Systemic lupus erythematosus (SLE) is a syndrome encompassing a spectrum of diseases defined by clinical criteria. To have SLE, a patient must have at least four of the following: 1) malar rash, 2) discoid rash, 3) photosensitivity, 4) oral ulcers, 5) arthritis, 6) serositis (pleuritis or pericarditis), 7) renal disorder, 8) neurologic disorder, 9) hematologic disorder, 10) immunologic disorder (anti-dsDNA, anti-Sm, false positive VDRL or anti-phospholipid antibody), and 11) anti-nuclear antibody (ANA) . Some patients have only photosensitive skin rash, joint pains and oral ulcers, while others have systemic vasculitis involving the skin, lungs, bowel, kidneys and central nervous system .
Serologic evidence of reactivity to antigens found in the nucleosome is common, including DNA, histones and various ribonucleoproteins . Reactivity to a large number of additional autoantigens, such as b2 glycoprotein 1, CD45 and platelet factor 4, can be found in individual patients . Both cell mediated and humoral autoreactivity participate in human SLE .
Many studies investigating SLE are hindered by a failure to isolate different patient subgroups, and study each in isolation. SLE encompasses so many different diseases, that very few features are common among all of them. A treatment or diagnostic test that is valid in one form may not be valid in another. Analyzing, for example, a drug in the treatment of SLE may reveal no significant benefit across the entire SLE population. However, that drug may be optimal therapy for one subgroup of SLE patients.
Prognosis of SLE has improved in the last 10 years, with improved medical technology and drugs. Nonetheless, infections, drug toxicities and disease complications are still responsible for earlier than normal demise of SLE patients . The disease manifestations which are the most difficult to diagnose, and treat appropriately, are lung and central nervous system involvement . The most deadly drugs needed in the care of SLE are corticosteroids. While they are essential in controlling certain disease manifestations, they also cause global immunosuppression leading to infection, osteoporosis leading to fractures, and atherosclerosis leading to early onset heart attacks and strokes. Clearly better drugs are needed, as well as more prudent use of available drugs . The appropriate care of SLE patients is currently as much an art as a science.
Significant advances have occurred in the last ten years regarding understanding of the immunologic abnormalities associated with SLE, but little is known regarding etiology, or the specific immunoregulatory aberrations which cause particular clinical manifestations. Genetic effects are important for the development of SLE, but are complex, and likely involve different overlapping genes in various patients . None of the single gene alterations which have been associated with SLE-like features in animals so far, have turned out to have primary relevance to human SLE . Several groups are currently focusing on finding additional genes relevant to human SLE by performing genetic analysis on additional animals with SLE-like illnesses . Other groups are using population based studies to map loci in the human genome associated with susceptibility to SLE . Both of these difficult, long-term approaches are likely to eventually yield interesting results. SADRC-WNY is taking a different approach, looking at genes selectively expressed in SLE patients, which is likely to provide complementary information.
Besides genetics, the environment plays a critical role in the development of SLE. In fact, some of the disorders which enhance susceptibility to SLE, such as complement deficiencies and IgA deficiency, may work by allowing infectious agents more easy and prolonged access to the host . The incidence of SLE has been steadily increasing in the industrialized world, and certain communities have enormously high prevalence rates . The same is true for other autoimmune diseases, such as Hashimoto thyroiditis, and for malignancies derived from immune cells, such as chronic lymphocytic leukemia and lymphoma. An infectious agent causing SLE has been sought, and not found . Certain infections, such as Parvovirus B19, however, induce a disease similar to SLE in selected patients . It is possible that many different infections can trigger SLE in various patients, or that the SLE - agent is difficult to identify. An endogenous retrovirus has recently been identified as a candidate etiologic agent in type I diabetes, which would not have been identified using the strategies previously utilized to find infectious agents in SLE . Participation of other types of environmental factors in the induction of SLE, such as chemicals and toxins, is more difficult to prove, and requires careful epidemiological studies. It is interesting that certain drugs are known to induce mild forms of SLE . Furthermore, SLE ,with a 9:1 female predominance, has some relationship to estrogen, and/ or other sex steroids . Several chemical pollutants have been shown to stimulate estrogen receptors.
Current therapies for SLE utilize medications that non-specifically block various inflammatory pathways. One of the difficulties in developing more specific therapies for SLE has been the failure to identify particular cellular and biochemical pathways that are selective to the type of autoimmunity and inflammation resulting in SLE. Almost every inflammatory pathway which has been studied in SLE, has contained abnormalities . Nonetheless, identification of events more proximal to disease initiation may lead to more selective therapies. Distinguishing which pathways are predominantly involved in the different forms of the disease, seen in various patients, may allow more precise interventions. And, understanding the mechanisms which perpetuate the disease may allow unique interventions, which do not have significant impact on other immune functions of patients.
One of the characteristics of SLE is a long term, high affinity response to self . This has the characteristics of a memory response . In the normal immune response, the first exposure to a particular antigenic challenge results in a low affinity, relatively inefficient response. At the same time, genetic changes are induced in a small subset of B and T lymphocytes that become memory cells, and are capable of responding to additional challenges from the same antigen more efficiently. Memory to certain antigens may last as long as 15 years. Elimination of all memory cells would not preclude the survival and normal functioning of primary cells needed for the initial response to infections, but would significantly reduce injury resulting from SLE . Ideally, a mechanism to eliminate only autoreactive memory cells would be found, leaving protective immunologic memory intact. SADRC-WNY is studying immunologic memory, and its regulation in SLE, as a major focus of its basic science studies.
Lupus Foundation of America: www.lupus.org
Hamline University Lupus Home Page: www.hamline.edu/lupus/index.html
Journal "Lupus": www.stockton-press.co.uk/lup/