(3) have SARS- CoV-2 carriage in their nasopharyngeal swab, as confirmed by real- time reverse transcription PCR analysis.
Data were collected from 17 patients with SLE between 29 March and 6 April ( tables 1 and 2 ). The initial symptoms of the first patient appeared on 5 March and those of the last patient on 26 March. The main comorbidities were obesity and chronic kidney disease, which were present in 10 (59%) and 8 (47%) patients, respectively. All patients except one had clinically quies- cent SLE, defined as a clinical Systemic LupusErythematosus Disease Activity Index (SLEDAI) score equal to 0. 6 The duration
18. Mitsikostas D.D., Sfikakis P.P., and Goadsby P.J. “A Meta-Analysis for Headache in Systemic LupusErythematosus: The Evidence and the Myth.” Brain: A Journal of
Neurology 127, no. Pt 5 (May 2004): 1200–1209.
19. Bertsias G.K., Ioannidis J.P.A., Aringer M., Bollen E., Bombardieri S., Bruce I.N., Cervera R., et al. “EULAR Recommendations for the Management of Systemic LupusErythematosus with Neuropsychiatric Manifestations: Report of a Task Force of the EULAR Standing Committee for Clinical Affairs.” Annals of the Rheumatic Diseases 69, no. 12 (December 2010): 2074–82.
RASopathies (Noonan syndrome (NS) and Noonan-related syndromes) are neurodevelopmental syndromes resulting from germline mutations in genes that participate in the rat sarcoma/mitogen-activated protein kinases (RAS/ MAPK) pathway (PTPN11, SOS1, RAF, KRAS or NRAS and SHOC2). Some monogenic conditions are associated with the development of systemic lupuserythematosus (SLE), and a few reports described the association of SLE, with NS.
Materials and Methods
Sera from patients and blood donors were collected (Laboratoire d’Immunologie, Hôpital Saint-Antoine, Paris, France), with approval of the Committee of the Biobanque du Centre hépatobiliaire, managed by the Biological Ressource Centre CRB Paris-Sud (http://www.chb.aphp.fr/ rechercheClinique/biobanque/index.phtml). All subjects signed a written informed consent. Forty five sera from patients with autoimmune hepatitis as defined by the International Autoimmune Hepatitis Group  positive for antinuclear antibodies detected by indirect immunofluorescence on HEP2- cell monolayers and unfixed cryostat sections of rat liver (cut- off positivity ≥1:80), were tested by immunoblotting, using nuclear proteins resolved by 10% SDS-PAGE as antigen. Nuclear fractions from rat liver homogenate were obtained by centrifugation on sucrose density gradient as described elsewhere . Sera were also collected from patients with pathologies known for high prevalence of anti-hnRNP A2/B1 autoantibodies, i.e., systemic lupuserythematosus SLE (n=30) and rheumatoid arthritis RA (n=57), diagnosed according to the criteria of the American College of Rheumatology. Sera from normal human blood donors (HD) (n=20) were included as negative controls. Sera that stained a double band at 36kDa on immunoblots were considered to be positive for anti-hnRNP A2/B1 autoantibodies, as described elsewhere . hnRNP A2/B1 was thus recognized by 24 SLE sera (80%), 12 RA sera (21%), and by 22 AIH sera (48%). All the sera from blood donors were negative. Eight sera of each population were
Systemic lupuserythematosus (SLE) is a heterogeneous autoimmune disease characterised by overproduction of type I interferons, hyperactivity of B cells with production of antibodies, presence of autoreactive T cells and activa- tion of NETosis [ 1 ]. In SLE patients with persistent disease activity despite antimalarials and low dose steroids, quality of life is adversely affected by the unpredictable risk of flares and by drug toxicity and accumulation of organ damage. Belimumab is the only treatment approved since 2011 in refractory mild to moderate SLE, especially with high activity and positivity of biomarkers [ 2 ]. Currently, many controlled phase II/III trials evaluating targeted therapies have failed to meet their primary end point [ 3 ]. Drugs primarily used in onco-haematology may exert targeted or pleiotropic immunological effects and thus be effective in SLE. Unfortunately, phase III clinical trials evaluating rituximab failed to meet their primary end point [ 4 , 5 ]. More recently, bortezomib, a proteasome inhibitor approved in multiple myeloma, demonstrated unacceptable toxicity in 12 SLE patients [ 6 ]. Trials evalu- ating new drugs such as Janus kinase or Bruton’s tyrosine kinase inhibitors are ongoing.
