Complement, adipocytes and the kidney

Abstract

The complement system has traditionally been thought of as a group of circulating proteins predominantly produced in the liver, with functions in both afferent and efferent arms of the immune response, primarily concerned with host defence. In recent years, it has become apparent that many tissues synthesize and secrete complement components and that the complement cascade may have previously unsuspected local actions in these tissues in health and disease. Perhaps one of the most surprising organs in this respect is adipose tissue. The adipocyte is capable of producing all the key components of the alternative pathway, and produces particularly abundant quantities of factor D, previously thought to be mainly produced by cells of the monocyte/macrophage lineage. Adipose tissue is probably the main source of factor D in vivo: factor D expression is decreased in various experimental models of obesity, and is increased in fasting or catabolic states, suggesting that factor D (and hence the alternative pathway) may play a role in physiological regulation of adipose tissue. Another link between adipocytes and the complement pathway is illustrated by the recent demonstration that the complement cleavage product C3a has potent activity as an acylation stimulating protein, promoting the esterification of fatty acids into triglyceride. The production of factor D by adipocytes probably underlies the association between complement activation by the autoantibody nephritic factor (NeF) and adipose tissue loss in partial lipodystrophy (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 levels of expression in the regions affected by adipocyte loss in PLD. This illustrates a novel concept in immunopathology: by expression of factor 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 that a similar mechanism may operate. Intrinsic renal cells are known to produce complement components, and NeF may lead to injury to these cells, aggravated perhaps by cytokines which are known to up-regulate complement 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 similar to the nephritis associated with NeF. Thus, recent advances in adipocyte biology have led to novel ideas about actions of complement, and similar principles may apply to physiology and pathology in the kidney.