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Systemic lupus erythematosis
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by variable clinical features, predominantly affecting females aged 20-30 years, with a significant incidence rate. Common symptoms include arthritis, fatigue, and various skin rashes, and the diagnosis requires meeting four of eleven specific criteria. Treatment depends on organ involvement and may include antimalarials, immunosuppressants, and corticosteroids, with ongoing research exploring targeted therapies.
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Systemic lupus erythematosis
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- 3. Systemic lupus erythematosus(SLE) is an autoimmune disease in which organs, tissues, and cells undergo damage mediated by tissue-binding autoantibodies and immune complexes. • The clinical course is variable and may be characterized by periods of remissions and of chronic or acute relapses. • Around 90% are females, the peak age at onset is bw 20-30 yrs. • The incidence is approximately 5 in 10,000 in most countries, with an especially high incidence of 8.7 in 100,000 in Brazil.
- 4. CLINICAL HETEROGENEITY OF SLE •The multifaceted nature of SLE is shown by the number of different organ systems that can be affected. • In addition, each organ-specific complication can manifest in different ways. • Arthritis and Arthralgia are the most common presenting feature.
- 5. SYMPTOMS Most common symptoms: •Mouth Sores • Hair Loss • Chest Pain • Extreme Fatigue • General Discomfort • Fever • Sunlight Sensitivity • Difficulty Breathing • Swollen Lymph Nodes • Skin Rashes (Butterfly Rash)
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- 7. SYSTEM SPECIFIC SYMPTOMS NervousSystem: Headaches, numbness, tingling, seizures, psychosis Digestive System: Nausea, vomiting, dyspepsia Cardiovascular System: Arrhythmias, pericarditis, myocarditis Respiratory System: Pleurisy, pleural effusion, pneumonitis, pulmonary hypertension Integumentary system: Raynaud’s phenomenon, malar rash Excretory system: Edema, weight gain, acute renal failure
- 8. CRITERIA FOR DIAGNOSIS OFSLE Internationally accepted criteria by American College of Rheumatology. Patient must have 4 or more criteria to establish diagnosis of disease
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- 10. GENETIC FACTORS • Theconcordance rate for SLE in monozygotic twins is 25% but only 2% in dizygotic twins, suggesting that genetic factors alone do not explain the phenotype of SLE. • C1Q and C4 single-gene defects. • Interferon (IFN) regulatory factor 5 (IRF5), mutations in which are associated with increases in the levels of the type 1 IFN family of molecules. • HLA DR and DQ alleles that are associated with the production of specific autoantibodies. • Complement deficiency states and certain Fc-γ receptor alleles predispose to SLE, and affect clearance of immune complexes • IL-21-R, CD40, PTPN22, TNFAIP3 etc.
- 11. ENVIRONMENTAL FACTORS Ultraviolet radiation-Langerhans cells of the skin and keratinocytes release significant amounts of interleukin-1 upon exposure to UV light. Infection: The normal immune response to bacterial and viral infections may spin-off into a state of B-cell hyperactivity, triggering a relapse. Infection, through the so-called molecular mimicry, can initiate an autoimmune response. Eg: Parvovirus, Epstein–Barr virus (EBV) infection.
- 12. Drugs- Drugs withDNA binding ability, can cause a drug-induced lupus-like syndrome. • cause DNA hypomethylation and thus transcription of genes at higher rates • such as hydantoin, isoniazid, hydralazine, procainamide, minocycline, and anti-tumor necrosis factor (TNF) biologics. Hormones: Estrogen, DHEA. Silica Exposure, Smoking. ENVIRONMENTAL FACTORS
- 13. HORMONAL FACTORS • Femalepredisposition suggest that endocrine factors are important. • When patients with SLE are given oestrogen and progesterone hormone- replacement therapy, their risk of SLE flare is 1.34 times that of women given placebo. • Low levels of dehydroepiandrosterone (DHEA) have been associated with predisposition to SLE.
- 14. PATHOGENESIS Extracellular double-stranded DNAoccurs mainly in the form of nucleosomes, which are fragments of chromatin that cells release when they undergo apoptosis. Pathogenic anti-ds-DNA autoantibodies bind to nucleosomes and gets deposit on different sites and induce the inflammatory reaction.
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- 16. IMMUNE RESPONSE ABNORMALITIES •SLE is caused by an autoimmune reaction in which the innate and adaptive immune systems direct an inappropriate immune response to nucleic acid- containing cellular particles. B-Cell Abnormalities Auto-Antibodies T-Cell Abnormalities Dendritic cell Abnormalities Antinuclear Antibodies DNA Antibodies
- 17. INNATE IMMUNITY ACTIVATION •Nucleic acid containing immune complexes and cytoplasmic DNA and RNA are potential stimuli for activation of TLRs and other receptors, leading to IFNα production. • Interferon α induces maturation of dendritic cells and drives monocytes to become more effective in stimulating allogeneic T cells. • IFNα can regulate the production of cytokines such as IL-10 and IL-12 by monocytes.
