enzymes has been investigated in many models of neurodegenerative diseases by using either genetic or pharmacological approaches. In the present review we provide a critical assessment of recent findings related to the role of NOX in the CNS as well as how the field has advanced over the last 5 years. In particular, we focus on the data derived from the work of a consortium (Neurinox) funded by the European Commission's Programme 7 (FP7). We discuss the evidence gathered from animal models and human samples linking NOX expression/activity with neuroinflammation in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Creutzfeldt-Jakob disease as well as autoimmune demyelinating diseases like multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP). We address the possibility to use measurement of the activity of the NOX2 isoform in blood samples as biomarker of disease severity and treatment efficacy in neurodegenerative disease. Finally we clarify key controversial aspects in the field of NOX, such as NOX cellular expression in the brain, measurement of NOX activity, impact of genetic deletion of NOX in animal models of neurodegeneration and specificity of NOX inhibitors.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.08.006DOI Listing
November 2017

Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps.

JCI Insight 2017 May 18;2(10). Epub 2017 May 18.

Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Internal Medicine 3 - Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen, Germany.

Many effector mechanisms of neutrophils have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) have been assigned a particularly detrimental role. Here we investigated the functional impact of neutrophils and NETs on a mouse model of lupus triggered by intraperitoneal injection of the cell death-inducing alkane pristane. Pristane-induced lupus (PIL) was aggravated in 2 mouse strains with impaired induction of NET formation, i.e., NOX2-deficient (Ncf1-mutated) and peptidyl arginine deiminase 4-deficient (PAD4-deficient) mice, as seen from elevated levels of antinuclear autoantibodies (ANAs) and exacerbated glomerulonephritis. We observed a dramatically reduced ability to form pristane-induced NETs in vivo in both Ncf1-mutated and PAD4-deficient mice, accompanied by higher levels of inflammatory mediators in the peritoneum. Similarly, neutropenic Mcl-1ΔMyelo mice exhibited higher levels of ANAs, which indicates a regulatory function in lupus of NETs and neutrophils. Blood neutrophils from Ncf1-mutated and human individuals with SLE exhibited exuberant spontaneous NET formation. Treatment with specific chemical NOX2 activators induced NET formation and ameliorated PIL. Our findings suggest that aberrant NET is one of the factors promoting experimental lupus-like autoimmunity by uncontrolled release of inflammatory mediators.
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http://dx.doi.org/10.1172/jci.insight.92920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436535PMC
May 2017

Cytokine correlation analysis based on drug perturbation.

Cytokine 2017 02 2;90:73-79. Epub 2016 Nov 2.

School of Bioscience, University of Skövde, 541 28 Skövde, Sweden. Electronic address:

Cytokines and chemokines play a crucial role in regulating the immune system. Understanding how these molecules are co-regulated is important to understand general immunology, and particularly their role in clinical applications such as development and evaluation of novel drug therapies. Cytokines are today widely used as therapeutic targets and as biomarkers to monitor effects of drug therapies and for prognosis and diagnosis of diseases. Therapies that target a specific cytokine are also likely to affect the production of other cytokines due to their cross-regulatory functions and because the cytokines are produced by common cell types. In this study, we have perturbated the production of 17 different cytokines in a preclinical rat model of autoimmune arthritis, using 55 commercially available immunomodulatory drugs and clinical candidates. The majority of the studied drugs was selected for their anti-inflammatory role and was confirmed to inhibit the production of IL-2 and IFN-γ in this model but was also found to increase the production of other cytokines compared to the untreated control. Correlation analysis identified 58 significant pairwise correlations between the cytokines. The strongest correlations found in this study were between IL-2 and IFN-γ (r=0.87) and between IL-18 and EPO (r=0.84). Cluster analysis identified two robust clusters: (1) IL-7, IL-18 and EPO, and (2) IL-2, IL-17 and IFN-γ. The results show that cytokines are highly co-regulated, which provide valuable information for how a therapeutic drug might affect clusters of cytokines. In addition, a cytokine that is used as a therapeutic biomarker could be combined with its related cytokines into a biomarker panel to improve diagnostic accuracy.
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http://dx.doi.org/10.1016/j.cyto.2016.10.015DOI Listing
February 2017

Animal Models of Rheumatoid Arthritis (I): Pristane-Induced Arthritis in the Rat.

