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Systemic Lupus Erythematosus

What is autoimmunity?

            “Diseases in which the pathology is caused by adaptive immune responses to self-antigens are called autoimmune diseases.” (Janeway et al. 2001)  Basically, in autoimmune diseases, the human immune system erroneously recognizes parts of the body as harmful antigens and so builds a response, targeting self-cells.  Autoimmunity is very complex.  There are many different autoimmune diseases, each affecting the body in vastly different ways.  Even patients with the same autoimmune disease may show different symptoms.  Millions of Americans are afflicted with an autoimmune disease, mostly women of childbearing age.  While there is clear evidence of a genetic factor, environment, hormones, aging, chronic stress, and pregnancy are also thought to play a role.  Generally, autoimmune diseases are lifelong conditions, although medication and treatment can make quality of life better for the patient. (National Institute of Allergy and Infectious Diseases 1999)


Background on Systemic Lupus Erythematosus

            This paper aims to describe the autoimmune disease known as Systemic Lupus Erythematosus (SLE).  SLE is a rheumatic disease that predominantly affects females. (Arbuckle et al. 2001, Gray-McGuire et al. 2000)  One source says as much as 90% (Gray-McGuire et al. 2000), while another source cites a sex ratio of about 10-20 women to men (Janeway et al. 2001)  SLE is more common in Hispanic and African-American women than in Caucasian women. (National Institute of Allergy and Infectious Diseases 1999, Gray-McGuire et al. 2000)  The disease occurs in 1 out of 2,000 Americans and in as many as 1 out of 250 African-American women.  Estrogen and other female hormones are considered to play a role since women are more likely to be affected. (Cleveland Clinic Health System 2001)  Exposure to sunlight has been shown to trigger the disease or worsen its development. (National Institute of Allergy and Infectious Diseases 1999, Rossiter 2002)  Estrogen and other female hormones are considered to play a role since women are more likely to be affected.  Symptoms for each patient will be different, and this makes the disease difficult to diagnose. (National Institute of Allergy and Infectious Diseases 1999, National Institute of Arthritis and Musculoskeletal and Skin Diseases 2003)


How does one develop SLE?

            The cause of SLE is not known.  As stated earlier, the symptoms vary greatly from patient to patient, as well as slightly between ethnic groups, and so diagnosis is difficult. (National Institute of Allergy and Infectious Diseases 1999, National Institute of Arthritis and Musculoskeletal and Skin Diseases 2003, Gray-McGuire et al. 2000)  Autoantibodies against nuclear, cytoplasmic and cell-surface antigens have been shown to be involved, as well as defective T and B cell lines. (Faber-Elmann et al. 2002)  However, there have been some studies that aim to determine the cause or causes SLE.

            Antibodies to double stranded DNA (dsDNA) are thought to be of importance in the pathogenesis of SLE.  These antibodies are observed in approximately 60-70% of SLE patients.  It is difficult to determine when at what point these antibodies develop and proliferate since patients are not identified until after autoimmunity is already in progress.  Using serum from military personnel that was stored before any diagnosis with SLE, Arbuckle et al. found that anti-dsDNA antibodies were present in the serum years before diagnosis of the actual disease.  This suggests that anti-dsDNA antibodies can be used as a marker for people who may be at risk for developing SLE.  Once present, these antibodies remain through onset of SLE, apparently even increasing until treatment starts.  The results of this study suggest that antibodies to dsDNA are a key component of the development of SLE. (Arbuckle et al. 2001)

            Researchers from the University of Minnesota in collaboration with the North Shore Long Island Jewish Research Institute used DNA microarrays to investigate genes in the peripheral blood cells of 48 SLE patients and 42 healthy controls.  Thousands of genes were studied, and 14 of these genes where linked to SLE patients manifesting a severe form of the disease.  Also, 161 of the genes studied demonstrated expression patterns that differed from the healthy controls.  The 14 genes are collectively referred to as the interferon (or IFN) expression signature.  The genes are turned on by interferon activity.  IFN is a family of proteins that is involved in immune response regulation.  The data show support for therapies that would block IFN pathways.  This may be able to help patients with a more severe form of the disease.  Knowing the pattern of gene expression will be useful in distinguishing those patients who are likely to have the highest benefit from the new treatments. (National Institute of Arthritis and Musculoskeletal and Skin Diseases 2003)  “Gene expression profiling in blood cells may also be useful in identifying disease pathways in other autoimmune and inflammatory disorders.” (National Institute of Arthritis and Musculoskeletal and Skin Diseases 2003)

