Mouse Models of Human Autoimmune Diseases: Essential Tools That Require the Proper Controls

What can we learn about human autoimmune disorders that have a genetic component -- such as systemic lupus erythematosus -- from mouse models

Autoreactive marginal zone B cells enter the follicles and interact with CD4+ T cells in lupus-prone mice

<p>Abstract</p> <p>Backgound</p> <p>Marginal zone B cells have been implicated in the production of autoantibodies in murine models of lupus. It has been suggested that they contribute to lupus immunopathogenesis through their enhanced effector functions and their repertoire that is biased toward autoreactive specificities. In the B6.NZM2410.<it>Sle.Sle2.Sle3 </it>(B6.TC) model of lupus, the majority of marginal zone B cells are located outside the marginal zone and inside the follicles. Genetic alterations of this strain have shown a correlation between autoimmune pathogenesis and the presence of intrafollicular marginal zone B cells. This study was designed first to strengthen our original observations and to determine how the marginal zone B cells from the lupus-prone mice respond to stimulations and interact with T cells.</p> <p>Results</p> <p>The intrafollicular location of B6.TC MZB cells starts before disease manifestations and puts MZB cells in direct contact with CD4⁺T cells. Two different autoreactive B cell receptor (BCR) transgenic models showed that the expression of the <it>Sle </it>susceptibility loci enhances the presence of MZB cells inside the follicles. <it>In vitro</it>, B6.TC MZB cells were better effectors than B6 MZB cells with enhanced proliferation and antibody (Ab) production, including anti-DNA Ab, in response to stimulation with TLR ligands, immune complexes or anti-CD40. Furthermore, B6.TC MZB and CD4⁺T cells showed a reciprocally enhanced activation, which indicated that their contacts inside B6.TC follicles have functional consequences that suggest an amplification loop between these two cell types.</p> <p>Conclusions</p> <p>These results showed that the NZM2410 susceptibility loci induce MZB cells to locate into the follicles, and that this breach of follicular exclusion occurs early in the development of the autoimmune pathogenesis. The enhanced responses to stimulation and increased effector functions of MZB cells from lupus-prone mice as compare to non-autoimmune MZB cells provide a mechanism by which the failure of MZB cell follicular exclusion contributes to the autoimmune process.</p

Spontaneous gelation of wheat gluten proteins in a food grade solvent

Structuring wheat gluten proteins into gels with tunable mechanical properties would provide more versatility for the production of plant protein-rich food products. Gluten, a strongly elastic protein material insoluble in water, is hardly processable. We use a novel fractionation procedure allowing the isolation from gluten of a water/ethanol soluble protein blend, enriched in glutenin polymers at an unprecedented high ratio (50%). We investigate here the viscoelasticity of suspensions of the protein blend in a water/ethanol (50/50 v/v) solvent, and show that, over a wide range of concentrations, they undergo a spontaneous gelation driven by hydrogen bonding. We successfully rationalize our data using percolation models and relate the viscoelasticity of the gels to their fractal dimension measured by scattering techniques. The gluten gels display self-healing properties and their elastic plateaus cover several decades, from 0.01 to 10000 Pa. In particular very soft gels as compared to standard hydrated gluten can be produced.Comment: Food Hydrocolloids, in pres

