Systemic Lupus Erythematosus: Pathogenesis & Organ Injury

Pathogenesis: losing tolerance to nuclear antigens

The core defect. SLE is a systemic autoimmune disease in which B and T cells lose tolerance to the cell's own nuclear material (DNA, nucleosomes, ribonucleoproteins). The resulting autoantibodies form immune complexes that injure many organs, and some antibodies attack blood cells directly.

Defective clearance. Apoptotic cells and neutrophil extracellular traps (NETs) release nuclear debris that is normally removed quickly, with help from early classical complement components that tag it for phagocytosis. Deficiency of C1q, C4 or C2 leaves this debris exposed: about 90% of people with C1q deficiency develop SLE, with C4 and then C2 deficiency carrying smaller risks. Persisting nucleosomes and ribonucleoproteins then activate autoreactive B and T cells.

The complement paradox: inherited early complement deficiency causes lupus, yet active lupus consumes complement, so C3 and C4 fall during flares.

The interferon loop. Plasmacytoid dendritic cells take up immune complexes containing DNA or RNA and sense the nucleic acid through endosomal TLR9 (DNA) and TLR7 (RNA), releasing large amounts of IFN-α. Most patients show an "interferon signature" of IFN-inducible gene expression in blood. Interferon matures dendritic cells and drives B cells toward antibody-secreting plasma cells, while excess BAFF (BLyS) prolongs autoreactive B-cell survival. These steps are drug targets: anifrolumab blocks the type I interferon receptor, belimumab neutralizes BAFF, and hydroxychloroquine blunts endosomal TLR signaling.

Who gets lupus. The female-to-male ratio is about 9:1 in the childbearing years, reflecting estrogen effects and a double dose of X-linked TLR7, which partly escapes X inactivation; men with Klinefelter syndrome (XXY) have a risk approaching that of women. Disease is more frequent and more severe in Black, Hispanic and Asian patients, and HLA-DR2 and HLA-DR3 raise risk. Ultraviolet light causes keratinocyte apoptosis that exposes nuclear antigens, explaining photosensitivity and sun-triggered flares; certain drugs induce a lupus-like syndrome.

Two hypersensitivity mechanisms. Most organ injury is type III: immune complexes deposit in glomeruli, skin, joints, serosa and vessel walls and activate complement, consuming C3 and C4. Cytopenias are type II: IgG autoantibodies coat red cells, platelets and leukocytes, which the spleen then clears, producing Coombs-positive warm autoimmune hemolytic anemia with spherocytes, thrombocytopenia and leukopenia or lymphopenia. Anemia of chronic disease is the most common anemia overall.

Autoantibodies and markers of activity

ANA. Because more than 95% of patients are ANA-positive, a negative ANA makes SLE very unlikely. A positive result alone is weak evidence: ANA also appears in healthy people (especially older women), other autoimmune diseases and drug-induced lupus.

Anti-dsDNA and anti-Smith. Both are specific for SLE. Anti-dsDNA titers rise with activity, particularly nephritis. Anti-Smith, directed against core proteins of the spliceosomal snRNPs, is the most specific test but is present in only a minority (more often in Black and Asian patients) and stays constant regardless of activity.

Drug-induced lupus. Hydralazine, procainamide, isoniazid, minocycline and TNF-α inhibitors are classic causes; slow acetylators are at higher risk with the drugs cleared by N-acetylation (hydralazine, procainamide, isoniazid). Patients have fever, arthralgia and serositis with anti-histone antibodies (TNF-inhibitor cases are often anti-dsDNA-positive instead), normal complement and rare kidney or CNS disease. It resolves after the drug is stopped.

Neonatal lupus. Maternal anti-Ro/SSA IgG, often with anti-La/SSB, crosses the placenta and can injure the fetal AV node, producing congenital complete heart block in a structurally normal heart, often with a transient rash and cytopenias. The heart block is permanent and often needs a pacemaker, whereas the rash and cytopenias fade as maternal IgG is cleared.

Mixed connective tissue disease. High-titer anti-U1 RNP with Raynaud phenomenon, puffy swollen hands, arthritis and myositis defines this overlap of SLE, systemic sclerosis and polymyositis features.

