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Monocyte recruitment by HLA IgG-activated endothelium: the relationship between IgG subclass and Fc?RIIa polymorphisms.

ABSTRACT: It is currently unclear which donor specific HLA antibodies confer the highest risk of antibody-mediated rejection (AMR) and allograft loss. In this study, we hypothesized that two distinct features (HLA IgG subclass and Fc? receptor [Fc?R] polymorphisms) which vary from patient to patient, influence the process of monocyte trafficking to and macrophage accumulation in the allograft during AMR in an interrelated fashion. Here, we investigated the contribution of human IgG subclass and Fc?R polymorphisms in monocyte recruitment in vitro by primary human aortic endothelium activated with chimeric anti-HLA I human IgG1 and IgG2. Both subclasses triggered monocyte adhesion to endothelial cells, via a two-step process. First, HLA I crosslinking by antibodies stimulated upregulation of P-selectin on endothelium irrespective of IgG subclass. P-selectin-induced monocyte adhesion was enhanced by secondary interactions of IgG with Fc?Rs, which was highly dependent upon subclass. IgG1 was more potent than IgG2 through differential engagement of Fc?Rs. Monocytes homozygous for Fc?RIIa-H131 adhered more readily to HLA antibody-activated endothelium compared with Fc?RIIa-R131 homozygous. Finally, direct modification of HLA I antibodies with immunomodulatory enzymes EndoS and IdeS dampened recruitment by eliminating antibody-Fc?R binding, an approach that may have clinical utility in reducing AMR and other forms of antibody-induced inflammation.

SUBMITTER: Valenzuela NM

PROVIDER: S-EPMC4439339 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Monocyte recruitment by HLA IgG-activated endothelium: the relationship between IgG subclass and FcγRIIa polymorphisms.

Valenzuela N M NM Trinh K R KR Mulder A A Morrison S L SL Reed E F EF

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20150203 6

It is currently unclear which donor specific HLA antibodies confer the highest risk of antibody-mediated rejection (AMR) and allograft loss. In this study, we hypothesized that two distinct features (HLA IgG subclass and Fcγ receptor [FcγR] polymorphisms) which vary from patient to patient, influence the process of monocyte trafficking to and macrophage accumulation in the allograft during AMR in an interrelated fashion. Here, we investigated the contribution of human IgG subclass and FcγR polym ...[more]

PMID: 25648976

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Project description:BackgroundFactors associated with IgG levels in adults with IgG subclass deficiency (IgGSD) are incompletely understood. We studied adults with IgGSD with subnormal IgG1 only, subnormal IgG1/IgG3, or subnormal IgG3 only without other subnormal IgG subclasses, IgA, or IgM. We compiled: age; sex; autoimmune condition(s) (AC); atopy; IgG, IgG subclasses, IgA, IgM; IgGsum (IgG1 + IgG2 + IgG3 + IgG4); and D (percentage difference between IgGsum and IgG). We compared attributes of patients with/without subnormal IgG (< 7.00 g/L; subnormal IgG1 subclass groups only) and analyzed IgGsum and IgG relationships. We performed backward stepwise regressions on IgG using independent variables IgG subclasses, age, and sex and on D using independent variables age and sex.ResultsThere were 39 patients with subnormal IgG1 only (89.7% women), 53 with subnormal IgG1/IgG3 (88.7% women), and 115 with subnormal IgG3 only (91.3% women). Fifteen patients (38.5%) and 32 patients (60.4%) in the respective subnormal IgG1 subclass groups had subnormal IgG. Attributes of patients with/without IgG < 7.00 g/L were similar, except that AC prevalence was lower in patients with subnormal IgG1 only and IgG < 7.00 g/L than ≥ 7.00 g/L (p = 0.0484). Mean/median IgG1 and IgG2 were significantly lower in patients with IgG < 7.00 g/L in both subnormal IgG1 subclass groups (p < 0.0001, all comparisons). Regressions on IgG in three subclass groups revealed positive associations with IgG1 and IgG2 (p < 0.0001 each association). Regressions on D revealed no significant association. IgG1 percentages of IgGsum were lower and IgG2 percentages were higher in patients with subnormal IgG1 subclass levels than subnormal IgG3 only (p < 0.0001 all comparisons).ConclusionsWe conclude that both IgG1 and IgG2 are major determinants of IgG in patients with subnormal IgG1, combined subnormal IgG1/IgG3, or subnormal IgG3 and that in patients with subnormal IgG1 or combined subnormal IgG1/IgG3, median IgG2 levels are significantly lower in those with IgG < 7.00 g/L than those with IgG ≥ 7.00 g/L.

Project description:Thyroid cancer is the most common endocrine malignancy. Although an association between inflammation and thyroid cancer has long been recognized, a cause-effect relationship at the molecular level has yet to be elucidated. We explored how inflammation could contribute to thyroid carcinogenesis in ThrbPV/PVPten+/- mice. The ThrbPV/PVPten+/- mouse expresses a dominantly negative thyroid hormone receptor β (denoted as PV) and a deletion of one single allele of the Pten gene. This mutant mouse exhibits aggressive follicular thyroid cancer similarly as in patients. We found significantly increased infiltration of inflammatory monocytes in thyroid tumors of ThrbPV/PVPten+/- mice, while no apparent changes in monocyte homeostasis in the bone marrow and blood of tumor-bearing mice. Using global gene expression profiling, we found altered expression of inflammation mediators in that the expression of Ptgs1, Sphk1, OPN, Chil1, Tnfrsf18, IL6, and Ccl12 genes was significantly increased and expression of Kit, Ly96, Ephx2, CD163, IL15, and Ccr2 was significantly decreased. Subsequent validation of the gene expression by mRNA analysis prompted us to further delineate the inflammatory role of osteopontin (OPN) in thyroid carcinogenesis because of its critical role in monocyte/macrophage functions and proinflammatory responses. We found that the protein abundance of OPN and its receptor, integrin β1, was highly increased and, concurrently, the downstream effectors AKT and NF-κB were significantly elevated to drive thyroid tumor progression of ThrbPV/PVPten+/- mice. These results demonstrated that increased inflammation driven by elevated expression of immune-related genes and cytokines promoted thyroid cancer progression. Importantly, we uncovered OPN as a novel regulator in inflammatory response during thyroid carcinogenesis. These preclinical findings suggested that OPN can be a potential target for thyroid cancer therapy via modulation of inflammatory signaling.

Dataset Information

Monocyte recruitment by HLA IgG-activated endothelium: the relationship between IgG subclass and Fc?RIIa polymorphisms.

Publications

Monocyte recruitment by HLA IgG-activated endothelium: the relationship between IgG subclass and FcγRIIa polymorphisms.

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