Microbial influences on severity and sex bias of systemic autoimmunity

Commensal microbes have the capacity to affect development and severity of autoimmune diseases. Germ-free (GF) animals have proven to be a fine tool to obtain definitive answers to the queries about the microbial role in these diseases. Moreover, GF and gnotobiotic animals can be used to dissect the complex symptoms and determine which are regulated (enhanced or attenuated) by microbes. These include disease manifestations that are sex biased. Here, we review comparative analyses conducted between GF and Specific-Pathogen Free (SPF) mouse models of autoimmunity. We present data from the B6;NZM-Sle1NZM2410/AegSle2NZM2410/AegSle3NZM2410/Aeg−/LmoJ (B6.NZM) mouse model of systemic lupus erythematosus (SLE) characterized by multiple measurable features. We compared the severity and sex bias of SPF, GF, and ex-GF mice and found variability in the severity and sex bias of some manifestations. Colonization of GF mice with the microbiotas taken from B6.NZM mice housed in two independent institutions variably affected severity and sexual dimorphism of different parameters. Thus, microbes regulate both the severity and sexual dimorphism of select SLE traits. The sensitivity of particular trait to microbial influence can be used to further dissect the mechanisms driving the disease. Our results demonstrate the complexity of the problem and open avenues for further investigations

Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis.

The K/BxN mouse is a spontaneous model of arthritis driven by T cell receptor transgenic CD4+ T cells from the KRN strain that are activated by glucose-6-phosphate isomerase (GPI) peptides presented by the H-2g7 allele from the NOD strain. It is a model of autoimmune seropositive arthritis because the production of anti-GPI IgG is necessary and sufficient for joint pathology. The production of high levels of anti-GPI IgG requires on the expansion of CD4+ follicular helper T (Tfh) cells. The metabolic requirements of this expansion have never been characterized. Based on the therapeutic effects of the combination of metformin and 2-deoxyglucose (2DG) in lupus models that normalized the expansion of effector CD4+ T cells. We showed that the CD4+ T cells and to a lesser extent, the B cells from K/BxN mice are more metabolically active than the KRN controls. Accordingly, preventive inhibition of glycolysis with 2DG significantly reduced joint inflammation and the activation of both adaptive and innate immune cells, as well as the production of pathogenic autoantibodies. However, contrary to the lupus-prone mice, the addition of metformin had little beneficial effect, suggesting that glycolysis is the major driver of immune activation in this model. We propose that K/BxN mice are another model in which autoreactive Tfh cells are highly glycolytic and that their function can be limited by inhibiting glucose metabolism

The granulocyte colony stimulating factor pathway regulates autoantibody production in a murine induced model of systemic lupus erythematosus

INTRODUCTION: An NZB-derived genetic locus (Sle2c2) that suppresses autoantibody production in a mouse model of induced systemic lupus erythematosus contains a polymorphism in the gene encoding the G-CSF receptor. This study was designed to test the hypothesis that the Sle2c2 suppression is associated with an impaired G-CSF receptor function that can be overcome by exogenous G-CSF. METHODS: Leukocytes from B6.Sle2c2 and B6 congenic mice, which carry a different allele of the G-CSF receptor, were compared for their responses to G-CSF. Autoantibody production was induced with the chronic graft-versus-host-disease (cGVHD) model by adoptive transfer of B6.bm12 splenocytes. Different treatment regimens varying the amount and frequency of G-CSF (Neulasta(®)) or carrier control were tested on cGVHD outcomes. Autoantibody production, immune cell activation, and reactive oxygen species (ROS) production were compared between the two strains with the various treatments. In addition, the effect of G-CSF treatment was examined on the production autoantibodies in the B6.Sle1.Sle2.Sle3 (B6.TC) spontaneous model of lupus. RESULTS: B6.Sle2c2 and B6 leukocytes responded differently to G-CSF. G-CSF binding by B6.Sle2c2 leukocytes was reduced as compared to B6, which was associated with a reduced expansion in response to in vivo G-CSF treatment. G-CSF in vivo treatment also failed to mobilize bone-marrow B6.Sle2c2 neutrophils as it did for B6 neutrophils. In contrast, the expression of G-CSF responsive genes indicated a higher G-CSF receptor signaling in B6.Sle2c2 cells. G-CSF treatment restored the ability of B6.Sle2c2 mice to produce autoantibodies in a dose-dependent manner upon cGVHD induction, which correlated with restored CD4(+ )T cells activation, as well as dendritic cell and granulocyte expansion. Steady-state ROS production was higher in B6.Sle2c2 than in B6 mice. cGVHD induction resulted in a larger increase in ROS production in B6 than in B6.Sle2c2 mice, and this difference was eliminated with G-CSF treatment. Finally, a low dose G-CSF treatment accelerated the production of anti-dsDNA IgG in young B6.TC mice. CONCLUSION: The different in vivo and in vitro responses of B6.Sle2c2 leukocytes are consistent with the mutation in the G-CSFR having functional consequences. The elimination of Sle2c2 suppression of autoantibody production by exogenous G-CSF indicates that Sle2c2 corresponds to a loss of function of G-CSF receptor. This result was corroborated by the increased anti-dsDNA IgG production in G-CSF-treated B6.TC mice, which also carry the Sle2c2 locus. Overall, these results suggest that the G-CSF pathway regulates the production of autoantibodies in murine models of lupus

