Lupus

PRIMER
Box 2 | Chronic viral infection as a model for SLE pathogenesis
Recent data have characterized a distinction between effective immune responses in
the setting of some viral infections (for example, lymphocytic chorimeningitis virus
(LCMV), Armstrong strain or simian immunodeficiency virus infection in African green
monkeys) and a chronic and damaging immune response to infection with other viruses
(for example, LCMV clone 13 or human immunodeficiency virus type 1 (HIV‐1)). Chronic
and damaging immune responses to infection are associated with sustained production
of type I interferons (IFNs), a sustained signature of increased expression of type I
IFN-induced gene transcripts, altered T cell function and chronic tissue inflammation
and damage. The immune alterations observed in systemic lupus erythematosus (SLE)
show a clear resemblance with the chronic immune response associated with
well-described models of virus infections. Among the immune alterations observed in
patients with SLE that are also characteristic of chronic virus infection are a sustained
expression of type I IFNs; increased and sustained production of pro-inflammatory
mediators, such as IL‐6, IL‐10 and tumour necrosis factor (TNF); altered expression of
some cell surface receptors, including programmed death ligand 1 (PDL1) and
TNF-related apoptosis-inducing ligand (TRAIL; also known as TNFSF10); and a shift in
T cell differentiation towards a T follicular helper cell phenotype. The consequences of
these altered immune functions include sustained and poorly regulated macrophage
activation; impaired T cell function and regulation of cell death; excessive B cell
differentiation; the production of autoantibodies and immune complexes; and
widespread tissue and organ inflammation and damage.
T cells derived from patients with SLE studied ex vivo
show hypomethylation of CG‐rich DNA sequences and
promoters of IFN-regulated genes 68 . Epigenetic modifications
might thus contribute to the SLE phenotype, as
DNA demethylation of mouse and human T cells results
in T cell-proliferative responses to usually subthreshold
interactions with autologous macrophages. Increased
expression of lymphocyte function-associated antigen
1 (LFA1) is the most likely factor responsible for
the produc tive interactions between macrophages and
T cells that result in increased T cell proliferation.
Generalized lymphocytopaenia is a typical
character istic of SLE, but the expansion of specific
T cell populations has been described. The population
of T follicular helper cells, which promote differentiation
of autoantibody-producing B cells, is expanded
in SLE 69 . As T follicular helper cells may be essential
for the differ entiation of pathogenetic autoantibodyproducing
B cells, they represent an important therapeutic
target. The expansion of a population of CD8 +
cells with a memory phenotype is associated with
poor prognosis of SLE, possibly owing to their role in
mediating tissue damage 70 . Regulatory T (T reg
) cells,
with the capacity to suppress immune responses, and
T helper 17 (T H
17) cells, which promote inflammation
by the production of IL‐17, have been intensively studied
in recent years. Some studies have shown a relative
depletion in the number of T reg
cells, increased numbers
of T H
17 cells and increased levels of IL‐17 in SLE 71 . The
functional consequences of these alterations in human
SLE are still not clear. Decreased production of IL‐2 is
a character istic feature of T cells derived from patients
with SLE and of the T cells of individuals without SLE
who also carry the MHC 8.1 haplotype 37 . Although IL‐2
deficiency was initially linked to the poor proliferative
responses of SLE T cells stimulated with autologous
T cells, allogeneic T cells or soluble antigen, the recognition
that IL‐2 is important for the maintenance of
T reg
cells suggests another mechanism through which
impaired production of IL‐2 might contribute to
immune system activation and autoimmunity 72 .
B cells. B cell regulation is also impaired in SLE, contributing
to the production of autoantibodies, cytokines and
augmented presentation of antigen to T cells. Increased
availability of T cell help for B cell differentiation as
well as B cell survival, proliferation and differenti ation
factors (including BAFF and IL‐21) and activation
of TLRs all contribute to autoimmunity, but intrinsic
differences in threshold for the activation and signalling
of B cells in mouse lupus models have also been
described 73 . SLE-associated genetic variants encoding
several kinases, phosphatases and adaptor molecules,
such as BLK, BANK and PTPN22, contribute to altered
counter-selection of self-reactive B cells or antigenmediated
B cell activation 42 . SLE memory B cells show
modest decreases in the expression of the inhibitory
Fc receptor FCGR2B, and mouse B cells studied in an
in vitro system demonstrate altered cytokine production
when engaged by nucleic acid-containing immune
complexes 74,75 . Long-lived plasma cells are maintained
by chemokines and stromal cell products in protective
bone marrow niches and are proposed sources of
anti‐Sm and anti‐Ro autoantibodies that are refractory
to modulation by immunosuppressive or B cell depletion
therapy 76 . By contrast, circulating plasmablasts (plasma
cell progenitors) are sources of anti-dsDNA antibodies,
the levels of which fluctuate in some patients in association
with variations in disease activity and might be
more amenable to anti-B cell therapy 77 .
Autoimmunity in SLE
Autoantibodies are traditionally viewed as essential
mediators of pathology in SLE, particularly when they
form immune complexes. Virtually all patients with SLE
are positive for ANAs or other characteristic SLE autoantibodies
(BOX 1). Autoantibodies in SLE can be categorized
in relation to their targets: DNA and DNA-binding
proteins, which are typically aggregated with histones in
nucleosomes; RNA and RNA-associated proteins, which
are aggregated in cytoplasmic or nuclear ribonucleoprotein
particles; β2‐glycoprotein 1 in association with
phospholipids; and cell membrane proteins, typically
those expressed on blood cells. Among those, antidsDNA
and anti‐Sm are most specific for SLE. Anti‐C1q
antibodies, which recognize neo-epitopes of C1q bound
to early apoptotic cells, are associated with SLE activity
and with proliferative lupus nephritis and are thought to
be pathogenetic 78 .
The pathogenetic antibodies in SLE undergo
immuno globulin class switching driven by CD4 + T helper
cells or TLR ligands together with IL‐21 or BAFF. A shift
from a predominant polyclonal IgM profile towards
IgG occurs over time in most patients with SLE and
with disease progression and development of tissue
damage. Class-switched IgG antibodies are better able
to access extravascular spaces than IgM antibodies.
Some IgM antibodies that have self-reactivity are viewed
as protective, with the switch from IgM to IgG or IgA
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