The Autoimmune Risk R262W Variant of the Adaptor SH2B3 Improves Survival in Sepsis

Area of Science:

• Genetics and Immunology
• Infectious Disease Research

Background:

• The rs3184504 single-nucleotide polymorphism (SNP) is associated with increased risk for autoimmune and cardiovascular diseases, with enrichment in European populations.
• The evolutionary mechanism driving the selective sweep of this allele remains unclear.

Purpose of the Study:

• To investigate the role of the rs3184504*T allele and its associated protein, SH2B3, in sepsis.
• To understand the impact of SH2B3 function on sepsis outcomes and immune response.

Main Methods:

• Analysis of a human sepsis cohort for association with the rs3184504*T allele.
• Utilizing SH2B3-deficient (Sh2b3-/-) and knockin mouse models challenged with polymicrobial sepsis (cecal ligation and puncture).
• Assessing survival, morbidity, organ damage, bacterial clearance, and immune cell recruitment and function.

Main Results:

• The rs3184504*T allele, causing a loss-of-function in SH2B3 (p.R262W), was associated with reduced sepsis mortality.
• SH2B3 deficiency in mice improved survival and reduced organ damage during sepsis, characterized by enhanced monocyte phagocytosis and myelopoiesis.
• Homozygous knockin mice with a hypomorphic SH2B3 allele also showed improved sepsis outcomes.

Conclusions:

• Hypomorphic SH2B3 function confers a survival advantage in sepsis by enhancing immune responses.
• Balancing selection may have contributed to the prevalence of the rs3184504 autoimmune risk allele due to its protective effect in sepsis.