SLE or “lupus” is used to describe a chronic potentially debilitating or fatal autoimmune disease in which the immune system attacks the body’s cells and tissue. SLE is a prototype autoimmune and multifactorial disease characterized by the presence of autoantibodies to a diverse array of nuclear antigens including DNA, RNA and histones. These naturally occurring autoantibodies are heterogenous, exhibiting a wide heterogeneity in the recognition of nucleosides and nucleotides.
Causes:
The specific cause of SLE is unknown. SLE is considered to be a multifactorial condition with both genetic and environmental factors involved. However, it is known that a group of genes on chromosome 6 that code for the human leukocyte antigens play a major role in a person’s susceptibility or resistance. The specific HLA antigens are DR2 and DR3. Femailes in their childbearing years (18-45) are also 8-10 times more likely to acquire SLE than men.
Deficiency in Complement Components:
Deficieincy of C1q, Clr, Cls or C4 is closely linked to defvelopment of systemic lupus erhthematosus (SLE) (as well as rheumatoid srthrisis) thought be be due in part to the inability of complement to clear immune complexes and dysing cells. Small complexes are cleaved from the circulation when they bind to complement receptors on macrophages in the speen and liver. Without complement, the complexes can grow too large to be easily cleared. The resulting aggregates can activate the alternative pathway, allowing C3 to be deposited into the matrix, with re-solubilized complexes that can be dealt with by the clearance through the liver and spleen. Failing this, these large complexes are no longer soluble and form deposits in the tissues and become a site of inflammation. Dying cells if not cleared by non-inflammatory CP activity, may serve as sources of altered self-antigens with the potential for inducing autoantibodies. (US Patent Applicaiton No: 15/895,551, published as US 2019/0247560).
–C2 deficiency: is the most common complement deficiency in Caucasian populations with a frequency estimated between 1-10,000 for homozygous C2 deficiency patients. C2 deficiency is found in a slightly higher proportion of SLE patietns comapred to healthy controls. (US Patent Applicaiton No: 15/895,551, published as US 2019/0247560).
Diagnostic Tests:
There is no single test that can diagnose SLE. Some tests include urinalysis to detect kidney problems, tests to measure the amount of complement proteins in the blood, complete blood cell counts to detect hematological disords and an ANA test to detect antinuclear antibodies in the blood. Studies from various laboratories have shown that after modification with ROS, DNA becomes highly immunogenic (Tasneedm, J. Autoimm. 2001, 199-205). Blount has postulated ROS-modified DNA as a more discriminating antigen for the diagnosis of SLE.
Complement Components: Measurement of serum C3 and serum C4 has traditionally been the gold standard for monitoring disease activity in patients with SLE. Howevere, tseveral major weakness of this approach are the wide range of variation of serum C3 and serum C4 levels among healthy individuals which overlaps with that observed in patients with SLE. Another problem is that C3 and C4 are precursors rather than products of complement activation. Kao (Arthritis Rheum. 2010 March; 62(3): 837-844) disclose that proteolytic fragments of complement component C4, particularly C4d, are present on the surface of normal erythrocytes and that patients with SLE have significantly higher levels of erythrocyte bound C4d and lower levels of erythrocyte expressing complement receptor 1 than patients with other diseases and healthy controls.
Symptoms:
There are 11 criteria that help doctors tell the difference between people who have SLE and other connective tissue diseases. If a person displays 4 or more of the following 11 criteria, the person fulfills the requirement for diagnosis of SLE. 1. Malar rash (a butterfly shaped rash over the cheeks and across the bridge of the nose) 2. discoid rash (scaly disk shaped sores on the face, nect and chest 3. serositis (inflammation of the lining around the heart, lungs, abdomen, causing pain and shortness of breath 4. photsensitivity (skin rash as an unusual reaction to sunlight 5. sores and ulcers on the tongue, mouth or in the nose, 6, arthritis, 7, kideny disorder such as persistent protein or cellular cysts in the urine 8. central nervous system problems including seizures and psychosis and 9. blood problems such as low white blod cell count, low lymphoctye count, low platelet count or hemolytic anemia, 10. immune system problems such as prsence of abnormal autoantibodies to double stranded NA and 11. presence of abnormal antinuclear antibodies in the blood.
While for the most part antigenic DNA is localised to the cell nucleus and presumably becomes available as a result of cell death, evidence has been presented for the existence of DNA that is associated with the outer leaflet of the plasma membrane. This cmDNA can be a specific target for IgG autoantibodies from SLE patients. It has also been shown that autantibodies from SLE patients show a specificity, unrelated to ds- or ss-DNA which can be visible and can serve as a marker for SLE (Servais, Ann Rhuem Dis 1998, 606-618).
Treatment:
Traditional Treatment: Traditional treatments of SLE include non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors and salicylates (such as aspirin), anti-malarials such as hydroxychloroquine, quinacrine, corticosteroids and immunosuppressants such as methotrexate (Rheumatrex).
Antibody Treatment: Various antibodies which target relevant biomolecular markers believed to be involved in SLE are now available. ——-INF-alpha: Rontalizumab targes IFNalpha which is expressed by DCs.
–CD80/86: Abatacept targets CD80/86 on MDC which interacts with CD28 on T cells. At the B cell-T cell interaction level, Abatocept targets CD80/86 on B cells which is necessary for interaction with CD28 on T cells. Lupuzor targets T cells.
–CD22: Epratuzumab targets CD22 and Retuximab targets CD20 on B cells (Ding, Current Opinion in Pharmacology, 2013, 13: 405-412). Originally developed for the treatment of non-Hodgkin lymphoma, epratuzumab has now been reported to be effective, with a very good safety profile, in two prototype autoimmune diseases, systemic lupus erythematosus and primary Sjogren’s syndrome (Dorner, “Targeting CD22 as a strategy for treating systemic autoimmune diseases” Therapeutics and Clinical Risk Management 2007: 3(5) 953-959).
CAR T cells:
–CD19 CART cells are being explored for treating systemic lupus erythematosus (SLE) which is caused by B cells. Depleting B cells is an unwanted side effect for cancer patients but is beneficial for lupus patients. (Ferriera “using Regulatory T cells for treatment of Type 1 diabetes, Part 2” BioProcess International 21(5) March 2023).