Activity markers. Flares lower C3, C4 and total hemolytic complement (CH50) and raise anti-dsDNA. The ESR rises, but the CRP often stays normal, so a high CRP in a febrile patient points to infection or serositis rather than a routine flare.

Skin, joints and serosa

Mucocutaneous disease. The malar (butterfly) rash spares the nasolabial folds and worsens with sunlight. Discoid lupus produces scarring plaques with follicular plugging and scarring alopecia. Subacute cutaneous lupus forms annular or psoriasiform, photosensitive, nonscarring plaques, is strongly linked to anti-Ro, and can be triggered by drugs such as thiazides, terbinafine and proton pump inhibitors. Painless oral ulcers (often on the hard palate) and nonscarring alopecia are common. Skin biopsy shows interface dermatitis with immunoglobulin and complement deposited along the dermoepidermal junction.

Joints. A symmetric small-joint polyarthritis resembles RA but is nonerosive. Ligament and capsule laxity can produce ulnar deviation and swan-neck deformities that are reducible (Jaccoud arthropathy).

Serositis. Pleuritis causes pleuritic chest pain with exudative effusions, and pericarditis is the most common cardiac manifestation of SLE.

Lupus nephritis

Class IV. Endocapillary proliferation involves at least half of the glomeruli, and subendothelial immune deposits thicken capillary walls into rigid "wire loops." Immunofluorescence is granular and "full house" (IgG, IgA, IgM, C3 and C1q), unlike the linear IgG of anti-GBM disease or the pauci-immune pattern of ANCA vasculitis. Patients have hematuria with RBC casts, hypertension and falling GFR, often with heavy proteinuria.

Class V. Subepithelial deposits thicken the basement membrane, which grows "spikes" between them on silver stain, and cause nephrotic syndrome with edema, hyperlipidemia and a risk of renal vein thrombosis.

Biopsy classification guides therapy: proliferative (III/IV) and membranous (V) disease need immunosuppression.

Heart, blood vessels, brain and clotting

Libman-Sacks endocarditis. Small, warty, sterile vegetations sit on both surfaces of the valve leaflets, most often the mitral valve. This form of nonbacterial thrombotic endocarditis is linked to antiphospholipid antibodies; it is usually silent but can cause regurgitation or emboli. Rheumatic verrucae, by contrast, line the closure line, and carcinoid plaques favor right-sided valves.

Premature atherosclerosis. Chronic inflammation, glucocorticoids, hypertension, renal disease and antiphospholipid antibodies accelerate coronary atherosclerosis, so young women with SLE have a markedly increased risk of myocardial infarction. Mortality is bimodal: early deaths come from active disease and infection, later deaths from cardiovascular disease.

Neuropsychiatric lupus. Manifestations include seizures, psychosis, cognitive dysfunction, mood disorders, stroke (often antiphospholipid-related), aseptic meningitis, transverse myelitis and neuropathy. Mimics must be excluded first: infection, uremia, electrolyte disturbances, hypertensive encephalopathy (PRES) and steroid-induced psychosis, which usually appears within the first weeks of high-dose therapy and improves with tapering.

Antiphospholipid antibodies. Lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein I antibodies cause venous and arterial thrombosis, recurrent pregnancy loss, livedo reticularis and thrombocytopenia. Lupus anticoagulant prolongs the aPTT in vitro, and a mixing study does not correct it, yet patients clot in vivo. Anticardiolipin reacts with the cardiolipin in nontreponemal tests, producing a false-positive VDRL or RPR.

Treatment and pharmacology

Hydroxychloroquine for all. It reduces flares, organ damage, thrombosis and mortality and is continued through pregnancy. Because it accumulates in the retinal pigment epithelium, patients need a baseline eye examination and yearly screening after 5 years of use.

Lupus nephritis. Induction combines glucocorticoids with mycophenolate or IV cyclophosphamide; mycophenolate or azathioprine then maintains remission. Mycophenolate works selectively on lymphocytes because they depend on de novo purine synthesis and lack an adequate salvage pathway.

Mycophenolate, cyclophosphamide and methotrexate are teratogenic; before conception, patients switch to pregnancy-compatible drugs such as azathioprine while continuing hydroxychloroquine.