Anti‐chromatin and anti‐C1q antibodies in systemic lupus erythematosus compared to other systemic autoimmune diseases

Anti-Ro/SSA antibodies are among the most frequently detected autoantibodies against extractable nuclear antigens and have been associated with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). Although the presence of these autoantibodies is one of the criteria for the diagnosis and classification of SS, they are also sometimes seen in other systemic autoimmune diseases. In the last few decades, the knowledge of the prevalence of anti-Ro/SSA antibodies in various autoimmune diseases and symptoms has been expanded, and the clinical importance of these antibodies is increasing. Nonetheless, the pathological role of the antibodies is still poorly understood. In this paper, we summarize the milestones of the anti-Ro/SSA autoantibody system and provide new insights into the association between the autoantibodies and the pathogenesis of autoimmune diseases.

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Therapeutic Plasma Exchange as Management of Complicated Systemic Lupus Erythematosus and Other Autoimmune Diseases

Autoimmune Diseases ◽

10.1155/2019/5350960 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

David Aguirre-Valencia ◽

Juan Naranjo-Escobar ◽

Iván Posso-Osorio ◽

María Carmenza Macía-Mejía ◽

Ivana Nieto-Aristizábal ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Autoimmune Diseases ◽

Plasma Exchange ◽

Lupus Erythematosus ◽

Clinical Characteristics ◽

Diffuse Alveolar Hemorrhage ◽

Therapeutic Plasma Exchange ◽

Systemic Lupus ◽

Systemic Autoimmune Diseases ◽

Main Complication

Introduction. Autoimmune diseases include a diverse and complex group of pathologies with a broad clinical spectrum due to the production of autoantibodies, which generates multisystemic compromise. Therapeutic plasma exchange (TPE) is a good additive treatment for immunosuppression due to its action over the autoantibodies. Objectives. To describe the main clinical characteristics and outcomes of patients with systemic lupus erythematosus and other systemic autoimmune diseases managed with TPE. Methodology. This descriptive retrospective study enrolled patients with systemic autoimmune diseases who received TPE. Results. In total, 66 patients with a median age of 33.5 years (24-53 years) were included; the majority were females [n=51 (77.27%)]. Forty (60.61%) patients were diagnosed with systemic lupus erythematosus. In these cases, the main indication for TPE was diffuse alveolar hemorrhage (DAH; n=20, 30.3%) and neurolupus (n=9, 13.6%). No TPE-related deaths occurred, and the main complication was hemorrhage, without significant differences among the four types of TPE solutions used. The overall outcome was improvement in 41 (62.12%) patients. Conclusion. TPE is safe and effective in patients with severe manifestations of autoimmune diseases.

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AB1275 HYDROCEPHALUS IN AUTOIMMUNE DISEASES: A SERIES OF CHALLENGING CASES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6465 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1929.3-1929

Author(s):

N. El Ghobashy

Keyword(s):