3.4.4 Systemic LupusErythematosus associated to PID
Systemic LupusErythematosus (SLE) is a chronic autoimmune disease with potential lethal outcome. The variable severity and heterogeneous features of the disease spreads from indolent to life threatening (table 1). Although any gender and ages can be affected, the clinical manifestations occur mainly in female patients between puberty and menopause. Currently, there is no cure to SLE but therapies allow remission of the disease. It is well described that the disease is caused by the production of auto-antibody, mainly anti-nuclear antibodies that targets several different components of the cell’s nucleus (e.g. anti-DNA auto-antibody, anti-Smith au-antibody, anti-phospholipid auto-antibody). Therefore, about all the tissues of the human body are potentially affected by autoimmunity and inflammation. This self- targeting leads to the aberrant production of type 1 IFNs. Initial manifestations identified in a patient are commonly fever, arthritis and malar rashes, with unexplained remissions and relapses. Late complication can reach to severe cardiac, renal and neurological symptoms.
RESULTS DcR3 Tg islets secrete DcR3
To continuously supply biologically active DcR3 to islets, DcR3 Tg mice were generated in both the C3H x C57BL/6 and C57BL/6 backgrounds, using the human β-actin promoter, as described in our previous publication (19). Two Tg mouse lines were generated. Line 754, originally in the C3H x C57BL/6 background, was backcrossed to the C57BL/6 background for 8 generations. Line 17139 was generated in the C57BL/6 background. Both lines have a similar phenotype. They are fertile and present no gross anomalies before 5 months of age (19). After 5 months, these mice develop a systemic lupuserythematosus-like syndrome (19). For this study, only 2- to 5 month-old mice were used. We demonstrated that DcR3 Tg islet cells from both lines were able to secrete DcR3 into culture supernatants at 8-15 ng/ml/200 islets within 24 h, as expected (Fig. 1). The remaining results in this study were from line 754 islets, but line 17139 islets behaved similarly.
characteristics, hydroxychloroquine use and immunosuppressive treatments
We read with interest the article of Bozzalla Cassione et al about COVID-19 incidence in their systemic lupuserythematosus (SLE) cohort. 1 Their study adds useful epidemiological informa- tion about COVID-19 risk in SLE. 1 They suggest that hydroxy- choloroquine was not protective, but could not draw definite conclusion and open the question to immunosuppressive drugs’ influence. We would like to share analysis of our SLE cohort (n=225) that can help to answer these questions and determine COVID-19 infection risk factors.
For SLE patients, clinical and biological manifestations as well as treatments received and disease activity evaluated using the Systemic LupusErythematosus Disease Activity Index (SLEDAI) [ 26 ] at the time of sampling were recorded. The SLE patients were divided into two groups for further analyses: a group with quiescent or “low disease activity” (n = 88) and a group with active or “high disease activity” (n = 77), according to the physician in charge and respectively with a SLEDAI score 4 and >4. All patients with renal involvement had an active lupus nephritis (LN) documented by kidney biopsy (classes I, II, III, IV or V of the ISN/RPS classification) [ 27 ]. Samples were collected just before kidney biopsy. Active proliferation was defined by the presence of at least one glomerulus showing cellular or fibro-cellular crescent or endocapillary proliferation on kidney biopsy (classes III and IV).
9. Groot, N.; de Graeff, N.; Avcin, T.; Bader-Meunier, B.; Brogan, P.; Dolezalova, P.; Feldman, B.; Kone-Paut, I.; Lahdenne, P.; Marks, S.D.; et al. European evidence-based recommendations for diagnosis and treatment of childhood-onset systemic lupuserythematosus: The SHARE initiative. Ann. Rheum. Dis. 2017, 76, 1788–1796. [ CrossRef ]
10. Tett, S.E.; Cutler, D.J.; Day, R.O.; Brown, K.F. A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers. Br. J. Clin. Pharmacol. 1988, 26, 303–313. [ CrossRef ]
l’Informatique et des Libertés”, CNIL N°2030950vO). The study has also been registered to clinicaltrial.gov (N° NCT03063281). The study was done in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. For SLE patients, clinical and biological manifestations and disease activity, evaluated using Systemic LupusErythematosus Disease Activity Index (SLEDAI) at the time of sampling, were recorded. The SLE patients were divided into two groups for further analyses: a group with “low disease activity” (SLEDAI score ≤ 4, n = 88) and a group with “high disease activity” (SLEDAI score > 4, n = 77), according to the physician in charge. All patients with renal involvement had an active LN, defined by the presence of a significant proteinuria (≥ 0.5 g/day) and/or the presence of hematuria, aseptic leukocyturia or urinary casts, which was documented by renal biopsy and classified according to the ISN/RPS classification. Samples were collected just before kidney biopsy. Active proliferative LN was defined as a class III or IV LN with activity, +/- class V, as opposed to non-proliferative LN (classes I, II or isolated V).
human lupus including the development of lupus nephritis. As early as 20 weeks of age, Lyn deficient mice show glomerular deposits of anti-dsDNA IgG antibodies and circulating immune complexes. They develop impaired renal function and ultimately die of renal failure [48,49]. Interestingly, it has been shown that Lyn expression is decreased in peripheral B cells of some SLE patients  and recently a single nucleotide polymorphism in the promoter region of the Lyn gene was linked with SLE patients of northern European heritage . Of particular note, the described polymorphism was associated with autoantibody production. Thus, while yet undefined, the role of this Lyn polymorphism in the development of SLE is of considerable interest. Nonetheless, in animal models, the role of Lyn in controlling B cell responsiveness (and thus antibody production) is well appreciated; less is known about its contributory role in other cellular compartments that may also contribute in the pathogenesis of SLE.
