Autoimmune Disease:Systemic Lupus Erythematosus - Term Paper Example

IMMUNOLOGY- AUTOIMMUNE DISEASE: SYSTEMIC LUPUS ERYTHROMATOSUS (LUPUS) Student’s name: Instructor’s name: Institution: Course: Date: TABLE OF CONTENTS TITLE PAGE Abstract 2 SYSTEMIC LUPUS ERYTHEMATOSUS (LUPUS) Basic mechanism 3 Diagnosis of SLE 6 Treatment of SLE 9 References 11 LIST OF TABLE AND FIGURES TABLE 1: Showing the diagnosis criteria of SLE 7 Chart 1: Showing the diagnosis procedure of SLE 8 Abstract Systemic lupus erthromatosus (SLE) is also referred to the great imitator. This is because it has got a variety of symptoms that are often confused with other health problems. Lupus is a chronic disease that causes inflammation. It affects body organs such as the kidney, skin, joints, lungs and the nervous system (Ginzler and Tayar, 2013, p. 1). The etiology of SLE includes both genetic and environmental factors and it is more common in women than men. The pathogenesis of SLE involves a variety of cells and molecules that take part in apoptosis, innate and adaptive immune responses (Bertisias et. al, 2012, p. 479). Lupus is more prevalent in urban than rural areas and it has increased forty times maybe due to improved diagnosis. This report will focus on the basic mechanism of the disease, etiology and pathogenesis, diagnosis and treatment. SYSTEMIC LUPUS ERYTHEMATOSUS (LUPUS) Basic mechanism Systemic lupus erythematosus (lupus) (SLE) is an autoimmune disease that is characterized by production of antibodies to components of the cell nucleus and this leads to a variety of clinical manifestations (Mok and Lau, 2003, p. 2). This disease exerts effects on the peripheral nerves and this makes more tissues to be susceptible to damage (Oster, 2012, p. 353). SLE affects the heart and the cardiovascular system and this may contribute to embolic strokes, it also has an effect on the kidney causing kidney dysfunction or renal failure which eventually results in uremic encephalopathy (Oster, 2012, p. 353). The mechanism of clear, however, the general principle of SLE is that the antibodies or immune complexes may attack the blood supply to the neural structures (Oster, 2012, p. 354). The primary immunogens that initiate pathogenic autoimmune response in SLE are the nucleosomes. The production of anti nuclear antibodies in human lupus is mediated by MHC class II restricted, cognate interaction between the autoimmune T helper cells and the autoimmune B cells (Datta, 1997, p. 247). The pathogenic T helper cells and the B cells have a regulatory defect in the CD40 ligand. This ligand works by mediating the stimulatory signals that sustain production of antibodies. The pathogenic T and B cells in lupus can be blocked by developing specific immunotherapy (Datta, 1997, 248). SLE has got multiple immune abnormalities that are characterized by synthesis of different autoantibodies (Alvarado et. al, 2006, p. 1). Autoantibodies in lupus have got some properties that make them cause diseases (Rahman and Isenberg, 2008, p. 930). Studies were done on mice and they revealed that the IgG antibodies have high affinity to bind to double stranded DNA and are associated with tissue damage (Rahman and Isenberg, 2008, p. 932). Antigen driven process refers to the way in which antigens bind to the surface of the B lymphocytes thus making the cells to proliferate. This antigen driven process can occur only in B lymphocytes that are stimulated by the T lymphocytes as well as by the antigen (Rahman and Isenberg, 2008, p. 933). SLE is also characterized by B cell hyperactivity, increased rate of lymphoid cell apoptosis and enhanced synthesis of IL- 10. The T cells of patients with SLE exhibit diminished in vitro response to different stimuli and also a defective production and response to IL- 2 (Alvarado et. al, 2006, p. 2). Patients with SLE manifest impairment of T cell function and lymphopenia. Studies done on mice has also revealed that the reactive SLE anti lymphocyte antibodies of the IgG class interfere with the normal functions of the T cells, thus it is possible that the antibodies are important in the defective T cell functions (Marimoto et. al, 1984, p. 690). SLE is characterized by abnormal B cell activation and differentiation to plasma effector cells. The abnormal plasma effector cells in SLE secrete pathogenic autoantibodies and these include those that are specific to double stranded DNA (Grammer and Lipsky, 2003, p. 22). The genetic susceptibility of the SLE includes genes that affect differentiation and survival of plasma cells. SLE also affect genes that influence activation, proliferation, cytokine and chemokine responsiveness and T and B cells that are involved and humoral immunity (Grammer and Lipsky, 2003, p. 21). Cytokines are a group of soluble proteins and peptides that are produced and released by immune system cells. They act as regulators and modulate the functional activities of cells and tissues (Urra and Torre, 2012, p. 1). Cytokines also take part in differentiation, maturation and activation of immune system and