Systemic Lupus Erythematosus ◽

Case Report ◽

Autoimmune Diseases ◽

Laboratory Investigation ◽

Lupus Erythematosus ◽

Normal Liver ◽

Communicating Hydrocephalus ◽

Systemic Lupus ◽

Systemic Autoimmune Diseases ◽

Mri Brain

Background:Hydrocephalus can be a rare neurological manifestation but lethal complication of various SAIDs, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), sarcoidosis, and primary vasculitis. The commonly used medical management programs based on the etiology of hydrocephalus are anti-inflammatory or anti infectious therapies, while surgical management such as ventriculoperitoneal shunts is effective most of the time (Wei Jetal.,2019).Objectives:To analyze the diagnosis and managment of hydrocephalus associated with autoimmune diseasesMethods:A retrospective case series study was conducted at Rheumatology department.Cairo university.Files were retrieved from the hospital archives by screening records from Jan 2014to Jan2019. Medical records were screened for data regarding the clinical manifestation and outcomeof hydrocephalus associated with autoimmune disease.Results:Case (1)Male patient 28 yrs old diagnosed a systemic lupus erythematosus The patient was controlled on low dose steroid and azathioprine. In 2019: the patient presented with headache and blurring of vision. Fundus examination showed grade 2 to 3 papilledema. MRI brain showed: Non obustrcutive hydrocephalus. MRA & MRV: normal laboratory investigation was done and showed consumed c3 & c4. ESR: 35 mm/hour. Hb: 12.3g/dl. WBC:6.38 cells/cm3. normal liver and kidney function. Neurosurgery consultation was done and recommended urgent ventriculo –peritoneal shunt. follow up fundus showed improvement of papilledema. The patient was discharged on steroids 30 mg and mycophenolate mofetyl: 2gram with improvement of his condition.Case (2)Female patient 22 yrs old diagnosed as systemic lupus erythematosus onset 2010. In 2018 she started to develop quadriparesis started in left side followed by Right side associated with attacks of Tonic colonic convulsions. MRI brain showed: Marked communicating hydrocephalus with markedly reduced cerebral hemisphere white matter. MRV & MRA: normal. Her laboratory investigation showed ESR: 49 mm/h. HB: 10.3 mg/dl, WBC: 5.9 cells/ mm3. Normal platelet count. normal liver & kidney function. Normal c3 & c4. neurosurgery consultation was done. Urgent ventriculoperitoneal shunt was done with improvement of her condition. The patient was discharged on solupred 20 mg along with azathioprine.Conclusion:VPS along with medical treatment with steroids and immunosuppresion represent an effective treatment protocol.References:[1]Wei J, Yin H, Wang L, Cui L, Wang R. Systemic autoimmune diseases complicated with hydrocephalus: pathogenesis and management. Neurosurg Rev. 2019 Jun;42(2):255-261.[2]Wei J, Yin H, Wang L, Cui L, Wang R. Systemic autoimmune diseases complicated with hydrocephalus: pathogenesis and management. Neurosurg Rev. 2019 Jun;42(2):255-261.[3]Tang SC, Lee CF, Lee CW, Jeng JS. Systemic lupus erythematosus flare up manifestations as cerebral and subarachnoid hemorrhage. Lupus 2011; 20: 1211-13[4]Kitching GB, Thompson JR, Hasso AN, Hirst AE. Angiographic demonstration of lupus cerebral phlebitis with communicating hydrocephalus. Neuroradiology 1977; 14: 59-63.[5]Mortifee PRS, Bebb RA, Stein H. Communicating hydrocephalus in systemic lupus erythematosus with antiphospholipid antibody syndrome. J Rheumatol 1992; 19: 1299-302.[6]Honda K, Matsumoto M, Kaneko T, KAmei I, Tatsumi H, Murai N, et al. Linear deposition of immunoglobulins and complement components on the dura in normal pressure hydrocephalus complicating systemic lupus erythematosus. J Clin Neurosci 2004; 11: 561-63.[7]Koga H, Ooch IN, Osato S, Ishida I, Hirakata H, Okuda S, Fujishima M (1994) Case report: Wegener’s granulomatosis accompanied by communicating hydrocephalus. Am J Med Sci 307:278–281[8]Bertken RD, Cooper VR (1997) Wegener granulomatosis causingsellarmass,hydrocephalus,andglobalpituitaryfailure.WestJMed 1997; 167:44–47[9]Scarrow AM, Segal R, Medsger TAJ, Wasko MC (1998) Communicating hydrocephalus secondary to diffuse meningeal spread of Wegener’s granulomatosis: case report and literature review. Neurosurgery 1998;43:1470–1473Disclosure of Interests:None declared

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OP0005 ELEVATED STAT1 EXPRESSION BUT NOT PHOSPHORYLATION IN LUPUS B CELLS CORRELATES WITH DISEASE ACTIVITY AND INCREASED PLASMABLAST SUSCEPTIBILITY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2955 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 4-5

Author(s):

