Autoimmune disease occurs: inappropriate response of the immune system against self-components 2 types of autoimmune diseases: Organ specific (directed to a target antigen unique to a specific organ or gland) Systemic -> has a broad range of antigens and involves many organs and tissues Responses in SLE: widespread inflammation in multiple organs, blood vessels, and other connective tissues in the body Inflammation is caused by a profound immune alteration that leads to the development of T cell and antibody responses Tissue damage occurs as a result of cell mediated immune responses and direct damage caused by auto-antibodies or accumulation of immune complexes Autoantibodies found in SLE: DNA, histones, RBCs, platelets, leukocytes, clotting factors Autoantibodies specific for RBC’s and platelets can lead to complement-mediated lysis
Disease Course and Cause of Death: Series of Flare and Remissions Multiple causes of death Symptoms: fever, weight loss, rash (butterfly rash), hair loss, oral ulceration, central nervous system involvement (Cognitive Dysfunction, Lupus Headache, Seizures) Nephritis (Kidney problems), Joint Pain/Arthritis (Arthralgia), blood disorders, liver problems (serositis) What causes the symptoms? Most of the symptoms of this disease result from the formation of immune complexes that deposit within various tissues where they recruit complement and inflammatory cells to cause disease Type III hypersensitivity reaction
What causes SLE is still unknown but it is thought to have a multi-faceted etiology. There are possible genetic and environmental factors Genetic factors: Predispose an individual to have this disease 10% of individuals who have this disease have a family member who also has this disease. Clear gender and cultural bias for this disease: women are 10 times more likely than men to get this disease. African American women (40% of all cases) and Hispanic women are more likely to get this disease than Caucasian women. Genes that control the predisposition to have an autoimmune disease are heterogeneous and are not completely understood at this time Gene that are thought to be related: MHC alleles, complement genes (C4, C2), cytokine genes, and complement receptors Environmental factors can trigger the disease in genetically predisposed individuals: Most correlated is the presence of female hormone ultraviolet light, certain drugs, various infectious agents
T cells play a significant role in the pathogenesis of SLE. Autoreactive T cells are found in the periphery of healthy individuals and those with SLE Normally cells are anergic or undergo activation-induced cell death In order for T cells to react with self antigen they must lose their self-tolerance. Potential mechanisms of this loss include the exposure of cryptic or neoepitopes, abnormal antigen processing, inappropriate help, excess co stimulation, abnormal activation threshold for signaling cells insufficient or inappropriate T regulatory cells Abnormalities in the co stimulatory signals could be one factor that leads to the loss of T cell self-tolerance. There is impaired regulation of the expression of the CD40 ligand (CD40L) in individuals with SLE; it is hyperexpressed. This leads to the activation of lupus T cells through subthreshold stimuli and presentation of apoptotic material by APC. Proliferation of these T cells is necessary to sustain autoantibody producing B cells. This occurs partly because of the prolonged costimulation of the cell through the CD40/CD40L interaction (Hoffman 2004). Once T cell tolerance is lost the T cell is able to react with a number of self-antigens.
B cell produce cytokines which directly affect the organs diversification of antigen-driven responses. The initial autoimmune response has not yet been determined, but it has been suggested that this response is restricted to a few epitopes One theory Antigen-driven response is restricted to a few epitopes Antigenic epitopes are present on apoptotic cells processed and presented by APC to activated Th cells. The T cells then provide the help necessary to create the first autoreactive B cells. The epitopes on the variable region of Ig on these autoreactive B cells are then processed and presented. This stimulates a second round of T helper cells. This process continues and over time this response amplifies and instead of just responding to that specific epitope response diversify to include different antigens Release of antibodies which bind to their antigens to form immune complexes build up in areas such as blood vessels and the kidney Complement system is called upon to clear up these immune complexes -> inflammation and tissue damage Type III hypersensitivity reaction Direct release of cytokines which leads to tissue damage
A lot of auto-antibodies being secreated which react with self antigen They bind to form an immune complex Complement system is activated to clear these immune complexes lead to tissue damage Complement activation leads to complement intermediates that mediate mast-cell degranulation chemotactically attract neutrophils Stimulate the relase of lytic enzymes from neutrophils trying to phagocytose the immune complexes unsuccessful b/c anchored in membranes causes the most damage in SLE
Therapies do not cure, only alleviate symptoms. They work by providing nonspecific supression of the immune system (do not distinguish between pathologic autoimmune response and protective immune response) The first therapies used for the treatment of SLE were cytotoxic drugs. These treatments were not very successful and left researchers looking for more effective therapies Immunosuppressions are given with the intent to slow proliferation of lymphocytes. By depressing immune response in general, such drugs can reduce severity of autoimmune symptoms. Put patient at greater risk for infection or development of cancer because the immune system is suppressed in general. The most common immunosuppression used is cyclophosphamide. This drug is a lymphocyte proliferation inhibitor. A more recently discovered drug, mycophenolate mofetil, targets both B and T cells and has been found to be as effective as cyclophosphamide (Franchin 2004). Although immunosuppressions have been very successful at treating SLE they have dangerous, toxic side effects (Sidiropoulos 2004). Researchers are currently in the process of looking for new treatments for SLE. Two possible treatments that are being investigated include hormonal modulation and cytokine inhibition (Franchin 2004).