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1.  Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus 
Annals of the rheumatic diseases  2011;70(12):2071-2074.
Autologous hematopoietic stem cell transplantation (AHSCT) has been proposed as a treatment modality which may arrest the autoimmune disease process and lead to sustained treatment-free remissions. Since the first consensus statement in 1997, approximately 200 autologous bone marrow or hematopoietic stem cell transplantations have been reported world-wide for SLE. The current state of AHSCT in SLE was reviewed at a recent meeting of the Autoimmune Working Party of the European Group for Blood and Marrow Transplantation. There was general agreement among experts in this field, that in patients with severe SLE refractory to conventional immunosuppressive therapies, AHSCT can achieve sustained clinical remissions (ranging from 50–70% disease free survival at 5 years) associated with qualitative immunological changes not seen with other forms of therapy. However, this clinical benefit is associated with an increase in short-term mortality in most but not all studies. Improving patient selection, long-term follow up of patients after AHSCT, optimization of induction and maintenance therapy along with detailed analysis of the immune system are identified as key areas for future research. Optimally, AHSCT should be compared to conventional therapy in randomized controlled trials. Development of stronger transplant registries, defining a core set of clinical data and standardizing biologic sample collections would make future collaborations and comparison of various studies more feasible.
PMCID: PMC3923531  PMID: 21873334
2.  Cognitive Dysfunction and Dementia in Primary Sjögren's Syndrome 
ISRN Neurology  2013;2013:501327.
Background. Primary Sjögren's syndrome (PSS) is a frequent systemic autoimmune disease. In this study, we aimed to explore the cognitive impairment and the correlations with brain MRI. Methods. Twenty-five patients (mean age 55 ± 11.8 years, 21 females) with PSS were prospectively selected and tested with a French translation of the Brief Repeatable Battery for Neuropsychological Examination. The results were compared with the scores for 25 matched patients with multiple sclerosis (MS) and 25 controls. Brain lesions were assessed by brain MRI using the Wahlund classification. Results. Fifteen of the 25 PSS patients (60%) presented with cognitive disorders versus 19/25 MS patients (76%). Five patients had dementia in the PSS group. Speed of information processing, attention, immediate and long-term memory, and executive functions were frequently impaired. The mean duration of cognitive complaints was 5.6 ± 6.1 years, and the mean duration of PSS was 15.8 ± 14.0 years. A trend towards a correlation was found between the severity of cognitive impairment and the degree of white matter lesions (WML) (P = 0.03, rho = 0.43). Conclusion. Cognitive impairment—mild or dementia—exists in patients with PSS. Further MRI studies are needed to better understand the precise neural basis of cognitive impairment in PSS patients.
PMCID: PMC3793286  PMID: 24224097
3.  Carabin deficiency in B cells increases BCR-TLR9 costimulation-induced autoimmunity 
EMBO Molecular Medicine  2012;4(12):1261-1275.
The mechanisms behind flares of human autoimmune diseases in general, and of systemic lupus in particular, are poorly understood. The present scenario proposes that predisposing gene defects favour clinical flares under the influence of external stimuli. Here, we show that Carabin is low in B cells of (NZB × NZW) F1 mice (murine SLE model) long before the disease onset, and is low in B cells of lupus patients during the inactive phases of the disease. Using knock-out and B-cell-conditional knock-out murine models, we identify Carabin as a new negative regulator of B-cell function, whose deficiency in B cells speeds up early B-cell responses and makes the mice more susceptible to anti-dsDNA production and renal lupus flare after stimulation with a Toll-like Receptor 9 agonist, CpG-DNA. Finally, in vitro analysis of NFκB activation and Erk phosphorylation in TLR9- and B-cell receptor (BCR)-stimulated Carabin-deficient B cells strongly suggests how the internal defect synergizes with the external stimulus and proposes Carabin as a natural inhibitor of the potentially dangerous crosstalk between BCR and TLR9 pathways in self-reactive B cells.
PMCID: PMC3531602  PMID: 23109291
autoimmunity; B cells; Carabin; mouse models; systemic lupus erythematosus
4.  Macroautophagy is deregulated in murine and human lupus T lymphocytes 
Autophagy  2012;8(7):1113-1123.
Macroautophagy was recently shown to regulate both lymphocyte biology and innate immunity. In this study we sought to determine whether a deregulation of autophagy was linked to the development of autoimmunity. Genome-wide association studies have pointed out nucleotide polymorphisms that can be associated with systemic lupus erythematosus, but the potential role of autophagy in the initiation and/or development of this syndrome is still unknown. Here, we provide first clues of macroautophagy deregulation in lupus. By the use of LC3 conversion assays and electron microscopy experiments, we observed that T cells from two distinct lupus-prone mouse models, i.e., MRLlpr/lpr and (NZB/NZW)F1, exhibit high loads of autophagic compartments compared with nonpathologic control CBA/J and BALB/c mice. Unlike normal mice, autophagy increases with age in murine lupus. In vivo lipopolysaccharide stimulation in CBA/J control mice efficiently activates T lymphocytes but fails to upregulate formation of autophagic compartments in these cells. This argues against a deregulation of autophagy in lupus T cells solely resulting from an acute inflammation injury. Autophagic vacuoles quantified by electron microscopy are also found to be significantly more frequent in T cells from lupus patients compared with healthy controls and patients with non-lupus autoimmune diseases. This elevated number of autophagic structures is not distributed homogeneously and appears to be more pronounced in certain T cells. These results suggest that autophagy could regulate the survival of autoreactive T cell during lupus, and could thus lead to design new therapeutic options for lupus.
PMCID: PMC3429547  PMID: 22522825
systemic lupus erythematosus; lupus-prone mice; macroautophagy; T lymphocytes
5.  B Cell Signature during Inactive Systemic Lupus Is Heterogeneous: Toward a Biological Dissection of Lupus 
PLoS ONE  2011;6(8):e23900.