PLoS One 2016 26;11(5):e0155936. Epub 2016 May 26.

Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

Background: To facilitate the development of therapies for rheumatoid arthritis (RA), the Innovative Medicines Initiative BTCure has combined the experience from several laboratories worldwide to establish a series of protocols for different animal models of arthritis that reflect the pathogenesis of RA. Here, we describe chronic pristane-induced arthritis (PIA) model in DA rats, and provide detailed instructions to set up and evaluate the model and for reporting data.

Methods: We optimized dose of pristane and immunization procedures and determined the effect of age, gender, and housing conditions. We further assessed cage-effects, reproducibility, and frequency of chronic arthritis, disease markers, and efficacy of standard and novel therapies.

Results: Out of 271 rats, 99.6% developed arthritis after pristane-administration. Mean values for day of onset, day of maximum arthritis severity and maximum clinical scores were 11.8±2.0 days, 20.3±5.1 days and 34.2±11 points on a 60-point scale, respectively. The mean frequency of chronic arthritis was 86% but approached 100% in long-term experiments over 110 days. Pristane was arthritogenic even at 5 microliters dose but needed to be administrated intradermally to induce robust disease with minimal variation. The development of arthritis was age-dependent but independent of gender and whether the rats were housed in conventional or barrier facilities. PIA correlated well with weight loss and acute phase reactants, and was ameliorated by etanercept, dexamethasone, cyclosporine A and fingolimod treatment.

Conclusions: PIA has high incidence and excellent reproducibility. The chronic relapsing-remitting disease and limited systemic manifestations make it more suitable than adjuvant arthritis for long-term studies of joint-inflammation and screening and validation of new therapeutics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155936PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881957PMC
July 2017

The probability of speciation on an interaction network with unequal substitution rates.

Math Biosci 2016 08 10;278:1-4. Epub 2016 May 10.

Department of Mathematics, Trinity University, United States.

Speciation is characterized by the development of reproductive isolating barriers between diverging groups. A seminal paper of a mathematical model of speciation was published by Orr (1995), extended by Livingstone et al. (2012) to incorporate interaction networks. Here, we further develop the model to take into account the possibility of different substitution rates for network nodes of different connectivity. Mathematically, this amounts to sampling nodes from an undirected graph where the inclusion probability for a given node depends on its degree (number of connecting edges). We establish formulas for the rate of speciation and identify a crucial parameter that is a measure of the deviation from simple random sampling.
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http://dx.doi.org/10.1016/j.mbs.2016.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797833PMC
August 2016

Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics.

Am J Hum Genet 2014 Oct 18;95(4):345-59. Epub 2014 Sep 18.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Statistics, Rice University, Houston, TX 77005, USA; Department of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. Interestingly, new mutations in X-linked recessive disease show elevated familial recurrence rates. In male offspring, these mutations must be inherited from mothers. We previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. In this paper, we extend and formalize the model to provide analytical results and flexible formulas. The results implicate parent of origin and parental mosaicism as central variables in recurrence risk. Consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers age. Notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. Subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. Conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. Parental somatic mosaicism considerably elevates risk for both parents. These findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. We provide a convenient online tool and source code implementing our analytical results. These tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures.
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http://dx.doi.org/10.1016/j.ajhg.2014.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185125PMC
October 2014

Thioredoxin as a putative biomarker and candidate target in age-related immune decline.

Biochem Soc Trans 2014 Aug;42(4):922-7

*School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, U.K.