            There is high heritability in this disease.  Monozygotic twins formed from the same egg, and therefore genetically identical, show a 25-69% correlation rate, as opposed to dizygotic twins and normal siblings who show only 2-3% concordance.  The results of the study by Gray-McGuire et al. discovered an SLE susceptibility locus on the long arm of chromosome 4 in positions 16-15.2 in European American populations.  There are about 70 genes in this position and they are shown to be linked.  All of the genes have been identified with an autoimmune disease, or appear to be involved with one.  Several of the genes are vital to B and T cell activity, CD38 being an example.  An epistatic relationship is seen between that locus on chromosome 4 and the position 5 on the long arm of chromosome 5. (Gray-McGuire et al. 2000) Epistasis is “an interaction between genes, in which the presence of a particular allele of one gene determines whether another gene will be expressed.” (Purves et al. 1998)  However, this may not be the case.  Mozes and Shoenfeld have demonstrated that susceptibility to and development of SLE is mapped to 2 linked genes, one on chromosome 7 and the other on 14. (Mozes and Shoenfeld 1994)  More research will have to be done in order to know conclusively which genes SLE can be mapped to.

            Each of these experiments and other like them are leading the way in a discovery to the cause of SLE.  Once the cause is known, the disease can be recognized early on and treated accordingly.  Perhaps with enough research there will someday be a way to prevent the disease altogether.


What are the symptoms of SLE?

Outward Manifestations

The most common outward symptom of SLE is development of rashes.  Raised or flat malar rashes that occur across the bridge of the nose and on the cheeks are also called butterfly rashes.  Raised discoid rashes may also occur on the hand or other body parts. (Rossiter 2002)  Sunlight usually aggravates these rashes. (Rossiter 2002, National Institute of Allergy and Infectious Diseases 1999)  Oral ulcers and arthritis are not uncommon, and in fact are listed as criteria for lupus diagnosis.  SLE patients also show neurological symptoms, such as seizures and/or psychosis.  (Rossiter 2002).  Zapor et al. determined that echolalia was linked to SLE.  Echolalia is an abnormal speech pattern in which a person repeats constantly what is heard.  Neurological manifestations are most likely due to the affect of autoantibodies on the central nervous system.  Studies are not conclusive, but antilymphocytotoxic antibodies have been seen in SLE patients with cognitive dysfunctions. (Zapor et al.2001)  If you are interested in more neurological studies of SLE, Neuropsychiatric Manifestations of Systemic Lupus Erythematosus, edited by P.M. Moore and R.G. Lahita is full of different experiments describing various neuropsychiatric symptoms in SLE patients.  These outward manifestations are for the most part due to what is going on inside the body.  Below is a description of studies that have described cellular symptoms of SLE.


Cellular Symptoms

Estrogen Receptors: Since hormones have been indicated as an important factor to SLE (Putterman and Naparstek 1994), Kassi et al. decided to investigate alpha and beta estrogen receptors in SLE patients.  Although the hypothesis was valid, the results showed that there was no significant difference between SLE and healthy patient estrogen receptors.  However, concentration of estrogen receptor may play a role, and so experiments are further being conducted. (Kassi et al. 2001)

C1q: About 1% of SLE patients inherit a homozygous complement deficiency, C2 being the most common among Caucasians.  Acquired complement deficiencies are common, C3 marking the shortcoming.  Patients with C3 and C2 deficiencies are not extremely likely to develop SLE.  There is a high correlation, however, of SLE patients with C4, C1r, and C1s.  C1q shows the highest correlation, with 98% of patients with a defective C1q gene developing SLE.  C1q deficiency can be identified at a young age in SLE patients.  So far, single base mutations causing a stop codon, frameshift mutations, and amino acid residue exchange have been identified in the faulty genes. (Stone et al. 2000)

