Hematology & immune disorders

• WASP protein structure:
  • WASP gene encodes a 502 amino acid protein expressed exclusively in the cytoplasm of hematopoietic cells
  • C terminal tripartite domain of WASP contains a common actin monomer binding motif, the verprolin homology domain (V) and a central acidic region (A) that is capable of activating the actin related protein (Arp)2/3 complex, a potent nucleator of actin polymerization (Annu Rev Cell Dev Biol 2002;18:247)
    • A proline rich region in exon 10 required for optimal actin polymerization activity has been shown to be indispensable for effective recruitment of WASP to the immunologic synapse in T cells (Immunity 2003;18:141)
  • N terminal region of WASP allows recruitment of the WASP interacting protein (WIP); in resting lymphocytes, WASP constitutively associates with WIP, stabilizing the inactive conformation of WASP (Mol Cell 2002;10:1269)
  • Following interaction with the T cell antigen receptor, WIP is phosphorylated, resulting in disengagement of WASP from the WIP / WASP complex, thus allowing WASP activation by Cdc42, which leads to actin polymerization and stabilization of actin filaments (Cell 2002;111:565)
• WASP mutation spectrum:
  • Total of 141 unique WASP mutations were detected in 262 patients; the most common WAS mutations were missense mutations (35.3%), followed by splice site mutations (19.4%), deletions (17.6%) and nonsense mutations (15.4%); insertions and complex mutations made up less than 13% of the mutations identified (Blood 2004;104:4010)
  • Missense mutants that cause the immune disorder Wiskott-Aldrich syndrome (WAS) map primarily to the enabled / VASP homology 1 (EVH1) domain of the actin regulatory protein WASP; more than 300 such mutations have been described (Ann Diagn Pathol 2019;43:151413)
• Functional mechanisms:
  • Affects functions of both T and B cells
  • WAS mutants can cause a downregulation of T cell receptor signaling through reduced stability of the immune synapse following its formation, which may result in failure of immune activation (Immunology 2010;131:466, Haematologica 2011;96:1415)
  • Besides the WASP regulation of the cytoskeleton dependent immune synapse formation, the interaction between the translocation of the transcription factor of nuclear factor of activated T cells (NFAT) and the Ena-VASP homology domain (EVH1) of WASP, prevents Th1 cytokines secretion from the CD4+ cells, while increasing the relative amount of Th2 cytokines (J Exp Med 2018;215:1009, Ann Diagn Pathol 2019;43:151413)

• Spleen in Wiskott-Aldrich syndrome (WAS) patients shows:
  • Significant depletion of the white pulp, affecting both T and B cell areas
  • Splenic marginal zone in patients with WAS is severely depleted
  • Follicles are heterogeneous in morphologic appearance
  • Red pulp plasma cells in WAS patients are similar to those in control subjects (Am J Surg Pathol 1999;23:182)
• Lymph node biopsy shows preserved architecture with prominent reactive follicles and eosinophils in paracortex; however, the reduction in germinal center has been confirmed in WAS protein deficient murine model (Cell Immunol 2019;341:103919)

• See Pathophysiology

A postnatal day 12 male infant presented with thrombocytopenia. Cardiopulmonary and abdomen examination showed no obvious abnormalities. Results of blood tests before admission were as follows: white blood cell 9.7 x 10⁹/L, hemoglobin 156 g/L, platelet 50 x 10⁹/L, neutrophil 58%, lymphocyte 25%. The immune function examination and blood lymphocyte subsets tests were mildly abnormal. The child died from brain bleeding shortly after admission. The family history documented that the infant’s uncle died in infancy due to repeated infections. His mother was physically healthy. A panel of gene mutation studies was performed and a loss of function mutation was detected in one of the genes. Which of the following genes is the most likely mutated in this child?

1. CXCR4
2. FAS
3. IL7R
4. RAG1/2
5. WASP

E. WASP gene

Comment Here

Reference: Wiskott-Aldrich syndrome