Systemic Lupus Erthymatosus
Introduction to the Immune System
The human immune system is a group of mechanisms that helps the body to fight off infections caused by pathogens. The mechanisms of the immune system include intracellular sensors and signaling molecules that are in all cells, and specialized hematopoietic cells and serum proteins that provide ways for recognizing pathogens in any site in the body [book]. The first part of the immune system that a pathogen encounters is the skin. If a pathogen is able to breach the skin, the chances of an infection increase greatly. Other susceptible areas of the body include the mucosal epithelia of the gastrointestinal, respiratory, and urogenital tracts. Because of the increased susceptibility, these parts of the body are rich in immune defense mechanisms [book].
The immune system is further divided into two systems: the innate immune system and the acquired immune system. The innate immune system is the body’s first line of defense and consists of molecules and cells that determine recognize might work better the difference between the body’s own cells and infectious agents. The cells of the innate immune system are known as leukocytes. These innate leukocytes are natural killer cells, mast cells, eosinophils, basophils; and the phagocytic cells including macrophages, neutrophils and dendritic cells [book].
The innate immune system is the immediate response to a pathogen, but it is not a long-lasting protective immune response. Since microbes are capable of mutating at rather quick rates, it would be assumed that the microbes would evolve ways to avoid our immune system. umm but the innate immune system recognizes parts of the microbe that are nessiary for their survival. for exmaple, gram negative bacteria cannot mutated out LPS from there outermembrane becuase LPS is nessicary for the stability of it. SO i would doulble chekc this or reword it because right now it is not true. For this reason, the human immune system has evolved to form an immune system which, unlike the innate immune system, has a “memory” that allows for recognition of a pathogen much quicker if it were re-introduced into the body. The adaptive immune system is activated by the innate immune system and can provide a stronger defense each time the pathogen is encountered.
The adaptive immune response is mediated by lymphocytes, which produce antibodies in response to an encounter with a pathogen. Lymphocytes are classified into two types: T cells and B cells. T cells mature in the thymus and activate other cells of the immune system, along with killing virus-infected cells. B cells mature in bone marrow and secrete antibodies [book]. I feel like this paragraph should be part of the preceding paragraph, not on its own
Introduction to Autoimmune Diseases
When the immune system malfunctions and fails to recognize the difference between self-cells and a foreign agent, the result is an autoimmune disease. The failure to recognize self-cells results in the production of self-antibodies, or autoantibodies, which attack the body’s own cells and tissues. The production of these autoantibodies results in inflammation and damage of the cells or tissues affected. The cause of an autoimmune disease is unknown, but it is suggested that one’s genes may play a role in the susceptibility of an autoimmune disease. There are two categories of autoimmune diseases: systemic, affecting the whole body; and localized, affecting only one organ of the body. Although an effort is made to distinguish a difference between these two categories, the difference between them often times becomes blurred due to one organ indirectly affecting other parts of the body.
Lupus
Systemic lupus erythematosus (SLE or lupus) is an autoimmune disease in which an individual produces antibodies that attack the body’s own tissues, which are presenting self-antigens resulting in inflammation and death of the body’s cells [5] [22]. Symptoms of lupus include fatigue, joint pain and swelling, skin rashes, and chest pain as well as neuropsychiatric symptoms including amnesia, dementia, mood disorders, strokes, and seizures [9] [23]. More severe complications of lupus include nephritis, central nervous system vasculitis, pulmonary hypertension, interstitial lung disease, and stroke [23].
Types of Lupus
Most often when people refer to lupus they mean the systemic form or SLE. SLE is the most extreme form of lupus, and may have effects on all different systems of the body [website]. No two people with SLE experience the same kind of symptoms, with many patients going through stages of remission, with no visible symptoms, and flares, where the disease becomes more active and symptoms are more evident [website].
Other than SLE, other types of lupus include; or : drug-induced lupus erythematosus, discoid lupus erythematosus, and neonatal lupus. Drug-induced lupus (DILE) is a lupus-like disorder that is caused by agents such as physical, chemical, and food products [Drug-induced lupus: an update]. The most common drugs known to lead to the development of DILE are; procainamide, a drug used for heart abnormalities, hydralazine, used in controlling hypertension, and isoniazid, a drug used in the treatment of tuberculosis [Lupus Foundation]. Symptoms of DILE are similar to that of SLE, but DILE is a reversible condition while SLE is not. Discoid lupus is a form of SLE affecting only the skin, which is accompanied by light sensitivity, prominent red-purple lesions, or a scaly rash [autoantibodies to evolutionarily conserved…]. Sometimes patients with discoid lupus may develop the systemic form of lupus. This evolution of discoid lupus to SLE cannot be prevented with treatment of discoid lupus, and is often is unpredicted [website]. Neonatal lupus erythematosus occurs in infants when autoantibodies are transferred through the placenta from the mother to the fetus. This only occurs in around 5% of individuals born from individuals with lupus [Lupus Foundation]. Although rare, infants born with neonatal lupus may have skin rashes, problems with their liver or blood, or congenital heart block. [Neonatal lupus erythematosus complicated]. Non-cardiac symptoms generally subside after one year without treatment [52-kDaro/ssa].
