Systemic Lupus Erythematosus: Multiple Immunological Phenotypes in a Complex Genetic Disease

Anna‐Marie Fairhurst*; Amy E. Wandstrat†; Edward K. Wakeland*    * Center for Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas
† Rheumatic Diseases Division, The University of Texas Southwestern Medical Center, Dallas, Texas

1 Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is classically associated with the production of pathogenic autoantibodies to a spectrum of nuclear antigens. SLE usually presents with a diverse array of clinical symptoms, which often reflect the consequences of injury to multiple organ systems. This clinical heterogeneity results from tissue damage targeted by autoantibody and inflammatory processes initiated as a consequence of deposition of complement‐fixing immune complexes (ICs). Severe complications, which ultimately develop in about 50% of lupus patients, can manifest as a variety of clinical problems, including nephritis, central nervous system vasculitis, pulmonary hypertension, interstitial lung disease, and stroke. Current treatments for SLE involve a variety of immunosuppressive drug therapies, including hydroxychloroquine, steroids, and cytotoxic drugs. Although these therapies allow management of disease severity for many patients, a variety of deleterious drug side effects and therapy‐resistant disease symptoms significantly diminish the quality of life for many SLE patients.

The extensive clinical heterogeneity exhibited by this disease complicates diagnosis and has led to the development of guidelines requiring that patients fulfill any 4 of 11 criteria to be diagnosed with SLE (Hochberg, 1997; Tan et al., 1982). Currently, more than 400,000 individuals in the United States are diagnosed with SLE, and possibly an equal number fulfill 2 or 3 of the 11 criteria but are not diagnosed with SLE. Further, the incidence of disease appears to have increased threefold over the last 40 years, possibly due to improvements in the detection of mild disease (Lawrence et al., 1998; Uramoto et al., 1999). There is a significant variation in both the incidence and severity of disease among ethnic groups, with African Americans, African Caribbeans, Hispanic Americans, and Asians all having a higher incidence and greater disease severity than European and American Caucasians (Hochberg, 1985; Jimenez et al., 2003; Lawrence et al., 1989; Serdula and Rhoads, 1979; Vilar and Sato, 2002). The majority of patients with SLE have disease onset between the ages of 16–55.

Although the factors responsible for the initiation of SLE are poorly understood, genetic predisposition is firmly established as a key element in susceptibility. However, despite over a decade of intensive investigations of the genetic basis for SLE susceptibility in humans, very few causative disease alleles have been clearly identified. This is due to a variety of factors, both technical and biological, which have impacted the successful application of classic analytical approaches to the discovery of causative disease alleles in complex systems. Despite this complexity, new insights have been obtained through the analysis of animal models and focused studies on disease progression in human patient populations. Furthermore, recent advances in our understanding of the human and mouse genomes are providing tools that will significantly enhance future genetic analyses of SLE susceptibility. Here, we will overview our current understanding of the immunological pathogenesis and the genetic basis for susceptibility to SLE of both human and murine lupus.

1.1 Clinical Presentation

A typical patient with SLE is a young woman in her childbearing years who presents with intermittent fatigue, joint pain and swelling, skin rashes, low white blood cell count, and chest pains due to pleuritis. Approximately one‐half of lupus patients will manifest the more severe complications of the disease, which can include nephritis, central nervous system vasculitis, pulmonary hypertension, interstitial lung disease, and stroke. The most characteristic clinical feature of SLE is the production of high‐titered anti‐nuclear autoantibodies (ANAs). Although a variety of organ systems can be targeted in human SLE, targeting of the kidneys is the most severe clinical pathology. Kidney pathology is initiated predominantly through the deposition of ANA‐containing ICs, which initiates a robust inflammatory response, leading to destruction of the glomeruli and subsequent nephritis and proteinuria. Many of the clinical manifestations correlating with morbidity and death are associated with renal failure (Balow, 2005).

The disease course of SLE is quite variable, with pathogenesis commonly following a relapsing and remitting course, with slow progression to more severe clinical disease. This variability is typified by the diagnosis criteria set by the American Rheumatism Association (ARA), which are presented in Table 1. The presence of any 4 disease features from a list of 11 qualifies a diagnosis of “definitive” SLE (Table 1; Tan et al., 1982). These features are diverse and include molar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis (pleuritis or pericarditis), renal disorder (persistent proteinuria or cellular casts), neurological disorder (seizures or psychosis), hematological disorder (hemolytic anemia with reticulocytosis, leukopenia, lymphopenia, or thrombocytopenia), immunological disorder (anti‐DNA, anti‐SM, anti‐phospholipid antibodies), and anti‐nuclear antibody (ANA; Hochberg, 1997; Tan et al., 1982).

The heterogeneity in pathogenesis is also demonstrated by the diverse array of methods proposed for the measurement of disease...