Abstract
Located contiguously on the long arm of the second chromosome are gene paralogs encoding the immunoglobulin-family co-activation receptors CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). CD28 and CTLA4 share the same B7 ligands yet each provides opposing proliferative signals to T cells. Herein, we describe for the first time two unrelated subjects with coexisting CD28 and CTLA4 haploinsufficiency due to heterozygous microdeletions of chromosome 2q. Although their clinical phenotype, multi-organ inflammatory disease, is superficially similar to that of CTLA4 haploinsufficient autoimmune lymphoproliferative syndrome type V (ALPS5) patients, we demonstrate our subjects’ underlying immunopathology to be distinct. Unlike ALPS5 T cells which hyperproliferate to T-cell receptor-mediated activation and infiltrate organs, T cells from our subjects are hypoproliferative and do not. Instead of T cell infiltrates, biopsies of affected subject tissues demonstrated infiltrates of lineage negative lymphoid cells. This histologic feature correlated with significant increases in circulating type 3 innate lymphoid cells (ILC3s) and ILC3 cytokines, interleukin 22, and interleukin-17A. CTLA4-Ig monotherapy, which we trialed in one subject, was remarkably effective in controlling inflammatory diseases, normalizing ILC3 frequencies, and reducing ILC3 cytokine concentrations.
Highlights
Located contiguously on the long arm of the second chromosome are gene paralogs encoding CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4)
Combined CD28/CTLA4 Haploinsufficiency-Associated Inflammation either directly inhibit T-cell receptor (TCR) signaling in cis or out-compete CD28 for B7 ligands in trans [1,2,3,4]
Our subjects’ CD28-haploinsufficient T cells display low in vivo proliferative histories and divide poorly in vitro to TCR-mediated activation, we demonstrate B7 blockade with CTLA4-Ig to be a highly effective anti-inflammatory monotherapy in this clinical context
Summary
Located contiguously on the long arm of the second chromosome are gene paralogs encoding CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Both are immunoglobulin-family coactivation receptors that share the same B7 ligands yet each provides opposing proliferative signals to T cells [1]. CD28 is a potent T-cell receptor (TCR) costimulatory molecule, whereas CTLA4 can Combined CD28/CTLA4 Haploinsufficiency-Associated Inflammation either directly inhibit TCR signaling in cis or out-compete CD28 for B7 ligands in trans [1,2,3,4]. Heterozygous CTLA4 loss-offunction mutations (CTLA4wt/mut) were identified in autoimmune lymphoproliferative syndrome type V patients (ALPS5; OMIM #616100) [6, 7]. CTLA4wt/mut T cells hyperproliferate in vitro, and inflamed ALPS5 patient organs exhibit gross lymphocytic infiltrates
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