LTβR deficiency causes lymph node aplasia and impaired B cell differentiation

Area of Science:

• Immunology
• Genetics
• Developmental Biology

Background:

• Secondary lymphoid organs (SLOs) are crucial for adaptive immunity, facilitating immune cell interactions and B cell differentiation.
• Functional hyposplenism, absent tonsils, and lymph node aplasia lead to recurrent infections, indicating a severe immune defect.

Purpose of the Study:

• To investigate the genetic basis of a severe inborn error of immunity characterized by the absence of SLOs.
• To elucidate the role of lymphotoxin beta receptor (LTβR) signaling in the development and function of SLOs and the adaptive immune system.

Main Methods:

• Studied three patients from two families with clinical manifestations of SLO deficiency.
• Performed genetic analysis to identify mutations in the LTBR gene.
• Assessed immune cell populations and function, including B cells, T helper cells, and immunoglobulin levels.
• Utilized an ex vivo coculture system to evaluate B cell differentiation potential.

Main Results:

• Identified biallelic loss-of-function mutations in LTBR, encoding LTβR, in all affected patients.
• LTβR deficiency resulted in hypogammaglobulinemia, diminished memory B cells, regulatory T cells, and follicular T helper cells.
• B cell differentiation was normal in vitro, suggesting the defects were due to impaired stromal cell interactions rather than intrinsic B cell abnormalities.

Conclusions:

• LTβR signaling is essential for the development and maintenance of SLOs in humans.
• LTβR deficiency represents a novel inborn error of immunity primarily caused by a stromal defect affecting SLO formation and function.
• This study underscores the critical role of stromal-immune cell interactions in orchestrating adaptive immunity.