COMPLEMENT, ADIPOCYTES AND THE KIDNEY

The complement system has traditionally been thought of as a group of circulating proteins predominantly produced in the liver, with functio ns in both afferent and efferent arms of the immune response, primaril y concerned with host defence. In recent years, it has become apparent that many tissues synthesize and secrete complement components and th at the complement cascade may have previously unsuspected local action s in these tissues in health and disease. Perhaps one of the most surp rising organs in this respect is adipose tissue. The adipocyte is capa ble of producing all the key components of the alternative pathway, an d produces particularly abundant quantities of factor D, previously th ought to be mainly produced by cells of the monocyte/macrophage lineag e. Adipose tissue is probably the main source of factor D in vivo: fac tor D expression is decreased in various experimental models of obesit y, and is increased in fasting or catabolic states, suggesting that fa ctor D (and hence the alternative pathway) may play a role in physiolo gical regulation of adipose tissue. Another link between adipocytes an d the complement pathway is illustrated by the recent demonstration th at the complement cleavage product C3a has potent activity as an acyla tion stimulating protein, promoting the esterification of fatty acids into triglyceride. The production of factor D by adipocytes probably u nderlies the association between complement activation by the autoanti body nephritic factor (NeF) and adipose tissue loss in partial lipodys trophy (PLD): in vitro data indicate that serum containing NeF causes complement-mediated lysis of adipocytes. There is preliminary evidence of a regional variation in factor D gene expression with higher level s of expression in the regions affected by adipocyte loss in PLD. This illustrates a novel concept in immunopathology: by expression of fact or D the adipocyte contributes to its own destruction when the normal regulation of the alternative pathway is subverted by the presence of NeF. In relation to the nephritis associated with NeF, we postulate th at a similar mechanism may operate. Intrinsic renal cells are known to produce complement components, and NeF may lead to injury to these ce lls, aggravated perhaps by cytokines which are known to up-regulate co mplement protein expression in renal cells. Other situations by which dysregulation of the alternative pathway occurs may lead to nephritis by a similar mechanism. For example, in rare human cases with factor H deficiency, and in a recently described variety of Yorkshire pig with factor H deficiency, nephritis is common and is histologically simila r to the nephritis associated with NeF. Thus, recent advances in adipo cyte biology have led to navel ideas about actions of complement, and similar principles may apply to physiology and pathology in the kidney .