non immune cells. SLE can result from cytokine dysregulation which causes loss of immune tolerance. There are several cytokines that are associated with SLE and these include IL- 6, interferon (IFN), IL- 17, B lymphocyte stimulator and IL- 10. These cytokines promote B cell survival and autoantibody production in SLE (Urra and Torre, 2012, p. 2). Regulation of lymphocyte development and tolerance is caused due to increased expression of two cytokines and these ate IL- 10 and IL- 21. IL- 17 is a cytokine that is dysregulated in lupus, thus enhancing the pathogenesis of the disease (Poole et. al, 2010, p. 1). Various mouse models have been developed in order to help understand the pathogenesis, cellular and genetic mechanisms of SLE. The classic models developed include the F1 hybrid of the New Zealand black (NZB) and New Zealand white strains known as NZB/W F1 (Pathak and Mohan, 2011, p. 1). A study was done in mice and this revealed that NZB mice died prematurely due to hepatosplenomegaly and autoimmune hemolytic anemia. Another study was done and it showed spontaneous appearance of different autoimmune disease in hybrid mice of NZB and NZW. This was characterized by anti nuclear antibodies, glomerulonephritis, lupus erythematosus cells and premature death. However, these features are not found in humans (Huston and Steinberg, 1979, p. 290). The NZB mice spontaneously develop autoimmune hemolytic anemia and immune complex renal disease. Only NZB mice and their hybrids are capable of generating anti X antibodies (Huston and Steinberg, 1979, p. 291). Mating of NZB and NZW mice result in the F1 hybrid. In this hybrid, the predominant autoimmune condition changes from NZB hemolytic anemia to proliferative glomerulonephritis. The F1 mice also develop LE cells and antinuclear bodies which makes it a better model for human SLE than NZB mice (Huston and Steinberg, 1979, p. 291). In animal models of SLE, the autoantibody production is associated with polyclonal T and B activation. The models have shown that the lupus prone mice develop spontaneous T activation to several peptides derived from regions of autoantibodies that have heavy chains (Singh et. al, 1998, p. 1841). Immunization of the whole autoantibody molecule, recalls T cell proliferative and helper responses to the individual determinants develop MHC class II matched animals and this provides evidence of in vivo processing of Ig molecules in autoimmune and normal strains (Singh et. al, 1998, p. 1841). Research using another model also showed that two VH peptides derived from anti DNA modulated anti DNA production and disease in vivo (Singh et. al, 1998, p. 1842). Diagnosis of SLE SLE is a multisystem inflammatory disorder, therefore it is very difficult for it to be diagnosed by a single diagnostic marker. It is however, identified through a combination of clinical and laboratory criteria (Gill et. al, 2003, p. 2179). A study done on SLE in England proved that it is more prevalent in women than in male. The study estimated that 200 cases of 10, 000 women who are 18 to 65 years of age are mostly diagnosed with SLE. SLE manifests as a variety of symptoms. The manifestations are associated with the skin, muscoskeletal and hemotologic involvement (Gill et. al, 2003, p. 2180). During the prognosis of the disease, it is important to estimate the remission and end organ damage. The assessment of damage has got two vital factors and these include possible adverse effects of treatment and the end organ damage which occurs as the disease progresses (Swaak et. al, 1999, p. 954). Patients with SLE have a high risk of developing coronary artery disease. The clinical manifestations of SLE are fundamentally the same in both children and adults. In children, the disease is manifested as fever, rash, arthritis and renal development (Gill et. al, 2003, p. 2180). Clinical diagnosis of SLE is done through assessment of clinical features and investigations of all the organs that can be affected by SLE. Some of the symptoms that occur in SLE include oral ulcers, fever, chest pains, hair fall, and photosensitive rashes. Clinical examinations done on the organs include routine urinalysis and measurement of blood pressure (Cervere et. al, 2007, p. 22). Almost all organs may be affected during active SLE, thus the American College of Rheumatology has come up with a criteria to diagnose the disease (Bartels and Muller, 2013, p. 2). The American College of Rheumatology came up with the diagnosis criteria of SLE as shown in the table below Table 1 Criterion Definition Malar rash Fixed, flat or raised, over the malar eminences tending to spare the nasolabial folds Discoid rash Erythematous, raised patches with adherent keratotic scaling and follicular plugging; possibly atrophic scarring in older lesions. Photosensitivity Skin rash as a result of unusual reaction to sunlight, as determined by patient history or physician observation Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by physician Arthritis Non erosive arthritis involving two or more peripheral