What causes lupus?
Lupus is caused by a complex interplay of genes, hormones, and environmental factors. When patients first present signs of lupus, they are often asked whether they have a family member—a mother, aunt, sister, or other relative—with lupus or another autoimmune condition. Researchers were first drawn to the link between genes and lupus because of the clustering of lupus in families and the increased prevalence of the disease among certain ethnic groups. For example, the risk for development of lupus in siblings of individuals with the disease is about 20 times higher than that of the general population. In addition, even healthy family members of people with lupus are more likely to test positive in several lupus-related medical tests, including ANAs and the false-positive test for syphilis. However, the presence of genes predisposing a person to lupus does not necessarily mean that the individual will develop the disease. While researchers are confident that lupus is caused by both genes and environmental triggers, they cannot determine which factor sets the disease in motion or how precisely these two elements interact. Research into both areas seeks to draw light upon this subject.
Genes Associated with Lupus
Our knowledge of the genes associated with lupus and other autoimmune diseases is growing, but certain genes have been identified that provide insight into an individual’s chance of developing lupus.
MHC class II and III represent two families of genes known to be associated with lupus. Major histocompatability complex (MHC) genes help to shape your immune response by coding for proteins that function in response to invaders (antigens). The strength of the association of MHC II genes with lupus varies by ethnicity. MHC III genes code for components of the complement system, a group of proteins that interact to clear immune complexes and affect your body’s inflammatory response. Specifically, lupus involves defects of the genes for complement proteins C4 and C2.
Other genes have also been associated with the development of lupus. Among these are genes that code for variants of opsonins, molecules that make it easier for cells in your immune response to initiate certain steps. [Specifically, opsonins are involved in the facilitation of phagocytosis, the process in which cells called macrophages swallow antibodies carrying invading particles (antigens).] The specific opsonins involved are two proteins called mannose binding protein and C-reactive protein.
Genes that code for complement receptors and antibody receptors are also known to be associated with lupus. These receptors are responsible for detecting and binding to pathogens in the body. In addition, genes for cytokines, molecules that function as signaling molecules in your immune system, have also been implicated in the association with lupus. Specifically, researchers have focused on cytokines called tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10).
Genes that code for molecules called Fcγ-receptors that function to “catch” antibodies carrying antigens also have been linked to lupus nephritis (lupus affecting the kidneys). Specifically, researchers have targeted variants of this gene that cause these receptors to function poorly, causing inefficient clearance of immune system cells from the body.
Hormones and Environmental Factors
Women are 9 times more likely than men to develop lupus. This phenomenon can be explained by sex hormones and the resulting relative strengths of the female and male immune systems. The female body generates and uses larger quantities of estrogen, while the male body relies on hormones called androgens. Estrogen is known to be an “immunoenhancing” hormone, which means that women have stronger immune systems than men. For this reason, the incidence of autoimmune diseases is generally higher in women than in men. Such an observation make sense in light of the evolutionary need for women to survive to nurture their children.
In addition, certain environmental factors have been linked to the development of lupus. These environmental contributors are difficult to isolate, but researchers have established links between lupus and a variety of toxins, such as cigarette smoke, silica, and mercury. Infectious disease agents such as the Epstein-Barr Virus (EBV, which causes mononucleosis or “mono”), herpes zoster virus (the virus that causes shingles), and cytomegalovirus have also been implicated. Certain drugs can cause lupus-like syndrome and exposure to ultraviolet light and stress are known to aggravate lupus symptoms, but none of these factors have been identified as direct causes of the disease.
- Miller, Frederick W., and Glinda S. Cooper. “Environmental Aspects of Lupus.” Dubois’ Lupus Erythematosus. Ed. Daniel J. Wallace and Bevra Hannahs Hahn. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2007. 21-33.
- Salmon, Jane E., and Robert P. Kimberly. “Systemic Lupus Erythematosus.” Hospital for Special Surgery Manual of Rheumatology and Outpatient Orthopedic Disorders: Diagnosis and Therapy. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2006. 221-38.
- Tsao, Betty P. and Hui Wu. “The Genetics of Human Lupus.” Dubois’ Lupus Erythematosus. Ed. Daniel J. Wallace and Bevra Hannahs Hahn. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2007. 54-81.
- Wallace, Daniel J. The Lupus Book: A Guide for Patients and Their Families. 1st ed. New York: Oxford UP, 1995. 37-45.