ABSTRACT
Immunogenetic studies have suggested that autoantibody production is commonly associated with particular human leukocyte antigens (HLA) class II genotypes in certain autoimmune diseases. The objective of this study was to investigate whether the production of anti-ß2-glycoprotein I antibody (aß2GPI) was associated with particular HLA-DQ alleles in patients with recurrent miscarriage (RM). The HLA-DQ genotypes in 126 patients with RM were determined using the polymerase chain reaction-sequence-specific primer method. Both the IgG and IgM isotypes of aß2GPI were measured via enzyme-linked immunosorbent assay. Positive results for either IgG or IgM on two occasions within an interval of 12 weeks were defined as antiphospholipid antibody-positive. The frequencies of the HLA-DQA1*01:02 [odds ratio (OR) 3.4, 95% confidence interval (CI) 1.6-7.0, Pc = 0.018] and HLA-DQB1*02:01 alleles (OR 4.6, 95% CI 2.1-10.2, Pc = 9.18 × 10(-4)) were significantly increased in aß2GPI-positive RM patients compared with aß2GPI-negative RM patients. These results suggest that the HLA-DQA1*0102 and HLA-DQB1*0201 alleles may be involved in the production of aß2GPI in RM patients.
Subject(s)
Abortion, Habitual/genetics , Alleles , Autoantibodies/blood , Autoimmune Diseases/genetics , HLA-DQ alpha-Chains/immunology , HLA-DQ beta-Chains/immunology , Abortion, Habitual/blood , Abortion, Habitual/immunology , Abortion, Habitual/pathology , Adult , Autoimmune Diseases/blood , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Female , Gene Expression , Gene Frequency , Genetic Predisposition to Disease , HLA-DQ alpha-Chains/genetics , HLA-DQ beta-Chains/genetics , Histocompatibility Testing , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Pregnancy , beta 2-Glycoprotein I/blood , beta 2-Glycoprotein I/immunologyABSTRACT
Tumor vessels are known to be abnormal, with typically aberrant, leaky and disordered vessels. Here, we investigated whether polarized macrophage phenotypes are involved in tumor abnormal angiogenesis and what is its mechanism. We found that there was no difference in chemotaxis of polarized M1 and M2 macrophages to lewis lung carcinoma (LLC) cells and that either M1 or M2 macrophage-conditioned media had no effect on LLC cell proliferation. Unexpectedly, the M2 but not M1 macrophage-conditioned media promoted the proliferation of human umbilical vein endothelial cells (HUVECs) and simultaneously increased endothelial cell permeability in vitro and angiogenic index in the chick embryo chorioallantoic membrane (CAM). The treatment with M2 but not M1 macrophage-conditioned media increased autophagosomes as well as microtubule-associated protein light chain 3B (LC3-B) expression (a robust marker of autophagosomes) but decreased p62 protein expression (a selective autophagy substrate) in HUVECs, the treatment with chloroquine that blocked autophagy abrogated the abnormal angiogenic efficacy of M2 macrophage-conditioned media. These results were confirmed in urethane-induced lung carcinogenic progression. Urethane-induced lung carcinogenesis led to more M2 macrophage phenotype and increased abnormal angiogenesis concomitant with the upregulation of LC3-B and the downregulation of p62. Clodronate liposome-induced macrophage depletion, chloroquine-induced autophagic prevention or salvianolic acid B-induced vascular protection decreased abnormal angiogenesis and lung carcinogenesis. In addition, we found that the tendency of age-related M2 macrophage polarization also promoted vascular permeability and carcinogenesis in urethane carcinogenic progression. These findings indicate that the M2 macrophages induce autophagic vascular disorder to promote lung cancer progression, and the autophagy improvement represents an efficacious strategy for abnormal angiogenesis and cancer prevention.
