susceptibility to the disease. sle is regarded as a prototype disease due to the significant overlap in its symptoms with other autoimmune diseases. drug reactions drug-induced lupus erythematosus is a (generally) reversible condition that usually occurs in people being treated for a long-term illness. drug-induced lupus mimics sle. however, symptoms of drug-induced lupus generally disappear once the medication that triggered the episode is stopped. more than 38 medications can cause this condition, the most common of which are procainamide, isoniazid, hydralazine, quinidine, and phenytoin. non-systemic forms of lupus discoid (cutaneous) lupus is limited to skin symptoms and is diagnosed by biopsy of rash on the face, neck, scalp or arms. approximately 5% of people with dle progress to sle. pathophysiology sle is triggered by environmental factors that are unknown. in sle, the body's immune system produces antibodies against self-protein, particularly against proteins in the cell nucleus. these antibody attacks are the immediate cause of sle. sle is a chronic inflammatory disease believed to be a type iii hypersensitivity response with potential type ii involvement. reticulate and stellate acral pigmentation should be considered a possible manifestation of sle and high titers of anti-cardiolipin antibodies, or a consequence of therapy. people with sle have intense polyclonal b-cell activation, with a population shift towards immature b cells. memory b cells with increased cd27+/igd—are less susceptible to immunosuppression. cd27-/igd- memory b cells are associated with increased disease activity and renal lupus. t cells, which regulate b-cell responses and infiltrate target tissues, have defects in signaling, adhesion, co-stimulation, gene transcription, and alternative splicing. the cytokines b-lymphocyte stimulator (blys), also known as b-cell activating factor (baff), interleukin 6, interleukin 17, interleukin 18, type i interferons, and tumor necrosis factor α (tnfα) are involved in the inflammatory process and are potential therapeutic targets. sle is associated with low c3 levels in the complement system. cell death signaling apoptosis is increased in monocytes and keratinocytes expression of fas by b cells and t cells is increased there are correlations between the apoptotic rates of lymphocytes and disease activity. necrosis is increased in t lymphocytes. tingible body macrophages (tbms) – large phagocytic cells in the germinal centers of secondary lymph nodes – express cd68 protein. these cells normally engulf b cells that have undergone apoptosis after somatic hypermutation. in some people with sle, significantly fewer tbms can be found, and these cells rarely contain material from apoptotic b cells. also, uningested apoptotic nuclei can be found outside of tbms. this material may present a threat to the tolerization of b cells and t cells. dendritic cells in the germinal center may endocytose such antigenic material and present it to t cells, activating them. also, apoptotic chromatin and nuclei may attach to the surfaces of follicular dendritic cells and make this material available for activating other b cells that may have randomly acquired self-protein specificity through somatic hypermutation. necrosis, a pro-inflammatory form of cell death, is increased in t lymphocytes, due to mitochondrial dysfunction, oxidative stress, and depletion of atp. clearance deficiency clearance deficiency impaired clearance of dying cells is a potential pathway for the development of this systemic autoimmune disease. this includes deficient phagocytic activity, impaired lysosomal degradation, and scant serum components in addition to increased apoptosis. sle is associated with defects in apoptotic clearance, and the damaging effects caused by apoptotic debris. early apoptotic cells express “eat-me” signals, of cell-surface proteins such as phosphatidylserine, that prompt immune cells to engulf them. apoptotic cells also express find-me signals to attract macrophages and dendritic cells. when apoptotic material is not removed correctly by phagocytes, they are captured instead by antigen-presenting cells, which leads to the development of antinuclear antibodies. monocytes isolated from whole blood of people with sle show reduced expression of cd44 surface molecules involved in the uptake of apoptotic cells. most of the monocytes and tingible body macrophages (tbms), which are found in the germinal centres of lymph nodes, even show a definitely different morphology; they are smaller or scarce and die earlier. serum components like complement factors, crp, and some glycoproteins are, furthermore, decisively important for an efficiently operating phagocytosis. with sle, these components are often missing, diminished, or inefficient. macrophages during sle fail to mature their lysosomes and as a result have impaired degradation of internalized apoptotic debris, which results in chronic activation of toll-like receptors and permeabilization of the phagolysosomal membrane, allowing activation of cytosolic sensors. in addition, intact apoptotic debris recycles back to the cell membrane and accumulate on the surface of the cell. recent research has found an association between certain people with lupus (especially those with lupus nephritis) and an impairment in degrading neutrophil extracellular traps (nets). these were due to dnase1 inhibiting factors, or net protecting factors in people's serum, rather than abnormalities in the dnase1 itself. dnase1 mutations in lupus have so far only been found in some japanese cohorts. 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 secondary necrosis of the cells if this ability is disturbed. necrotic cells release nuclear fragments as potential autoantigens, as well as internal danger signals, inducing maturation of dendritic cells (dcs) since they have lost their membranes' integrity. increased appearance of apoptotic cells also stimulates inefficient clearance. that leads to the maturation of dcs and also to the presentation of intracellular antigens of late apoptotic or secondary necrotic cells, via mhc molecules. autoimmunity possibly results from the extended exposure to nuclear and intracellular autoantigens derived from late apoptotic and secondary necrotic cells. b and t cell tolerance for apoptotic cells is abrogated, and the lymphocytes get activated by these autoantigens; inflammation and the production of autoantibodies by plasma cells is initiated. a clearance deficiency in the skin for apoptotic cells has also been observed in people with cutaneous lupus erythematosus (cle). germinal centers germinal centres in a person with sle and controls (schematic). red: cd68 in tingible body macrophages; black: tunel positive apoptotic cells. 