Multiple antigens are altered on T and B lymphocytes from peripheral blood and spleen of patients with Wiskott-Aldrich syndrome

Abstract

SUMMARYThe gene for Wiskott-Aldrich syndrome (WAS) has been recently identified and cloned, but our knowledge of downstream events affected in WAS is limited to a few leucocyte cell surface molecules. To identify cell surface molecules whose abnormal expression could contribute to the functional impairment observed in WAS B and T lymphocytes, we studied the expression of a large panel of antigens on peripheral blood lymphoid cells (PBLC) and on isolated lymphocyte subpopulations from the spleen of WAS patients. WAS T lymphocytes from peripheral blood express increased levels of the activation antigens 4F2, CD49d, CD49e, CD53 and the activation/memory marker CD45RO. In the spleen, however, WAS patients have more CD45RA CD4 and CD8 T lymphocytes than normal individuals, suggesting the selective accumulation of presumably naive cells in the WAS spleen. Interestingly, the naive phenotype of the lymphocytes that seem to accumulate in the WAS spleen is confirmed by the absence of increased expression of several activation antigens on their surface, and this correlated with their increased expression of CD43. These lymphocyte abnormalities were accompanied by an abnormal distribution of lymphocyte subsets within the spleen architecture, in particular by the lack of well developed germinal centres and T cell areas. We also found abnormal expression of CD43 and other sialyated proteins such as CDw75 and CD76, whose expression requires the action of specific sialyltransferases. This study shows that the combined impairment in cellular and humoral immunity observed in WAS is the result of multiple molecular abnormalities on the surface of WAS lymphocytes, that in turn might result in recirculation/migration anomalies.

Mixed chimera status of 12 patients with Wiskott-Aldrich syndrome (WAS) after hematopoietic stem cell transplantation: evaluation by flow cytometric analysis of intracellular WAS protein expression

“…Patients with WAS were previously found to have a marked number of CD45RA Ϫ /RO ϩ T cells in their peripheral blood before HST. 22 We also observed this in 2 of the patients we examined before HST, whose ratio of CD45RA ϩ /RO Ϫ to CD45RA Ϫ /RO ϩ cells was comparable to that in age-matched controls (data not shown). Thus, the results obtained with 3-color FCM-WASP in this study may represent the outcome under a condition of competition between WASP bright and WASP dim memory T cells.…”

“…5 However, the recent finding of X-linked neutropenia with WASP mutation (L270P) may indicate that WASP is at least expressed in myeloid precursor cells. 22 To evaluate the MC status of granulocytes, we sequenced DNA from purified granulocytes from some of our patients with WAS. By comparing nucleotide signals of the wild-type and mutant at the mutation site and taking donor type into consideration, we could estimate roughly the proportion of donor and recipient cells in this cell population.…”

Phenotypic perturbation of B cells in the Wiskott–Aldrich syndrome

“…The deficit of CD27 + B-cells is consistent also with histomorphometric findings for patient secondary lymphoid organs. Cellular architectural defects identified in germinal centres ranged from a lack of defined structure [45] to a gross morphological defect characterized as 'burnt out' morphology [46]. The reduction of marginal zone thickness was also reported in spleen sections [46].…”

All roads lead to actin: the intimate relationship between TCR signaling and the cytoskeleton

“…The mammalian WASP family proteins [WASP, N‐WASP, and WASP‐family verprolin‐homologous proteins (WAVEs)] activate the Arp2/3 complex and are thus key to nucleation of new actin filaments in mammalian cells (reviewed in 58, 70, 74–76). The significance of WASP was recognized when mutations in WASP were defined as the causative agent in the human Wiskott–Aldrich syndrome (77, 78). T cells from WAS patients have abnormal microvilli, cell surface markers, polarization, and motility.…”