Primary Immune Regulatory Disorders (PIRD): Longitudinal Study of Clinical Presentation, Treatment and Outcomes

National Institute Of Allergy And Infectious Diseases

Investigators

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Abstract

During the Fiscal Year 2025 (October 24- August 25) I obtained the following results: A) Molecular and cellular characterization of novel genetic defects leading to IEI with features of immune dysregulation (PIRD). This collaborative effort with scientist at the Imagine Institute in Paris, France and Rockefeller in NYC allowed us to describe a novel IEI due to deficiency of the human lymphocytic surface receptor LY9. Patients manifest with TB due to selective impairment in IFN-γ production by TH1* cells and immune dysregulation. TH1* cells express higher levels of LY9 than other CD4+ T cells. Mechanistically, LY9 polarizes naïve CD4+ T cells toward memory TH1* cells by inducing T-bet via signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) and RORγT (thymus-specific retinoid-related orphan receptor γ) without SAP. LY9 costimulation enhances TCR-driven IFN-γ production of memory TH1*, but not TH1, cells in a T cell-intrinsic manner via NFAT1 (nuclear factor of activated T cells 1) and RORγT. (1). Another collaboration with the Imagine Institute in France allowed us to report 6 adults from 4 kindreds and 3 ancestries carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID) with immune dysregulation. Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells but profound T cell lymphopenia, low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output but not to the same extent of patients with IL7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development. (2). B) Studies on the immuno-pathogenesis leading to the broad clinical spectrum of known IEI. In collaboration with Dr. Rosenzweig’s group at the NIH, we have expanded the phenotype and molecular pathology of PSMB10 deficiency. A patient with a heterozygous variant in PSMB10 (p.G201R) was identified. He presented with severe B-, natural killer-, and T-cell lymphopenia, with a progressive increase in memory CD4+ T cells and loss of CD8+ T cells. The patient's CD34+ cells showed a normal early T-cell development but slightly impaired generation of CD3+TCR αβ+ cells in artificial thymic organoids, and human thymus single-cell RNA sequencing demonstrated that PSMB10 is expressed in different subsets of cortical and medullary thymic epithelial cells. Collectively, we showed that PSMB10 mutations affect positive selection of CD8 T cells, generation of a diverse T-cell repertoire, and negative selection of autoreactive T cells supporting immune dysregulation. The PSMB10 G201R variant is associated with reduced immunoproteasome expression levels that appear to play vital roles in both hematopoietic and extra hematopoietic immune system development and function. This observation suggests possible benefit from thymus implantation (3). In another project the artificial thymic organoid system has been useful in dissecting the cause of T cell lymphopenia of a patient with TP63 deficiency. Ex vivo T cell differentiation was evident with the artificial organoid system, suggesting that a thymic stromal cell defect may be the cause of the T cell lymphopenia. Consistent with this, interrogation of publicly available data indicated that TP63 expression in the human thymus is restricted to thymic epithelial cells. Based on these data, congenital athymia was suspected and the patient received an allogenic cultured thymus tissue implant (CTTI) instead of bone marrow transplantation. This was the first report of suspected congenital athymia and successful treatment with CTTI associated with TP63 variant (4). B) Studies on the immuno-pathogenesis leading to the broad clinical spectrum of known PIRDs. In another study at the NIH we showed that hypomorphic RAG deficiency in humans (157 patients) while allows for generation of T and B cells also leads to signatures of immune dysregulation including production of autoantibodies to a broad range of self-antigens, including type I interferons. T helper 2 (TH2) cell skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas more hypomorphic forms of RAG deficiency are associated with a type 1 immune profile both in blood and tissues. We used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis to define the cell lineage–specific contribution to the immunopathology of the distinct RAG phenotypes. These insights may help improve the diagnosis and clinical management of the various forms of the disease (5). Furthermore, we identified the immunopathological and microbial signatures associated with IBD in patients with partial RAG deficiency (pRD) and in a mouse model of pRD (Rag1w/w) with spontaneous development of colitis. pRD patients with IBD and Rag1w/w mice showed a systemic and colonic Th1/Th17 inflammatory signature. Restriction of fecal microbial diversity, abundance of pathogenic bacteria, and depletion of microbial species producing short-chain fatty acid were observed, which were associated with impaired induction of lamina propria peripheral Treg cells in Rag1w/w mice. Antibiotics ameliorated gut inflammation in Rag1w/w mice, but only bone marrow transplantation (BMT) rescued the immunopathological and microbial signatures. Our findings shed new light in the pathophysiology of gut inflammation in pRD and establish a curative role for BMT to resolve the disease phenotype (6).