Fig. 5.28
Autoimmunity. It is proposed that CD4+ T cells responding to an as yet unidentified antigen accumulate in the skin and release cytokines that activate inflammatory cells and fibroblasts. Although inflammatory infiltrates in the affected skin typically are sparse, they include activated CD4+ TH2 cells. Several cytokines, including IL-13 produced by TH2 cells and TGF-β produced by macrophages and other cell types, stimulate synthesis of collagen and extracellular matrix proteins (e.g., fibronectin) in fibroblasts. Other cytokines recruit leukocytes and propagate the chronic inflammation.
The presence of various autoantibodies, notably ANAs, provides diagnostic and prognostic information. It has been postulated that these antibodies stimulate fibrosis, but the evidence in support of this idea is not convincing.
Vascular damage. Microvascular disease is consistently present early in the course of systemic sclerosis. Telltale signs of endothelial activation and injury and increased platelet activation have been noted. However, the cause of the vascular injury is not known; it could be the initiating event or the result of chronic inflammation, with mediators released by inflammatory cells inflicting damage on microvascular endothelium. Repeated cycles of endothelial injury followed by platelet aggregation lead to release of platelet and endothelial factors (e.g., PDGF, TGF-β) that trigger endothelial proliferation and intimal and perivascular fibrosis. Eventually, widespread narrowing of the microvasculature leads to ischemic injury and scarring. The pulmonary vasculature is frequently involved, and the resulting pulmonary hypertension is a serious complication of the disease.
Fibrosis. The progressive fibrosis characteristic of the disease may be the culmination of multiple abnormalities, including the accumulation of alternatively http://ebooksmedicine.net
EXTERNAL STIMULI? GENETIC SUSCEPTIBILITY EXTERNAL STIMULI?
Fig. 5.28 Amodelforthepathogenesisofsystemicsclerosis.Unknownexternalstimulicausevascularabnormalitiesandimmuneactivationingeneticallysusceptibleindividuals,andbothcontributetotheexcessivefibrosis.Endothelial injury Pulmonary arterial hypertension Synthesis of extracellular matrix proteins: fibrosis involving skin and parenchymal organs Ischemia, repair Proliferative and obliterative vasculopathy Tand B-cell activation Production of pro-fibrotic cytokines (e.g., TGF-˜, IL-13, PDGF) Autoantibodies T B activated macrophages, actions of fibrogenic cytokines produced by infiltrating leukocytes, hyperresponsiveness of fibroblasts to these cytokines, and scarring following ischemic damage caused by the vascular lesions. Studies with cultured fibroblasts from patients have suggested an intrinsic abnormality that causes the cells to produce excessive amounts of collagen.
MORPHOLOGYInsystemicsclerosis,themostprominentchangesoccurintheskin,alimentarytract,musculoskeletalsystem,andkidney,butlesionsalsoareoftenpresentinthebloodvessels,heart,lungs,andperipheralnerves.