Fabian Hauck, Germany
Klinikum der Universität München Dr von Hauner Children's HospitalPresenter of 4 Presentations
HETEROZYGOUS OAS1 GAIN-OF-FUNCTION VARIANTS CAUSE A POLYMORPHIC AUTOINFLAMMATORY AND IMMUNODEFICIENCY SYNDROME
Abstract
Background and Aims
The genetic, molecular, and cellular analysis of autoinflammatory and immunodeficiency disorders contributes to our understanding of human immunity and leads to the development of targeted therapies. Oligoadenylate synthase 1 (OAS1) is an intracellular double-stranded RNA sensor that generates the second messenger 2'-5'-oligoadenylate to activate RNaseL as a means of antiviral defense. We analyzed four unrelated patients with a polymorphic syndrome of fever, dermatitis, pulmonary alveolar proteinosis, inflammatory bowel disease, and hypogammaglobulinemia.
Methods
We performed exome and transcriptome sequencing, RNA and protein biochemistry, heterologous and autologous molecular and cellular functional analyses, cellular and serologic immune phenotyping, and allogeneic hematopoietic stem cell transplantation.
Results
We found three de novoheterozygous OAS1variants in four unrelated patients. Variant OAS1 proteins showed double-stranded RNA-independent increased in vitro enzyme activity. They constitutively activated RNaseL resulting in increased RNA cleavage in a heterologous cell system as well as in primary monocytes and B cells. This lead to an increased interferon response, spontaneous monocyte and B cell apoptosis, impaired monocyte and B cell differentiation and function, and impaired cellular co-stimulation towards T cells. Allogeneic hematopoietic stem cell transplantation corrected the otherwise lethal phenotype.
Conclusions
Heterozygous OAS1 gain-of-function variants cause a polymorphic autoinflammatory and immunodeficiency syndrome that can be cured by allogeneic hematopoietic stem cell transplantation. OAS1 emerges as a critical regulator of monocyte and B cell human biology.
EBV POSITIVE SMOOTH MUSCLE TUMORS AS MANIFESTATION OF INBORN ERRORS OF IMMUNITY
Abstract
Abstract Body
EBV positive smooth muscle tumors are a rare oncological entity that can develop in secondary immunodeficiency such as human immunodeficiency virus-infection or solid organ transplantation. In addition, in rare pediatric cases EBV positive smooth muscle tumors can develop in the context of primary immunodeficiency such as CARMIL2 deficiency. In secondary immunodeficiency and when the underlying condition can not be cured, the treatment of EBV positive smooth muscle tumors is based on surgery in combination with antiretroviral and reduced or altered immunosuppressive pharmacotherapy, respectively. However, when cellular immunity cannot be reestablished or EBV positive smooth muscle tumors cannot completely be resected, long-term survival is poor. Importantly, allogeneic hematopoietic blood stem cell transplantation resulted in cure of immunodeficiency and EBV positive smooth muscle tumors in a GATA-2 deficient patient and is ongoing in a CARMIL2 deficient patient. Thus, in the absence of secondary immunodeficiency patients presenting with EBV positive smooth muscle tumors should be thoroughly evaluated for primary immunodeficiency disorders and patients with known primary immunodeficiency presenting with smooth muscle tumors should be evaluated for an underlying ectopic EBV infection. Allogeneic hematopoietic stem cell transplantation should be taken into consideration in these cases.