The oxidoreductase Trx-1 (thioredoxin 1) is highly conserved and found intra- and extra-cellularly in mammalian systems. There is increasing interest in its capacity to regulate immune function based on observations of altered distribution and expression during ageing and disease. We have investigated previously whether extracellular T-cell or peripheral blood mononuclear cell Trx-1 levels serve as a robust marker of ageing. In a preliminary study of healthy older adults compared with younger adults, we showed that there was a significant, but weak, relationship with age. Interestingly, patients with rheumatoid arthritis and cancer have been described by others to secrete or express greater surface Trx-1 than predicted. It is interesting to speculate whether a decline in Trx-1 during ageing protects against such conditions, but correspondingly increases risk of disease associated with Trx-1 depletion such as cardiovascular disease. These hypotheses are being explored in the MARK-AGE study, and preliminary findings confirm an inverse correlation of surface Trx-1 with age. We review recent concepts around the role of Trx-1 and its partners in T-cell function on the cell surface and as an extracellular regulator of redox state in a secreted form. Further studies on the redox state and binding partners of surface and secreted Trx-1 in larger patient datasets are needed to improve our understanding of why Trx-1 is important for lifespan and immune function.
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http://dx.doi.org/10.1042/BST20140162DOI Listing
August 2014

Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders.

Am J Hum Genet 2014 Aug 31;95(2):173-82. Epub 2014 Jul 31.

Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Institute of Mother and Child, Warsaw 01-211, Poland. Electronic address:

New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.
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http://dx.doi.org/10.1016/j.ajhg.2014.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4129404PMC
August 2014

Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature.

Antioxid Redox Signal 2014 Dec 29;21(16):2231-45. Epub 2014 Jul 29.

1 Medicity Research Laboratory, University of Turku , Turku, Finland .

Aims: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the phagocyte reactive oxygen species (ROS)-producing NOX2 enzyme complex and characterized by recurrent infections associated with hyperinflammatory and autoimmune manifestations. A translational, comparative analysis of CGD patients and the corresponding ROS-deficient Ncf1(m1J) mutated mouse model was performed to reveal the molecular pathways operating in NOX2 complex deficient inflammation.

Results: A prominent type I interferon (IFN) response signature that was accompanied by elevated autoantibody levels was identified in both mice and humans lacking functional NOX2 complex. To further underline the systemic lupus erythematosus (SLE)-related autoimmune process, we show that naïve Ncf1(m1J) mutated mice, similar to SLE patients, suffer from inflammatory kidney disease with IgG and C3 deposits in the glomeruli. Expression analysis of germ-free Ncf1(m1J) mutated mice reproduced the type I IFN signature, enabling us to conclude that the upregulated signaling pathway is of endogenous origin.

Innovation: Our findings link the previously unexplained connection between ROS deficiency and increased susceptibility to autoimmunity by the discovery that activation of IFN signaling is a major pathway downstream of a deficient NOX2 complex in both mice and humans.

Conclusion: We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans.
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http://dx.doi.org/10.1089/ars.2013.5828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224049PMC
December 2014

Pharmacological Potential of NOX2 Agonists in Inflammatory Conditions.

Antioxid Redox Signal 2015 Aug 26;23(5):446-59. Epub 2014 Feb 26.

2 Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Stockholm, Sweden .

Significance: New insights into the role of reactive oxygen species (ROS) show that activators of the phagocyte NADPH oxidase 2 (NOX2) complex have the potential to be therapeutic in autoimmune and inflammatory conditions. It is, however, essential to elucidate the consequence of targeting the NOX2 complex, as it might lead to different outcomes depending on disease context and specificity, dose, and timing of ROS production.

Recent Advances: Increasing evidence is suggesting that the role of the NOX2 complex is far more complex than previously anticipated. In addition to the well-described antimicrobial response, ROS also have immune and inflammatory regulatory effects. Compounds increasing NOX2-dependent ROS production have been shown to be effective both in preventing and in treating inflammatory manifestations in animal models of autoimmune diseases. Altogether, these results suggest the possibility of activating the NOX2 complex for the treatment of autoimmune inflammatory diseases while restoring and maintaining a balanced ROS regulation.

Critical Issues: The complexity of the NOX system and the derived ROS is important and must be considered when designing the programs for the development of NOX2-activating drugs, as well as for validation of selected hits, to successfully identify substances effective in treating inflammatory and autoimmune conditions. In addition, it is important to consider the complex downstream immunological effects and safety for drugs that increase the production of ROS.

