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Cell Biomarkers in Lupus: Value for Diagnostic and Drug Therapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 21351

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Special Issue Editors

Dr. Jaime Sancho

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Guest Editor

Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, (IPBLN-CSIC), Granada, Spain
Interests: autoimmunity; proteomics; cell signaling; CD38 function

Dr. Esther C. Zumaquero

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Guest Editor

Department of Microbiology, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
Interests: autoimmunity; lupus; plasma cell differentiation; flow cytometry

Dr. Mercedes Zubiaur

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Guest Editor

Chief, Department of Cellular Biology and Immunology, Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, (IPBLN-CSIC), Granada, Spain
Interests: autoimmunity; extracellular vesicles; cell signaling; CD38 function, microRNAs, psoriasis

Special Issue Information

Dear colleagues,

CD38 is a transmembrane glycoprotein with receptor-mediated signaling capabilities and is an enzyme that catalyzes nicotinamide adenine dinucleotide (NAD⁺) or nicotinamide adenine dinucleotide phosphate (NADP⁺) to produce molecules involved in Ca²⁺ messenger signaling. Moreover, in closed environments, CD38 in combination with other ectoenzymes is involved in the production of adenosine, an immunosuppressive nucleoside.Systemic lupus erythematosus (SLE) is an autoimmune disorder that is characterized by dysregulated immunity against the self, with abnormal production of autoantibodies that cause end-organ damage through immune complex deposition and chronic inflammation.In active SLE patients, the expression of CD38 in several immune cell types including T cells, plasma cells, regulatory B cells, and monocytes is significantly higher than in normal subjects. In contrast, SLE patients that develop anti-CD38 antibodies have a relatively well-controlled disease, suggesting that anti-CD38 therapy may be useful to deplete harmful effector T cells and autoantibody-producing plasma cells. However, in SLE the function of many of these cells seems to be intrinsically impaired, which poses the question of whether abnormal CD38 expression is rather a consequence of this abnormal function. This Special Issue of IJMS on the Cell biomarkers in Lupus: value for diagnostic and drug therapy welcomes contributions from basic and clinical scientists in the form of original research paper or reviews. We encourage papers starting from experimental observations and ending with a perspective related to the focus. The aim of the issue is to contribute to identify new cell biomarkers for early diagnosis of lupus or with prognostic and predictive value for therapy. In the long term, these studies may contribute to better select SLE patients that benefit for a given therapeutic approach. Studies with animal models of the disease are also encouraged.

Dr. Jaime Sancho
Dr. Esther C. Zumaquero
Dr. Mercedes Zubiaur
Guest Editors

Manuscript Submission Information

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Keywords

CD38
systemic lupus erythematosus
anti-CD38 mAb therapy
experimental lupus models
extrafollicular B cell activation pathway
regulatory B and T cells

Published Papers (5 papers)

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Research

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22 pages, 4234 KiB

Open AccessArticle

Impaired Differentiation of Highly Proliferative ICOS⁺-Tregs Is Involved in the Transition from Low to High Disease Activity in Systemic Lupus Erythematosus (SLE) Patients

by Florian Kälble, Lisa Wu, Hanns-Martin Lorenz, Martin Zeier, Matthias Schaier and Andrea Steinborn

Int. J. Mol. Sci. 2021, 22(17), 9501; https://doi.org/10.3390/ijms22179501 - 31 Aug 2021

