title: The relationship between CR3 deficiency and neutrophil actin assembly.
abstract: Polymorphonuclear leukocytes (PMN) with a deficiency of the complement receptor type 3 (CR3) membrane glycoprotein family have impairments in the ability to adhere to surfaces as well as chemotactic and phagocytic defects, processes that require a functional contractile apparatus. PMN from the patient with neutrophil actin dysfunction (NAD) displayed similar functional characteristics to those with CR3 deficiency suggesting the two disorders may be the same disease. In order to evaluate the relationship between CR3 deficiency and actin assembly, actin filament assembly was measured in PMN from six previously reported homozygotes (two severe and four moderate CR3-deficient patients) as well as five heterozygotes for CR3 deficiency. PMN from all patients had normal unstimulated concentrations of F-actin and after exposure to the chemotactic peptide FMLP (5 x 10(-7) mol/L for 5 to 40 seconds at 25 degrees C) assembled actin normally. Pretreatment of normal PMN with concentrations of monoclonal anti-alpha CR3 antibody, capable of blocking PMN adherence, also failed to impair FMLP-induced actin filament assembly. CR3 glycoprotein expression was measured in PMNs from the mother, father, and older sister of the NAD patient (N Engl J Med 291:1093, 1974). Actin filament assembly was recently shown to be defective in PMNs from all three family members. The total concentrations of the alpha and beta CR3 subunits were below normal in PMN detergent extracts from the mother (25% of simultaneous controls) and older sister (56% of control). PMN surface expression of these two subunits was also found to be depressed (mother, 50%; older sister, 63% of control). These findings suggest these two NAD family members are heterozygote carriers for CR3 deficiency as well as NAD. Simultaneous studies of the father, however, demonstrated normal total concentrations of both the alpha and beta CR3 subunits (126% of controls) as well as normal surface expression of both subunits after phorbol myristate acetate stimulation and incubation at 37 degrees C (mean, 112% of controls) but slightly lower than normal levels after FMLP stimulation (mean, 83%). These findings indicate that CR3 deficiency generally is not associated with defective actin filament assembly and support the conclusion that NAD represents a unique kindred in which PMN actin function differs from previously reported genotypes of CR3 deficiency.
authors.affiliation: Infectious Disease Division, University of Pennsylvania School of Medicine, Philadelphia 19104.
authors.forename: F S
authors.initials: FS
authors.lastname: Southwick
authors.forename: T H
authors.initials: TH
authors.lastname: Howard
authors.forename: T
authors.initials: T
authors.lastname: Holbrook
authors.forename: D C
authors.initials: DC
authors.lastname: Anderson
authors.forename: T P
authors.initials: TP
authors.lastname: Stossel
authors.forename: M A
authors.initials: MA
authors.lastname: Arnaout
mesh_terms: D000199:Actins / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D000328:Adult; D000911:Antibodies, Monoclonal / Q000502:physiology; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D003179:Complement C3b / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism / Q000502:physiology; D005260:Female; D006580:Genetic Carrier Screening; D006098:Granulocytes / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008297:Male; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology*; D011951:Receptors, Complement / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D017463:Receptors, Complement 3b
chemical_list: D000199:Actins; D000911:Antibodies, Monoclonal; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D003179:Complement C3b