A. Aue ◽

F. Szelinski ◽

S. Weißenberg ◽

A. Wiedemann ◽

T. Rose ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cells ◽

Autoimmune Diseases ◽

Disease Activity ◽

B Cell ◽

Lupus Erythematosus ◽

Type I ◽

Type I Ifn ◽

Systemic Lupus ◽

B Cell Subsets

Background:Systemic lupus erythematosus (SLE) is characterized by two pathogenic key signatures, type I interferon (IFN) (1.) and B-cell abnormalities (2.). How these signatures are interrelated is not known. Type I-II IFN trigger activation of Janus kinase (JAK) – signal transducer and activator of transcription (STAT).Objectives:JAK-STAT inhibition is an attractive therapeutic possibility for SLE (3.). We assess STAT1 and STAT3 expression and phosphorylation at baseline and after IFN type I and II stimulation in B-cell subpopulations of SLE patients compared to other autoimmune diseases and healthy controls (HD) and related it to disease activity.Methods:Expression of STAT1, pSTAT1, STAT3 and pSTAT3 in B and T-cells of 21 HD, 10 rheumatoid arthritis (RA), 7 primary Sjögren’s (pSS) and 22 SLE patients was analyzed by flow cytometry. STAT1 and STAT3 expression and phosphorylation in PBMCs of SLE patients and HD after IFNα and IFNγ incubation were further investigated.Results:SLE patients showed substantially higher STAT1 but not pSTAT1 in B and T-cell subsets. Increased STAT1 expression in B cell subsets correlated significantly with SLEDAI and Siglec-1 on monocytes, a type I IFN marker (4.). STAT1 activation in plasmablasts was IFNα dependent while monocytes exhibited dependence on IFNγ.Figure 1.Significantly increased expression of STAT1 by SLE B cells(A) Representative histograms of baseline expression of STAT1, pSTAT1, STAT3 and pSTAT3 in CD19+ B cells of SLE patients (orange), HD (black) and isotype controls (grey). (B) Baseline expression of STAT1 and pSTAT1 or (C) STAT3 and pSTAT3 in CD20+CD27-, CD20+CD27+ and CD20lowCD27high B-lineage cells from SLE (orange) patients compared to those from HD (black). Mann Whitney test; ****p≤0.0001.Figure 2.Correlation of STAT1 expression by SLE B cells correlates with type I IFN signature (Siglec-1, CD169) and clinical activity (SLEDAI).Correlation of STAT1 expression in CD20+CD27- näive (p<0.0001, r=0.8766), CD20+CD27+ memory (p<0.0001, r=0.8556) and CD20lowCD27high (p<0.0001, r=0.9396) B cells from SLE patients with (A) Siglec-1 (CD169) expression on CD14+ cells as parameter of type I IFN signature and (B) lupus disease activity (SLEDAI score). Spearman rank coefficient (r) was calculated to identify correlations between these parameters. *p≤0.05, **p≤0.01. (C) STAT1 expression in B cell subsets of a previously undiagnosed, active SLE patient who was subsequently treated with two dosages of prednisolone and reanalyzed.Conclusion:Enhanced expression of STAT1 by B-cells candidates as key node of two immunopathogenic signatures (type I IFN and B-cells) related to important immunopathogenic pathways and lupus activity. We show that STAT1 is activated upon IFNα exposure in SLE plasmablasts. Thus, Jak inhibitors, targeting JAK-STAT pathways, hold promise to block STAT1 expression and control plasmablast induction in SLE.References:[1]Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.[2]Lino AC, Dorner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016;269(1):130-44.[3]Dorner T, Lipsky PE. Beyond pan-B-cell-directed therapy - new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol. 2016;12(11):645-57.[4]Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1136-45.Disclosure of Interests:Arman Aue: None declared, Franziska Szelinski: None declared, Sarah Weißenberg: None declared, Annika Wiedemann: None declared, Thomas Rose: None declared, Andreia Lino: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen

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OP0039 ALPN-303, AN ENHANCED, POTENT DUAL BAFF/APRIL ANTAGONIST ENGINEERED BY DIRECTED EVOLUTION FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND OTHER B CELL-RELATED AUTOIMMUNE DISEASES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.727 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 21.2-21

