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Characterization of patients with an increased susceptibility to bacterial
infections and a genetic deficiency of leukocyte membrane complement
receptor type 3 and the related membrane antigen LFA-1
GD Ross, RA Thompson, MJ Walport, TA Springer, JV Watson, RH Ward, J Lida, SL Newman, RA Harrison and PJ Lachmann
Three children from two unrelated families had a history of recurrent
bacterial infections, and their neutrophils were shown to have deficient
phagocytic and respiratory responses and possible deficiencies in
chemotaxis or adherence. Their neutrophils were strikingly deficient in the
ability to ingest or give a respiratory burst in response to unopsonized
bakers' yeast or zymosan (Z). Tests for neutrophil and monocyte CR1
(C3b/iC3b receptor) and CR3 (iC3b receptor) demonstrated rosettes with both
EC3b and EC3bi. However, EC3bi were bound only to CR1, and not to CR3,
because EC3bi rosettes were inhibited completely by anti-CR1. Neutrophils,
monocytes, and natural killer (NK) cells also did not fluorescence stain
with monoclonal antibodies specific for the alpha-chain of CR3 (anti-Mac-1,
anti-Mol, OKM1, and MN-41). Quantitation of C receptors with 125I
monoclonal anti-CR1 and anti-CR3 indicated that neutrophils from each
patient expressed normal amounts of CR1 per cell but less than 10% of the
normal amount of CR3. Examination of neutrophils by sodium dodecyl
sulfate-polyacrylamide gel electrophoresis demonstrated that a normal
glycoprotein of approximately 165,000 daltons was missing. Immunoblotting
of these gels indicated that the missing band was the alpha-chain of CR3.
Subsequent analysis of all three patients' cells also demonstrated a
deficiency of LFA-1 alpha-chain and the common beta- chain that is shared
by the CR3/LFA-1/p150,95 membrane antigen family. The deficiency of LFA-1
probably explained the absent NK cell function, as normal NK cell activity
is inhibited by anti-LFA-1 but not by anti- CR3. The reduced phagocytic and
respiratory responses to Z were probably due to CR3 deficiency, because
treatment of normal neutrophils with anti-CR3, but not anti-FLA-1, inhibits
responses to Z by 80% to 90%. Ingestion of Staphylococcus epidermidis by
normal neutrophils was shown to be partially inhibited by monoclonal
antibodies to the alpha- chain of either CR3 or LFA-1, and monoclonal
antibody to the common beta-chain inhibited ingestion by 75%. Thus, both
CR3 and LFA-1 may have previously unrecognized functions as phagocyte
receptors for bacteria. The absence of this type of nonimmune recognition
of bacteria by these children's neutrophils may be one of the reasons for
their increased susceptibility to bacterial infections.
Volume 66,
Issue 4,
pp. 882-890,
10/01/1985
Copyright © 1985 by The American Society of Hematology
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