Atherosclerosis, autoimmunity, and vascular‐associated lymphoid tissue

Atherosclerosis is a multifactorial disease induced by the effects of various risk factors on appropriate genetic backgrounds. It is characterized by vascular areas containing mononuclear and proliferating smooth muscle cells,as well as extracellularmatrix (ECM)2 components resulting in hardening and thickening (arteriosclerosis) of the arterial wall. In a strict sense, atherosclerotic lesions are localized in the inlima; they also contain foam cells and deposits of cholesterolcrystalsmanifested as fatty streaks and, finally, as atheroscleroticplaques. Fatty streaks are whitish, cushion-like lesions of the arterial intima harboring abundant lipid-laden macrophages, so-called foam cells, which are considered precursors of the fully developed plaques that may finally exulcerate and even calcif’. The main theories of atherogenesis are the “response to injury” (1) and the “response to altered lipoprotein” (2) hypotheses. The response to injury hypothesis postulates an alteration of the intima by various risk factors (mechanical injury, chemically altered low density lipoproteins [LDL], viruses, toxins) that initiates a primary endothelial dysfunction and subsequent changes in permeability, expression of adhesion molecules, and release of chemotactic and growth factors. Consequently, platelets and monocytes become activated and attach to these endothelial cells. Bloodderived monocytes transmigrate into the subendothelial space and transform into macrophages; smooth muscle cells (SMC) are attracted from the media to the same site. Both monocytes/macrophages and SMC possess the so-called scavenger receptor, which binds chemically altered (oxidized LDL {oxLDL]), but not native, LDL in a nonsaturable fashion. By uptake of oxLDL, macrophages and SMC develop into foam cells, and the deposition of collagenous and noncollagenous ECM components, especially in the peripheral “shoulder” region and the superficial “cap” area, complete the pathohistological appearance of fatty streaks and atherosclerotic plaques, respectively. The response toaltered lipoprotein hypothesis is based on the concept that lipoproteins can be chemically modified and are then able to induce foam cell formation by monocytes/macrophages and SMC. In recent years it has become evident that modification of lipoproteins does not occur primarily in the circulation or during transgression through the endothelium, but they rather accumulate in native form in the subendothelial space, where the lipoproteins are retained and oxidized. Accumulation of oxLDL, therefore, is not only the result of increased influx from the serum into the arterial intima but, conversely, is also due to a diminished efflux with subsequent foam cell formation. This “response to LDL retention” hypothesis (3) is thus a special variant of the response to altered LDL concept. Thus far, these latter theories have not explained why atherosclerotic lesions develop at certain arterial predilection sites or why the disease does not affect the venous vascular bed.