Phenotypic and pathomechanistic overlap between tapasin and TAP deficiencies

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Human tapasin deficiency is an autosomal-recessive inborn error of immunity.
• It is characterized by significantly reduced cell surface expression of major histocompatibility complex class I (MHC-I).

Purpose of the Study:

• To evaluate the immunologic and clinical consequences of tapasin deficiency.
• To investigate the underlying molecular mechanisms and potential therapeutic strategies.

Main Methods:

• Whole genome sequencing identified a novel homozygous variant in TAPBP.
• Western blot and flow cytometry assessed protein expression and cell surface MHC-I levels.
• HEK293T cells were used to silence TAPBP expression via small interfering RNAs.

Main Results:

• A TAPBP deletion (c.312del, p.(K104Nfs∗6)) caused tapasin deficiency in a patient with recurrent infections and herpes zoster.
• Reduced TAP1 and TAP2 expression and impaired MHC-I trafficking to the plasma membrane were observed.
• Interferon-alpha improved cell surface MHC-I expression in affected cells, indicating a potential therapeutic avenue.

Conclusions:

• Tapasin deficiency is a rare inborn error of immunity with overlapping features to TAP deficiencies.
• The study elucidates the pathomechanism involving impaired MHC-I trafficking.
• Interferon-alpha presents a promising therapeutic strategy for tapasin deficiency.