Future Directions: There is a strong potential for the development of ROS-inducing drugs, targeting the NOX2 complex, which are effective and safe, for the treatment of inflammatory autoimmune disorders. In such drug development, one must carefully investigate the pharmaceutical properties, including both efficacy and safety of the drugs. In addition, the immunological pathways of this new treatment strategy need careful examination.
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http://dx.doi.org/10.1089/ars.2013.5788DOI Listing
August 2015

A Discrete-Time Branching Process Model of Yeast Prion Curing Curves.

Math Popul Stud 2013 27;20(1):1-13. Epub 2013 Jan 27.

Communicated by Peter Jagers and Christine Jacob.

The infectious agent of many neurodegenerative disorders is thought to be aggregates of prion protein, which are transmitted between cells. Recent work in yeast supports this hypothesis, but suggests that only aggregates below a critical size are transmitted efficiently. The total number of transmissible aggregates in a typical cell is a key determinant of strain infectivity. In a discrete-time branching process model of a yeast colony with prions, prion aggregates increase in size according to a Poisson process and only aggregates below a threshold size are transmitted during cell division. The total number of cells with aggregates in a growing population of yeast is expressed.
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http://dx.doi.org/10.1080/08898480.2013.748566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168217PMC
January 2013

Identification of a region in p47phox/NCF1 crucial for phagocytic NADPH oxidase (NOX2) activation.

J Leukoc Biol 2013 Mar 27;93(3):427-35. Epub 2012 Dec 27.

MediCity Research Laboratory, University of Turku, Turku, Finland.

A point mutation in the mouse Ncf1(m1J) gene decreases production of ROS by the phagocytic NOX2 complex. Three mRNA splice variants are expressed, but only one is expressed as a protein, although at lower levels than the WT NCF1 (also known as p47phox). Our aim was to investigate whether the mutant p47phox, lacking 8 aa, is active, but as a result of its low expression, ROS production is decreased in Ncf1(m1J) mice, or whether the mutant p47phox completely lacks the capability to activate the NOX2 complex. The p47phox mutant (Δ228-235), which was equal to the protein in Ncf1(m1J) mice, failed to activate the NOX2 complex. When the deleted region was narrowed down to 2 aa, the p47phox protein remained inactive and failed to translocate to the membrane upon activation. Single amino acid substitutions revealed Thr233 to be vital for ROS production. Residues Tyr231 and Val232 also seemed to be important for p47phox function, as p47phox_Y231G and p47phox_V232G resulted in a >50% decrease in ROS production by the NOX2 complex. In addition, we identified the epitope of the D-10 anti-p47phox mAb. In conclusion, the p47phox protein variant expressed in Ncf1(m1J) mice is completely defective in activating the NOX2 complex to produce ROS, and the effect is dependent on SH3 region amino acids at positions 231-233, which are vital for the proper assembly of the NOX2 complex.
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http://dx.doi.org/10.1189/jlb.1211588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579024PMC
March 2013

Superoxide dismutase 3 limits collagen-induced arthritis in the absence of phagocyte oxidative burst.

Mediators Inflamm 2012 5;2012:730469. Epub 2012 Mar 5.

Medicity Research Laboratory, University of Turku, Tykistökatu 6 A, 20520 Turku, Finland.

Extracellular superoxide dismutase (SOD3), an enzyme mediating dismutation of superoxide into hydrogen peroxide, has been shown to reduce inflammation by inhibiting macrophage migration into injured tissues. In inflamed tissues, superoxide is produced by the phagocytic NOX2 complex, which consists of the catalytic subunit NOX2 and several regulatory subunits (e.g., NCF1). To analyze whether SOD3 can regulate inflammation in the absence of functional NOX2 complex, we injected an adenoviral vector overexpressing SOD3 directly into the arthritic paws of Ncf1(∗/∗) mice with collagen-induced arthritis. SOD3 reduced arthritis severity in both oxidative burst-deficient Ncf1(∗/∗) mice and also in wild-type mice. The NOX2 complex independent anti-inflammatory effect of SOD3 was further characterized in peritonitis, and SOD3 was found to reduce macrophage infiltration independently of NOX2 complex functionality. We conclude that the SOD3-mediated anti-inflammatory effect on arthritis and peritonitis operates independently of NOX2 complex derived oxidative burst.
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http://dx.doi.org/10.1155/2012/730469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317049PMC
September 2012

A stochastic model for the development of Bateson-Dobzhansky-Muller incompatibilities that incorporates protein interaction networks.

