Pathophysiology
Summary
Systemic lupus erythematosus (SLE) is a complex autoimmune disease that predominantly affects young women between their 20s and 30s. SLE is a textbook example of autoimmunity, in which the immune system erroneously targets the body's own cells. Genetic factors play a significant role in this predisposition; certain human leukocyte antigen (HLA) alleles, including HLA-B27, an MHC class I allele, as well as HLA-DR & HLA-DQ, which code for MHC class II molecules, are known contributors. These genetic factors, along with environmental triggers such as infections, drugs like procainamide & hydralazine, and toxins like cigarette smoke combine to initiate the autoimmune process. Molecular mimicry can also occur in certain infections, further fueling the autoimmune response.
SLE is associated with the production of various auto-antibodies, particularly the presence of anti-nuclear antibodies (ANAs)anti-double-stranded DNA and anti-Smith antibodies, as well as anti-U1 RNP antibodies and anti-Ro/La antibodies. Other autoantibodies linked to SLE include those RBC, platelet, and lymphocyte antibodies, causing conditions such as autoimmune hemolytic anemia, immune thrombocytopenia, and decreased lymphocyte count respectively. Notably, the antiphospholipid antibodies in SLE can give rise to antiphospholipid syndrome, characterized by a pro-thrombotic state and risk of pregnancy loss. Drug-induced lupus, in contrast to SLE, manifests with anti-histone antibodies and manifests as fatigue and arthralgia without involvement of the skin, kidneys, or CNS.
The pathogenesis of SLE involves the formation of immune complexes when ANAs bind to their respective antigens. These complexes deposit in various tissues, igniting inflammation through a type III hypersensitivity reaction. Activation of the classical complement pathway ensues, resulting in tissue damage. This is often indicated by decreased levels of C3 and C4 during disease flares.
Clinically, SLE manifests a broad spectrum of symptoms. These range from constitutional symptoms to more specific issues such as glomerulonephritis, characterized by immune complex deposition in renal glomeruli. Cutaneous symptoms include the hallmark malar rash or discoid rashes, often exacerbated by UV light. Immunofluorescence of SLE-affected skin shows Ig and complement deposition. Multiple organ systems can be affected in SLE, resulting in arthritis, vasculitis, Raynaud phenomenon, pericarditis, and Libman-Sacks endocarditis (predominantly affecting the mitral valve). Neurological manifestations include cognitive impairment, seizures, & stroke.
Lesson Outline
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FAQs
In autoimmune diseases, the immune system erroneously targets self-antigens, causing damage to the body's own tissues. In SLE, a complex autoimmune disorder, the formation of auto-antibodies is a key factor in its pathogenesis. These auto-antibodies target antigens usually confined to the cell nucleus. They form immune complexes that deposit in various tissues, activating the classical complement pathway and leading to inflammation and tissue injury.
Genetic predisposition significantly influences the risk of developing autoimmune diseases. Specific human leukocyte antigen (HLA) alleles, including HLA-B27, HLA-DR, and HLA-DQ, are associated with a heightened risk for autoimmune conditions. In the context of SLE, the presence of HLA-DR and HLA-DQ alleles, which encode for MHC Class II molecules, increases susceptibility.
Several environmental triggers can initiate autoimmune diseases. Infections, either viral or bacterial, can incite the immune system to attack self-antigens, possibly due to molecular mimicry. Specific drugs like procainamide, hydralazine, and isoniazid can induce autoimmune responses, leading to conditions such as drug-induced lupus. Toxins like cigarette smoke have also been linked to autoimmune diseases, specifically rheumatoid arthritis. Additionally, estrogen exposure may increase the risk of developing SLE.
SLE can present with various hematological abnormalities, including autoimmune hemolytic anemia and immune thrombocytopenia. Autoimmune hemolytic anemia occurs due to antibodies targeting red blood cells, leading to their premature destruction. Immune thrombocytopenia is caused by antibodies against platelets, resulting in low platelet counts and an increased risk of bleeding. Additionally, SLE may lead to a decreased lymphocyte count, specifically affecting regulatory T cells, due to the presence of antibodies against lymphocytes.
SLE is characterized by a range of specific auto-antibodies. The disease frequently presents with anti-double stranded DNA antibodies, which are highly specific to SLE. Other associated antibodies include anti-Smith, anti-Ro (SSA), anti-La (SSB), and anti-U1 RNP antibodies. These auto-antibodies form immune complexes that deposit in tissues, triggering inflammation and resulting in tissue damage.