ETUDE MORPHO-GRANULOMETRIQUE ET STRUCTURALE DES SEMOULES DE BLE DUR PROPRIETES D'HYDRATATION ET D'AGGLOMERATION

International audienceLes propriétés d'hydratation et d'agglomération de la semoule de blé dur dépendent des caractéristiques de la matière à granuler, du liquide de granulation et de l'outil de granulation. Dans le procédé de fabrication des graines de couscous, la formation, la croissance et la densification des grains de semoule sont effectuées par addition d'eau, mélange et roulage. Une étude de caractérisation de la semoule de blé dur a été entreprise à différentes échelles d'observation : macroscopique, mésoscopique et moléculaire afin de comprendre les mécanismes d'hydratation et d'agglomération. La semoule de blé dur constitue une population de particules hétérogènes en granulométrie et en composition biochimique. Si cette hétérogénéité se traduit par des modifications des propriétés d'hydratation, d'autres études sont nécessaires pour mieux appréhender son influence sur les propriétés d'agglomération

196 Non response after cardiac resynchronisation therapy is associated with a more severe cardiomyopathy

BackgroundCardiac resynchronisation therapy (CRT) has been shown to improve clinical status in heart failure patients. Some patients treated by CRT fail to respond to the treatment. Predisposing factors for non-response should be investigated to optimize patient selection.ObjectiveThe purpose of the study was to evaluate before device implantation and 3, 6 and 12 month after, echocardiographic and biological parameters with respect to CRT response.MethodsThirty two patients with heart failure (72% of men; age 66±10 years; 59% non-ischaemic cardiomyopathy; NYHA III–IV; left ventricular ejection fraction (LVEF) 22.7±6.7%; QRS width 146±26ms) were implanted with CRT device and followed during twelve month. Responders (R) were defined as patients with improvement of one or more NYHA functional class, with a significant improvement in quality of life and without episode nor hospitalization for heart failure during follow-up.Results34% of the patients constitute the non-responder group (NR). No difference between R and NR was observed in LVEF, QRS width, NYHA, cardiovascular risk factors nor drug medication. Non-ischaemic dilated cardiomyopathy was significantly more present in R (71% vs 27%; p=0.03). Before CRT, NR had more important left ventricular end-diatolic diameter, left ventricular end-systolic diameter and more elevated left pressions. Atrioventricular dyssynchrony was significantly more observed in R (66% vs 9%; p=0.006) so as intraventricular dyssynchrony (95% vs 27%; p=0.001).BNP is significantly more elevated in NR (602±385 vs 320±361; p=0.03) before CRT.After 3 and 6 month, a significant decrease in left ventricular end-diatolic and end-systolic diameters, LVEF and normalisation of left and right pressions occur in R. Likewise, BNP levels were lower in R.ConclusionsNR patients have before implantation a more severe cardiomyopathy. At follow-up, left ventricular remodelling could only be observed in R patients. These data suggest that cardiac CRT should not be proposed too late so that left ventricular remodelling could be expected