CD59: CD59 is a part of signal transduction and T cell activation.  It also acts in lysis prevention of self cells by complement, although this function is not entirely defined.  Abnormal regulation of apoptosis has long thought to play a role in autoimmune diseases.  Expression of CD59 on activated T cells from SLE and Sjögren’s syndrome (SS) patients and stimulation of apoptosis of these cells were analyzed by Tsunoda et al.  CD59 expression was found to be decreased on activated CD8+ T cells and in vitro, there was a higher rate of apoptosis observed on the CD59 diminished T cells.  The decreased expression may boost the susceptibility of activated cytotoxic T cells to apoptosis. (Tsunoda et al. 2000)

Fas: Continual lymphocyte activation and autoantibody production in SLE may be due to increased apoptosis of peripheral blood mononuclear cells (PBMC).  In SLE patients, apoptosis of these cells has been shown to be higher when compared to normal patients. The increased lymphocyte activation found in vivo contributes to higher membrane expression of Fas.  The higher Fas expression leads to the increased percentage of apoptotic lymphocytes.  (That sounds a bit circular, but if I’m summarizing right, and I’d like to think I am, that’s what it says.)  The increased apoptotic levels may be due to slower clearance seen in SLE patients. (Bijl et al. 2001)

MMP-9: Cytokines, particularly Tumor Necrosis Factor (TNF)-alpha and interleukin (IL)-1, have been shown to have a part in the pathogenesis of SLE.  Those two cytokines are known to induce matrix metalloproteinases (MMPS), a family of zinc containing proteinases that help modify the extracellular matrix in normal tissues.  The MMPs also play a role in pathological processes.  MMP-9 was demonstrated to be elevated significantly in 68% of SLE patients.  Why or how this increase occurs is not known.  Speculatively, MMP-9 is coming from SLE affected organs, such as the lungs or the kidneys.  High levels of MMP-9 are correlated with pneumonitis, neurological diseases, and discoid rashes.  Sex hormones, especially progesterone, have been shown to control the activity and production of MMP-9.  Surprisingly, MMP-9 activity in females did not correlate strongly with SLE, but did so in male patients.  Measurement of MMP-9 in SLE patients may be able to provide valuable information when treating patients with drugs that interfere with MMP-9 activity. (Faber-Elmann et al. 2002)

            Immunoglobulins: The markers of SLE tend to be anti-DNA antibodies, but up to 50 other autoantibodies that could take part in the disease. (Mozes and Shoenfeld 1994, Sun et al. 2000)  In diseased female mice, the Ig levels are 2-3 times higher than non-diseased mice. After 1 month IgM is specific for antinuclear antigens like ds or single stranded DNA (ssDNA – this is closely related to the development of nephritis), ds RNA, histones, and tRNA. By 5-7 months, IgG is more dominant, with subclasses IgG 2a and 2b present more frequently than the others. (Putterman and Naparstek 1994)  IgG antibodies to dsDNA play a role in nephritis.  The idiotype on IgG is not unique to SLE patients.  It occurs on a small percentage of healthy patients, but occurs in higher concentrations in the sera of SLE patients. (Zhang et al. 2001)  Granular deposits of IgG and C3 are found on the kidneys of infected mice, and deposits of IgG, C3, and protein gp 70, which is found on viral coats, can be found on walls of cardiac vessels. When castrated or treated with estrogens, male mice show female patterns of autoimmune symptoms, specifically early IgG switch of anti-DNA antibodies.  Females treated with male hormones show later switching to IgG anti-DNA antibodies and accordingly a longer lifespan. (Putterman and Naparstek 1994)

High levels of anti-DNA antibodies are associated with higher levels of circulating immune complexes and decreased levels of complement. (Putterman and Naparstek 1994, Sun et al. 2000)  The antibodies bind with DNA to form the circulating complexes.  These complexes can then deposit in different tissues and cause inflammation. (Sun et al. 2000)  At 8 months, high levels of antihistone antibodies are present in all mice.  In mice the histones targeted are H2B and H3, while H1 and H2B are targeted in humans.  Anti-RNA antibodies in mice recognize a three nucleotide sequence of ssRNA. (Putterman and Naparstek 1994) 

