Studies on Cystic Fibrosis Using Isoelectric Focusing. II. Demonstration of Deficient Proteolytic Cleavage of α2-Macroglobulin in Cystic Fibrosis Plasma

Letter to the Editor: Is Cystic Fibrosis Protein a Diagnostic Marker for Individuals Who Harbor the Defective Gene?

“…(This would be analogous to hemophilia, which was originally thought to be a single disease but later shown to include two separate entities, one due to factor VIII deficiency and another to factor IX deficiency, and Wiskott-Aldrich syndrome, in which some patients appear to have monocyte defects but others have normal monocytes.) For example, in our own work on the a*-macroglobulin in CF we have clearly delineated two types of CF patients (16,18); and with regard to the CFP, there is always a small population of "sweat test-positive" homozygotes for C F who, along with their obligate heterozygote parents, are negative for CFP (10,17,19). This apparent discordance might be due to problems inherent in the sweat test, which is known not to be 100% accurate (23), but is used in conjunction with other clinical findings in the diagnosis of CF.…”

“…Since the obligate heterozygote camer expresses only a partial defect in az-macroglobulin, as evidenced by electrofocusing (16,18) and other techniques (S), the carrier may be essentially asymptomatic in vivo due to the existence of other as yet unknown mechanisms which compensate in part for the az-macroglobulin defect. In vitro, these compensatory mechanisms may not operate, and therefore the gene defect (Le., the generation of CFP and ciliary dyskinesia factors by cells in culture) may be fully expressed in both the obligate camer and homozygote for CF (20).…”

“…In addition, we have been studying the possible role of abnormal regulation of serine proteases by the a;-macroglobulin found in CF plasma in the eeneration or abnormal metabolism of C3a, kinins, 'CFP, and cifary dysinesia factors (16). Recently, using short term leukocyte cultures and long term lymphoid lines (12,13,15), we have found evidence that a-macroglobulin may be partly responsible for controlling the metabolism of C3a and the ciliary dyskinesia factors, and that it is most likely also responsible for controlling the metabolism and function of CFP.…”

Binding of 125I-Labeled Proteinases to Plasma Proteins in Cystic Fibrosis

“…Among other findings, it has been reported that an a2M-protease complex is missing in most CF patients (26,32) and that binding of trypsin and other proteinases to a2M is decreased in plasma of CF patients with respect to normal controls (25,32). In addition, a deficiency of arginine esterase activity has been reported in CF patients (22).…”

A Monoclonal Antibody Recognizes Structural Variation in Cystic Fibrosis α2-Macroglobulin

“…" Cystic fibrosis has been studied for many years although no biochemical or structural defect has been established (28). The probable involvement of a2M in the pathology of cystic fibrosis has been suggested by several groups based upon their work on isoelectric focusing of serum samples (29) and immunological and biochemical examination of protease-a2M complexes (22)(23)(24)(25). However, recent reports have failed to confirm differences in structure and protease binding capabilities of cystic fibrosis and normal a2M (5,7,8,19).…”