Category: General autoimmunity
SLE is a systemic autoimmune disease notably characterized by the production of pathologic autoantibodies by B cells. Deficiencies in proteins implicated in the clearance pathway, such as the complement C4, have been rapidly associated with SLE susceptibility. The human complement C4 locus encodes two paralogous genes, C4A and C4B that are 99% identical but differ in the isotypic region, which defines covalent binding chemical specificity. Interestingly, human genetic studies showed that C4A allele is protective against SLE development while C4B is not.
In order to understand the functional differences of the two isoforms in vivo, we used CRISPR/Cas9 technology to convert the murine isotypic region into either human C4A or C4B sequence. These newly generated mice were then crossed with the lupus mouse strain 564lgi to compare C4A and C4B functions in autoimmunity.
Our results showed that despite similar C4 expression levels in both strains, C4B.564Igi mice exhibited a higher percentage of autoreactive B cells in secondary lymphoid organs compared to C4A.564Ig. Besides, germinal center number and size in spleen were decreased in C4A.564Igi mice compared to C4B.564Igi mice, reflecting a dampening of immune responses. By using the mouse model AicdaCreERT2-EYFP, we were able to identify a strong decrease of the memory B cell population in C4A.564Igi compared to C4B.564Igi mice. Finally we showed that compared to C4B, C4A is more efficient to induce apoptotic bodies uptake by macrophages in vivo. Thus, this study demonstrates that C4A binds immune complexes more efficiently than C4B and therefore help maintain tolerance in periphery.
Lea Simoni– Post-doctoral fellow / PhD, Boston Children's Hospital / Harvard Medical School, Program in Cellular and Molecular Medicine
Jessy Presumey– Boston Children's Hospital / Harvard Medical School, Program in Cellular and Molecular Medicine
Cees van der Poel– Boston Children's Hospital / Harvard Medical School, Program in Cellular and Molecular Medicine
Michael Carroll– Boston Children's Hospital / Harvard Medical School, Program in Cellular and Molecular Medicine