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Systemic lupus erythematosus

(SLE) is a multiorgan system autoimmune disease with numerous immunological and clinicalmanifestations. It is characterized by an autoantibody response to nuclear and cytoplasmic antigens. The disease mainly involves theskin, joints, kidneys, blood cells, and nervous system. Diagnosing and managing SLE in the emergency department can be verychallenging if it is not considered in one's differential diagnosis. Also, the laboratory testing of SLE may be unavailable on anemergent basis.

Pathophysiology

Systemic lupus erythematosus (SLE) is a multifactorial disease involving genetic, environmental, and hormonal factors. Its precise pathogenesis is unclear. There is growing evidence in favor of a clearance deficiency of apoptotic cells as the core mechanism in the pathogenesis of SLE.Defective clearance of apoptotic cells causes secondary necrosis with release of intracellular content andinflammatory mediators. Macrophages respond and present self-antigens to T and B cellsPathogenic autoantibodies are the primary cause of tissue damage in patients with lupus. The production of these antibodies arises bymeans of complex mechanisms involving every key facet of the immune system.The abnormal cellular and humoral response to theformation of these autoantibodies is modulated by genetic, environmental, and hormonal factors:

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Genetic factors

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Genes of the MHC HLA-A1, B8, and DR3 have been linked to lupus.

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Genetic deficiency of complement factors C1q, C2, or C4

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Environmental factors

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Occupational exposure - Silica, pesticides, mercury

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Drugs - Many drugs have been implicated in drug-induced lupus.

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Sunlight

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Epstein-Barr virus (EBV) has also been identiﬁed as a possible factor in the development of lupus.

Classification

Lupus is a chronicautoimmune diseasein which the body's own defense system attacks otherwise healthy tissue. Clinically, it canaffect multiple organ systems including the heart, skin, joints, kidneys and nervous system. There are several types of lupus; ingeneral, when the word lupus alone is used, reference is to systemic lupus erythematosus, as discussed in this article. Other typesinclude:Other types include:

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Chronic cutaneous lupus erythematosus

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Discoid lupus erythematosus, a skin disorder that causes a red, raised rash on the face andscalp. Discoid lupus occasionally (1–5%) develops into SLE.

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Localized discoid lupus erythematosus

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Generalized discoid lupus erythematosus

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Childhood discoid lupus erythematosus

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Chilblain lupus erythematosus (Hutchinson)

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Lupus erythematosus-lichen planus overlap syndrome

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Lupus erythematosus panniculitis (Lupus erythematosus profundus)

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Subacute cutaneous lupus erythematosus, which causes nonscarring skinlesionson patchesof skin exposed to sunlight.

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Tumid lupus erythematosus

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Verrucous lupus erythematosus (Hypertrophic lupus erythematosus)

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Neonatal lupus erythematosus, a rare disease affecting babies born to women with SLE,Sjögren'ssyndrome, or sometimes no autoimmune disorder. It is theorized that maternal antibodies attackthe fetus, causing skin rash; liver problems; low blood counts, which gradually fade; and heartblock, leading tobradycardia.

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Childhood systemic lupus erythematosus, the pediatric variant of systemic lupus erythematosus.

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Drug-induced lupus erythematosus, a drug-induced form of SLE; this type of lupus can occurequally in either sex.

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Lupus nephritis, an inflammation of thekidneyscaused by SLE.

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Complement deficiency syndromes

Causes

Despite the dramatic rise in Lupus research in recent years, the exact cause of the disease remains unknown. Indeed, consensus is stilllacking on whether Lupus is a single condition or a group of related diseases. SLE is a chronicinflammatorydisease believed to be atype III hypersensitivityresponse with potentialtype IIinvolvement,

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characterized by the body's production of antibodies against thenuclear components of its own cells. There are three mechanisms by which lupus is thought to develop: genetic predisposition,environmental triggers and drug reaction (drug-induced lupus).

