Skip to main content

Advertisement

Disturbed B-lymphocytes selection in autoimmune lymphoproliferative syndrome

Article metrics

  • 1130 Accesses

Meeting abstract

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphoproliferative disease, autoimmune cytopenias and increased susceptibility to lymphoid malignancies. Central to the pathophysiology of the disease are defects in the FAS signaling leading to impaired lymphocyte homeostasis. Most of the patients harbor heterozygous germline or somatic mutations in FAS. The hallmark of the disease is the impaired FAS-mediated apoptosis of activated T cells and presence of atypical "double-negative" T cells (CD3+TCRalpha/beta+CD4-CD8-). While FAS is essential for deletion of autoreactive B cells in the germinal center in murine models, the role of FAS in human B cell selection and development of autoimmunity in patients carrying FAS mutation is unclear.

We analyzed patients with somatic FAS mutation or germline FAS mutation plus somatic loss-of-heterozygosity allowing to compare the fate of B cells with impaired versus normal FAS signaling within the same individual. We found in the class-switched memory B cells: 1) accumulation of FAS- mutated B cells, 2) a failure to enrich single V genes and in single V-D, D-J gene combinations of the B cell receptor variable region, 3) increased frequency of variable regions with higher content of positively charged amino acids and longer CDR3 and 4) maintenance of polyreactive specificities. Importantly, FAS-deficient switched memory B cells showed increased rates of somatic hypermutation. Our data uncover a defect in B cell selection in ALPS patients and indicate a role for B cell dysregulation in the pathogenesis of autoimmunity and B-cell lymphoma in ALPS patients.

Author information

Correspondence to Aleš Janda.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Keywords

  • Germinal Center
  • Charge Amino Acid
  • Lymphoid Malignancy
  • Somatic Hypermutation
  • Single Versus