1) healthy donors with florid germinal centres show giant tingible body macrophages (tbm) containing ingested apoptotic cells and no uningested apoptotic cells outside the tbm. 2) people with follicular lymphoma show small tingible body macrophages (tbm) containing few ingested apoptotic cells however, there are no uningested apoptotic cells outside the tbm. 3) some with sle (1) show a lack of tbm and many uningested apoptotic cells decorating the surfaces of spindle-shaped cells, presumably follicular dendritic cells (sle 1). 4) some people with sle show tbm containing few ingested apoptotic cells and many uningested apoptotic cells outside the tbm (sle 2). however, about 50 % of people with sle show rather normal germinal centre. in healthy conditions, apoptotic lymphocytes are removed in germinal centers (gc) by specialized phagocytes, the tingible body macrophages (tbm), which is why no free apoptotic and potential autoantigenic material can be seen. in some people with sle, a buildup of apoptotic debris can be observed in gc because of an ineffective clearance of apoptotic cells. close to tbm, follicular dendritic cells (fdc) are localised in gc, which attach antigen material to their surface and, in contrast to bone marrow-derived dc, neither take it up nor present it via mhc molecules. autoreactive b cells can accidentally emerge during somatic hypermutation and migrate into the germinal center light zone. autoreactive b cells, maturated coincidentally, normally do not 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 serves as 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 chronic autoimmune disease may be the consequence. anti-nrnp autoimmunity anti-nrnp autoantibodies to nrnp a and nrnp c initially targeted restricted, proline-rich motifs. antibody binding subsequently spread to other epitopes. the similarity and cross-reactivity between the initial targets of nrnp and sm autoantibodies identifies a likely commonality in cause and a focal point for intermolecular epitope spreading. others elevated expression of hmgb1 was found in the sera of people and mice with systemic lupus erythematosus, high mobility group box 1 (hmgb1) is a nuclear protein participating in chromatin architecture and transcriptional regulation. recently, there is increasing evidence hmgb1 contributes to the pathogenesis of chronic inflammatory and autoimmune diseases due to its inflammatory and immune stimulating properties. diagnosis micrograph showing vacuolar interface dermatitis, as may be seen in sle. h&e stain. micrograph of a section of human skin prepared for direct immunofluorescence using an anti-igg antibody. the skin is from a person with systemic lupus erythematosus and shows igg deposits at two different places. the first is a bandlike deposit along the epidermal basement membrane ("lupus band test" is positive); the second is within the nuclei of the epidermal cells (antinuclear antibodies are present). laboratory tests antinuclear antibody (ana) testing and anti-extractable nuclear antigen (anti-ena) form the mainstay of serologic testing for sle. if ana is negative the disease can be ruled out. several techniques are used to detect anas. the most widely used is indirect immunofluorescence (if). the pattern of fluorescence suggests the type of antibody present in the people's serum. direct immunofluorescence can detect deposits of immunoglobulins and complement proteins in people's skin. when skin not exposed to the sun is tested, a positive direct if (the so-called lupus band test) is evidence of systemic lupus erythematosus. ana screening yields positive results in many connective tissue disorders and other autoimmune diseases, and may occur in normal individuals. subtypes of antinuclear antibodies include anti-smith and anti-double stranded dna (dsdna) antibodies (which are linked to sle) and anti-histone antibodies (which are linked to drug-induced lupus). anti-dsdna antibodies are highly specific for sle; they are present in 70% of cases, whereas they appear in only 0.5% of people without sle. laboratory tests can also help distinguish between closely related connective tissue diseases. a multianalyte panel (map) of autoantibodies, including ana, anti-dsdna, and anti-smith in combination with the measurement of cell-bound complement activation products (cb-caps) with an integrated algorithm has demonstrated 80% diagnostic sensitivity and 86% specificity in differentiating diagnosed sle from other autoimmune connective tissue diseases. the map approach has been further studied in over 40,000 patients tested with either the map or traditional ana testing strategy (tana), demonstrating patients who test map positive are at up to 6-fold increased odds of receiving a new sle diagnosis and up to 3-fold increased odds of starting a new sle medication regimen as compared to patients testing positive with the tana approach. the anti-dsdna antibody titers also tend to reflect disease activity, although not in all cases. other ana that may occur in people with sle are anti-u1 rnp (which also appears in systemic sclerosis and mixed connective tissue disease), ss-a (or anti-ro) and ss-b (or anti-la; both of which are more common in sjögren's syndrome). ss-a and ss-b confer a specific risk for heart conduction block in neonatal lupus. other tests routinely performed in suspected sle are complement system levels (low levels suggest consumption by the immune system), electrolytes and kidney function (disturbed if the kidney is involved), liver enzymes, and complete blood count. the lupus erythematosus (le) cell test was commonly used for diagnosis, but it is no longer used because the le cells are only found in 50–75% of sle cases and they are also found in some people with rheumatoid arthritis, scleroderma, and drug sensitivities. because of this, the le cell test is now performed only rarely and is mostly of historical significance. diagnostic criteria some physicians make a diagnosis based on the american college of rheumatology (acr) classification criteria. however, these criteria were primarily established for use in scientific research, including selection for randomized controlled trials, which require higher confidence levels. as a result, many people with sle may not meet the full acr criteria. criteria the american college of rheumatology (acr) established eleven criteria in 1982, which were revised in 1997 as a classificatory instrument to operationalise the definition of sle in clinical trials. they were not intended to be used to diagnose individuals and do not