Systemic lupus erythematosus is an autoimmune disease with a significant
genetic component to susceptibility. Some environmental risks are known, and
identification of specific genetic factors promises to define new molecular
targets for therapy. Broad immunosuppression will be replaced by early, selective,
and individualized intervention. Mortality rates will decline, and insights
into therapy may apply to other autoimmune conditions.
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease
involving both humoral and cellular aspects of the innate and acquired immune
systems. Lupus is characterized by autoantibodies with a spectrum of specificities
that participate in disease pathogenesis. Lupus occurs worldwide and affects
females more commonly than males (10:1), and some racial groups, such as blacks
and Hispanics, more commonly and severely than others.1
Autoimmune diseases may currently affect tens of millions of US residents.
Lupus, predominantly a disease of younger women, shortens life expectancy,
creates significant morbidity, and accounts for substantial total health care
Clinical management of SLE is based on use of nonsteroidal anti-inflammatory
drugs (NSAIDs), the addition of hydroxychloroquine and other agents originally
developed as antimalarials, targeted and judicious use of glucocorticoids,
including large intravenous doses, and aggressive use of other immunosuppressive
agents, such as cyclophosphamide. Vigorous management of comorbid conditions,
including hypertension and infection, has decreased mortality in persons with
The immune system plays a crucial role in the pathogenesis of both active
inflammatory and noninflammatory mechanisms of organ damage in SLE. Autoreactivity
encompasses a broad range of specificities that can include inciting antigens
and other antigens through spreading of the immune response. Nucleosomes,
apoptotic material, and efficient pathways for routine, nonimmunogenic clearance
appear pivotal in pathogenesis of SLE. Equally, effector pathways for inflammation
are critical for the development of end-organ damage.
Lupus involves abnormal activity of the immune system in response to
environmental stimuli encountered by the genetically susceptible host. Family
studies emphasize the heritability of the SLE diathesis, but susceptibility
is polygenic, involving multiple genes with a threshold effect. Deficiencies
of complement and other opsonins, genetic variants of IgG and C-reactive protein
receptors, and inflammatory cytokine promoter variants have been implicated
as components of genetic susceptibility factors.4
Breaks in tolerance and immune hyperactivity lead to tissue injury by both
myeloid and lymphoid effector cells. The presence of autoantibodies and autoreactive
T cells indicates broad involvement of the immune system, and noninflammatory
mechanisms also contribute to vascular and organ injury.
Animal models and clinical observations suggest that different sets
of genes can produce similar clinical phenotypes. Consequently, identification
of both environmental events and genetic susceptibility factors is critical
for understanding SLE.
Substantial investigative efforts are focused on studying SLE multiplex
families and affected sibling pairs to establish regions of linkage in the
genome with the SLE phenotype.5,6
Identification of candidate genes associated with disease susceptibility,
severity, and response to therapy is progressing in parallel, and elucidation
of gene expression profiles in immune cells may identify targets for intervention
and guide the discovery of new candidate genes.
Although apoptosis per se does not appear to be grossly defective in
SLE, the processing of apoptotic cells and debris contribute to immune dysregulation.
Apoptotic material may alter the local tissue environment and the presentation
of self as antigenic. Therefore, the determinants of tolerance and the pathways
that circumvent tolerance are central to the lupus diathesis. (Figure 1)
The Human Genome Project will provide the framework for understanding
the basis of individual genetic susceptibility to and severity of SLE. The
strong heritability, measured by the risk of disease among siblings, and the
convergence of several investigative groups on specific genetic regions of
interest underscore the promise of this approach. Nonetheless, the task of
unraveling this complex, and perhaps heterogeneous, disease is daunting. Effective
collaborations with large cohorts of both simplex and multiplex families will
be essential. Appropriate understanding of "phenotype" and access to state-of-the-art
informatics tools are essential for this undertaking.
The ability to take the discoveries from genetics, functional genomics,
and pathophysiology to the bedside will require appropriate clinical tools
to evaluate efficacy and outcomes. Many of these tools are at hand, and they
must be woven into an overall effort addressing new therapies.
The next 25 years will contain remarkable progress in the understanding
and management of SLE. Identification of susceptibility genes and their contribution
to disease pathways will provide insight into the understanding of environmental
triggers. Assessment of individual genetic "portfolios" with gene array technology,
combined with advances in knowledge about exogenous stimuli, will facilitate
prevention of SLE. New markers of immune activation and deviation will enable
early therapeutic intervention. Biotechnology will provide more effective
means of immunomodulation, perhaps through antigen-specific tolerance induction,
selective deletion of activated immune cells, or interruption of inflammatory
cascades. Glucocorticoid use will decline and alkylating agents will no longer
be part of the therapeutic armamentarium. Early, effective interventions will
reduce comorbidities, which will be attenuated further by aggressive management
of the causes of morbidity.
Gene therapy for such a complex genetic disease will be used first for
drug delivery, not germ line modification. Discoveries in one autoimmune disease
will have lessons and applications for other diseases. More targeted therapies
will replace broad, nonspecific immunosuppression for most treatment.
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