Cited by 5 | Viewed by 1951

Abstract

Dysregulations in the differentiation of CD4⁺-regulatory-T-cells (Tregs) and CD4⁺-responder-T-cells (Tresps) are involved in the development of active systemic lupus erythematosus (SLE). Three differentiation pathways of highly proliferative inducible costimulatory molecule (ICOS)⁺- and less proliferative ICOS⁻-CD45RA⁺CD31⁺-recent-thymic-emigrant (RTE)-Tregs/Tresps via CD45RA⁻CD31⁺-memory-Tregs/Tresps (CD31⁺-memory-Tregs/Tresps), their direct proliferation via CD45RA⁺CD31⁻-mature naïve (MN)-Tregs/Tresps, and the production and differentiation of resting MN-Tregs/Tresp into CD45RA⁻CD31⁻-memory-Tregs/Tresps (CD31⁻-memory-Tregs/Tresps) were examined in 115 healthy controls, 96 SLE remission patients, and 20 active disease patients using six color flow cytometric analysis. In healthy controls an appropriate sequence of these pathways ensured regular age-dependent differentiation. In SLE patients, an age-independently exaggerated differentiation was observed for all Treg/Tresp subsets, where the increased conversion of resting MN-Tregs/Tresps particularly guaranteed the significantly increased ratios of ICOS⁺-Tregs/ICOS⁺-Tresps and ICOS⁻-Tregs/ICOS⁻-Tresps during remission. Changes in the differentiation of resting ICOS⁺-MN-Tresps and ICOS⁻-MN-Tregs from conversion to proliferation caused a significant shift in the ratio of ICOS⁺-Tregs/ICOS⁺-Tresps in favor of ICOS⁺-Tresps and a further increase in the ratio of ICOS⁻-Tregs/ICOS⁻-Tresps with active disease. The differentiation of ICOS⁺-RTE-Tregs/Tresps seems to be crucial for keeping patients in remission, where their limited production of proliferating resting MN-Tregs may be responsible for the occurrence of active disease flares. Full article

(This article belongs to the Special Issue Cell Biomarkers in Lupus: Value for Diagnostic and Drug Therapy)

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19 pages, 3178 KiB

Open AccessArticle

Dysregulated CD38 Expression on Peripheral Blood Immune Cell Subsets in SLE

by Marie Burns, Lennard Ostendorf, Robert Biesen, Andreas Grützkau, Falk Hiepe, Henrik E. Mei and Tobias Alexander

Int. J. Mol. Sci. 2021, 22(5), 2424; https://doi.org/10.3390/ijms22052424 - 28 Feb 2021

Cited by 16 | Viewed by 4565

Abstract

Given its uniformly high expression on plasma cells, CD38 has been considered as a therapeutic target in patients with systemic lupus erythematosus (SLE). Herein, we investigate the distribution of CD38 expression by peripheral blood leukocyte lineages to evaluate the potential therapeutic effect of CD38-targeting antibodies on these immune cell subsets and to delineate the use of CD38 as a biomarker in SLE. We analyzed the expression of CD38 on peripheral blood leukocyte subsets by flow and mass cytometry in two different cohorts, comprising a total of 56 SLE patients. The CD38 expression levels were subsequently correlated across immune cell lineages and subsets, and with clinical and serologic disease parameters of SLE. Compared to healthy controls (HC), CD38 expression levels in SLE were significantly increased on circulating plasmacytoid dendritic cells, CD14⁺⁺CD16⁺ monocytes, CD56⁺ CD16^dim natural killer cells, marginal zone-like IgD⁺CD27⁺ B cells, and on CD4⁺ and CD8⁺ memory T cells. Correlation analyses revealed coordinated CD38 expression between individual innate and memory T cell subsets in SLE but not HC. However, CD38 expression levels were heterogeneous across patients, and no correlation was found between CD38 expression on immune cell subsets and the disease activity index SLEDAI-2K or established serologic and immunological markers of disease activity. In conclusion, we identified widespread changes in CD38 expression on SLE immune cells that highly correlated over different leukocyte subsets within individual patients, but was heterogenous within the population of SLE patients, regardless of disease severity or clinical manifestations. As anti-CD38 treatment is being investigated in SLE, our results may have important implications for the personalized targeting of pathogenic leukocytes by anti-CD38 monoclonal antibodies. Full article

(This article belongs to the Special Issue Cell Biomarkers in Lupus: Value for Diagnostic and Drug Therapy)

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13 pages, 2500 KiB

Open AccessArticle

Salivary Immunoglobulin Gamma-3 Chain C Is a Promising Noninvasive Biomarker for Systemic Lupus Erythematosus

by Ju-Yang Jung, Jin-Young Nam, Keun-Sil Ryu, In-Ok Son, Joo-Ho Shin, Wook-Young Baek, Hyoun-Ah Kim and Chang-Hee Suh

Int. J. Mol. Sci. 2021, 22(3), 1374; https://doi.org/10.3390/ijms22031374 - 29 Jan 2021