Genetics

The first mechanism may arise genetically. Research indicates that SLE may have ageneticlink. Lupus does run in families, but nosingle "lupus gene" has yet been identified. Instead, multiple genes appear to influence a person's chance of lupus developing whentriggered by environmental factors. The most important genes are located onchromosome 6, where mutations may occur randomly(

de novo

) or be inherited. Additionally, people with SLE have an altered RUNX-1 binding site, which may be either cause or contributor (or both) to the condition. Altered binding sites for RUNX-1 have also been found in people withpsoriasisandrheumatoid arthritis.

Environmental triggers

The second mechanism may be due to environmental factors. These factors may not only exacerbate existing lupus conditions, butalso trigger the initial onset. They include certain medications (such as someantidepressantsandantibiotics

), extreme stress, exposureto sunlight, hormones, and infections. Some researchers have sought to find a connection between certain infectious agents (viruses and bacteria), but no pathogen can be consistently linked to the disease. UV radiation has been shown to trigger the photosensitivelupus rash, but some evidence also suggests that UV light is capable of altering the structure of the DNA, leading to the creation of autoantibodies. Some researchers have found that women withsiliconegel-filled breast implantshave produced antibodies to their owncollagen, but it is not known how often these antibodies occur in the general population and there is no data that show theseantibodies causeconnective tissue diseasessuch as lupus.

Drug reactions

Drug-induced lupus erythematosusis a reversible condition that usually occurs in patients being treated for a long-term illness. Drug-induced lupus mimics systemic lupus. However, symptoms of drug-induced lupus generally disappear once a patient is taken off themedication which triggered the episode. There are about 400 medications currently in use that can cause this condition, though themost common drugs are procainamide,hydralazineandquinidine.

Non-SLE forms of lupus

Discoid (cutaneous) lupus is limited to skin symptoms and is diagnosed via biopsy of skin rash on the face, neck or scalp. Often ananti-nuclear antibody(ANA) test for discoid patients is negative or a low-titre positive. About 10% of discoid lupus patientseventually develop SLE.

Pathophysiology

Lupus is an example of pathophysiology,a disturbance of the normal functioning of the body. One manifestation of lupus isabnormalities in apoptosis, a type of programmed cell death in which aging or damaged cells are neatly disposed of as a part of normalgrowth or functioning.

Transmission

In SLE, the body's immune system produces antibodies against itself, particularly against proteins in the cell nucleus. SLE is triggered by environmental factors that are unknown."All the key components of the immune system are involved in the underlying mechanisms" of SLE, according to Rahman, and SLEis the prototypical autoimmune disease. The immune system must have a balance (homeostasis)between being sensitive enough to protect against infection, and being too sensitive and attacking the body's own proteins (autoimmunity). From an evolutionary perspective, according to Crow, the population must have enough genetic diversity to protect itself against a wide range of possibleinfection; some genetic combination's result in autoimmunity. The likely environmental triggers include ultraviolet light, drugs, andviruses. These stimuli cause thedestructionof cells and expose their DNA,histones,and other proteins, particularly parts of the cell nucleus. Because of genetic variations in different components of the immune system, in some people the immune system attacksthese nuclear-related proteins and produces antibodies against them. In the end, these antibody complexes damage blood vessels incritical areas of the body, such as theglomeruliof the kidney; these antibody attacks are the cause of SLE. Researchers are nowidentifying the individual genes, the proteins they produce, and their role in the immune system. Each protein is a link on theautoimmune chain, and researchers are trying to find drugs to break each of those links.

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SLE is a chronicinflammatorydisease believed to be atype III hypersensitivityresponse with potentialtype IIinvolvement.

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Abnormalities in apoptosis

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Apoptosisis increased inmonocytesandkeratinocytes

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Expressionof Fas byB cellsand T cellsis increased

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There are correlations between the apoptotic rates of lymphocytes and disease activity

Tangible body macrophages (TBMs) are large phagocytic cells in thegerminal centersof secondarylymph nodes. They express CD68 protein. These cells normally engulf B cells which have undergone apoptosis after somatic hypermutation .In some patients with SLE,significantly fewer TBMs can be found, and these cells rarely contain material from apoptotic B cells. Also, uningested apoptoticnuclei can be found outside of TBMs. This material may present a threat to the tolerization of B cells and T cells.Dendritic cellsin thegerminal center may endocytose such antigenic material and present it to T cells, activating them. Also, apoptotic chromatin andnuclei may attach to the surfaces of follicular dendritic cells and make this material available for activating other B cells which mayhave randomly acquired self-specificity throughsomatic hypermutation .Clearance deficiency

