Lupus

PRIMER
restriction 36 , these SLE-associated variants encode for
proteins involved in cytokine signalling (for example,
signal transducer and activator of transcrip tion 4
(STAT4)) and in the efficiency of signalling downstream
of T cell and B cell surface antigen receptors
(for example, tyrosine-protein phosphatase
non- receptor type 22 (PTPN22), tyrosine-protein kinase
LYN, B cell scaffold protein with ankyrin repeats
(BANK), B lymphocyte tyrosine kinase (BLK) and
tumour necrosis factor- α-induced protein 3 (TNFAIP3))
(REF. 42) (BOX 3). SLE-associated variants in kallikreinencoding
genes are associated with protection from or
vulnerability to renal damage, and overexpression of
Klk1 in the kidneys of a mouse model of SLE reduced
inflammation and oxidative damage 43 .
Female predominance
Among the characteristic features of SLE, the extreme
sex skewing remains poorly understood. Hormonal
contributions to immune system activation represent a
component of the female predominance of the disease.
Oestrogen can modulate the activation of lymphocytes,
and prolactin is expressed at increased levels in
serum of patients with SLE compared with controls,
but the specific mechanisms by which prolactin might
alter immune function in SLE are not clear. In addition
to a contribution of hormones to increased immune
activation, additional concepts should be entertained
to understand the female predominance in SLE. The
prevalence of Klinefelter syndrome, which is characterized
by a 47XXY genotype, is increased 14‐fold among
men with SLE compared with men without SLE, suggesting
that an X chromosome gene-dose effect is an
important contributor to SLE susceptibility 44 . The
carefully orchestrated genomic events in germ cells
and associated somatic cells in the ovaries, with periods
of genome hypomethylation, might provide a source of
stimulatory nucleic acid-containing complexes that
could access TLR-dependent or TLR-independent
pathways and result in immune activation 45 .
Environmental triggers
Clinical manifestations that are present at the time
of diagnosis, including fatigue and arthralgias (joint
pain), have led to the suggestion that a viral infection
— especially with EBV — might trigger the disease.
The T cell response to EBV infection can be defective
in patients with SLE, which might contribute to
the increased numbers of EBV-infected mononuclear
cells and increased copy number of EBV DNA in the
blood of patients with SLE 46 . EBV might contribute to
innate immune system activation and B cell differentiation,
and could stimulate the production of autoantibodies
that are specific for amino acid sequences
shared by self-proteins and EBV-encoded proteins.
EBV-encoded small RNAs induce immune activation
through the expression of type I IFNs after binding
to dsRNA-dependent protein kinase and activating
a TLR-independent pathway. In addition, antibodies
specific for the viral Epstein–Barr nuclear antigen 1
(EBNA1) protein can crossreact with dsDNA, suggesting
that EBV infection could induce an auto immune
response 47 . The molecular basis of this apparent crossreactivity
is not fully understood, but might be based
on common conformational epitopes between DNA
and EBNA1.
Two well-described triggers of SLE — UV light
and certain drugs (TABLE 2) — are likely to promote
the pathogenesis of SLE through their effects on DNA.
UV light can induce DNA breaks that might alter
gene expression, generate nucleic acid fragments or
lead to apoptotic or necrotic cell death. Altered DNA
methylation has been proposed as a likely mech anism
of drug-induced SLE 48 . For example, hydralazine
inhibits extracellular signal-regulated kinase pathway
signalling, which results in decreased expression of
DNA methyltransferase 1 (DNMT1) and DNMT3A,
enzymes that mediate DNA methylation 49 . Altered DNA
methylation modifies gene expression and might also
expose potential ligands for TLR-mediated immune
system activation.
Table 1 | Incidence and prevalence of SLE in selected countries
Country or population Incidence (per 100,000) Prevalence (per 100,000)
Total Women Men Total Women Men Black
people
United States (Georgia) 15 5.6 9.2 1.8 73 128 15 119 33
United States (Michigan) 16 5.5 9.3 1.5 73 129 13 112 48
Barbados 22 NA 12.2* 0.8* NA 153* 10* NA NA
Denmark 17 1 NA NA 28 NA NA NA NA
United Kingdom 20 4.6 7.8 1.3 88 152 22 525* 124
American Indian Health Service 23 7.4 10.4 NA 178 271 54 NA NA
Taiwan 26 4.9 ‡ NA NA 98 ‡ NA NA NA NA
Korea 27,28 NA NA NA 19–22 ‡ NA NA NA NA
2.5 ‡ NA NA 27 ‡ NA NA NA NA
Australia 24,25 NA NA NA NA NA NA 74 § 19
NA NA NA 45 NA NA 93 NA
White
people
NA, not available; SLE, systemic lupus erythematosus. *The majority of the study population are black people of African-Caribbean
origin. ‡ Chinese origin. § Indigenous Australians.
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