Genetics and Lupus
Genetic predisposition is an important factor for the development of SLE, with 20% of people with lupus having a parent or sibling that also has the disease [Lupus Foundation]. Although genetics play a role, environmental factors also play a large role in the development of lupus. No single chromosome is thought to be directly related to SLE; however, recent murine studies have suggested that there are multiple genetic loci contributing to autoimmunity [6]. These genetic loci contribute by either increasing or decreasing susceptibility for SLE or other autoimmune diseases. One example is CD24, an autosomal gene which codes for the cell surface protein, CD24, which deals with clonal expansion of T cells after their migration to the central nervous system. Studies have shown that a two nucleotide deletion in the non-coding region of CD24 mRNA reduces one’s risk of developing SLE by 2-3 times [23]. Other proteins that affect T cell proliferation are CD40, CD80, and CD54. An increase in the expression of CD40 and a decrease in the expression of CD80 and CD54 are linked to SLE. The over-expression of CD40 is thought to be caused by an environmental stimulus, rather than a genetic factor. Also, an increase in CD40 may play a role in disease pathogenesis since it is present in one’s system months before the onset of SLE symptoms [7].
SLE susceptibility is also linked to the presence of three loci, I think this coma needs to be a : or ; Sle1, Sle2, and Sle3. These three loci are associated with different lupus phenotypes but for the full-blown development of SLE (marked by anti ds-DNA, nephritis, lymphadenopathy, splenomegaly, and mortality) an epistatic interaction of Sle1 with other loci is required. Findings of a study done on murine models shows that the expression of Slebz prohibits the deletion of immature B cells, therefore enabling the possibilities of the B cells to get stimulated ion, Just to Clarify that I would put "B cell stimulation" by self-antigens. Also, results from this study showed that expression of Slebz makes dendritic cells (DCs). This is crucial in SLE because DCs play a major role in the perpetuation of autoimmunity, both systemically and locally [24].
Diagnosis of Lupus
SLE is difficult to diagnose due to the fact that many of the symptoms associated with SLE are also symptoms of other diseases. The Lupus Foundation estimates that 1.5 to 2 million people in the United States have some form of lupus, but due to its difficulty in diagnosing this number may be higher [Lupus Foundation]. For a doctor to diagnose someone with SLE, there are three things that a doctor will review: the individual’s medical history, the analysis of routine laboratory procedures, and some specialized tests related to their immune status. To be diagnosed with SLE, an individual must show signs of abnormalities in several organ systems [lupus foundation]. Tests that an individual might undergo if they he/she show symptoms of SLE include sedimentation rate and C-protein reactive binding (elevated levels are due to inflammation), serum protein analysis (test for irregular rates of gammaglobulin and albumin), blood counts (test for anemia and low platelet counts), and routine chemistry panels (to determine kidney, liver, and muscle involvement) [lupus foundation].
Researchers have also found different ways to come to a lupus diagnosis. These include testing for the presence of anti-DNA antibodies which may be the cause of some renal and brain manifestations of SLE [16, 9]. Another recent study has shown that the presence of certain proteins, Fas and Bcl-2, in kidney cells may also be a diagnostic marker [10]. could you explain what fas and bcl-2 is? These proteins are also higher in the blood serum of those with lupus compared to those that do not have lupus [10].
The Immune System and Lupus
Certain parts of the innate immune system are thought to be closely linked to the pathogenesis of SLE. A study done in lupus-prone mice showed that after the onset of SLE, dendritic cells (DCs) expressed decreased levels of CD80 and CD54, normal levels of CD86, and increased levels of CD40 [7]. The overexpression of CD40 is most relevant because it is suggests that it may be linked to SLE development. CD40 triggering could be responsible for the over-stimulation of DCs to live longer, which would result in an excess production of pro-inflammatory cytokines that would send activation signals to autoreactive T and B cells [7].
