Prostaglandins and Cyclic Nucleotides in the Chédiak-Higashi Syndrome and Experimental Systemic Lupus Erythematosus

Abstract

Prostaglandins and cyclic nucleotides are important regulators of cell function and immune/inflammatory responses. Chediak-Higashi (CH) syndrome in man is a genetic disorder characterized by pale skin, hair, and eye color, abnormal lysosomes, and recurrent infections. Oculocutaneous pigment dilution and impaired leukocyte function appear to be due to a defect in microtubule assembly. Whereas human peripheral blood polymor-phonuclear (PMN) leukocytes do not form surface caps with concanavalin A (Con A) except after treatment with agents such as colchicine that inhibit microtubule assembly, CH PMN leukocytes exhibit spontaneous cap formation. This capping is inhibited by cyclic GMP (cGMP) and by cholinergic agonists that increase cellular cGMP generation. The extensive assembly of microtubules seen with the electron microscope in normal human PMN leukocytes incubated with Con A does not occur in PMN leukocytes from CH patients. Incubation of CH PMN leukocytes with cGMP or agents that increase cellular cGMP results in a marked increase in microtubule numbers when cells are exposed to Con A. Because ascorbic acid increases human leukocyte cGMP levels in vitro, CH patients have been treated with vitamin C. Early results in approximately 6 CH patients indicate that vitamin C therapy restores leukocyte function and prevents recurrent infections. A disease similar to human systemic lupus erythematosus develops in New Zealand black and white (NZB/W) mice; it is characterized by impaired cell-mediated immunity, enhanced humoral immune responses, circulating antibodies to nuclear antigens, and immune-complex. glomerulonephritis. Treatment of NZB/w mice with prostaglandin E1 prevents glomerular deposition of immunoglobulins and complement, the development of proliferative glomerulonephritis, and prolongs their survival.