Cited by 4 | Viewed by 2207

Abstract

We aimed to characterize the salivary protein components and identify biomarkers in patients with systemic lupus erythematosus (SLE). A proteomic analysis using two-dimensional gel electrophoresis and mass spectrometry was performed to determine the alterations of salivary proteins between patients with SLE and healthy controls, and the concentrations of the candidate proteins were measured through Western blot analysis and the enzyme-linked immunosorbent assay. The 10 differentially expressed protein spots were immunoglobulin gamma-3 chain C region (IGHG3), immunoglobulin alpha-1 chain C region, protein S100A8, lactoferrin, leukemia-associated protein 7, and 8-oxoguanine DNA glycosylase. The patients with SLE exhibited enhanced salivary IGHG3 (3.9 ± 2.15 pg/mL) and lactoferrin (4.7 ± 1.8 pg/mL) levels compared to patients with rheumatoid arthritis (1.8 ± 1.01 pg/mL and 3.2 ± 1.6 pg/mL, respectively; p < 0.001 for both) or healthy controls (2.2 ± 1.64 pg/mL and 2.2 ± 1.7 pg/mL, respectively; p < 0.001 for both). The salivary IGHG3 levels correlated with the erythrocyte sedimentation rate (r = 0.26, p = 0.01), anti-double-stranded DNA (dsDNA) antibody levels (r = 0.25, p = 0.01), and nephritis (r = 0.28, p = 0.01). The proteomic analysis revealed that the salivary IGHG3 levels were associated with SLE and lupus disease activity, suggesting that salivary IGHG3 may be a promising noninvasive biomarker for SLE. Full article

(This article belongs to the Special Issue Cell Biomarkers in Lupus: Value for Diagnostic and Drug Therapy)

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Review

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44 pages, 999 KiB

Open AccessReview

Biomarkers Associated with Organ-Specific Involvement in Juvenile Systemic Lupus Erythematosus

by James Greenan-Barrett, Georgia Doolan, Devina Shah, Simrun Virdee, George A. Robinson, Varvara Choida, Nataliya Gak, Nina de Gruijter, Elizabeth Rosser, Muthana Al-Obaidi, Maria Leandro, Michael S. Zandi, Ruth J. Pepper, Alan Salama, Elizabeth C. Jury and Coziana Ciurtin

Int. J. Mol. Sci. 2021, 22(14), 7619; https://doi.org/10.3390/ijms22147619 - 16 Jul 2021

Cited by 13 | Viewed by 5697

Abstract

Juvenile systemic lupus erythematosus (JSLE) is characterised by onset before 18 years of age and more severe disease phenotype, increased morbidity and mortality compared to adult-onset SLE. Management strategies in JSLE rely heavily on evidence derived from adult-onset SLE studies; therefore, identifying biomarkers associated with the disease pathogenesis and reflecting particularities of JSLE clinical phenotype holds promise for better patient management and improved outcomes. This narrative review summarises the evidence related to various traditional and novel biomarkers that have shown a promising role in identifying and predicting specific organ involvement in JSLE and appraises the evidence regarding their clinical utility, focusing in particular on renal biomarkers, while also emphasising the research into cardiovascular, haematological, neurological, skin and joint disease-related JSLE biomarkers, as well as genetic biomarkers with potential clinical applications. Full article

(This article belongs to the Special Issue Cell Biomarkers in Lupus: Value for Diagnostic and Drug Therapy)

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18 pages, 825 KiB

Open AccessReview

by María Morell, Francisco Pérez-Cózar and Concepción Marañón

Int. J. Mol. Sci. 2021, 22(13), 7143; https://doi.org/10.3390/ijms22137143 - 01 Jul 2021

Cited by 17 | Viewed by 6192

Abstract

The kidney is one of the main organs affected by the autoimmune disease systemic lupus erythematosus. Lupus nephritis (LN) concerns 30–60% of adult SLE patients and it is significantly associated with an increase in the morbidity and mortality. The definitive diagnosis of LN can only be achieved by histological analysis of renal biopsies, but the invasiveness of this technique is an obstacle for early diagnosis of renal involvement and a proper follow-up of LN patients under treatment. The use of urine for the discovery of non-invasive biomarkers for renal disease in SLE patients is an attractive alternative to repeated renal biopsies, as several studies have described surrogate urinary cells or analytes reflecting the inflammatory state of the kidney, and/or the severity of the disease. Herein, we review the main findings in the field of urine immune-related biomarkers for LN patients, and discuss their prognostic and diagnostic value. This manuscript is focused on the complement system, antibodies and autoantibodies, chemokines, cytokines, and leukocytes, as they are the main effectors of LN pathogenesis. Full article

(This article belongs to the Special Issue Cell Biomarkers in Lupus: Value for Diagnostic and Drug Therapy)

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