Anti-CD16 autoantibodies and delayed phagocytosis of apoptotic cells in primary biliary cirrhosis

Abstract

Primary biliary cirrhosis is characterized by chronic hepatic inflammation and immune mediated apoptosis of bile duct epithelial cells. Delayed macrophage phagocytosis of opsonized apoptotic cells, noted in other autoimmune diseases, may promote inflammation. Recent studies suggest serum anti-CD16 autoantibodies contribute to impaired macrophage phagocytosis by blocking complement receptor 3 (CR3) signaling via CD16. Therefore, serum anti-CD16 levels and the ability of monocyte derived macrophages from individuals with PBC to phagocytosis apoptotic cells were compared to controls. The mean level of anti-CD16 IgM autoantibodies (0.86+/-0.62 v. 0.35+/-0.22, respectively, p=0.031) was increased in PBC compared to control sera, and mean PBC phagocytosis of opsonized apoptotic cells was significantly decreased compared to controls (23.9+/-12.2% v. 43.9+/-14.4%, respectively, p=0.020). However, PBC phagocytosis of opsonized apoptotic cells was not significantly affected by the presence or absence of autologous serum (20.8+/-13.5% v. 23.9+/-12.2%, respectively, p=0.560). PBC phagocytosis of opsonized apoptotic cells inversely correlated with CD16 (and CR3) expression levels on Day 5 after culture in the presence or absence of autologous serum (r=-0.546, p=0.033 and r=-0.519, p=0.042, respectively). Phagocytosis of non-opsonized apoptotic cells did not correlate with CD16 or CR3 expression (p>0.050). In conclusion, PBC macrophage phagocytosis of opsonized apoptotic cells is impaired, irrespective of serum factors and may increase hepatic inflammation.

Primary biliary cirrhosis: A 2010 update

“…Neighbouring cholangiocytes have the ability to destroy the apoptotic cells by phagocytosis and to express the M2 epitope [81,82]. This is a rational explanation for the tissue specificity of the autoimmune process.…”

The consequences of apoptosis in autoimmunity

“…An anomaly of apoptosis in biliary epithelial cells (BEC) has been hypothesized as a source of antigens that could be responsible for activation of autoreactive T cells. It is known that macrophage phagocytosis of opsonized apoptotic cells is delayed in PBC [19] and that oxidative stress [16] induce apoptosis in BEC. However, how the mitochondrial antigens ultimate become exposed to the immune system is still unknown.…”

“…The impact of apoptosis on immunity has been extensively investigated [2,13] and several reports suggest a correlation between apoptosis and autoimmunity through an impairment of apoptosis [14][15][16] or an ineffective removal of apoptotic cells [17][18][19][20]. Moreover, recent data have demonstrated that autoantigens are found within apoptotic bodies [21] and that apoptotic cells are critical in the presentation of antigens [22], activation of innate immunity and regulation of macrophage cytokine secretion [23].…”

Innate Immunity and Primary Biliary Cirrhosis

“…The apoptosis of BEC has been proposed as a potential source of "neo-antigens" that are responsible for activating autoreactive lymphocytes, as many autoantigens are selectively modified during apoptosis [87] and may facilitate molecular mimicry [10] or autoimmunity [88]. It has been demonstrated that PDC-E2 maintains its immunogenicity in BECs whereas in other cells types it is abrogated after apoptosis [89][90][91][92][93][94].…”