- 18. DENDRITIC CELL ABNORMALITIES •Dendritic cells may present autoantigen to T and B-cells at increased rates in patients with SLE. • Interferonα and circulating immune complexes (acting through Fc receptors and TLR9) stimulate dendritic cell function in SLE.
- 19. B CELL ABNORMALITIES •B cell regulation is impaired in SLE, contributing to the production of autoantibodies, cytokines and augmented presentation of antigen to T cells. • Increased availability of T cell help for B cell differentiation as well as B cell survival, proliferation and differentiation factors (including BAFF and IL-21) and activation of TLRs all contribute to autoimmunity. • SLE-associated genetic variants encoding several kinases, phosphatases and adaptor molecules, contribute to altered counter-selection of self-reactive B cells or antigen- mediated B cell activation.
- 20. • Feedback mechanismsin the down regulation of B-cell responses appear to be deficient in SLE. SLE memory B cells show modest decreases in the expression of the inhibitory Fc receptor FCGR2B. • Long-lived plasma cells are maintained by chemokines and stromal cell products in protective bone marrow niches - proposed sources of anti-Sm and anti-Ro autoantibodies. B CELL ABNORMALITIES
- 21. AUTO-ANTIBODIES • An autoantibodyis an antibody produced by the immune system that is directed against one or more of the individual's self antigen(s). • Self antigens may be found in all cell types (e.g. chromatin, centromeres) or be highly specific for a specific cell type in one organ of the body (e.g. thyroglobulin in cells of the thyroid gland). • They may comprise proteins, nucleic acids, carbohydrates, lipids or various combinations of these. • Also referred to as natural antibodies.
- 22. • Autoantibodies areessential mediators of pathology in SLE, particularly when they form immune complexes. • Virtually all patients with SLE are positive for ANAs or other characteristic SLE autoantibodies. • Autoantibodies in SLE can be categorized in relation to their targets: • DNA and DNA-binding proteins, which are typically aggregated with histones in nucleosomes. • RNA and RNA-associated proteins, which are aggregated in cytoplasmic or nuclear ribonucleoprotein particles; • β2-glycoprotein, in association with phospholipids; and • cell membrane proteins, typically those expressed on blood cells. AUTO-ANTIBODIES
- 23. • ANA, AntidsDNA and anti-Sm are most specific for SLE. • Anti-C1q antibodies, are associated with SLE activity and with proliferative lupus nephritis and are thought to be pathogenetic.
- 24. • The pathogenicantibodies in SLE undergo immuno globulin class switching driven by CD4+ T helper cells or TLR ligands together with IL-21 or BAFF. • A shift from a predominant polyclonal IgM profile towards IgG occurs over time in most patients with SLE and with disease progression and development of tissue damage. • Class-switched IgG antibodies are better able to access extravascular spaces than IgM antibodies • Some IgM natural antibodies react with apoptotic cells and inhibit their activation through TLRs. • Some antibodies unexpectedly bind to two distinct self-antigens. • For eg, some anti-dsDNA antibodies also bind to a peptide that is a feature of glutamate receptors on central nervous system neurons
- 25. T CELL ABNORMALITIES •Deficiencies or alterations in T cell signalling, in the production of cytokines, in proliferation and in regulatory functions have been documented in patients with SLE. • T cells derived from patients with SLE readily express CD40 ligand (CD40L) after activation and maintain the expression of this important co- stimulatory molecule longer than T cells derived from healthy controls. • Substitution of the T cell receptor-ζ (TCRζ) chain with the common-γ chain (TCRγ)- lead to augmented intra cellular calcium signalling and hyperpolarization of mitochondria, which can sensitize T cells for necrosis.
- 26. • T cellsderived from patients show hypomethylation of CG-rich DNA sequences and promoters of IFN-regulated genes. • The population of T follicular helper cells, which promote differentiation of autoantibody-producing B cells, is expanded in SLE. • Relative depletion in the number of Treg cells, increased numbers of TH17 cells and increased levels of IL-17 in SLE. T CELL ABNORMALITIES
- 27. IMMUNE COMPLEXES • ICare formed at increased rates in patients with SLE, the clearance rate of circulating IC is decreased, as a consequence of several factors. • IC are cleared by the Fc receptor bearing cells of the reticuloendothelial system. • Many patients with lupus have alleles of Fc receptors that bind IgG with less avidity. This results in slower immune complex clearance.