Author(s):

S. R. Dillon ◽

L. S. Evans ◽

K. E. Lewis ◽

J. Yang ◽

M. W. Rixon ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Autoimmune Diseases ◽

B Cell ◽

Directed Evolution ◽

Human Lymphocyte ◽

Lupus Erythematosus ◽

Plasma Cells ◽

Systemic Lupus ◽

Cynomolgus Monkeys

Background:BAFF and APRIL are TNF superfamily members that form homo- and heteromultimers that bind TACI and BCMA on B cells; BAFF also binds BAFF-R. BAFF and APRIL support B cell development, differentiation, and survival, particularly for plasmablasts and plasma cells, and play critical roles in the pathogenesis of B cell-related autoimmune diseases. In nonclinical models, inhibition of either BAFF or APRIL alone mediates relatively modest effects, whereas their co-neutralization dramatically reduces B cell function, including antibody production. Fc fusions of wild-type (WT) TACI (e.g. atacicept and telitacicept) target both BAFF and APRIL and have demonstrated promising clinical potential in e.g. systemic lupus erythematosus (SLE) and IgA nephropathy but have not yet clearly exhibited long-term and/or complete disease remissions.Objectives:To generate a dual BAFF/APRIL antagonist with inhibitory activity superior to WT TACI and BCMA and with the potential to improve clinical outcomes in B cell-mediated diseases.Methods:Our directed evolution platform was used to identify a potent variant TNFR domain (vTD) of TACI that exhibits significantly enhanced affinity for BAFF and APRIL as compared to WT TACI; this TACI vTD domain was fused to a human IgG Fc to generate the therapeutic candidate ALPN-303. ALPN-303 was evaluated for functional activity in: 1) human lymphocyte assays, 2) the NOD.Aec1Aec2 spontaneous model of Sjogren’s syndrome (SjS), 3) the bm12-induced mouse model of lupus, 4) the (NZB/NZW)F1 spontaneous model of lupus, and 5) preclinical rodent and cynomolgus monkey pharmacokinetic/pharmacodynamic studies.Results:ALPN-303 inhibited BAFF- and APRIL-mediated signaling in vitro in human lymphocyte assays, with significantly lower IC50 values than WT TACI-Fc and belimumab comparators. In all mouse models evaluated, administration of ALPN-303 rapidly and significantly reduced key lymphocyte subsets including plasma cells, germinal center B cells, and follicular T helper cells. ALPN-303 significantly reduced autoantibodies and sialadenitis in the spontaneous SjS model, inhibited glomerular IgG deposition in the bm12-induced model of lupus, and potently suppressed anti-dsDNA autoAbs, blood urea nitrogen levels, proteinuria, sialadenitis, kidney lesions, and renal immune complex deposition in the NZB/W lupus model. As compared to WT TACI-Fc, ALPN-303 exhibited higher serum exposure and significantly and persistently decreased titers of serum IgM, IgG, and IgA antibodies in mice and cynomolgus monkeys (Figure 1).Figure 1.ALPN-303 induces more potent suppression, as compared to WT TACI-Fc, of serum immunoglobulins following a single 9 mg/kg IV infusion (on Day 0; arrows) in female cynomolgus monkeys.Conclusion:ALPN-303 is a potent BAFF/APRIL antagonist derived from our directed evolution platform that consistently demonstrates encouraging immunomodulatory activity and efficacy in vitro and in vivo, superior in preclinical studies to anti-BAFF antibody and WT TACI-Fc. This novel Fc fusion molecule demonstrates favorable preliminary developability characteristics, including higher serum exposures and more potent immunosuppressive activities, which may enable lower clinical doses and/or longer dosing intervals than WT TACI-Fc therapeutics. ALPN-303 may thus be an attractive development candidate for the treatment of multiple autoimmune and inflammatory diseases, particularly B cell-related diseases such as SLE, SjS, and other connective tissue diseases. Preclinical development is underway to enable the initiation of clinical trials later this year.Disclosure of Interests:Stacey R. Dillon Shareholder of: Alpine Immune Sciences, Bristol Myers Squibb, Employee of: Alpine Immune Sciences, Bristol Myers Squibb, Lawrence S. Evans Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Katherine E. Lewis Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Jing Yang Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Mark W. Rixon Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Joe Kuijper Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Dan Demonte Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Janhavi Bhandari Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Steve Levin Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Kayla Kleist Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Sherri Mudri Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Susan Bort Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Daniel Ardourel Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Michelle A. Seaberg Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Rachel Wang Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Chelsea Gudgeon Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Russell Sanderson Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Martin F. Wolfson Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Jan Hillson Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Stanford L. Peng Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences

