nr. 477 - 2011 - Institut for Natur, Systemer og Modeller (NSM)

10 Type 1 Diabetes and Its Etiology
to divide. The findings of Höglund et al. (1999) corroborates that the T cells are first
stimulated in the lymph nodes. Other results favor the hypothesis 8 that activation
of intraislet macrophages initiates sustained β-cell death through macrophage-derived
pro-inflammatory cytokines 9 (Steer et al., 2006, p.263) – T cells become a key-factor in
the β-cell destruction at 4-5 weeks of age (Trudeau et al., 2003, p.219).
When the T cells divide they excrete cytokines of which interleukin-2 (IL-2) is especially
important. IL-2 is one of several cytokines that have been found to precipitate T1D
due to their cytotoxic 10 effect on β-cells. Two other important cytotoxic cytokines are
interleukin-1 (IL-1), and interferon-γ (IFN-γ), which are macrophage-derived.
Besides the role as an APC, and more importantly, according to Marée et al. (2006)
and Steer et al. (2006), macrophages also secrete cytokines themselves (Marée et al.
(2006), (Steer et al., 2006, p.253)) when they phagocytize apoptotic and necrotic βcells.
Recent results indicate that (some of the) cytokines secreted upon phagocytosis
of necrotic cells are cytotoxic, and thus further the death of β-cells by necrosis (Steer
et al., 2006, p.257) and apoptosis . But at the same time it has been found that β-cell
regeneration takes place in the midst of the inflammation (Akirav et al., 2008, p.2883).
One could speculate that this is due to some benign cytokines, but this is only speculation.
While dwelling on cytokines we will briefly introduce one discrepancy between
the NOD bio-model and humans, which, according to Steer et al. (2006) and Eizirk and
Darville (2001), is that in humans cytokines only induce β-cell apoptosis (for reasons we
will not get into here), whereas they induce apoptosis as well as necrosis in the NOD
mouse (and other bio-models) (Steer et al., 2006, p.263) (Eizirk and Darville, 2001,
p.s65). This illustrates that one should take care not to overextend the conclusions
drawn from the NOD-mouse model, and other bio-models, to apply to humans as well.
Sparre et al. (2005) provide arguments based of the genetic makeup of the NOD-mouse
as to why one must proceed cautiously when making conclusions based on these mice
(Sparre et al., 2005, p.443).
2.3 Summary and Discussion
We have learned that macrophages/dendritic cells, T cells and cytokines excreted from
these cells constitute a deadly combination, that ultimately leads to β-cell apoptosis or
necrosis (Yoon and Yun (2001)). It is debateable which are the most important. Eizirik
and Mandrup-Poulsen (2001) report that CD8 + are the most important T cells for the
initiation of the immune process that leads to sustained apoptosis, but CD8 + cells alone
cannot lead to diabetes. NOD macrophages are unable to present antigens and are as
such not important as APCs in the NOD bio-model of T1D, this implies that DC’s and
B cells are the important APCs in this bio-model (Eizirik and Mandrup-Poulsen, 2001,
p.2117). They also find that the cytotoxicity of the cytokines depends on the period in
the life of the NOD-mouse at which they are released (Eizirik and Mandrup-Poulsen,
2001, p.2119).
Despite all the recent advances one remaining mystery still needs to be solved: what
8 This is also the hypothesis that Marée et al. (2006) utilize in their mathematical model, though they
also recognize the significance of T cells.
9 A cytokine is a protein that stimulates cell proliferation and differentiation, but they can also be
harmful to other cells.
10 Cytotoxic means harmful to cells.