The adaptive immune system is also involved in patients with SLE. Recent studies have shown that Toll-like receptors (TLRs) may play a major role in the pathogenesis of autoimmunity, most notably TLR3,-7,-8, and -9. These receptors are intracellular receptors and recognize nucleic acid motifs (double-stranded or single-stranded RNA, as found in some viruses). Along with TLRs, it is thought that interferons (IFNs) are also thought to play a role in the pathogenesis of SLE. IFN-γ is considered a core cytokine in SLE pathogenesis, but recent studies show type-1 IFNs are also involved. Increased concentrations of IFN-α are directly linked to SLE activity and severity. The excess IFN-α concentration is thought to come from the main producers of type-1 IFNs, plasmacytoid dendritic cells (pDCs). pDCs secrete IFN-α in response to an infection by a DNA virus and following stimulation with CpG inhibitory oligodeoxynucleotides (ODNs) [17].
Another way in which the adaptive immune system is involved in the pathogenesis of SLE is the translation rates and initiation factors in patients with SLE. Translation rates are important in a cell because it regulates cell proliferation, which is accompanied by increased protein synthesis. Results from an experiment done by Annabelle Grolleau indicate that the modification of T cell gene expression and signaling that leads to SLE are due to abnormally increased expression of the protein kinase PKR. PKR does what exactly?Upregulation of PKR impairs cell functions that are exhibited by SLE immune cells. These functions include: cell proliferation, Fas-dependent apoptosis, cytokine gene expression, and signaling [13].
SLE pathogenesis and disease activity is also connected to immunoglobulin G (IgG) antibodies to ds-DNA markers in sera. These antibodies are rarely found in the blood of people with other diseases and therefore these antibodies are thought to be specific for SLE. Antibodies to DNA (anti-DNA) cause damage to tissues in the body, but the severity of the damage among anti-DNAs is variable. In a study conducted in mice, the properties that make anti-DNA pathogenic were investigated. Results showed two anti-dsDNA exists in sera of patients with SLE and the antibodies that recognize ds-DNA presented on DNA-binding proteins can be linked to SLE pathology because these antibodies are SLE specific [16].
Treatments of Lupus
Although SLE is not curable and the cause is unknown, treatments are available that alleviate symptoms and extend survival. Treatment approaches are different for each patient and depend greatly on the symptoms they display [Lupus Foundation]. Common medications prescribed for those with SLE often include; NSAIDs (non-steroidal anti-inflammatory drugs), which alleviate some pain and inflammation, corticosteroids, which are used to reduce inflammation and suppress the immune system, and cyclophosphamide, which also suppresses activated immune cells. Prolonged use of these therapies is often ineffective and with extensive use may be toxic to the body. Therefore, other therapies are undergoing research.
A possible factor that may contribute to autoantibody production is the reduction of apoptotic cell debris clearance by macrophages. Recent studies have shown that macrophages do play a role in SLE pathogenesis because they become activated during the development of SLE. For example, activated macrophages are prevalent in the kidneys of SLE patients and enhance the production of inflammatory cytokines like INF-γ, TNF-α and reactive oxygen species, but are absent in the kidneys of healthy individuals. I think this last sentence might be a run on, double check Therapies that would prevent the recruitment, proliferation, and activation of macrophages would alleviate symptoms and slow tissue destruction. Activated macrophages express the β form of the cell surface folate receptor (FR-β). Folate targets attached drugs to FR-expressing cells; therefore, it is suggested that drugs can be delivered specifically to activated macrophages without harming healthy tissue. As seen in a study done at Purdue University, folate-hapten-targeted immunotherapy (FHTI) was administered to mice at ten weeks of age that had started showing signs of SLE. FHTI eliminated all histological signs of glomerulonephritis and inflammatory damage done to other tissues, as well as showing decreased amounts of macrophages in the treated mice. The mice showed normal behavior and treatment with FHTI extended their life [22].
The Effects of Lupus on Different Organ Systems
Lupus, due to its autoimmune characteristic, causes damage and inflammation to many different organs and organ systems within the body. The most severe manifestations of the disease, however, most commonly occur in the kidneys, skin, joints, vascular and nervous system.