joints, characterized by swelling, tenderness, or effusion Serositis Pleuritis, by convincing history of pleuritic pain, rub heard by physician, or evidence of pleural effusion; or pericarditis documented by electrocardiography, rub heard by physician, or evidence of pericardial effusion Renal disorder Persistent proteinuria, > 500 mg per 24 hours (0.5 g per day) or > 3+ if quantitation is not performed; or cellular casts (may be red blood cell, hemoglobin, granular, tubular, or mixed cellular casts) Neurological disorder Seizures or psychosis occurring in the absence of offending drugs or known metabolic derangement (e.g., uremia, ketoacidosis electrolyte imbalance) Hematplogic disorder hemolytic anemia with reticulocytosis; or leukopenia, < 4,000 per mm3 (4.0 _ 109 per L) on two or more occasions; or lymphopenia, < 1,500 per mm3 (1.5 _ 109 per L) on two or more occasions; or thrombocytopenia, < 100 _ 103 per mm3 (100 _ 109 per L) in the absence of offending drugs Immunologic disorder Antibody to double-stranded DNA antigen (anti-dsDNA) in abnormal titer; or presence of antibody to Sm nuclear antigen (anti-Sm); or positive finding of antiphospholipid antibody based on an abnormal serum level of IgG or IgM anticardiolipin antibodies, a positive test result for lupus anticoagulant using a standard method, or a false-positive serologic test for syphilis that is knownto be positive for at least 6 months and is confirmed by negative Treponema pallidum immobilization or fluorescent treponemal antibody absorption test Antinuclear antibodies An abnormal antinuclear antibody titer by immunofluorescence or equivalent assay at any time and in the absence of drugs known to be associated with drug-induced lupus (Adapted from Bartels and Muller, 2013, p. 4) The flow chart below shows how SLE can be diagnosed Chart 1 Patient presenting with disease manifestations involving two or more organ systems ANA testing Titer ≥ 1:40 Titer < 1:40 Consider referral to rheumatologist for full strong argument against SLE; SLE evaluation, including the following: alternative explanation for 1. ACR diagnostic criteria organ system manifestations 2. Laboratory tests: complete blood should be pursued count; urinalysis; serum creatine level; and antiphospholipid, antidsDNA, and anti-Sm antibodies Explanation found Zero to three four or more No explanation found ACR criteria ACR criteria Consider referral to Rheumatologist if No SLE or SLE Sufficient to question of SLE Incomplete SLE rule out SLE or incomplete SLE Remains (Adapted from Gill et. al, 2003, 2183) Treatment of SLE There are some factors that need to be considered while developing the drugs used to treat SLE. Some of these considerations include early phase clinical development whereby the appropriate dose is identified. Another factor is the efficacy considerations. This where the evidence needed to support approval of medical products for SLE is similar to that for medical products for other indications (Strand et. al, 2010, p. 3). The activity of SLE has got three patterns and these are flare chronic and long quiescence. The disease activity can be measured with validated instruments such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the Safety of Estrogen in Lupus Erythematosus National Assessment (SELENA)-SLEDAI, the British Isles Lupus Assessment Group scale (BILAG), the European Concensus Lupus Activity Measure (ECLAM), or the Systemic Lupus Activity Measure (SLAM), which are good predictors of damage, reversible inflammation, and mortality (Bailey et. al, 2011, p. 2) The current treatment for SLE include use of non steroidal anti inflammatory drugs, antimalarial agents, high dose immunoglobulins, corticosteroids and cytotoxic immunosuppressive agents (Bezalel et. al, 2012, p. 508). These drugs are effective, however, they are only specific to some adverse effects of SLE, and thus there is introduction of current therapies to treat SLE. These therapies include B cell targeted therapy and therapy using rituximab (anti- DC20 MAB) (Bezalel et. al, 2012, p. 508). The B cell targeted therapy is an effective therapy in SLE because it involves the reduction in the production of autoantibody production and prevention of antigens presenting to T cells (Bezalel et. al, 2012, p. 509). References Alvarado- Sanchez, B., Hernandez- Castro, B., Portales- Perez, D., Baranda, L., Espinosa, E., Mendoza, C., Tejeda, A. and Amaro, R. 2006. Regulatory T cells in patients with systemic lupus erythematosus. Journal of autoimmunity, pp. 1- 9 Bailey, T., Rowley, K. and Bernknopf, A. 2011. A review of systemic lupus erythematosus and current treatment options. Formulary journal Bartels, C. and Muller, D. 2013. Systemic lupus erythematosus (SLE) clinical presentation. Medscape Bazalel, S., Asher, I., Elbirt, D. and Sthoeger, Z. M. 2012. Novel biological treatments for systemic lupus erythematosus: Current and future modalities. 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J. and Torre, M. 2012. Cytokines and systemic lupus erythematosus. Intechopen journal Read More