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Serum levels and gene polymorphisms of angiopoietin 2 in systemic lupus erythematosus patients

Scientific Reports ◽

10.1038/s41598-020-79544-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jia-Min Wang ◽

Wang-Dong Xu ◽

Zhi-Chao Yuan ◽

Qian Wu ◽

Jie Zhou ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Gene Polymorphisms ◽

Serum Levels ◽

Healthy Individuals ◽

Systemic Lupus ◽

Potential Biomarker ◽

Angiopoietin 2 ◽

Inflammatory Autoimmune Diseases

AbstractThis study aimed to discuss association between serum Angiopoietin2 (Ang2) levels, Ang2 gene polymorphisms and systemic lupus erythematosus (SLE) susceptibility. It was carried out by 235 SLE, 342 other inflammatory autoimmune diseases patients and 380 healthy individuals. Serum Ang2 levels was examinated by ELISA, and Ang2 rs12674822, rs1823375, rs1868554, rs2442598, rs3739390 and rs734701 polymorphisms were genotyped using KASP. Increased Ang2 concentrations in SLE patients were observed compared with healthy controls and patients with other inflammatory autoimmune diseases. For allelic contrast, except for rs1823375 (P = 0.058) and rs2442598 (P = 0.523), frequencies of alleles for other polymorphisms were significantly different between SLE patients and controls. Genotypes for rs12674822 (TT), rs1868554 (TT, TA and TT+TA), rs734701 (TT) were negatively correlated with SLE susceptibility (OR = 0.564 for rs12674822; OR = 0.572, OR = 0.625, OR = 0.607 for rs1868554; OR = 0.580 for rs734701). Patients carrying rs1868554 T allele and rs3739390 G allele were more likely to develop hematuria (P = 0.039; P = 0.003). The G allele frequencies of rs12674822 and rs2442598 were higher in SLE patients with proteinuria (P = 0.043; P = 0.043). GC genotype frequency of rs3739390 was higher in patients with ds-DNA (+) (P = 0.024). In summary, SLE had increased serum Ang2, which may be a potential biomarker, and the polymorphisms correlated with SLE.

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AB0998 Effects of Rituximab Therapy in 9 Children with Refractory Autoimmune Diseases (Systemic Lupus Erythematosus and ANCA Positive Vasculitis) – Single Centre Expirience

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-eular.6056 ◽

2015 ◽

Vol 74 (Suppl 2) ◽

pp. 1232.1-1232

Author(s):

M. Frković ◽

I. Malčić ◽

D. Batinić ◽

D. Milošević ◽

M. Jelušić

Keyword(s):

Systemic Lupus Erythematosus ◽

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Single Centre

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Extracellular Vesicles Tune the Immune System in Renal Disease: A Focus on Systemic Lupus Erythematosus, Antiphospholipid Syndrome, Thrombotic Microangiopathy and ANCA-Vasculitis

International Journal of Molecular Sciences ◽

10.3390/ijms22084194 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4194

Author(s):

Martina Mazzariol ◽

Giovanni Camussi ◽

Maria Felice Brizzi

Keyword(s):