Cytokines: IL-10 is overproduced in SLE patients, and plays a role in B cell differentiation as well as overproduction of immunoglobulins.  It also inhibits T cell proliferation and down regulates antigen presenting functions of monocytes, partially explaining the nonfunctional T helper cells and antigen presenting cells in SLE patients.  IL-10 generates the production of platelet activating factor (PAF) in patients with active SLE.  PAF is a secondary mediator of inflammation.  After activating PAF, IL-10 supposedly switches from an anti-inflammatory to a pro-inflammatory, thus causing tissue damage. (Bussolati et al. 2000)  Anti-DNA antibodies were only found to increase production of IL-10, leaning the immune response toward a T helper 2 pathway, enhancing the production of autoantibodies. (Sun et al. 2000)

IL-1, IL-6, and TNF-alpha were all shown to be overexpressed in SLE patients.  These cytokines are pro-inflammatory, and facilitate tissue damage in addition to activating a B cell response.  Anti-dsDNA can apparently induce release of IL-1 and IL-6 from endothelial cells and enter nuclei to induce cytokine release from functionally altered cells. (Sun et al. 2000)

In experimental mice, SLE seemed to have to phases.  The first was an increase in T helper 1 cytokines, followed by an increase in T helper 2 cytokines.  However, TNF-alpha and IL-1 were present the entire course of the disease. (Sun et al. 2000)


Effect of SLE on Select Organs and Cells in Mice





Cardiovascular disease


B cells

·        Polyclonal B-cell hyperactivity is present in all murine models.

·        xid gene: X-linked recessive, “causes deletion or delays maturation of a certain subset of mature B cells” that recognize polysaccharide antigens that contain repeating sequences.

·        Lack or deficiency in suppressor T cells may cause increased B cell function.

(All of the information for this section comes from Putterman and Naparstek 1994)


How can SLE be treated?

            Medications and/or therapies are often used to suppress the response of the immune system.  The medications are collectively referred to as immunosuppressive medications and include corticosteroids, methotrexate, cyclophosphamide, azathioprine, and cyclosporin. (National Institute of Allergy and Infectious Diseases 1999)  Corticosteroid treatment is correlated with a decrease in anti-dsDNA antibodies.  When levels of anti-dsDNA antibodies are high, treatment with steroids can be a preventive method to control relapses. (Arbuckle et al. 2001)  Anti-malarials (like hyrdoxychloroquine), non-steroidal anti-inflammatory drugs (including ibuprofen and naproxen), and new generation non-steroidal anti-inflammatory drugs (like celecoxib and rofecoxib) can also be used to treat SLE. (Rossiter 2002) Side effects of these drugs can be serious, and therefore patients must be monitored closely. (National Institute of Allergy and Infectious Diseases 1999)


What research is currently being conducted?

The National Institute of Allergy and Infectious Diseases is concentrating on five main areas.  First, researchers are studying the immune system during the progression of an autoimmune disease. Second, there are studies on the genetic role of autoimmunity.  Third, the part of infectious agents plays in causing or progressing the development of an autoimmune disease.  In the fourth place, animal models provide a great model for study.  Lastly, researchers are trying to gain insight into the effects that therapy may have on the immune system in autoimmune patients. (National Institute of Allergy and Infectious Diseases 1999)  While these studies are general, they are still valuable to learning about SLE.



Arbuckle, M.R., James, J.A., Kohlhase, F., Rubertone, M.V., Dennis, G.J., and Harley, J.B. 2001. Development of Anti-dsDNA Autoantibodies to Clinical Diagnosis of Systemic Lupus Erythematosus. Scand. J. Immunol. 54: 211-219


Bijl, M., Horst, G., Limburg, P.C., and Kallenberg, G.M. 2001. Anti-CD3-induced and anti-Fas-induced apoptosis in systemic lupus erythematosus (SLE). Clin. Exp. Immunol. 123: 127-132


