title: Exploring the Complexity of Systemic Lupus Erythematosus: Navigating Immuno-Pathologies in a Brief Overview
title: Systemic Lupus Erythematosus
titleType: Subtitle
title: Immunopathology
titleType: Subtitle
Creators: name: Saeed, Iqra Takreem
name: Khaliq, Hafiz Muhammad Haseeb
name: Rana, Sidra
name: Arshad, Adnan
Publisher: name: Zenodo
Year: 2022

description: Abstract: Systemic Lupus Erythematosus (SLE) is an autoimmune disorder, with multisystem mechanism that still remains unidentified. The literature reveals that genes and environments are quite involved in lupus development. It has been found that epigenetics have a significant influence on SLE. The article concentrates on immunopathology associated with SLE. SLE is multifactorial disease that occurs due to innate and adaptive immunity response pathways. Autoreactive B-cell activation due to T-cells lead to immune complexes deposition in tissues leading to an auto-immune reaction. Due to high immune system involvement SLE can have organ or systemic progression. SLE, thus, has varying effects on organs due to immune system involvement

Keywords: Systemic lupus erythematous (SLE), Immunopathology, Multifactorial disease, T cells regulation
description: INTRODUCTION

Systemic lupus erythematosus (SLE) is an autoimmune disease which affects virtually any organ in the body and encompass a wide range of severity of symptoms, ranging from comparatively mild manifestations (e.g. skin rash or non-erosive arthritis) to seriously debilitating complications, such as lupus nephritis, neuropsychiatric disorders and other major organ involvements [1]. SLE has a clear genetic susceptibility along with various environmental triggers associated with the onset and disease progression. Lupus can devastate and progress to vital organs including kidney and CNS. SLE symptoms can range from mild cutaneous to fatal organ damage.

PATHOGENESIS 

 SLE has a wide set of environmental and epigenetic influences altering genome expression leading to disease development.  Environmental mediation factors such as UVB radiation, infections, and toxins induce immune suppressive mechanisms leading to genetic susceptibility and aberrant autoimmune mechanisms [2].   SLE can be caused by immune cells initiating a feed-forward loop of adaptive and innate immune response due to a probable cell apoptotic debris. SLE can be stated as an immune response leading to simultaneous auto-antibody generation and immune complexes reactivation (T cells B cells, complement activation, and cytokine response). This results in extensive tissue damage leading to SLE complications [1].

T/B CELL SIGNALING: Susceptibility genes involved in T/B cell-signaling activate adaptor molecules, kinases, and cytokines that regulate immune reactivation.  II human leukocyte antigen (HLA) region encodes molecules involved in antigen presentation [2, 3].  SLE represents as a hyperactive immune response with high levels of surface expression of HLA-DR2 and HLA-DR3 alleles. Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is another gene that encodes a tyrosine phosphatase that alters T-cell receptor (TCR) and B-cell receptor (BCR) signaling leading to enhanced B-cell auto reactivity in SLE.   Another adaptor/scaffold protein associated with aberrant B-cell activation is C-Src tyrosine kinase and BANK1C-terminal Src kinase (CSK) is a protein-encoding gene. Lymphocyte differentiation and proliferation is regulated by transcription factors including ETS1, IKZF1, IKZF2, IKZF3, RAG1, RAG2, FASLG, FAS, SHOC2, and KRAS encoding SLE susceptibility genes [4].  


ROLE OF T CELLS: SLE pathogenesis is affected by secreting inflammatory cytokines leading to generate auto-antibodies inducing cascade of autoreactive memory T cell. While, some patients were also reported to have abnormal expression of T cells subsets expressing abnormal function [5].

SLE AND TFH HYPER-MUTATION: T follicular cells result into isotype switching and germinal cell induction. Tfh is also involved in cytokine IL-21 induced B cell differentiation into memory B cells and antibody-generating plasmablasts. Myeloid antigen-presenting cells have ligand OX40 that leads to pathological Tfh expansion [6].   TLR7 activation from circulating RNA-containing immune complexes results into OX40 ligand expression. SLE complications result from expansion of the TFH cell subset with enhanced antibody production [7].

ROLE OF REGULATORY T CELLS: Regulatory T (Treg) cells are a unique T-cell subset population that is immune repressive by deactivating autoreactive lymphocytes in healthy individuals. Treg cells development is IL­2 activity dependent.  SLE can be characterized by T-cell cytokine imbalance and decrease IL2 can often lead to Treg cell development and function [8]. IL2 also plays a role in restricting the expression of IL­17, which is pro-inflammatory and its elevated levels in SLE contribute to local tissue damage [9]. IL2 depression in T cells due to loss of transcription factor activator protein (AP-1) also progresses SLE.

ROLE OF B CELLS: B cells have response to antigens and autoantibody production causing SLE progression. Pathway involved include toll-like receptor (TLR) pathway, stimulation via beta cell-activating factor (BAAF), and B-cell receptor (BCR) mediated activation. [2].

