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Background <p>Polyvalent IgG (pIgG/IVIg), derived from thousands of donors, exerts broad immunomodulatory effects; however, its direct cellular targets and genome-wide regulatory impacts remain incompletely defined.</p> Methods <p>Peripheral blood mononuclear cells (PBMCs) from 20 healthy donors were cultured for 72&#xa0;h with pIgG (100&#xa0;µg/mL) or mock conditions. Cell viability, phenotype, memory subsets, chemokine receptors, and intracellular cytokines were assessed by flow cytometry. Differential gene expression, miRNA/sRNA profiles, and pathway enrichments were analyzed by RNA-seq and small-RNA sequencing. Proteome-wide IgG binding was mapped using human proteome microarrays across lymphoid subsets, and pathogen-derived linear epitope recognition was evaluated using a 4,345-epitope infectious-disease microarray.</p> Results <p>pIgG preserved PBMC viability but significantly modulated immune function: it reduced IL-17⁺ CD4⁺ T cells and tissue-resident memory T cells, decreased IL-4⁺ CD8⁺ T cells, enhanced IFN-γ⁺ γδ T cells, downregulated CCR5 and CCR6, and expanded IL-10⁺ B cells while reducing IL-13⁺ and IL-17⁺ B cells. Transcriptomic analysis revealed 4,820 upregulated and 2,160 downregulated genes, with enrichment of MHC class II and TCR-signaling pathways and selective modulation of cytokine, chemokine, CD, and HLA genes. Innate sensors—including TLR4, TLR8, and NLR4—were downregulated. Small-RNA analysis identified 19 differentially expressed miRNAs and 79 novel sRNAs, indicating epigenetic remodeling. Proteome-wide profiling detected ~ 130 IgG-recognized proteins per lymphocyte subset and 180 shared targets enriched in cytosolic, vesicular, and endocytic pathways. Pathogen-epitope profiling identified 948 recognized sequences from 56 viruses, 21 bacteria, and 12 parasites.</p> Conclusions <p>pIgG functions as a multilayered immunoregulator that attenuates Th17-associated inflammation, promotes IL-10–mediated regulatory circuits, and modulates receptor signaling and antigen-processing pathways. These findings underscore its potential for broad therapeutic immunomodulation.</p>

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System-wide immunoregulation by polyvalent IgG: integrating transcriptomic, miRNA, and proteomic landscapes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月30日

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  • João Vitor da Silva Borges,
  • Lhays Ozório Passos,
  • Nicolle Rakanidis Machado,
  • Lais Alves do Nascimento,
  • Beatriz Oliveira Fagundes,
  • Isabela Siuffi Bergamasco,
  • Anna Luisa Baratelli Moreira,
  • Natali Espasiani Cilento,
  • Sabri Saeed Sanabani,
  • Jefferson Russo Victor

摘要

Background

Polyvalent IgG (pIgG/IVIg), derived from thousands of donors, exerts broad immunomodulatory effects; however, its direct cellular targets and genome-wide regulatory impacts remain incompletely defined.

Methods

Peripheral blood mononuclear cells (PBMCs) from 20 healthy donors were cultured for 72 h with pIgG (100 µg/mL) or mock conditions. Cell viability, phenotype, memory subsets, chemokine receptors, and intracellular cytokines were assessed by flow cytometry. Differential gene expression, miRNA/sRNA profiles, and pathway enrichments were analyzed by RNA-seq and small-RNA sequencing. Proteome-wide IgG binding was mapped using human proteome microarrays across lymphoid subsets, and pathogen-derived linear epitope recognition was evaluated using a 4,345-epitope infectious-disease microarray.

Results

pIgG preserved PBMC viability but significantly modulated immune function: it reduced IL-17⁺ CD4⁺ T cells and tissue-resident memory T cells, decreased IL-4⁺ CD8⁺ T cells, enhanced IFN-γ⁺ γδ T cells, downregulated CCR5 and CCR6, and expanded IL-10⁺ B cells while reducing IL-13⁺ and IL-17⁺ B cells. Transcriptomic analysis revealed 4,820 upregulated and 2,160 downregulated genes, with enrichment of MHC class II and TCR-signaling pathways and selective modulation of cytokine, chemokine, CD, and HLA genes. Innate sensors—including TLR4, TLR8, and NLR4—were downregulated. Small-RNA analysis identified 19 differentially expressed miRNAs and 79 novel sRNAs, indicating epigenetic remodeling. Proteome-wide profiling detected ~ 130 IgG-recognized proteins per lymphocyte subset and 180 shared targets enriched in cytosolic, vesicular, and endocytic pathways. Pathogen-epitope profiling identified 948 recognized sequences from 56 viruses, 21 bacteria, and 12 parasites.

Conclusions

pIgG functions as a multilayered immunoregulator that attenuates Th17-associated inflammation, promotes IL-10–mediated regulatory circuits, and modulates receptor signaling and antigen-processing pathways. These findings underscore its potential for broad therapeutic immunomodulation.