Bussolati, B., Rollino, C., Mariano, F., Quarello, F., and Camussi, G. 2000. IL-10 stimulates production of platelet-activating factor by monocytes of patients with active systemic lupus erythematosus (SLE). Clin. Exp. Immunol. 122: 471-476


Cleveland Clinic Health System. November 28, 2001. “What You Need to Know About Systemic Lupus Erythematosus (SLE)” (April 12, 2003)


Faber-Elmann, A., Sthoeger, Z., Tcherniack, A., Dayan, M., and Mozes, E. 2002. Activity of matrix metalloproteinase-9 is elevated in sera of patients with systemic lupus erythematosus. Clin. Exp. Immunol. 127: 393-398


Gray-McGuire, C., Moser, K.L., Gaffney, P.M., Kelly, J., Yu, H., Olson, J.M., Jedrey, C.M., Jacobs, K.B., Kimberly, R.P., Neas, B.R., Rich, S.S., Behrens, T.W., and Harley, J.B. 2000. Genome Scan of Human Systemic Lupus Erythematosus by Regression Modeling: Evidence of Linkage and Epistasis at 4p16-15.2. Am. J. Hum. Genet. 67: 1460-1469


Janeway, C., P. Travers, M. Walport, and M. Shlomchik. 2001. Immunobiology, 5th ed. Garland, NY, pp. 505, 685


Kassi, E.N., Vlachoyiannopoulos, Moutsopoulos, H.M., Sekeris, C.E., and Moutsatsou, P. 2001. Molecular analysis of estrogen receptor alpha and beta in lupus patients. Euro. J. Clin. Invest. 31: 86-93


Mozes, E., and Shoenfeld, Y. “Experimental Systemic Lupus Erythematosus: Role of the Idiotypic Network” In Autoimmune Models: A Guidebook, edited by I.R. Cohen and A. Miller, 217-243. San Diego: Academic P, Inc., 1994.


National Institute of Allergy and Infectious Diseases. September 27, 1999. “Understanding Autoimmune Diseases” (April 16, 2003). 


National Institute of Arthritis and Musculoskeletal and Skin Diseases. February 2003. “Genetic "Signature" Linked to Severe Lupus Symptoms” (April 16, 2003).


Purves, W.K., Orians, G.H., Heller, H.C., and Sadava, D. 1998. Life: The Science of Biology, 5th ed. W.H. Freeman, Salt Lake City, glossary.


Putterman, C. and Naparstek, Y. “Murine Models of Spontaneous Systemic Lupus Erythematosus.” In Autoimmune Models: A Guidebook, edited by I.R. Cohen and A. Miller, 217-243. San Diego: Academic P, Inc., 1994.


Rossiter, R. 2002. Caring for the patient with systemic lupus erythematosus. ANJ 47: 1-4


Stone, N.M., Williams, A., Wilkinson, J.D., and Bird, G. 2000. Systemic lupus erythematosus with C1q deficiency. Brit. J. Dermatol. 142: 521-524


Sun, K.H., Yu, C.L., Tang, S.J., and Sun, G.H. 2000. Monoclonal anti-double-stranded DNA autoantibody stimulates the expression and release of IL-1β, IL-6, IL-8, IL-10 and TNF-α from normal human mononuclear cells involving in the lupus pathogenesis. Immunology 99: 352-360


Tsunoda, S., Kawano, M., Koni, I., Kasahara, Y., Yachie, A., Miyawaki, T., and Seki, H. 2000. Diminished Expression of CD59 on Activated CD8+ T Cells Undergoing Apoptosis in Systemic Lupus Erythematosus and Sjögren’s Syndrome. Scand. J. Immunol. 51: 293-299


Zapor, M., Murphy, F.T., and Enzenauer, R. 2001. Echolalia as a Novel Manifestation of Neuropsychiatric Systemic Lupus Erythematosus. Southern Medical J. 94: 70-72


Zhang, W., Winkler, T., Kalden, J.R. and Reichlin, M., 2001. Isolation of Human Anti-idiotypes Broadly Cross Reactive with Anti-dsDNA Antibodies from Patients with Systemic Lupus Erythematosus. Scand. J. Immunol. 53: 192-197




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