Rakesh K. Mishra, PhD
Autoimmune Disease Center The Feinstein Institute for Medical Research, 350 Community Drive Manhasset, New York, USA E-mail: rakeshadams@gmail.com
INTRODUCTION
Systemic lupus erythematosus (SLE) is autoimmune disease characterised by a myriad of immune system aberrations that involve B-cells, T-cells, and cells of the monocytic lineage, resulting in polyclonal B-cell activation, increased numbers of antibody producing cells, hypergammaglobulinaemia, autoantibody production, and immune complex formation. It appears that excessive and uncontrolled T-cell help in the differentiation and activation of autoantibody forming B-cells is probably a final common pathway.1 B-cell activation is abnormal in patients with SLE. The number of B-cells at all stages of activation is increased in the peripheral blood of patients with active SLE.2
Abnormalities in T-cell function are also evident in patients with SLE. The total number of peripheral blood T-cells is usually reduced, probably because of the effects of antilymphocyte antibodies3 there is a skewing of T-cell function towards B-cell help, leading to enhanced antibody production.3 Experiments have shown that the early events of T-cell activation are defective in patients with SLE compared with controls.
The NF-κB/Rel family includes NF-κB1 (p50/p105), NF-κB2 (p52/p100), p65 (RelA), RelB, and c-Rel). Most members of this family (RelB being one exception) can homodimerize, as well as form heterodimers with each other. The most prevalent activated form of NF-κB is a heterodimer consisting of a p50 or p52 subunit and p65, which contains transactivation domains necessary for gene induction.1 The NF-κB target genes are involved in different aspects of immune functions, ranging from the development, activation, and differentiation of lymphocytes to the maturation and inflammatory functions of innate immune cells. The NF-κB factors are normally sequestered in the cytoplasm via association with a family of inhibitory proteins, including inhibitor of κB-alpha (IκBα) and related ankyrin repeat-containing proteins. In addition,the IκB family also includes the precursor proteins of NF-κB1 and NF-κB2, p105 and p100, which contain a C-terminal IκB-like structure and inhibitthe nuclear translocation of specific NF-κB members.2 Proteasome-mediated processing of p105 and p100 involves selective degradation of their C-terminal IκB-like structure, leading to the generation of re- spective mature NF-κB subunits, p50 and p52, and the nuclear translocation of sequestered NF-κB proteins. The latent NF-κB complexes can be activated by various immune stimuli, which involves two major signaling pathways: the canonical and noncanonical pathways.2 Both the canonical and noncanonical NFκB pathways play a critical role in regulating immune activation and tolerance. Recent studies have emphasized diverse.
NF-κB has been implicated in the pathogenesis of autoimmune disease, such as rheumatoid arthritis (RA), type I diabetes, multiple sclerosis and SLE. During the SLE pathogenesis nuclear NF-κB promotes the aviation of T and B-cells in SLE.3,4 Multiple number of evidences point out the crucial role of NFκB signaling for the proper maturation and development of lymphocytes and dendritic cells. Abnormal NF-κB signaling lead to the secretions of auto reactive T-cells, which have a critical role in SLE and promotes plasma cell development, linking linear ubiquitination to multiple autoimmune diseases.5
Innate immunity may have a great influence in autoimmunity through Toll-like receptors. (Figure 1) TLR7 and TLR9 are expressed in endosomal compartments ligation induce signal transduction via the myeloid differentiation primary-response protein 88 (MyD88).6,7 A common adaptor protein, which interacts with IRAK1/4 (Interleukin-1 receptor-associated kinase 1/4) and TRAF6 (TNF receptor-associated factor 6) to form the MyD88/IRAK1/IRAK4/TRAF6 complex. Subsequently, IRAK1 and TRAF6 dissociate from the receptor complex and interact with kinases IKKβ (Iκβ kinases) resulting in the activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B-cells), permitting the expression of genes of proinflammatory cytokine and chemokines.8 On the other hand, the transcription factor IRF7 (Interferon regulatory factor 7) can bind to the MyD88/IRAK1/IRAK4 complex, and its activation is dependent upon TLR7 requiring the TRAF3 (TNF receptor-associated factor 3) protein, which joins IRAK1 and IKKα kinases to produce IFN-α. The activation of NF-κB is important for eliciting innate immune responses as well as for the subsequent development of adaptive immune responses.9
Figure 1: Overview of NF-κB signaling pathway.