- 30. DIAGNOSIS The diagnosis ofSLE is made based on clinical manifestations and laboratory tests, including the detection of autoantibodies, functional tests and imaging. Health care providers tend to use the revised American College of Rheumatology (ACR) classification criteria for SLE. Proposed by the ACR in 1971, revised in 1982 and 1997 • Need 4 of 11 criteria for diagnosis of SLE • Not perfect, but have over 90% sensitivity and specificity
- 31. TREATMENT • Treatment isdetermined by organ involvement. • Photosensitive rashes are treated by sun avoidance, sun block, and by hydroxychloroquine, an antimalarial drug with an immunomodulating effect. • Arthritis is managed with NSAIDs and with hydroxychloroquine; severe cases may require immunosuppressive drugs, including methotrexate or leflunomide. • Mild serositis may be controlled with NSAIDs, whereas severe cases may require initial high-dose corticosteroid therapy.
- 32. • Severe hemolyticanemia or thrombocytopenia is treated with corticosteroids and/or intravenous immunoglobulin. • Severe internal organ involvement will require immuno-suppressive regimens. • Rapidly progressive nephritis may require intravenous cyclophosphamide, usually given monthly for six months as “induction therapy” followed by maintenance regimen of mycophenolate mofetil, azathioprine, or quarterly cyclophosphamide. TREATMENT
- 33. • Seizures dueto active lupus are treated with both corticosteroids and anti-epileptics. • Psychosis can be caused by both SLE and by high-dose corticosteroids. • New approaches : • Target B cells by rituximab and monoclonal antibodies directed against the B lymphocyte stimulator protein. • Anti-C5 antibody that disrupts complement activation TREATMENT
- 34. REFERENCE • Medical Immunology6th Edition- Gabriel Virella • Essentials of Clinical Immunology- Helen Chapel, Mansel Haeney • Autoimmune Diseases- Noel R Rose, Ian R Mackay • Systemic lupus erythematosus- Arvind Kaul, Caroline Gordon • Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis- Chandra Mohan and Chaim Putterman • New insights into the immunopathogenesis of systemic lupus erythematosus- George C. Tsokos, Mindy S. Lo
Editor's Notes
- #4 Almost 90% of all cases occur in women Overall, SLE affects women eight times more often than it does in men At age 30 years, the ratio of women to men is 10:1 The ratio at age 65 years, the ratio appears to be about 3:1 The prevalence rate among women between age 15 and 64 years is 1 in 700 women Symptoms usually appears between ages 15 and 25 years The prevalence in the general population is about 1 in 1000
- #9 Malar rash • Fixed, flat or raised erythema (superficial reddening of the skin) over the malar eminences, but tends to spare the nasolabial folds Discoid rash • Erythematous raised patches with adherent keratotic scaling and follicular plugging • Atrophic scarring may occur in older lesions Photosensitivity • Skin rash as a result of unusual reaction to sunlight • Diagnosis is based on patient history or physician observation Oral ulcers • Oral or nasopharyngeal ulceration, usually painless and based on physician examination Non-erosive arthritis • Tenderness, swelling or effusion in two or more peripheral joints Pleuritis or pericarditis • Pleuritis is defined by a convincing history of pleuritic pain, rubbing heard by a physician or evidence of pleural effusion • Pericarditis is documented by an electrocardiogram, rubbing heard by a physician or evidence of pericardial effusion Renal disorder* • Persistent proteinuria of >0.5 g daily or >3 on urine dipstick if quantification is not performed • Cellular casts in urine, including red blood cells or haemoglobin, and can be granular, tubular or mixed Neurological disorder • Seizures or psychosis in the absence of offending drugs or known metabolic derangements, such as uraemia, ketoacidosis or electrolyte imbalance Haematological disorder* • Haemolytic anaemia with reticulocytosis • Leukocytopaenia: <4,000 per mm3 on two or more occasions • Lymphocytopaenia: <1,500 per mm3 on two or more occasions • Thrombocytopaenia: <100,000 per mm3 in the absence of causative drugs Immunological disorders* • Anti‑DNA autoantibody • Anti‑Sm autoantibody • Antiphospholipid autoantibodies (including an abnormal serum level of IgG or IgM anticardiolipin autoantibodies, a positive test result for lupus anticoagulants using a standard method, or a false‑positive test result for >6 months confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test) Positive antinuclear autoantibody • An abnormal titre of antinuclear autoantibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drug
- #17 CR2 (a complex of CD21, CD19, and CD81)
- #24 which recognize neo-epitopes of C1q bound to early apoptotic cells,