A New Leukocyte Hyperadhesion Syndrome of Delayed Cord Separation, Skin Infection, and Nephrosis

Abstract

Leukocyte adhesion deficiency (LAD) I is a well-described genetic disorder in which leukocytes are unable to migrate to sites of inflammation due to mutations in the ITGB2 gene coding for the b subunit of b2 (CD18) leukocyte integrins. The classic symptoms of the disease present in the newborn period as failure of separation of the umbilical cord and recurrent bacterial infections, which continue throughout life. We report on a patient with these clinical manifestations but with normal ITGB2 gene sequencing excluding LAD-I, normal carbohydrate-deficient transferrin testing excluding LAD-II, and normal platelet function excluding LAD-III. With testing for CD18 integrin function by flow cytometry, adhesion assay analysis, and timelapse microscopy, we found the patient' s T lymphocytes to express normal levels of b1 and b2 integrins but to be highly adhesive to integrin ligands and to display decreased migration compared with control T lymphocytes. The hyperadhesiveness of the cells suggests that they might be prevented from reaching infected tissues. Interestingly, administration of glucocorticoids, for the patient' s nephrotic syndrome, alleviated the patient' s chronic diarrhea and decreased the incidence of skin infections. The hyperadhesiveness rather than adhesion deficiency of the patient' s leukocytes suggests that a novel lesion in a pathway regulating integrin adhesion is responsible for the patient' s unique LAD-I-like symptoms. Pediatrics 2014;133:e257-e262

Characterization of single amino acid substitutions in the β2 integrin subunit of patients with leukocyte adhesion deficiency (LAD)-1

“…His normal platelet function also excludes him for having LAD-III. Interestingly, his leukocytes were found to be hyperadhesive and slow in migration [48]. This report is therefore in line with our observation that LAD-1 patients expressing hyperadhesive integrins could display the symptoms of leukocyte adhesion deficiency.…”

Activation and suppression of hematopoietic integrins in hemostasis and immunity

“…18,41,42 Interestingly, hyperadhesive leukocytes have also been described in an individual with leukocyte defects, whereas platelet function was normal. 43 Because mutations in genes encoding leukocyte integrins were not disclosed, this patient may carry a mutation in a protein that suppresses integrin activation. 43 Although the importance of reversing leukocyte integrins to their inactive conformation has been long recognized, the underlying mechanisms have remained enigmatic.…”

“…43 Because mutations in genes encoding leukocyte integrins were not disclosed, this patient may carry a mutation in a protein that suppresses integrin activation. 43 Although the importance of reversing leukocyte integrins to their inactive conformation has been long recognized, the underlying mechanisms have remained enigmatic. Potential mechanisms include proteolytic cleavage of integrins and their activators by calpain or phosphorylation of integrin cytoplasmic tails, particularly at the T/S region and the NxxY motifs (Figure 2).…”