Math Biosci 2012 Jul 29;238(1):49-53. Epub 2012 Mar 29.

Department of Biology, Trinity University, 1 Trinity Place, San Antonio, TX 78212, USA.

Speciation is characterized by the development of reproductive isolating barriers between diverging groups. Intrinsic post-zygotic barriers of the type envisioned by Bateson, Dobzhansky, and Muller are deleterious epistatic interactions among loci that reduce hybrid fitness, leading to reproductive isolation. The first formal population genetic model of the development of these barriers was published by Orr in 1995, and here we develop a more general model of this process by incorporating finite protein-protein interaction networks, which reduce the probability of deleterious interactions in vivo. Our model shows that the development of deleterious interactions is limited by the density of the protein-protein interaction network. We have confirmed our analytical predictions of the number of possible interactions given the number of allele substitutions by using simulations on the Saccharomyces cerevisiae protein-protein interaction network. These results allow us to define the rate at which deleterious interactions are expected to form, and hence the speciation rate, for any protein-protein interaction network.
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http://dx.doi.org/10.1016/j.mbs.2012.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797834PMC
July 2012

Modeling and estimating bacterial lag phase.

Math Biosci 2011 Dec 1;234(2):127-31. Epub 2011 Oct 1.

Trinity University, Mathematics Department, One Trinity Place, San Antonio, TX 78212, United States.

A branching process model of a bacterial population with initial lag phase is developed. Approximations are established in order to facilitate parameter estimation. The validity of approximations and estimation procedures is tested with simulated data.
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http://dx.doi.org/10.1016/j.mbs.2011.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225506PMC
December 2011

Copy number variation of the gene NCF1 is associated with rheumatoid arthritis.

Antioxid Redox Signal 2012 Jan 23;16(1):71-8. Epub 2011 Aug 23.

Medical Inflammation Research, Department of Experimental Medical Science, Lund University, Sweden.

Aims: The aim of this study was to investigate genetic variants in the gene neutrophil cytosolic factor 1 (NCF1) for association with rheumatoid arthritis (RA). In rodent models, a single-nucleotide polymorphism (SNP) in Ncf1 has been shown to be a major locus regulating severity of arthritis. Ncf1 encodes one of five subunits of the NADPH oxidase complex. In humans the genomic structure of NCF1 is complex, excluding it from genome-wide association screens and complicating genetic analysis. In addition to copy number variation of NCF1, there are also two nonfunctional pseudogenes, nearly identical in sequence to NCF1. We have characterized copy number variation and SNPs in NCF1, and investigated these variants for association with RA.

Results: We find that RA patients are less likely to have an increased copy number of NCF1, 7.6%, compared with 11.6% in controls; p=0.037. We also show that the T-allele of NCF1-339 (rs13447) is expressed in NCF1 and significantly reduces reactive oxygen species production.

Innovation: This is the first finding of genetic association of NCF1 with RA. The detailed characterization of genetic variants in NCF1 also helps elucidate the complexity of the NCF1 gene.

Conclusion: These data suggest that an increased copy number of NCF1 can be protective against developing RA and add support to previous findings of a role of NCF1 and the phagocyte NADPH oxidase complex in RA pathogenesis.
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http://dx.doi.org/10.1089/ars.2011.4013DOI Listing
January 2012

Positioning of a polymorphic quantitative trait nucleotide in the Ncf1 gene controlling oxidative burst response and arthritis severity in rats.

Antioxid Redox Signal 2011 Jun 31;14(12):2373-83. Epub 2011 Mar 31.

Medical Inflammation Research, C12 BMC, Lund University, Lund, Sweden.

