Phenotypic and pathomechanistic overlap between tapasin and TAP deficiencies.

BACKGROUND: Human tapasin deficiency was reported to cause an autosomal recessive inborn error of immunity (IEI), characterized by substantially reduced cell surface expression of major histocompatibility complex class I (MHC-I). OBJECTIVE: To evaluate the immunological and the clinical consequences of tapasin deficiency. METHODS: A novel homozygous variant in TAPBP was identified by means of whole genome sequencing (WGS). The expression of tapasin and both subunits of the transporter associated with antigen presentation (TAP) were evaluated by western blotting. Cell surface and intracellular expression of MHC class I has been evaluated by flow cytometry. Small interfering RNAs (siRNAs) were used for silencing TAPBP expression in HEK293T cells. RESULTS: We identified a deletion in TAPBP (c.312del, p.(K104Nfs*6)) causing tapasin deficiency in a patient with bronchiectasis and recurrent respiratory tract infections as well as herpes zoster. Besides substantial reduction in TAP1 and TAP2 expression, PBMC from this patient and TAPBP knockdown HEK293T cells, displayed reduced cell surface expression of MHC-I, while reduction in intracellular expression of MHC-I was less prominent, suggesting a defect in MHC-I trafficking to the plasma membrane. Interferon-α (IFN-α) improved cell surface expression of MHC-I in tapasin deficient lymphocytes and TAPBP knockdown HEK293T, representing a possible therapeutic approach for tapasin deficiency. CONCLUSION: Tapasin deficiency is a very rare IEI, whose pathomechanism and clinical spectrum overlaps with TAP deficiencies.

Rituximab to treat prolidase deficiency due to a novel pathogenic copy number variation in PEPD.

Prolidase deficiency (PD) is a rare autosomal recessive inborn error of immunity caused by biallelic homozygous or compound heterozygous loss-of-function mutations in PEPD, the gene that encodes prolidase. PD typically manifests with variable dysmorphic features, chronic cutaneous ulcers, recurrent infections and autoimmune features, including systemic lupus erythematosus. So far, there is no consensus regarding treatment of PD and its autoimmune manifestations. Here, we present a 28-year-old female patient with PD due to a novel homozygous intragenic deletion in PEPD, diagnosed at the age of 6 years and 7 months with an undifferentiated connective tissue disease that, apart from its very early onset, would be consistent with the diagnosis of Sjögren's syndrome. Steroids and diverse conventional synthetic disease-modifying antirheumatic drugs failed to control PD-associated vasculitis and mucocutaneous ulcerations and led to infectious complications, including cytomegalovirus colitis. Introduction of rituximab (RTX) treatment in this patient led to sustained recession of mucocutaneous ulceration, enabling tapering of steroids. High interleukin-1ß (IL-1ß) production by this patient's monocytes, together with the detection of both IL-1ß and interleukin-18 (IL-18) in her serum, suggest enhanced inflammasome activation in PD, whereas the therapeutic efficacy of RTX implies a role for CD20 positive B cells in the complex immunopathogenesis of PD.