Systemic Lupus Erythematosus ◽

Immune System ◽

Autoimmune Diseases ◽

Extracellular Vesicles ◽

Antiphospholipid Syndrome ◽

Lupus Erythematosus ◽

Thrombotic Microangiopathy ◽

Coagulation Cascade ◽

Renal Diseases ◽

Systemic Lupus

Extracellular vesicles (EV) are microparticles released in biological fluids by different cell types, both in physiological and pathological conditions. Owing to their ability to carry and transfer biomolecules, EV are mediators of cell-to-cell communication and are involved in the pathogenesis of several diseases. The ability of EV to modulate the immune system, the coagulation cascade, the angiogenetic process, and to drive endothelial dysfunction plays a crucial role in the pathophysiology of both autoimmune and renal diseases. Recent studies have demonstrated the involvement of EV in the control of renal homeostasis by acting as intercellular signaling molecules, mediators of inflammation and tissue regeneration. Moreover, circulating EV and urinary EV secreted by renal cells have been investigated as potential early biomarkers of renal injury. In the present review, we discuss the recent findings on the involvement of EV in autoimmunity and in renal intercellular communication. We focused on EV-mediated interaction between the immune system and the kidney in autoimmune diseases displaying common renal damage, such as antiphospholipid syndrome, systemic lupus erythematosus, thrombotic microangiopathy, and vasculitis. Although further studies are needed to extend our knowledge on EV in renal pathology, a deeper investigation of the impact of EV in kidney autoimmune diseases may also provide insight into renal biological processes. Furthermore, EV may represent promising biomarkers of renal diseases with potential future applications as diagnostic and therapeutic tools.

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Immune deposit and vasculopathy in metabolic-active lung tissues of patients with pulmonary tuberculosis

10.1101/2021.02.09.430558 ◽

2021 ◽

Author(s):

Hui Ma ◽

Lin Wang ◽

Zilu Wen ◽

Xinchun Chen ◽

Haiying Liu ◽

...

Keyword(s):

Gene Expression ◽

Systemic Lupus Erythematosus ◽

Inflammatory Response ◽

Pulmonary Tuberculosis ◽

Autoimmune Diseases ◽

Metabolic Activity ◽

Lupus Erythematosus ◽

Immune Complexes ◽

Systemic Lupus ◽

Dsdna Antibodies

ABSTRACTMetabolic activity in pulmonary lesion is associated with disease severity and relapse risk in tuberculosis. However, the nature of the metabolic activity associated with tuberculosis in humans remains unclear. Previous works indicate that tuberculosis bears resemblance transcriptionally with systemic lupus erythematosus in peripheral blood, except that the plasma cell component was absent in tuberculosis. Here we reported that the missing transcriptional component was present within the metabolic active tissues in the lung of patients with sputum culture-negative tuberculosis, within which increased levels of circulating immune complexes and anti-dsDNA antibodies were found relative to nearby non-metabolic active tissues. Histological examination revealed specific vascular deposition of immune complexes, neutrophil extracellular traps, and vascular necrosis in the metabolic-active tissue. Thus, tuberculosis-initiated metabolic activity was associated with hyperactive antibody responses and vascular pathology, and shared features with systemic lupus erythematosus and other autoimmune diseases. We discussed these observations in the context of earlier literatures demonstrating that similar effects could be induced in humans and animal models by complete freund’s adjuvant, the most potent antibody response inducer ever reported. Our small case series, if verified in a larger size study, might help inform host-directed therapies to alleviate disease progression and augment treatment efficacy.IMPORTANCEIn patients with pulmonary tuberculosis, lung tissues were destroyed by a hyperactive inflammatory response towards M. tuberculosis. The mechanisms underlying the inflammatory response are still poorly understood. Using 18F-FDG avidity as a surrogate marker of inflammation, we have identified that hyper-inflamed tissues possessed features associated with systemic lupus erythematosus: gene expression signatures of plasma cell and immunoglobulins and increased levels of anti-dsDNA antibodies, immune deposits, and vasculopathy. This observation might suggest an explanation to why patients with tuberculosis share more gene expression signatures with autoimmune diseases than infectious diseases and why they are more likely to develop autoimmune diseases. Defining the inflammatory responses at the lesion could help inform host-directed therapies to intervene disease progression or even accelerate cure.

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