The Ncf1 gene, encoding the P47(PHOX) protein that regulates production of reactive oxygen species (ROS) by the phagocyte NADPH oxidase (NOX2) complex, is associated with autoimmunity and arthritis severity in rats. We have now identified that the single-nucleotide polymorphism (SNP) resulting in an M153T amino acid substitution mediates arthritis resistance and thus explains the molecular polymorphism underlying the earlier identified Ncf1 gene effect. We identified the SNP in position 153 to regulate ROS production using COS(PHOX) cells transfected with mutated Ncf1. To determine the role of this SNP for control of arthritis, we used the Wistar strain, identified to carry only the postulated arthritis resistant SNP in position 153. When this Ncf1 allele was backcrossed to the arthritis susceptible DA strain, both granulocyte ROS production and arthritis resistance were restored. Position 153 is located in the hinge region between the PX and SH3 domains of P47(PHOX). Mutational analysis of this position revealed a need for an -OH group in the side chain but we found no evidence for phosphorylation. The polymorphism did not affect assembly of the P47(PHOX)/P67(PHOX) complex in the cytosol or membrane localization, but is likely to operate downstream of assembly, affecting activity of the membrane NOX2 complex.
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http://dx.doi.org/10.1089/ars.2010.3440DOI Listing
June 2011

Can telomere shortening explain sigmoidal growth curves?

Authors:
Peter Olofsson

J Biol Dyn 2010 Nov;4(6):527-38

Department of Mathematics, Trinity University, One Trinity Place, San Antonio, TX 78212, USA.

A general branching process model is proposed to describe the shortening of telomeres in eukaryotic chromosomes. The model is flexible and incorporates many special cases to be found in the literature. In particular, we show how telomere shortening can give rise to sigmoidal growth curves, an idea first expressed by Portugal et al. [A computational model for telomere-dependent cell-replicative aging, BioSystems 91 (2008), pp. 262-267]. We also demonstrate how other types of growth curves arise if telomere shortening is mitigated by other cellular processes. We compare our results with published data sets from the biological literature.
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http://dx.doi.org/10.1080/17513750903377442DOI Listing
November 2010

Modeling growth and telomere dynamics in Saccharomyces cerevisiae.

J Theor Biol 2010 Apr 16;263(3):353-9. Epub 2009 Dec 16.

Trinity University, Mathematics Department, One Trinity Place, San Antonio, TX 78212, USA.

A general branching process is proposed to model a population of cells of the yeast Saccharomyces cerevisiae following loss of telomerase. Previously published experimental data indicate that a population of telomerase-deficient cells regain exponential growth after a period of slowing due to critical telomere shortening. The explanation for this phenomenon is that some cells engage telomerase-independent pathways to maintain telomeres that allow them to become "survivors." Our model takes into account random variation in individual cell cycle times, telomere length, finite replicative lifespan of mother cells, and survivorship. We identify and estimate crucial parameters such as the probability of an individual cell becoming a survivor, and compare our model predictions to experimental data.
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http://dx.doi.org/10.1016/j.jtbi.2009.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832845PMC
April 2010

A stochastic model of cell cycle desynchronization.

Math Biosci 2010 Feb 15;223(2):97-104. Epub 2009 Nov 15.

Trinity University, Mathematics Department, One Trinity Place, San Antonio, TX 78212, USA.

A general branching process model is suggested to describe cell cycle desynchronization. Cell cycle phase times are modeled as random variables and a formula for the expected fraction of cells in S phase as a function of time is established. The model is compared to data from the literature and is also compared to previously suggested deterministic and stochastic models.
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http://dx.doi.org/10.1016/j.mbs.2009.11.003DOI Listing
February 2010

Advanced intercross line mapping suggests that ncf1 (ean6) regulates severity in an animal model of guillain-barre syndrome.

J Immunol 2009 Apr;182(7):4432-8

Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.