Systemic lupus erythematosous (SLE) is an autoimmune disease with an important clinical and biological heterogeneity. B lymphocytes appear central to the development of SLE which is characterized by the production of a large variety of autoantibodies and hypergammaglobulinemia. In mice, immature B cells from spontaneous lupus prone animals are able to produce autoantibodies when transferred into immunodeficient mice, strongly suggesting the existence of intrinsic B cell defects during lupus. In order to approach these defects in humans, we compared the peripheral B cell transcriptomas of quiescent lupus patients to normal B cell transcriptomas. When the statistical analysis is performed on the entire group of patients, the differences between patients and controls appear quite weak with only 14 mRNA genes having a false discovery rate ranging between 11 and 17%, with 6 underexpressed genes (PMEPA1, TLR10, TRAF3IP2, LDOC1L, CD1C and EGR1). However, unforced hierarchical clustering of the microarrays reveals a subgroup of lupus patients distinct from both the controls and the other lupus patients. This subgroup has no detectable clinical or immunological phenotypic peculiarity compared to the other patients, but is characterized by 1/an IL-4 signature and 2/the abnormal expression of a large set of genes with an extremely low false discovery rate, mainly pointing to the biological function of the endoplasmic reticulum, and more precisely to genes implicated in the Unfolded Protein Response, suggesting that B cells entered an incomplete BLIMP1 dependent plasmacytic differentiation which was undetectable by immunophenotyping. Thus, this microarray analysis of B cells during quiescent lupus suggests that, despite a similar lupus phenotype, different biological roads can lead to human lupus.
PMCID: PMC3160348  PMID: 21886837
6.  MyD88 Negatively Controls Hypergammaglobulinemia with Autoantibody Production during Bacterial Infection▿  
Infection and Immunity  2008;76(4):1657-1667.
A large body of evidence has convincingly shown that Toll-like receptors are necessary sensors for infections with pathogens, but their activation was also suggested to generate autoimmunity. During experimental infections, the lack of these sensors or of their signaling molecules should lead to a deficient immune response. We found out that MyD88, the major adaptor of the Toll/interleukin-1 (Toll/IL-1) receptor signaling pathway, can actually act as a negative regulator of B-cell function in some settings. MyD88-deficient mice infected by Borrelia burgdorferi developed extreme hypergammaglobulinemia compared to wild-type animals, with high levels of immunoglobulin M (IgM) autoantibodies. In vivo, cell transfer experiments and cell blocking assays showed that this phenotype was not linked to the absence of MyD88 in B cells but rather to CD4 T-cell and likely dendritic cell dysfunctions leading to a Th1-to-Th2 cytokine switch. In addition, our results suggest a relative defect in the Ig class switch recombination process, since MyD88 knockout mice developed mostly IgM antibodies. Collectively, these data emphasize the complex role of the Toll/IL-1 receptor pathway in tuning the immune response against infection and avoiding autoimmunity.
PMCID: PMC2292895  PMID: 18227170
7.  Influenza Virus-Induced Type I Interferon Leads to Polyclonal B-Cell Activation but Does Not Break Down B-Cell Tolerance▿  
Journal of Virology  2007;81(22):12525-12534.
The link between infection and autoimmunity is not yet well understood. This study was designed to evaluate if an acute viral infection known to induce type I interferon production, like influenza, can by itself be responsible for the breakdown of immune tolerance and for autoimmunity. We first tested the effects of influenza virus on B cells in vitro. We then infected different transgenic mice expressing human rheumatoid factors (RF) in the absence or in the constitutive presence of the autoantigen (human immunoglobulin G [IgG]) and young lupus-prone mice [(NZB × NZW)F1] with influenza virus and looked for B-cell activation. In vitro, the virus induces B-cell activation through type I interferon production by non-B cells but does not directly stimulate purified B cells. In vivo, both RF and non-RF B cells were activated in an autoantigen-independent manner. This activation was abortive since IgM and IgM-RF production levels were not increased in infected mice compared to uninfected controls, whether or not anti-influenza virus human IgG was detected and even after viral rechallenge. As in RF transgenic mice, acute viral infection of (NZB × NZW)F1 mice induced only an abortive activation of B cells and no increase in autoantibody production compared to uninfected animals. Taken together, these experiments show that virus-induced acute type I interferon production is not able by itself to break down B-cell tolerance in both normal and autoimmune genetic backgrounds.
PMCID: PMC2168975  PMID: 17855528
8.  Autoantigen, innate immunity, and T cells cooperate to break B cell tolerance during bacterial infection 
Journal of Clinical Investigation  2005;115(8):2257-2267.
Autoantibody production during infections is considered to result from nonspecific activation of low-affinity autoreactive B cells. Whether this can lead to autoimmune disease remains uncertain. We show that chronic infection by Borrelia burgdorferi of Tg animals expressing human rheumatoid factor (RF) B cells (of low or intermediate affinities) in the absence or in the constitutive presence of the autoantigen (represented here by chimeric IgG with human constant region) breaks their state of immunological ignorance, leading to the production of RFs. Surprisingly, this production was more pronounced in intermediate-affinity RF Tg mice coexpressing the autoantigen. This overproduction was mediated by immune complexes and involved synergistic signaling between the B cell receptor and Toll-like receptors and T cell help. These findings indicate that chronic infection can activate autoreactive B cells with significant affinity and creates conditions that can drive them to differentiate into memory cells. Such cells may have some physiological yet undetermined role, but in autoimmune-prone individuals, this scenario may initiate autoimmunity.
PMCID: PMC1177998  PMID: 16041408

Results 1-8 (8)