www.symbiosisonline.org Symbiosis www.symbiosisonlinepublishing.com Review Article Journal of Rheumatology and Arthritic Diseases Open Access Interferons, B Cells and Neutrophils: Innate and Adaptive Allies in Systemic Lupus Erythematosus Alaa A A Mohamed 1*, Tamer A Gheita2 1Rheumatology, Rehabilitation and Physical Medicine department, Faculty of Medicine, Assiut University, Assiut, Egypt 2Rheumatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt Received: March 01, 2018; Accepted: March 15, 2018; Published: April 07, 2018 *Corresponding author: Alaa Mohamed, MD, PhD, Assiut University Hospital, Assiut, 71515, Egypt. Tel: +201018554227; E-mail: a.a.a.mohamed@ aun.edu.eg Granulocyte Colony Stimulating Factor; GM-CSF: Granulocyte Abstract PAD4: Systemic lupus erythematosus (SLE) is clinically and Deiminase-IV; ACPA: immunologically heterogeneous with variable organ involvement, Siglec-1:Macrophage Colony Stimulating Factor; PeptidylUNGAL: ArginineUrinary severity and therapeutic responses. B cells are known as mediators Anti-Citrullinated Peptide Antibodies; of disease manifestations. Therefore, disease control is targeted Sialic Acid-binding Ig-like Lectin-1; by inhibiting proliferation and inducing apoptosis of B cells via NeutrophilIntroduction Gelatinase-Associated Lipocalin. conventional cytotoxic drugs or newly developing biologics. However, the outcome of therapy is sometimes heterogeneous which further Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease characterized by involvement of all organs functions such as interferons (IFNs) cytokines and the innate cells, in the body. The clinical features of the disease are heterogeneous attracts to understand other immune mechanisms influencing B cell neutrophils. Successful management of SLE requires an understanding and run in a remitting-relapsing course with variable prognosis of how these factors interact, taking into consideration the patients’ variations in these factors which might confer heterogeneity in disease outcome. In this review, it will be focused on the existing data wide range of autoantibodies targeting particularly the nuclear [1]. SLE is characterized by the important role of B cells and the neutrophils in disease pathogenesis and the clinical impact in disease whether by standard cytotoxic drugs or by B-cell depletion assessmentin literature andon the their mutual potential influence blocking. between interferons, B cells and therapyantigens as and biologics. mediating However, the disease the heterogeneity [1, 2]. B cells among are targetedpatients Keywords: Systemic Lupus Erythematosus; B Cells; Neutrophils; in the clinical effects suggests the presence of underlying factors contributing to the development of B cells and their aberrant Cytokines and Inflammatory Mediators; Autoantigens and mechanisms such as plasmacytoid dendritic cells (pDCs), Toll- Autoantibodies Abbreviations likebehaviour receptors [3, (TLRs),4]. Research interferons has focused (IFNs), onneutrophils the role ofand innate gene SLE: Systemic Lupus Erythematosus; pDCs: Plasmacytoid Dendritic Cells ; TLRs: Toll-Like Receptors; IFNs: Interferons; mutationsIFNs are in thea biginitiation family and composed perpetuation of type-I of the diseasethat includes [5-7]. BAFF: APRIL: Ligand; PBMCs: PB: Plasma blast; PCs:B-Cell Plasma Activating Cells; Factor; CSR: Class ASwitch Proliferation-Induced Recombination; importantly IFN-α/β and type-II that includes IFN-γ [8]. IFN- Ig: Immunoglobulins;Peripheral BM: Blood Mononuclear Cells;IL: Interleukin; defenselike molecules mechanism have alsoagainst been viral described and bacterial as type-III infection. IFN, (IFN-λ1, They BCR: B Cell Receptor; mAb: SHM: areλ2, andsecreted λ3) [9].IFNs in response play ato physiologically activation of pathogenimportant recognition role in the AICDA: Bone Marrow; Deaminase; TNF-α: Monoclonal Antibodies;MyD88: mimicked antiviral response is appreciated in SLE in which IFNs DifferentiationSomatic Hyper PrimaryMutation; Response 88;Activation-Induced IFNAR: Cytidine receptors on the antigen presenting cells [10].A persistent Receptor; WT: WildTumor Type; NecrosisTH: T Helper; Factor-α IFNR: ; IFN Receptors; Myeloid Ab: ODN: Oligo Deoxy Nucleotides; NK: Interferon Natural Killer;Alpha drive autoimmune reactions [11]. IFNs expression and signature, NETs: Neutrophil Extracellular Traps; MZ: TACI: mainly type-I and -II, have been confirmed in SLE and also linked Antibody; haveto disease grasped activity attention in some as studies newly [12-14]. discovered IFN blocking partners therapies in SLE Ligand Interactor; LDGs: Low-Density Granulocytes; Marginal Zone; G-CSF: have demonstrated evidence of efficacy [15]. Of note, neutrophils Transmembrane Activator and Calcium Modulator