GENE REGULATORY EVENTS IN ESTABLISHING MATURE T CELL TOLERANCE

National Institute Of Allergy And Infectious Diseases

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Abstract

B cell expansion with NF-B and T cell anergy (BENTA) is a primary immunodeficiency disorder of humoral immunity discovered by our group 7 years ago. The disease caused by dominant activating mutations in the CARD11 gene that constitutive NF-B activation in B and T cells. The CARD11 protein is a scaffolding protein required for the transmission of signals from antigen receptors into the cell for NF-B activation in both B and T lymphocytes. It contains an N-terminal CARD domain, a central coiled-coil (CC) domain, and a C-terminal region containing a PDZ, an SH3, and a GUK domain. It serves as a central signaling adapter for transmission of signals from the antigen receptor in B and T cells especially induction of the transcriptional program mediated by NF-B. Afflicted patients manifest polyclonal expansion of B cells in early childhood with splenomegaly, lymphadenopathy, T cell dysfunction, mild autoimmunity, and susceptibility to opportunistic infections. We have discovered four BENTA cases in our collaborative center in Mumbai India with novel clinical manifestations. All patients harbored previously reported gain-of-function missense mutations (G123S, G123D, and C49Y) in the CARD11 gene. Severe infectious complications were noted for the first time in all our patients. All patients suffered severe respiratory infections with high grade fever leading to death before 3 years of age except P2 who required ventilator support at the initial stage of illness but recovered later. Patient P4 presented with hemophagic lymphohistiocytosis at the terminal stage of illness. Moreover, severe autoimmune manifestations and autoantibodies have not been previously reported in BENTA patients. However, all our patients exhibited significant autoimmunity with direct Coombs test and autoimmune hemolytic anemia along with immune thrombocytopenia in two patients (P1 and P2). In addition to this, other autoimmune manifestations like hives was noted in P4. Thus in the environment of a different country, in this case India, BENTA disease has a much more severe course then in the United States where it was initially discovered.