Background/Purpose:

The mechanisms of action of intravenous purified immunoglobulins (IVIG) in acute Kawasaki disease (KD) have been investigated in our laboratory and have led to a surprising revelation about the antiinflammatory effects of the constant region (Fc) of the IgG1 molecule: the expansion of Fc-specific natural (n) regulatory T cells (nTreg). This is the most relevant efferent arm of the immune response induced by IVIG in these patients as the development of arterial complications (CAA) correlates with lack of Fcspecific nTreg after therapy. We previously identified 16 Fc-derived peptides (15 amino acids long) that expand nTreg in vitro from KD patients after IVIG and healthy adult controls and determined their HLA binding affinity. Here we studied the response in vitro to the 16 most immunogenic Fc peptides in PBMC from KD subjects after IVIG, adult rheumatoid arthritis (RA) subjects and healthy adult donors to rank their immunodominance for pre-clinical development.

Methods:

The immunogenicity of Fc peptides was tested in vitro by stimulating PBMC with individual Fc peptides and Fc protein as a control (4×10⁵ cells /w in 96 flat bottomed plate) and by screening at day 4 for nTreg expansion with two analyses: 1) FACS staining to enumerate CD4+ CD25high T cells and 2) measurement of IL-10 by ELISA in culture supernatants.

Results:

nTreg from KD and RA patients responded poorly to the whole Fc protein but did respond to Fc peptides. KD subjects after IVIG, and healthy donors showed a similar pattern of nTreg response to Fc peptides. Fc 181-195 that binds multiple class II HLA alleles was immunodominant in the three cohorts. After IVIG, the large majority of KD patients recognize Fc 51-65 and Fc 56-70, which are promiscuous for HLA binding. Fc 21-35, with a monogamous HLA restriction to a common allele in the general population, was also immunodominant in the three cohorts. In the KD cohort, peptide-specific nTreg responses were documented even in children who developed CAA and whose PBMC failed to respond to the intact Fc after IVIG treatment.

Conclusion:

KD subjects prior to IVIG and RA subjects showed poor nTreg response to the intact Fc, but an excellent response to Fc peptides. These results highlight a possible defect in the antigen processing that jeopardizes immune regulation in rheumatic diseases that can be restored by immunodominant pan-HLA Fc peptides.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fc-derived-immunodominant-peptides-stimulate-natural-regulatory-t-cells-a-new-avenue-to-overcome-defects-in-the-fc-antigen-processing-and-restore-immune-regulation-in-rheumatic-diseases/