TLR9 stimulation leads to transitional B cell activation causing auto reaction of marginal zone B cells. Cytokine induced B cell stimulation leads to impairment of B cell tolerance. Significant levels of BAFF are exhibited in SLE patients with higher levels of anti-dsDNA, anti-histone, and anti cardiolipin antibodies [7].

 Aberrant Apoptotic Cell Clearance: Autoantigen increases as a result of dysregulated apoptosis and nuclear waste removal. SLE results as an immune mechanism impairment to maneuver correct cellular debris removal pathway [10].  Thus, pathogenesis is also induced by increased survival of defective lymphocytes.  Moreover, faulty removal due to aberrant apoptosis of complexes of IgG2- and IgG3 also results in ineffective clearance. Rheumatologically autoimmune diseases often translate as expressing receptors (Tyro-3, Axl, and Mer) (TAM) by phagocytes, macrophages, and natural killer cells [11]. The downstream activation of TAM receptors promotes the phagocytosis of apoptotic cells. This results in inhibition of signal transducer and activator of transcription 1 (STAT1) and the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) pathway.  

ROLE OF THE COMPLEMENT SYSTEM: SLE pathways is affected by complement dysfunction due to faulty apoptotic debris removal  and IC,  autoreactive CD+8 T cell hyperactivity, and tissue necrosis by initiation of the inflammatory cascade in organs with IC deposition [12]. C1q helps clearance of apoptotic debris and immune complexes and inhibits the CD8+ T cell response to auto-antigens by mitochondrial metabolism modulation. Faulty apoptotic elimination can lead to C1q homozygous deficiency leading to develop autoantibodies and a lupus-like syndrome [13].

APOPTOTIC CELL ELIMINATION AND IMMUNE COMPLEXES: Self-antigens exposure due to impaired apoptotic disposal initiates an autoimmune response. Moreover, IC response removal impairment from autoantibodies bound to antigens can magnify the inflammatory reaction [14]. HLA class III region genes encode products relevant to this pathway; C4A, C4B, C1QA, C1QB, and C1QC mutations are associated with monogenic forms of SLE [15]. 

ROLE OF TOLL-LIKE RECEPTORS: TLRs aberration is widely reported as an SLE. B cell lymphocytes associated with TLRs' dysfunctional mechanism signify SLE pathogenesis due to B-cell lymphocytes [16].TLRs are nuclear acid recognition receptors that initiate.  inflammation upon activation by nuclear antigens contained in IC or apoptotic waste.   TLRs serve as germline-encoded receptors that identify certain microorganisms and are usually the first line of defense against them, and primarily respond to endocytosed nucleic acids. Downstream activation of TLRs leads to activation of two transcription factors, interferon regulatory factor 3 (IRF3) and nuclear factor‑κB (NF-κB), this causes overexpression of type I interferon (IFN) that is significant in disease progress. TLR7 (receptor for single-stranded RNA) overexpression is linked with RNA-reactive autoantibodies and type IFN I production. TLR9 (receptor for DNA containing un-methylated CpG sequence motifs) overexpression associated with high levels of anti-dsDNA antibodies and increased disease development [17].

TYPE I INTERFERON SIGNALING: SLE-susceptibility genes have major involvement of proteins linked to production of IFN-I.   Another factor for disease proliferation is overexpression of Toll-like receptor 7(TLR7) due to IFN-I production [18]. MiR146a, RNASEH2C, SLC15A4, and IRAK1 and other genes are also involved in this pathway [19,20].

DISCUSSION

Cytokine upregulation and inflammation further fuel the immunopathogenesis of SLE. Dysregulated cytokine networks, particularly the overexpression of pro-inflammatory cytokines, contribute to tissue damage and systemic inflammation characteristic of SLE. Understanding these intricate signaling cascades provides valuable insights for targeted therapeutic interventions. Epidemiological studies also show SLE incidence triggered by exposure to smoke of cigarette, silica, oral contraceptives, ultraviolet B (UVB), drug use, and infection with Epstein-Barr virus (EBV).  Oxidative stress, cytokine upregulation and inflammation, systemic inflammation and epigenetic modification are symptoms of SLE progression. SLE has an initial phase called Preclinical lupus (PL) which is asymptomatic but has high disease risk.  Serum of patients showed higher levels of autoantibodies as associated with higher malignancies and carcinomas of organs especially Gestrointestinal, Brain and Stromal tumorigenesis [21-26]. A high number of antinuclear antibody (ANA), hematological and immunological disorders, arthritis, and cutaneous manifestations are most probable symptoms of PL. Thus, around 10% to 20% of PL often transcends into SLE. Immunosuppressive therapies like azathioprine and methotrexate are often considered helpful for PL treatment.
description: CONCLUSION

SLE has a wide spectrum disease symptoms ranging from mild to severe and even fatal. 50 years aged adults usually present cutaneous symptoms in form of malar rash and lupus nephritis. The disease is modulated by various factors including age, creed, gender, genetic makeup, and socioeconomic standing but has a remarkable involvement of immunomodulatory elements. The severity and complications of the disease are related to the immune responses.SLE has diverse and drastic clinical implications while serious diagnosis is needed for early intervention of disease.

 

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