Acute Loss of Apolipoprotein E Triggers an Autoimmune Response That Accelerates Atherosclerosis.

Objective- Dyslipidemia is a component of the metabolic syndrome, an established risk factor for atherosclerotic cardiovascular disease, and is also observed in various autoimmune and chronic inflammatory conditions. However, there are limited opportunities to study the impact of acquired dyslipidemia on cardiovascular and immune pathology. Approach and Results- We designed a model system that allows for the conversion to a state of acute hyperlipidemia in adult life, so that the consequences of such a transition could be observed, through conditionally deleting APOE (apolipoprotein E) in the adult mouse. The transition to hypercholesterolemia was accompanied by adaptive immune responses, including the expansion of T lymphocyte helper cell 1, T follicular helper cell, and T regulatory subsets and the formation of germinal centers. Unlike steady-state Apoe-/- mice, abrupt loss of APOE induced rapid production of antibodies recognizing rheumatoid disease autoantigens. Genetic ablation of the germinal center reduced both autoimmunity and atherosclerosis, indicating that the immune response that follows loss of APOE is independent of atherosclerosis but nevertheless promotes plaque development. Conclusions- Our findings suggest that immune activation in response to hyperlipidemia could contribute to a wide range of inflammatory autoimmune diseases, including atherosclerosis.

Cutting Edge: Marginal Zone Macrophages Regulate Antigen Transport by B Cells to the Follicle in the Spleen via CD21.

Marginal zone macrophages (MZM) are strategically located in the spleen, lining the marginal sinus where they sense inflammation and capture Ag from the circulation. One of the receptors expressed by MZM is scavenger receptor macrophage receptor with collagenous structure (MARCO), which has affinity for modified self-antigens. In this article, we show that engagement of MARCO on murine macrophages induces extracellular ATP and loss of CD21 and CD62L on marginal zone B cells. Engagement of MARCO also leads to reduction of Ag transport by marginal zone B cells and affects the subsequent immune response. This study highlights a novel function for MZM in regulating Ag transport and activation, and we suggest that MARCO-dependent ATP release regulates this through shedding of CD21 and CD62L. Because systemic lupus erythematosus patients were shown to acquire autoantibodies against MARCO, this highlights a mechanism that could affect a patient's ability to combat infections.

Reprogramming Tumor-Associated Macrophages by Antibody Targeting Inhibits Cancer Progression and Metastasis.

Tumors are composed of multiple cell types besides the tumor cells themselves, including innate immune cells such as macrophages. Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells present in the tumor microenvironment (TME). Here, they contribute to immunosuppression, enabling the establishment and persistence of solid tumors as well as metastatic dissemination. We have found that the pattern recognition scavenger receptor MARCO defines a subtype of suppressive TAMs and is linked to clinical outcome. An anti-MARCO monoclonal antibody was developed, which induces anti-tumor activity in breast and colon carcinoma, as well as in melanoma models through reprogramming TAM populations to a pro-inflammatory phenotype and increasing tumor immunogenicity. This anti-tumor activity is dependent on the inhibitory Fc-receptor, FcγRIIB, and also enhances the efficacy of checkpoint therapy. These results demonstrate that immunotherapies using antibodies designed to modify myeloid cells of the TME represent a promising mode of cancer treatment.

Up regulated complement and fc receptors in juvenile idiopathic arthritis and correlation with disease phenotype.

PURPOSE: The progress in identifying immunological mechanisms in juvenile idiopathic arthritis (JIA) has partly been hampered by the fact that the disease is heterogeneous. Here we have investigated complement and Fc receptors, as part of the inflammatory process, in two subgroups of JIA. METHODS: Blood from 26 patients with oligoarticular or polyarticular course type JIA and 21 healthy age and sex-matched controls were investigated by FACS and immunoassays. RESULTS: Increased numbers of monocytes and augmented plasma levels of C-reactive protein, C3a and IgG were found in both JIA subgroups. However, only polyarticular patients exhibited increased expression of Fc gamma receptor (FcγR) II and III and complement receptor (CR) 1 on monocytes along with enhanced CR1 expression on B cells. A correlation was observed between degree of receptor expression and C3a levels in the patients. CONCLUSIONS: Complement and Fc receptors are up regulated in children with multiple joint involvements, thus highlighting these pathways in the pathogenesis of polyarticular JIA.

Marginal zone B cells are naturally reactive to collagen type II and are involved in the initiation of the immune response in collagen-induced arthritis.

Antibodies against type II collagen (CII) are essential for development of collagen-induced arthritis (CIA), but how and where the B-cell response to CII is initiated is not fully known. We show here that naive DBA/1 mice display naturally reactive IgM and IgG anti-CII producing B cells prior to immunization. The CII-reactive B cells were observed in the spleen and recognized as marginal zone (MZ) B cells. After CII immunization, CII-specific B cells expanded rapidly in the spleen, in contrast to the lymph nodes, with the initial response derived from MZ B cells and later by follicular (FO) B cells. This was evident despite that the MZ B cells were subject to stringent tolerance mechanisms by having a greater Fc gamma receptor IIb expression than the FO B cells. Further, the MZ B cells migrated to the FO areas upon immunization, possibly providing antigen and activating FO T cells and subsequently FO B cells. Thus, around CIA onset increased numbers of IgG anti-CII producing FO B cells was seen in the spleen, which was dominated by IgG2a- and IgG2b-positive cells. These data demonstrate that CII-reactive MZ B cells are present before and expand after CII immunization, suggesting an initiating role of MZ B cells in the development of CIA.

Down regulation of Fc and complement receptors on B cells in rheumatoid arthritis.

B cell tolerance is regulated by receptors that modulate B cell receptor signaling, such as Fc gamma receptor IIb (FcγRIIb; CD32b) and complement receptors (CR) 1 and 2. Deficiency in these receptors may contribute to autoimmunity. To address this we have investigated the receptor expression in healthy individuals in comparison with rheumatoid arthritis (RA) patients. In healthy subjects we found that women had overall lower FcγRIIb expression on B cells than men that significantly decreased with age. RA patients had fewer FcγRIIb, CR1 and CR2 positive B cells and decreased receptor expressions compared to healthy subjects. Further, the RA B cells displayed a significantly increased proliferative response when cultured with interleukin-2 in vitro. In summary, the dysregulated B cells in RA are associated with lower FcγRIIb, CR1 and CR2 levels. The reduced FcγRIIb expression on B cells in women may influence the increased frequency of autoimmunity in women.