TLRs represent an important link between innate and adaptive immune responses.10,11 Several mechanisms have been proposed to explain the production of autoantibodies in diseased B-cells, including impaired survival or apoptosis signalling that may prevent negative selection, dysfunctional complement or inhibitory Fc-receptors, and the activation of TLR in response to the accumulation of apoptotic bodies. Studies have shown that abnormal stimulation of innate immunity may have a great influence on immunopathogenesis of SLE through Toll-like receptors.12,13 So far, 11 human TLRs have been identified, and TLR7 and TLR9 has been associated with SLE in both human and mouse models.14,15 Both receptors are found on endosomes of several immune cells, mainly antigen-presenting cells, such as dendritic and B-cells. The recognition and internalization, through the B-cell receptor, of nuclear self-antigens released as a consequence of apoptosis in SLE patients, can activate
TLR7 in endosomes of B-lymphocytes supporting its role in the production of autoantibodies.16,17 RNA-containing complexes must access the interior of the plasmacytoid dendritic cells (pDCs), through the Fc-receptors, thus providing a route of entry for RNA to reach TLR7, with the resulting INF-α production. INF-α influences the development, progression, and pathogenesis of SLE.18,19
Several studies have pointed to a relationship between NF-κB and lupus pathogenesis. Wen Zhang et al demonstrated that CD40-induced NF-κB signaling was constitutively activated in B-cells from active lupus patients. Including increased phosphorylation and degradation of IκB alpha, phosphorylation of P65 Aberrant CD40-Induced NF-κB Activation in Human Lupus B Lymphocytes.20 Mayyan women are more suitable to get lupus disease. Pacheo et al21 assess the role of TLR7, MyD88, and NF-κB p65 in B-lymphocytes of Mayan women with SLE and point out the increased expression of TLR7, MyD88, and NF-κB p65 in B-lymphocytes from Mayan women, which supports its role in the pathogenesis of SLE in this ethnic population of southeast of Mexico.21
Growing evidence suggests that recognition of nucleic acid motifs by Toll-like receptors may play a role in both the activation of antinuclear B-cells and in the subsequent disease progression after immune complex formation. TLRs expressed on various immune cells and upon detection of pathogens its trigger inflammation. For example, TLR7 has been associated with SLE in both human and mouse models. This receptor is found on endosomes of several immune cells, mainly antigenpresenting cells, such as dendritic and B-cells. The recognition and internalization, through the B-cell receptor, of nuclear selfantigens released as a consequence of apoptosis in SLE patients, can activate TLR7 in endosomes of B-lymphocytes supporting its role in the production of autoantibodies.22
Under basal conditions, NF-κB is maintained in the cytoplasm in an inactive state through inhibitors of κB (IκB). On activation, IκB rapidly undergoes phosphorylation and degradation, inducing nuclear translocation and gene expression. The A20-binding inhibitors of NF-κB (ABINs1-3) are suppressors of inflammation. Human polymorphisms in the gene encoding the ABIN1 protein have been identified and are associated with a predisposition for autoimmune disease. ABIN1[D485N] knockin mice show significant expansion of myeloid cells in various organs and these mice show enhanced NF-κB and MAPK activation after TLR stimulation and display a SLE-like phenotype including expansion of myeloid cells, leukocyte infiltrations in different parenchymatous organs, activated T- and B-lymphocytes, elevated serum Ig levels, and the appearance of autoreactive antibodies. Kidneys develop glomerulonephritis and proteinuria, reflecting tissue injury.23
Inhibition of NF-κB reduced production of inflammatory cytokines IL-1 and TNFα in the RA model. NF-κB might also control B-cell function via BAFF and BAFF-R. This result would suggest that not only T-helper cells but also B-cells are connected by NF-κB pathways in SLE and RA. Excessive BAFF signaling through BAFF-R results in prolonged B-cell survival and costimulates B- and T-cells. Instead of blocking BAFF-R or decreasing BAFF, reduction of BAFF-R numbers would also, theoretically, reduce the effects of BAFF-BAFF-R signaling in inflammatory autoimmune diseases.
Thomas enzler et al,24 examined which NF-κB pathway and which B-cell type are involved in development of SLE-like autoimmune disease in BAFF-Tg mice. In this study they have used genetic approach and found that both NF-κB signaling pathways contributed to disease development and possibility of controlling the amounts of BAFF-R and reducing the effects of BAFF-R signaling through NF-κB inhibition.
In other study conducted by Lee YH et al25 determine whether polymorphisms of the Toll-like receptor (TLR) genes are associated with susceptibility to SLE and this study suggests that TLR7, TLR8,
and TLR9 polymorphisms are associated with the development of SLE in Caucasian, Asian, and African populations.25
Genetic approaches have gained much power and popularity in identifying the component mechanism(s) underlying the pathogenesis of common human diseases. (Table 1) Genes that play a role in the NF-κB pathway downstream of TLR engagement have also been associated with increased SLE susceptibility. For example, both risk and protective haplotypes of IRAK1 (interleukin-1 receptor-associated kinase 1) have been associated with SLE. The X-linked IRAK1 gene encodes a kinase that acts as the MyD88 complex on/off switch for activation of the NFκB inflammatory pathway. TNFAIP3, also associated with SLE and subphenotypes including renal disease, encodes A20, a deubiquitinating enzyme that inhibits NF-κB, leading to protein degradation and interactions that inhibit NF-κB activity and TNF-mediated programmed death. A dinucleotide polymorphism just downstream of the TNFAIP3 promoter region was linked to the decreased expression of A20 in patients with SLE of Korean and European ancestry, and may be the risk haplotype functional variant. TNIP1 (TNFAIP3 interacting protein 1), encoding the A20-interacting protein, has also been associated with the risk of SLE. Additional genes within the NF-κB pathway associated with SLE susceptibility include: SLC15A4 (solute carrier family 15, member 4) encoding a peptide transporter that participates in NOD1-dependent NF-κB signalling; PRKCB (protein kinase C, β), which is involved in B-cell receptor-mediated NF-κB activation and UBE2L3 (ubiquitin-conjugating enzyme E2L 3), encoding the enzyme UBCH7, which participates in the ubiquitination of an NF-κB precursor, and may play a role in cell proliferation. A risk haplotype of UBE2L3 confers increased UBCH7 expression in patients with SLE; a variant contained in this haplotype has been associated with the presence of anti-dsDNA antibodies.26 (Paragraph adapted from Ornella Josephine, Ann Rheum Dis 2012)
CONCLUSION
In this review, we have summarized that aberrant activation of NF-κB in lupus disease. It is worth to point out here that NF-κB may play even more roles than mentioned above in the development of SLE, as exemplified by multiples studies in both mice and human patients. The significance of NF-κB activation in SLE suggests that inhibition of this signaling pathway provides novel strategies for the prevention and treatment of disease. It is hopeful that as we increase our understanding of the regulation of the NF-κB pathways, insights into the better design of drugs that effectively target NF-κB will be gained that will ultimately lead to better prevention and treatment of the disease.
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