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Sixteen inbred rat strains were examined for susceptibility and resistance to group A streptococcal cell wall-induced polyarthritis. The findings. indicated that 2 or more genetic loci, as well as sex-related factors, played a major role in determining susceptibility to arthritis in this model. Breeding studies demonstrated that susceptibility was a dominant or codominant trait. A positive association between the severity of arthritis and the development of chronic inflammation in multiple tissues was also observed. In strains that were relatively resistant to arthritis, chronic inflammation was generally limited to the spleen. Since translocation of the poorly degradable and phlogogenic streptococcal cell walls to the synovium and other tissues appears to initiate inflammation, these studies suggested that sus-

This paper reviews the experimental evidence for the proposal that hydrolytic enzymes are introduced into lysosomes of cultured fibroblasts only after secretion and receptormediated recapture.Key words: lysosornes, lysosomal enzymes, pinocytosis, secretion, of-biduronidase How are hydrolytic enzymes transferred from the site of their synthesis to lysosomes? In the usual concept of lysosome formation, the hydrolases proceed from rough t o smooth endoplasmic reticulum, then either t o the Golgi apparatus or t o a specialized region of the smooth endoplasmic reticulum known as GERL. There they are concentrated into small vesicles (primary lysosomes) which detach from the Golgi or from GERL. Eventually these vesicles fuse with phagocytic, pinocytic, or autophagic vacuoles which contain macromolecules t o be hydrolyzed but not the necessary enzymes. The organelles that result from the fusion -i.e., the secondary lysosomes -contain enzymes, substrates, and the appropriately acid environment for hydrolysis to take place (for reviews, see Refs. 1-4). The best evidence for the transport of the hydrolytic enzymes by way of primary lysosomes has been obtained in polymorphonuclear leukocytes. Particles which are rich in acid hydrolases and which correspond t o primary lysosomes -the azurophilic granuleshave been isolated by centrifugation and have been seen t o fuse with phagocytic vacuoles after ingestion of bacteria (2). However, the evidence is weaker for nonphagocytic mammalian cells, since primary lysosomes have not been isolated and their role in enzyme transport has been deduced from static morphological studies by electron microscopy. THE SECRETION-RECAPTURE HYPOTHESISAn alternative hypothesis would have hydrolytic enzymes secreted t o the cell exterior (perhaps through secretory vesicles), recaptured by a receptor-mediated endocytosis, and only then packaged into lysosomes (Fig. 1). Prior t o secretion, the enzymes would be equipped with a structural feature (a "recognition marker") to insure binding to the *Postdoctoral Fellow of the Arthritis Foundation

Less than 5% of samples in our study were benign, and 11.8% were nondiagnostic. Biopsy in smaller lesions was less accurate; therefore biopsy is less useful for these renal lesions. Because fine-needle aspiration (FNA) has higher sensitivity than core biopsy, an appropriate algorithm may be to begin with FNA and reserve core biopsy for cases in which an onsite cytotechnologist is unavailable or deems the sample of inadequate cellularity.