Phagocytosis Deficiency Precedes Autoimmunity
In Type 1 Diabetes
6/28/19
Non-obese diabetic (NOD) mice experience a wave of β cell apoptosis at around the second week of life. This is seen in other animals and is considered a natural remodeling of the tissue. NOD mice show an 80% slower phagocytic rate of activated macrophages compared to their healthy counterparts, the Balb/c mice, which do not develop spontaneous diabetes[1]. The inability to properly clear apoptotic cells results in secondary necrosis, which is known to trigger autoimmunity[2][3]. Marée et al. (2006) calculated that their phagocytic inefficiency is sufficient to explain the induction of autoimmunity after the wave of apoptosis and, thereby, to indirectly explain the origin of diabetes in the NOD mice[1]. However, Hauben et al. (2005) showed that autoimmunity is a beneficial response to the wave of apoptotic β cell death and that the inability to mount this protective autoimmune response is what leads to diabetes[4]. Since autoimmunity appears commonly during secondary necrosis and has protective effects, it should be considered the natural elaboration of the immune system when phagocytes are incapable of clearing a certain extent of apoptosis. Hauben and Schwartz (2003) suggested that a key protective effect of autoimmunity is the enhancement of phagocytosis of dead cells and necrotic cellular debris[5]. Instead of causing diabetes through triggering autoimmunity, as Marée suggested, a phagocytic deficiency may have a more pathological role by allowing the toxic necrotic debris to spread damage[6] to surrounding β cells.
First degree relatives of Type 1 diabetics who are at a high risk of developing diabetes and already show some glucose intolerance are seen to have decreased phagocytic function compared to healthy controls[7]. Recent onset diabetic patients who are treated with insulin, on the other hand, have normal phagocytic function, indicating that the deficiency of insulin before clinical onset and insulin treatment is the likely cause of the phagocytic deficiency instead of an inborn defect[7]. Longer term diabetics who are poorly controlled also show deficient phagocytosis which is normalized upon improved insulin therapy[8]. Indeed, phagocytosis has been seen to greatly depend on both glucose and insulin[9]. Therefore, the deficiency of insulin-producing β cells causing defective phagocytosis would create a vicious cycle where the improper clearance of necrotic cells worsens the degeneration. The buildup of secondary necrotic cells would also enhance autoimmunity, but the adaptive immune system, which exerts its protective autoimmune function in part by enhancing phagocytosis, is also diminished by insulin deficiency[10].
General insulin insufficiency may also explain the tendency for Type 1 diabetics to develop other “autoimmune diseases”, such as Hashimoto’s thyroiditis and celiac disease, since a resulting phagocytic deficiency will more likely advance autoimmunity after any tissue damage and also slow the rate of tissue healing.
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