Lupus eritematoso

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Review article
Mechanisms of Disease

Systemic Lupus Erythematosus
George C. Tsokos, M.D.
From the Division of Rheumatology, Beth
Israel Deaconess Medical Center, Harvard
Medical School, Boston. Address reprint
requests to Dr. Tsokos at the Division of
Rheumatology, Beth Israel Deaconess
Medical Center, Harvard MedicalSchool,
330 Brookline Ave., CLS 937, Boston, MA
02115, or at gtsokos@bidmc.harvard.edu.
N Engl J Med 2011;365:2110-21.
Copyright © 2011 Massachusetts Medical Society.

A

lthough the term “lupus erythematosus” was introduced by
19th-century physicians to describe skin lesions, it took almost 100 years to
realize that the disease is systemic and spares no organ and that it is caused
by anaberrant autoimmune response.1 The clinical heterogeneity of the disease forced
the establishment of 11 criteria (Table 1), with 4 needed for the formal diagnosis of
systemic lupus erythematosus (SLE).2 The involvement of vital organs and tissues such
as the brain, blood, and the kidney in most patients, the vast majority of whom are
women of childbearing age, impels efforts to developdiagnostic tools and effective
therapeutics (Fig. 1). The prevalence ranges from 20 to 150 cases per 100,000 population, with the highest prevalence reported in Brazil, and appears to be increasing as
the disease is recognized more readily and survival increases. In the United States,
people of African, Hispanic, or Asian ancestry, as compared with those of other racial
or ethnic groups, tend to havean increased prevalence of SLE and greater involvement
of vital organs. The 10-year survival rate is about 70%.3
The diverse clinical manifestations of SLE present a challenge to the clinician.
Several mechanisms lead to a loss of self-tolerance and organ dysfunction. This article
summarizes the genetic, epigenetic, environmental, hormonal, and immunoregulatory
factors that contribute to theexpression of tissue injury and clinical manifestations
and also describes efforts to develop rational treatments for the disease.

Influence s on SL E
Genetic Influences

Genetic factors confer a predisposition to the development of SLE.4 Although in
rare cases SLE may be associated with the deficiency of a single gene (e.g., the
complement components C1q and C4),4,5 the disease morecommonly results from
the combined effect of variants in a large number of genes. Lack of C4 has been
linked to decreased elimination of self-reactive B cells (compromising negative selection),6 whereas lack of C1q leads to deficient elimination of necrotic (waste)
material.7 Each allele contributes only minimally, and the cumulative effect of several genes is necessary to substantially increasethe risk of SLE.
Most single-nucleotide polymorphisms (SNPs) associated with SLE fall within noncoding DNA regions of immune response–related genes.8 Some genes have been associated with several autoimmune diseases (e.g., STAT4 and PTPN22 with rheumatoid
arthritis and diabetes); others appear to increase the risk of SLE specifically (Fig. 2).
Certain SNPs linked to SLE have been identified forgenes whose products may contribute to abnormal T-cell function in SLE (CD3-ζ 9 and PP2Ac10). A recent largescale replication study confirmed some of these associations and identified TNIP1,
PRDM1, JAZF1, UHRF1BP1, and IL10 as risk loci for SLE.11 Although these findings are
promising, the loci identified so far can account for only about 15% of the heritability of SLE.12 In addition, an alteredcopy number of certain genes, such as C4,13
FCGR3B,14 and TLR7,15 has been linked to disease expression.
2110

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