Genetics of Transfusion Recipient Alloimmunization: Can Clues from Susceptibility to Autoimmunity Pave the Way?

Abstract

The search for genetic determinants of alloimmunization in sickle cell disease transfusion recipients was based on two premises: i) that polymorphisms responsible for stronger immune and/or inflammatory responses and hemoglobin β^S mutation were co-selected by malaria; and ii) that stronger responder status contributes to development of lupus. We found a marker of alloimmunization in the gene encoding for Ro52 protein, also known as Sjögren syndrome antigen 1 (SSA1) and TRIM21. Surprisingly, the nature of the association was opposite of that with lupus; the same variant of a polymorphism (rs660) that was associated with lupus incidence was also associated with induction of tolerance to red blood cell antigens during early childhood. The dual function of Ro52 can explain this apparent contradiction. We propose that other lupus/autoimmunity susceptibility loci may reveal roles of additional molecules in various aspects of alloimmunization induced by transfusion as well as during pregnancy.

Are Immune Modulating Single Nucleotide Polymorphisms Associated with Necrotizing Enterocolitis?

“…TRIM21 is a tripartite motif protein that is located on chromosome 11p15.5 in the non-coding region of the gene and leads to a single base alteration from a C to T allele 28 29 42 . Depending on the context, TRIM21 can have proinflammatory or anti-inflammatory actions 43 . TRIM21 can also serve as an intracellular receptor for antigen-antibody complexes internalized via cell surface receptors that infectious agents use to enter the cells.…”

Fatal delayed haemolytic transfusion reaction in a patient without previous transfusions but with an obstetric history of 13 pregnancies

“…Failure to observe a higher frequency of alloimmunisation in females could have occurred if the males received more transfusions resulting in more challenges 15. In addition, as some aetiologies of DHTR remain unexplained since there are cases in which there is an absence of detectable alloantibodies,16 it is possible that some genetic factors may have facilitated the process of alloimmunisation among some patients 17…”

Identification of genetic biomarkers for alloimmunization in sickle cell disease

“…It is anticipated that additional variations in genes controlling inflammatory responses will be associated with protection or increased risk of alloimmunization, because the inflammatory status of the recipient can trigger the innate immune system to convert a tolerogenic event into an immunogenic one (Hendrickson et al , ; Zimring & Hendrickson, ; Tatari‐Calderone et al , ). Patients that suffer from acute illness, autoimmune disease or an inflammatory disorder show higher rates of alloimmunization in response to RBC transfusion (Hendrickson & Tormey, ; Evers et al , ).…”

“…Of interest, SCD patients display a high degree of inflammation and innate immune activation due to chronic haemolysis (Jison et al , ; Hibbert et al , ). Moreover, there is evidence suggesting a higher frequency of certain inflammatory or autoimmune conditions in the African population as a whole (Barnes, ; Lau et al , ; Mohan, ; Molokhia & McKeigue, ; Carter & Holditch‐Davis, ; Tatari‐Calderone et al , ). These findings may partly be explained by environmental factors, nonetheless, there is also a genetic component.…”