The exact mechanisms for the development of systemic lupus erythematosus (SLE) are still unclear sincethe pathogenesis is a multifactorial event. Beside discussed causations, impaired clearance of dying cellsis a potential pathway for the development of this systemicautoimmune disease. This includes deficientphagocytic activity, scant serum components in addition to increasedapoptosis.

Monocytesisolated fromwhole bloodof SLE patients show reduced expression of CD44 surface molecules involved in the uptake of apoptotic cells. Most of themonocytesand tingible body macrophages (TBM), which are found in the germinal centres of lymph nodes,even show a definitely different morphology in patients with SLE. They are smaller or scarce and die earlier. Serumcomponents like complement factors,CRPand someglycoproteinsare furthermore decisively important for an efficiently operating phagocytosis. In patients these components are often missing, diminished or inefficient.The clearance of early apoptotic cells is an important function in multicellular organisms. It leads to a progression of the apoptosis process and finally to secondarynecrosisof the cells, if this ability is disturbed. Necrotic cells release nuclear fragments as potentialautoantigens as well as internal danger signals, inducingmaturationof dendritic cells(DC), since they have lost their membranes integrity. Increased appearance of apoptotic cells also is simulating inefficient clearance. That leads to maturation of DC and also tothe presentation of intracellular antigens of late apoptotic or secondary necrotic cells, via MHC molecules.Autoimmunitypossibly results by the extended exposure to nuclear and intracellular autoantigens derived from late apoptotic andsecondary necrotic cells. B andT celltolerance for apoptotic cells is abrogated and thelymphocytesget activated by these autoantigens;inflammationand the production of autoantibodies by plasma cellsis initiated. A clearance deficiency in the skin for apoptotic cells has also been observed in patients with cutaneous lupus erythematosus (CLE).

Germinal centres

In healthy conditions apoptotic lymphocytes are removed in germinal centres by specialised phagocytes, the tingible bodymacrophages (TBM); that’s why no free apoptotic and potential autoantigenic material can bee seen.In some patients with SLE accumulation of apoptoticdebriscan be observed in GC, because of an ineffective clearance of apoptoticcells.In close proximity to TBM,follicular dendritic cells(FDC) are localized in GC, which attach antigen material to their surface and incontrast to bone marrow-derived DC, neither take it up nor present it via MHC molecules.AutoreactiveB cellscan accidentally emerge duringsomatic hypermutationand migrate into the GC light zone. Autoreactive B cells, maturated coincidently, normally don’t receive survival signals by antigen planted on follicular dendritic cells and perish by apoptosis.In the case of clearance deficiency apoptotic nuclear debris accumulates in the light zone of GC and gets attached to FDC. This servesas a germinal centre survival signal for autoreactive B-cells.After migration into the mantle zone autoreactive B cells require further survival signals from autoreactive helper T cells, which promote the maturation of autoantibody producing plasma cells and B memory cells.In the presence of autoreactive T cells a chronicautoimmune diseasemay be the consequence.

Anti-nRNP autoimmunity

Autoantibodiesto nRNP A and nRNP C initially targeted restricted,proline-rich motifs. Antibody binding subsequently spread to other epitopes.The similarity andcross-reactivitybetween the initial targets of nRNP and Sm autoantibodies identifies a likely commonality in cause and a focal point for intermolecular epitope spreading.

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Others

Elevated expression of HMGB1 was found in the sera of patients and mice with systemic lupus erythematosus, High Mobility GroupBox 1 (HMGB1) is anuclear protein participating inchromatinarchitecture andtranscriptional regulation.Recently, there is increasing evidence that HMGB1 contributes to the pathogenesis of chronicinflammatoryandautoimmune diseasesdue to its pro- inflammatory and immunostimulatory properties.

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