Obesity-Associated Autoantibody Production Requires AIM to Retain the Immunoglobulin M Immune Complex on Follicular Dendritic Cells

Abstract

Natural immunoglobulin M (IgM) is reactive to autoantigens and is believed to be important for autoimmunity. Blood pentameric IgM loaded with antigens forms a large immune complex (IC) that contains various elements, including apoptosis inhibitor of macrophage (AIM). Here we demonstrate that this IgM-AIM association contributes to autoantibody production under obese conditions. In mice fed a high-fat diet, natural IgM increased through B cell TLR4 stimulation. AIM associated with IgM and protected AIM from renal excretion, increasing blood AIM levels along with the obesity-induced IgM augmentation. Meanwhile, the AIM association inhibited IgM binding to the Fcα/μ receptor on splenic follicular dendritic cells, thereby protecting the IgM IC from Fcα/μ receptor-mediated internalization. This supported IgM-dependent autoantigen presentation to B cells, stimulating IgG autoantibody production. Accordingly, in obese AIM-deficient (AIM(-/-)) mice, the increase of multiple IgG autoantibodies observed in obese wild-type mice was abrogated. Thus, the AIM-IgM association plays a critical role in the obesity-associated autoimmune process.

Are Obesity-Related Insulin Resistance and Type 2 Diabetes Autoimmune Diseases?

“…Increased prevalence of positive autoantibody and T-cell responses are found to target a spectrum of self-antigens, including islet autoantigens but also autoantigens expressed in multiple cell types and tissues (11,49,53,(66)(67)(68). Among these are Golgi SNAP receptor complex member 1 (GOSR1) transcript variant 1, a protein involved in trafficking between the ER and Golgi compartments, phosphogluconate dehydrogenase, and GFAP.…”

MECHANISMS IN ENDOCRINOLOGY: The crosstalk between thyroid gland and adipose tissue: signal integration in health and disease

“…In obesity, the immunological tolerance can be affected both directly and indirectly, via an altered secretion of adipokines (predominantly leptin, adiponectin, and visfatin) and/or cytokines (interleukin 6 (IL6), tumor necrosis factor alpha, and interleukin 10 (IL10)). The final result would be a shift from Th2 to Th1 immune response; the latter being more prone to produce autoimmune reactions (112,113,114). The visceral adipose tissue (VAT) contains resident macrophages, endothelial cells, and T cells with biased T cell receptors, which may contribute to mount an immune response by producing excessive amounts of pro-inflammatory cytokines (115).…”

The human CD5L/AIM-CD36 axis: A novel autophagy inducer in macrophages that modulates inflammatory responses

“…To determine inhibition of ATG7 protein expression by siRNA treatment, 10 5 cells were transfected with the indicated siRNA (see below). Cells were then washed in cold TBS and lysed in TBS lysis buffer for 30 min at 4 C. Nuclei and cell debris were removed by centrifugation at 8000 £ g for 15 Fluorescence microscopy studies THP1 MK (5 £ 10 4 cells/well) or PB monocytes (10 5 cells/ well) were plated on Millicell EZ slides (Merck Millipore, PEZGS0816) and incubated with 1 mg/ml LPS or Pam3CSK4. Alternatively, cells were incubated in the presence or absence of 1 mM of 3-MA (Sigma-Aldrich, M9281), which was added 45 min prior to analysis.…”

“…15 Moreover, given that CD5L modulates the activity of MK, this protein has been implicated in a wider spectrum of biological functions, including the pathogenesis of several infectious and inflammatory processes, including cancer. [16][17][18][19][20][21][22] Early results from transgenic mice overexpressing CD5L indicate that this molecule supports the survival and phagocytic activity of MK in liver inflammatory lesions in fulminant hepatitis.…”