We here present the first genetic fine mapping of experimental autoimmune neuritis (EAN), the animal model of Guillain-Barré syndrome, in a rat advanced intercross line. We identified and refined a total of five quantitative trait loci on rat chromosomes 4, 10, and 12 (RNO4, RNO10, RNO12), showing linkage to splenic IFN-gamma secretion and disease severity. All quantitative trait loci were shared with other models of complex inflammatory diseases. The quantitative trait locus showing strongest linkage to clinical disease was Ean6 and spans 4.3 Mb on RNO12, harboring the neutrophil cytosolic factor 1 (Ncf1) among other genes. Polymorphisms in Ncf1, a member of the NADPH oxidase complex, have been associated with disease regulation in experimental arthritis and encephalomyelitis. We therefore tested the Ncf1 pathway by treating rats with a NADPH oxidase complex activator and ameliorated EAN compared the oil-treated control group. By proving the therapeutic effect of stimulating the NADPH oxidase complex, our data strongly suggest the first identification of a gene regulating peripheral nervous system inflammation. Taken together with previous reports, our findings suggest a general role of Ncf1 and oxidative burst in pathogenesis of experimental autoimmune animal models.
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http://dx.doi.org/10.4049/jimmunol.0803847DOI Listing
April 2009

A stochastic model of a cell population with quiescence.

Authors:
Peter Olofsson

J Biol Dyn 2008 Oct;2(4):386-91

Department of Mathematics, Trinity University, San Antonio, TX, USA.

A cell population in which cells are allowed to enter a quiescent (nonproliferating) phase is analyzed using a stochastic approach. A general branching process is used to model the population which, under very mild conditions, exhibits balanced exponential growth. A formula is given for the asymptotic fraction of quiescent cells, and a numerical example illustrates how convergence toward the asymptotic fraction exhibits a typical oscillatory pattern. The model is compared with deterministic models based on semigroup analysis of systems of differential equations.
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http://dx.doi.org/10.1080/17513750801956305DOI Listing
October 2008

Positional cloning of the Igl genes controlling rheumatoid factor production and allergic bronchitis in rats.

Proc Natl Acad Sci U S A 2008 Sep 8;105(37):14005-10. Epub 2008 Sep 8.

Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden.

Rheumatoid factors (RF), autoantibodies that bind the Fc region of IgG, are one of the major diagnostic marker in rheumatoid arthritis (RA) but occur with lower frequency also in other infectious and inflammatory conditions. Through positional cloning of the previously described quantitative trait locus (QTL) Rf1 in congenic and advanced intercrossed rats, we identified the Ig lambda light chain locus as a locus that regulates the production of RF in rats. The congenic rats produce RF-Ig lambda and have significant higher levels of RF-IgG and RF-IgM in serum, while the DA rat has an impaired RF production and does not produces RF-Ig lambda. Thus, we could investigate the role of RF in pristane-induced arthritis (PIA) as well as ovalbumin-induced airway inflammation. We show that there was no difference in the development and severity of PIA between congenic and parental DA rats, suggesting that RF using lambda light chains have no impact on PIA. However, the RF producing congenic rats developed a more severe airway inflammation as indicated in the significantly increased number of eosinophils in bronchoalveolar lavage fluid as well as total IgE in serum. In addition, RF congenic rats had a significantly enhanced immune response toward OVA due to increased OVA-Igk but not OVA-Igl antibodies, suggesting a possible involvement of RF in the regulation of the humoral immune response.
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http://dx.doi.org/10.1073/pnas.0803956105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2544569PMC
September 2008

Pristane-induced arthritis in the rat.

Methods Mol Med 2007 ;136:255-68

Medical Inflammation Research, Lund, Sweden.

A chronic relapsing arthritis develops after a single subcutaneous injection of small amounts of pristane; the pristane induced arthritis (PIA) model in the rat. PIA is characterized by a sudden onset of disease 2 wk after induction. The main pathological features of PIA include edema accompanied by an acute phase response, infiltration into the joint of mononuclear and polymorphonuclear cells, pannus formation, and erosion of cartilage and bone. PIA is a disease that is largely T-cell dependent that can be adoptively transferred by activated CD4+ T-cells. PIA in rats is followed clinically by macroscopic scoring and is characterized by an early acute phase of severe inflammation after onset that eventually gradually disappears to be followed by less severe relapsing phases of new inflamed joints and increasing cartilage erosion and joint deformity. PIA can be diagnosed by biochemical analyzes in plasma that reflects systemic inflammation (alpha1-acid glycoprotein (AGP) and IL-6) and cartilage erosion (COMP).
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http://dx.doi.org/10.1007/978-1-59745-402-5_19DOI Listing
December 2007