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Pathways Leading To An Immunological Disease LES
Pathways Leading To An Immunological Disease LES
doi:10.1093/rheumatology/kew427
Abstract
SLE is a chronic autoimmune disease caused by perturbations of the immune system. The clinical presen-
tation is heterogeneous, largely because of the multiple genetic and environmental factors that contribute to
disease initiation and progression. Over the last 60 years, there have been a number of significant leaps in
our understanding of the immunological mechanisms driving disease processes. We now know that multiple
leucocyte subsets, together with inflammatory cytokines, chemokines and regulatory mediators that are
normally involved in host protection from invading pathogens, contribute to the inflammatory events leading
to tissue destruction and organ failure. In this broad overview, we discuss the main pathways involved in
SLE and highlight new findings. We describe the immunological changes that characterize this form of
autoimmunity. The major leucocytes that are essential for disease progression are discussed, together
with key mediators that propagate the immune response and drive the inflammatory response in SLE.
Key words: systemic lupus erythematosus, SLE, SLE pathogenesis, autoantibodies, immunology, tolerance,
inflammation, tissue destruction
RE VI EW
. Innate and adaptive immune responses contribute to the autoimmune dysfunction observed in SLE.
. Autoantibodies form immune complexes that drive target organ inflammation in most individuals with SLE.
! The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use,
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Olga Zharkova et al.
connective tissues disorders. Later, the LE cell phenotype Additionally, the generation of de novo autoreactive B
was defined as an ANA reaction because it could be cells occurs after maturation as a result of somatic hyper-
reproduced from bone marrow preparations with the add- mutation in germinal centres (GCs) [29]. It is believed that
ition of SLE serum [7]. This observation and test provided the majority of pathogenic autoantibodies are somatically
the key to linking SLE to immunological dysfunction. The hypermutated, class-switched IgGs. This class-switching
LE test was subsequently replaced by serum ANA assays from IgM to IgG occurs primarily, but not solely, in GCs,
[8]. Since these early discoveries, there has been a dra- through interactions of the B cell with antigen and with
matic progression in our understanding of the immunolo- CD4+ T follicular helper (Tfh) cells, which are identified by
gical pathways driving disease. the markers CD4, inducible T-cell costimulator (ICOS), C-
The cellular roles of individual leucocytes, including B X-C chemokine receptor type 5 (CXCR5), CD57 and pro-
cells, T cells and myeloid cells, in the initiation and pro- grammed cell death protein 1 (PD-1) [12, 3033]. B cell
gression of SLE have been recently reviewed elsewhere activation in GCs is followed by expansion and differenti-
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SLE and immunological pathways
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Olga Zharkova et al.
contribute to altered T-cell tolerance and responsiveness clearance [64]. In SLE, reduced levels of CRP, which
[48]. Dysfunction in autoreactive T-cell anergy can be binds to nuclear proteins and phosphatidylethanolamine
mediated by several factors, including genetic variants, on damaged cell membranes, contribute to defects in cell
epigenetic modifications or alterations in gene regulation. debris clearance [69]. In addition, autoantibodies binding
Such dysfunction can result in hyperactive T-cell to opsonins on circulating necrotic cell debris can gener-
responses, disruption of T-cell trafficking patterns and ate ICs and promote pro-inflammatory responses and
alter the balance of T-cell pro-inflammatory and anti- tissue damage, as discussed below [69].
inflammatory cytokine production [48]. Neutrophils also undergo a unique process ultimately re-
Treg cells appear to play a major role in the maintenance sulting in cell death, known as NETosis, the release of neu-
of peripheral autoreactive T-cell anergy. Although reports trophil extracellular traps (NETs), which is enhanced in
of altered Treg numbers and function in SLE have been paediatric SLE [70, 71]. This specific form of liberating nu-
contradictory, Treg defects are observed in some SLE pa- clear contents is believed to contribute to the autoantigens
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SLE and immunological pathways
chemoattractive agents, which can recruit inflammatory differentiation of healthy control monocytes by SLE
cells. The C3b and C4b fragments bind ICs, which then serum was dependent on IFN-a and correlated with SLE
activate complement receptors on macrophages that disease activity. This has important implications, as it has
clear them from circulation in the spleen and liver. been proposed that lymph node myeloid dendritic cells
The complement system also plays a role in peripheral (mDCs) participate in the maintenance of peripheral toler-
tolerance. Genetic ablation of C4 in a murine model ance by regulating autoreactive T cells. IFN-a upregulates
reduced negative selection during the progression from costimulatory expression and TLR7 mRNA expression in
transitional to mature naive B cells [82]. These findings human mDCs, making them potentially potent antigen-
are consistent with the high frequency of patients with presenting cells for foreign and self-antigens [87]. In
deficiencies in early complement components who have BXSB and Y-autoimmune accelerator (Yaa)-associated
SLE or other autoimmune disorders [81, 83]. Taken to- murine models of lupus, a 2-fold increase in TLR7 expres-
gether, these studies demonstrate that while complement sion is required for the development of severe disease [34,
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Olga Zharkova et al.
accelerated lupus pathology, including increased auto- potential to play both positive and negative roles in pro-
antibody production and TLR-mediated cytokine produc- motion of disease manifestations.
tion [112]. These studies suggest that in addition to
mediating signalling by cytosolic sensors, STING might BAFF (CD257)
activate negative feedback mechanisms that control in- BAFF is primarily secreted by myeloid cells, but can also
flammatory responses. Further studies are warranted to be produced by other types of cells. It stimulates the ex-
gain a full understanding of the role of the cytosolic sen- pansion, differentiation and antibody production of B cells
sors and their signalling pathways in lupus. [128, 129], and its overexpression promotes loss of B-cell
tolerance [26]. It can be active in membrane or soluble
IL-6 form and it can bind to three receptors (transmembrane
IL-6 is a potent cytokine produced by innate and adaptive activator, calcium modulator, and cyclophilin ligand inter-
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SLE and immunological pathways
inflammatory responses. Autoantibodies can form ICs, ac- NIH grants AR067625 (PI, Satterthwaite) and AI122720
tivate innate or resident cells and directly induce target (PI, Satterthwaite).
organ injury. In addition to autoantibodies, defects in cell
Disclosure statement: The authors have declared no
death, cell clearance or phagocytic machinery can initiate
conflicts of interest.
complement activation, IC formation with ensuing myeloid
cell activation and cytokine production with resultant
autoimmune tissue destruction [145]. Infiltrating and resi- References
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