An unfortunate effect of SLE is renal damage. In some patients the damage progresses to the point of kidney failure (end-stage renal disease, or ESRD). Studies show that younger, hypertensive, African-American or Hispanic (from Texas) ethnicity individuals are more likely to develop kidney problems. As stated earlier, one’s genes could affect their his/her susceptibility of developing SLE. In particular, the low binding allele of FCGR3A (the FCGR3A*T allele) is thought to be associated with renal damage in patients with SLE. The genes FCGR2A and FCGR3B are also thought to be related to renal disease in patients with SLE. Test results suggest that the genetic factors influencing organ disease progression differ from the genetic factors that determine initial disease susceptibility. Results also showed that the low binding allele of FCGR3A affects the SLE phenotype because it lowers the capacity to handle immune complexes. However, once the organ damage is initiated the higher binding allele of FCGR3A may cause more activation and greater local damage [1].
Another study done on the effect of SLE on the kidneys examined increased serum levels of Bcl-2 and Fas proteins. Bcl-2 is responsible for cell survival, while Fas is responsible for apoptosis. It is known that apoptosis plays a role in autoimmune diseases because it regulates the number of B cells in an individual. As stated earlier, when the B cells attack the body’s own tissues, the result is an autoimmune disease. In SLE, the dysfunction of apoptosis can lead to a longer life of B cells and higher autoantibody levels. It is thought that variations in the concentrations of BCL-2 and Fas proteins may lead to lupus nephritis. Studies revealed that glomerular expression of BCL-2 and Fas proteins is only observed in patients with SLE and can therefore be used in the diagnosis of a patient. The reason for the elevated levels of these proteins is the occurrence of circulating T and B lymphocytes that express Bcl-2 and Fas at abnormally high concentrations. Overall, the co-expression of Bcl-2 and Fas proteins suggests that both apoptosis and proliferation play a role in lupus nephritis, which is found in many SLE patients [10].
Another system that is greatly affected by lupus is the vascular system, with complications including vasculitis, vasospasm, thromboembolism, and artherosclerosis [21, peripheral vascular disease]. Research has found that 6-10% of patients with lupus develop premature artherosclerosis, hardening of the blood vessels, with this becoming an important cause for death in patients with lupus [peripheral vasc disease].
SLE has also been known to affect the central nervous system (CNS) by producing anti-neuronal antibodies. When this occurs it is referred to as neuropsychiatric SLE (NPSLE) and can lead to impairment of cognition or mood disturbance [8]. In a study done that examined a magnetic resonance image (MRI) of the brain in a 69 year old male diagnosed with NPSLE, hyperintensities were found in the bilateral cerebellar hemispheres, middle cerebellar peduncles, periventricular white matter, and the deep white matter of the brain.
Prevalence of Lupus
Everyone may be at risk of getting lupus, but there are certain populations where the occurrence of the disease is more prevalent. Women, for example are more apt to get develop lupus, with 90% of all cases effecting women. Of these women with lupus, 80% are within child-bearing age, between 15-45 years of age [Lupus Foundation]. Also, women with ethnic backgrounds are more likely to develop the disease. African American women are three times more likely to develop the disease than Caucasian women, with Native Americans and Hispanic women also being more susceptible to the disease [Lupus Foundation]. Although ethnic women may be more susceptible to the disease, the symptoms they experience when they have the disease are often more severe. This sentence is awkward, try this…Ethnic women are not only more susceptible to the disease, but also experience more severe symptoms. African American and Hispanic women develop lupus at a younger age, and present with more symptoms [Lupus Foundation]. The more severe manifestations of the disease seen in these ethnicities include severe seizures and strokes in African American women, and increased occurrence of heart problems in Hispanic women [Lupus Foundation]. There has been no evidence as to why a difference in ethnicity would account for the more severe symptoms.
Men, although rare, may also develop lupus, and the possibility of developing lupus increases as men age. The increased occurrence of lupus in women compared to men is believed to be due to hormones. Researchers have come to this conclusion due to the increase in symptoms before menstrual cycles and during pregnancy, where estrogen is at its highest level [Lupus Foundation]. Drug-induced lupus is one form of lupus where the occurrence of the disease is greater in men than in women. This increase is due to the larger number of men taking the drugs associated with drug induced lupus [Lupus Foundation].
Conclusion
The immune system is our defense against many different pathogens, and when working properly, works to it defends us against foreign invaders with antibodies. In an autoimmune disease the body not only produces antibodies against invaders, but it also produces autoantibodies that attack our own tissues. Lupus is one such disease where the body’s immune system attacks itself, and this causes ing problems in many different organs and organ systems. Lupus may be genetically determined, but may also develop due to environmental factors. Anyone may develop lupus, but it is most commonly seen in African American and Hispanic women. The cause for autoimmune diseases in is unknown and there has been no found cure, but many research is being done in the area. Reread your last sentence, focusing from "but" on