Small populations of normal cells affect immunity in patients with XLP1

November 09, 2018

Tokyo Medical and Dental University (TMDU)-led study shows that, in some patients, somatic reversion of SLAM-associated protein expression in T cells leads to a mild form of X-linked lymphoproliferative syndrome type 1

Tokyo, Japan - Human SH2D1A mutations resulting in X-linked lymphoproliferative syndrome type 1 (XLP1) are associated with a unique susceptibility to the Epstein-Barr virus (EBV), which may lead to fatal infectious mononucleosis (FIM). Many studies have attempted to elucidate an appropriate treatment for XLP1 that does not involve hematopoietic stem cell transplantation (HSCT); clinical evidence supporting such treatments has been minimal, until now.

In a new study published in the Journal of Allergy and Clinical Immunology, an international research team led by experts from Tokyo Medical and Dental University (TMDU) investigate the mechanism of mild disease presentation in a family with XLP1 that did not undergo HSCT, and found evidence of somatic reversion, or a return to normal expression levels, of SLAM-associated protein (SAP) in T cells.

Patients with XLP1 are susceptible to severe complications of EBV infections, such as FIM, which has a high mortality rate. This is attributed to poor activation and cytotoxicity of the CD8+ T cell. The only effective treatment for XLP1 has been HSCT. Unfortunately, HSCT has a high risk of treatment-related mortality and many side effects.

"We analyzed the clinical features of 40 Japanese patients with XLP1," says Hirokazu Kanegane, corresponding author on the study. "We identified a family that did not experience FIM, although none of the members had undergone HSCT."

In the study, whole-exome sequencing of patients in the family with mild disease revealed a known mutation, which reduced the expression of SAP in T cells in affected patients. This conflicted with the mild disease presentation.

"We performed more detailed analyses of T cells in the affected family, and found small populations of CD4+ and CD8+ T cells expressing functional SAP at normal levels," says Akihiro Hoshino, lead author on the study. "Because this somatic reversion was present in multiple patients in the same family, it may be an inherited characteristic."

Small populations of T cells with normal SAP expression could modify the severity of disease in these patients. The researchers speculated that gene therapy or adoptive cellular therapy--which affect fewer cells than HSCT, but are much less dangerous--could be effective for treating patients with XLP1.

XLP1 is a disease with deficient immunity against EBV, which can result in fatal outcomes. Treatment has been limited to HSCT, which can be a dangerous approach. This study showed that small populations of normal T cells could reduce the severity of disease, suggesting that less invasive therapies may be useful in treatment of XLP1.
-end-
The article, "Modi?cation of cellular and humoral immunity by somatically reverted T cells in X-linked lymphoproliferative syndrome type 1," was published in the Journal of Allergy and Clinical Immunology at DOI: 10.1016/j.jaci.2018.07.044

Tokyo Medical and Dental University

Related Protein Articles from Brightsurf:

The protein dress of a neuron
New method marks proteins and reveals the receptors in which neurons are dressed

Memory protein
When UC Santa Barbara materials scientist Omar Saleh and graduate student Ian Morgan sought to understand the mechanical behaviors of disordered proteins in the lab, they expected that after being stretched, one particular model protein would snap back instantaneously, like a rubber band.

Diets high in protein, particularly plant protein, linked to lower risk of death
Diets high in protein, particularly plant protein, are associated with a lower risk of death from any cause, finds an analysis of the latest evidence published by The BMJ today.

A new understanding of protein movement
A team of UD engineers has uncovered the role of surface diffusion in protein transport, which could aid biopharmaceutical processing.

A new biotinylation enzyme for analyzing protein-protein interactions
Proteins play roles by interacting with various other proteins. Therefore, interaction analysis is an indispensable technique for studying the function of proteins.

Substituting the next-best protein
Children born with Duchenne muscular dystrophy have a mutation in the X-chromosome gene that would normally code for dystrophin, a protein that provides structural integrity to skeletal muscles.

A direct protein-to-protein binding couples cell survival to cell proliferation
The regulators of apoptosis watch over cell replication and the decision to enter the cell cycle.

A protein that controls inflammation
A study by the research team of Prof. Geert van Loo (VIB-UGent Center for Inflammation Research) has unraveled a critical molecular mechanism behind autoimmune and inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis.

Resurrecting ancient protein partners reveals origin of protein regulation
After reconstructing the ancient forms of two cellular proteins, scientists discovered the earliest known instance of a complex form of protein regulation.

Sensing protein wellbeing
The folding state of the proteins in live cells often reflect the cell's general health.

Read More: Protein News and Protein Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.