(Figure 4A) as evidenced by semiquantitative morpho- metrical evaluation, eg, by assessing the activity and chronicity scores of lupus nephritis (Figure 4B). The activity score, a composite score of mostly glomerular abnormali- ties, and glomerular IgG deposits were significantly re- duced by 100 as well as by 300 mg/kg 4SC-101 (Figure 4B). The chronicity score, a composite score of glomerular and interstitial scarring, was significant for the 300 mg/kg 4SC-101 group only. CYC was potent in reducing both parameters but not significantly different from 300 mg/kg 4SC-101. In 22-week-old vehicle-treated MRL lpr/lpr
populations. In addition, while miRNA-mediated deregulation in SLE has been studied mostly in whole blood or isolated T cells, there are fewer studies that systematically report miRNA changes in lupus B cells. Among the many immune cell types that have been involved in SLE, B-lymphocytes clearly play a central role in disease pathogenesis and progression. SLE is indeed characterized by abnormal B cell activation and differentiation to memory or plasma effector cells, associated with polyclonal B-cell hyper reactivity and formation of autoantibodies that target a variety of self-antigens. These autoantibodies are particularly fundamental in the pathogenesis of LN. Interestingly, miR-30a and miR-1246 control B cell hyperactivity through Lyn and EBF1 silencing, respectively, and their respective up- and down-regulation in B cells might contribute to SLE pathogenesis [8,9]. Among B cells, abnormal frequencies and functions of certain subsets, including disturbances of naive and memory B cells, have been reported in SLE patients . Although distinct miRNA profiles have been reported in PBMC or purified CD19 + B cells of patients with SLE [5,6], none of the previous studies investigated miRNA
Chemokines are small cytokine-like secreted proteins that govern migration of leukocytes to specific niches in lymphoid organs and inflammatory sites. They mediate their functions by binding and activating chemokine recep- tors, which belong to the seven-transmembrane G protein- coupled receptor family . The chemokine system influences the inflammatory development and progression of B-cell mediated autoimmune diseases including SLE [3,11,12]. In this study, we focused on the CXC α-chemo- kine Stromal cell Derived Factor-1 (SDF-1)/CXCL12, which together with its main receptor CXCR4, constitutes the chemokine/receptor axis attracting the greatest level of interest in autoimmunity . Many leukocytes, including B cells, express CXCR4 and CXCL12 is constitutively pro- duced by stromal, epithelial, and endothelial cells notably in lymphoid organs [14,15]. Given its ability to regulate B- cell ontogeny, differentiation and homing, recent attention has been directed to the CXCL12/CXCR4 axis in SLE pathophysiology. CXCL12 is upregulated in the tubules and glomeruli of nephritic kidneys from multiple lupus- prone mouse models (e.g. NZB/W, BXSB, MRL.lpr) and SLE patients as well [13,16,17]. Similarly, CXCR4 hyper- expression or -activity has been reported in various leukocyte subsets of lupus mouse models . Thus, in concert with CXCL12, CXCR4 could be pivotal for leukocyte trafficking into damaged kidneys from mice with lupus nephritis. In SLE patients, the situation is somewhat puzzling, as contradictory results have been reported for CXCR4 expression on peripheral blood lymphocytes. In- deed, some studies have documented down- or up- regulation of CXCR4 expression on SLE B cells, while others failed to detect any change in membrane CXCR4 expression [8,13,16,18]. To our knowledge, there is cur- rently no consensus on CXCR4 expression and its correl- ation with SLE.
81 d'œstrogènes. D'autre part, une étude prospective SELENA (Safety of Estrogens in LupusErythematosus National Assessment) [in100] ; a porté sur un collectif de 183 femmes lupiques dont avaient été exclues les patientes avec un syndrome d'anticorps antiphospholipides ou porteuses d'anticorps antiphospholipides. Les auteurs n'ont pas observé de différences dans le nombre de poussées chez les patientes sous CO (pilule triphasique 35 mg éthinylestradiol/0,5-1 mg noréthindrone) pendant un an par rapport aux femmes sous placebo. Une deuxième étude mexicaine  a randomisé 162 femmes entre une pilule estroprogestative de deuxième génération, un stérilet (DIU) et un microprogestatif. Là encore, aucune différence entre les trois groupes sur les critères cliniques ou les SLEDAI. Cinq grossesses ont été observées, deux sous CO, deux avec le microprogestatif et une avec le DIU.