IgG4 drives M2a macrophages to a regulatory M2b‐like phenotype: potential implication in immune tolerance

Abstract

Background Macrophages can be converted in vitro into immunoregulatory M2b macrophages in the presence of immune complexes ( IC s), but the role of the specific subclasses IgG1 or IgG4 in this phenotypic and functional change is not known. Objective We aimed to refine the original method by applying precisely defined IC s of the subclasses IgG4 or IgG1 constructed by two independent methods. Methods Monocyte‐derived macrophages ( MDM s) were treated with M‐ CSF , followed by IL ‐4/ IL ‐13 to induce the M2a allergic phenotype. To mimic unspecific or allergen‐specific IC s, plates were coated with myeloma IgG1 or IgG4, or with grass pollen allergen Phl p 5 followed by recombinant human Phl p 5‐specific IgG1 or IgG4. M2a polarized macrophages were then added, cultured, and examined for cellular markers and cytokines by flow cytometry, ELISA , and rt PCR . Alternatively, immune complexes with IgG1 or IgG4 were formed using protein L. Results IgG4 IC s down regulated CD 163 and CD 206 on M2a cells, and significantly increased IL ‐10, IL ‐6, TNF α, and CCL 1 secretion, indicating a shift to an M2b‐like phenotype. Treatment with IgG4 IC s resulted in expression of Fcγ RII and down modulation of Fcγ RII compared with IgG1 treated cells ( P = 0.0335) or untreated cells ( P < 0.00001). Conclusion Immune complexes with subclasses IgG1 and IgG4 can in vitro be generated by plate absorption, and in fluid form by protein L. Cross‐linking of Fcγ RII b by the IgG4 subclass redirects pro‐allergic M2a macrophages to an M2b‐like immunosuppressive phenotype. This suggests an interplay of macrophages with IgG4 in immune tolerance, likely relevant in allergen immunotherapy.

Induction of IgG2 and IgG4 B‐cell memory following sublingual immunotherapy for ryegrass pollen allergy

“…Our data are consistent with SLIT‐induced proliferation of allergen‐specific Treg, whereby increased IL‐10 production induces Ig class switching of allergen‐specific B cells to IgG 4 . B regulatory cells (Breg) and monocyte‐derived macrophages may also be an alternative source of IL‐10 in our in vitro assay, further enhancing IgG 4 class switching in response to RGP …”

A WAO — ARIA — GA2LEN consensus document on molecular-based allergy diagnosis (PAMD@): Update 2020

“…[44][45][46] In particular, IgG4 seems to have a direct role in the induction of tolerance. 47 This area of research should provide useful information regarding the inception, evolution, and diagnosis of allergic diseases, but there is currently no standardized way to apply these findings to PAMD@.…”

The Diverse Functions of the Ubiquitous Fcγ Receptors and Their Unique Constituent, FcRγ Subunit

“…The FcγR family perform paradoxical functions as activators or inhibitors because of their structural heterogeneity, and are involved in regulating various immune responses. Along with their essential role in specific binding to the Fc portion of antibody subsets, FcγRs calibrate multiple effector responses, such as antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), release of inflammatory substances, B cell activation, DC maturation, antigen presentation, the release of inflammatory substances, and macrophage polarization [1,22,[34][35][36].…”