and Cyclophilin pathogenesis via synthesizing IFNs and other pro-inflammatory Symbiosis Group *Corresponding author email: [email protected] Interferons, B Cells and Neutrophils: Innate and Adaptive Allies in Systemic Lu- Copyright: pus Erythematosus © 2018 Mohamed AAA, et al. IFNs also enhance the production of immunoglobulin’s. In review sheds the light on the interplay between IFNs, B cells mice models, it was shown that TLR ligand that result in type-I andcytokines neutrophils and enhancing for better autoantibodies elucidation ofproduction the comprehensive [16]. This IFN production cause T cell-independent antibody response. This interaction between them. response was associated with high titers of all IgG subclasses Interferons Enhance B cell Development and response is preserved with type-I IFN priming indicating that Immune Repertory type-I[29, 30]. IFN Moreover, induces long-term it was noticed antibody that production the secondary and memoryimmune Interferons protect B cells at various stages of development. One mechanism is through inducing the secretion of growth function [30]. On the other hand, lack of type-I IFN was associated atwith the absenceend of culture of IgG’s where in aspDCs-depleted virus-triggered human pDCs inducedPBMCs Bafter cell donorsfactors, orB-cell patients activating treated withfactor IFNs (BAFF) showed and that A uponproliferation- exposure culturing with live influenza virus despite the presence of B cells induced ligand (APRIL). In vitro and in vivo studies on healthy differentiationInterferons into Improve PCs[31]. Proficiency of Autoimmune to IFNs, BAFF and APRIL are up regulated in peripheral blood B Cells mononuclear cells (PBMCs), granulocytes and other cell types [17- IFNs not only affect the development of B cells but also affect stage20]. In in BAFF the transgenicperipheral micedevelopment; model, excess they BAFF mature acts and as acolonize rescuer to auto-reactive B cells that are normally deleted at the late T2 threshold of stimulation of B cell receptor (BCR) and induces the at the marginal zone are found to be rescued and repopulate on B cell functions as summarized in Table 1. Type-I IFN lowers the the splenic follicles. Also, auto-reactive B cells normally deleted the antigen presenting capacity of B cells as shown in splenic expression of MHC-II, CD69, CD86 and CD25, thus potentiating inexcess the class BAFF switch [21].BAFF recombination also enhances (CSR) plasma of immunoglobulin’s blast (PB) survival (Ig) the concentration and duration needed by anti-µ monoclonal and differentiation to plasma cells (PCs) [22]. BAFF/APRIL assist and BM B cells of the murine models. Additionally, it reduces the growth factors co-receptor, heparan sulphate, on murine from C (µ) to C (γ) and /or C (α)[18]. IFN type-I also up regulates antibodies (mAb) to produce maximum BCR internalization role in B cell immune response since its removal abrogates probably via enhancing calcium influx following BCR stimulation splenic B cells. Heparan sulphate is thought to play a significant [32]. (Table 1) The influence of type-I IFNs encompasses the TLRs of antibodyNoticeably, production the effect in response of IFNs to also APRIL involves [23]. stages of B cell ‘naive B cells increases the antigen presenting capacity. This B cells. CpG-mediated TLR-9 activation of healthy donors development in bone marrow (BM). In SLE BM, transitional B results in IgM secretion with CSR and somatic hyper mutation cells, particularly T2, are shown to be significantly higher in IFN- the(SHM), differentiation via activation-induced of CpG-activated cytidine naïve deaminase B cells into (AICDA) memory up high SLE BM as compared to IFN-low SLE BM and healthy controls, regulation, and ultimately IgG production [33]. It also induces which could be attributed to the high expression of BAFF induced by IFN-α in BM[24, 25].Furthermore, the memory fraction in BM cells and increases the production of IL-1β, IL-10, IL-6 and tumor showed significant reduction in the un switched memory CD27/ necrosis factor-α (TNF-α) and myeloid differentiation primary Ig D+ and expansion of the switched CD27/IgD- memory B cells response 88 (MyD88) expression with further enhancement of In this context, pristane treated interferon alpha receptor within SLE a high-IFNparallel response BM. This in was the linked memory to more B cells autoantibodies in the peripheral and CpG function [34]. chemokine expression in the high-IFN BM and was associated complexes compared with pristane-treated wild type (WT) with (IFNAR) 2 -/- mice failed to produce IgG antibodies against immune bloodContrarily, [24]. IFN type-I showed a selective inhibition of interleukin (IL)-7 dependent growths and proliferation of pre-B cell lines