Brynja Kohler

Understanding Sub-Dominant/Cryptic Peptides and Determinant Spreading in Autoimmunity

Brynja Kohler
Jorge Carneiro

We came up with a simple model of how an immune response might turn autoreactive in order to illustrate and better understand this dynamical system. In the model, pathogenic peptides are displayed on the class II MHC molecules of professional APCs, initiating an immune response. The population of the CD4+ T cell clones specific for the displayed pathogen (driver clones, D) replicate and become active depending on the amount of pathogen in the system. Both Th1 and Th2 type cells respond, however, active Th1 type cells, in particular, lead to increased inflammation which influences the display of sub-dominant or previously cryptic self peptides on the APCs. An autoreactive Th1 type cell that is specific for such a self determinant would also contribute to the overall inflammation in the system. With this very simple system we could make some illustrative simulations by changing a single parameter in the model. We ran the test of having a constant level of pathogen for some time, and then setting the pathogen to zero, as if it were suddenly eliminated. We could observe how this would lead to autoimmunity or not based on the parameter which represents the sensitivity of the process of displaying self determinants to the inflammation level. If the inflammation doesn't cause enough self determinant to be displayed, the autoreactive cells won't proliferate enough to initiate an autoimmune disease. However once a threshhold of autoimmune cells are generated the autoreactive cells could take over.

We then began to modify the model to see what kind of behaviors could emerge when regulatory cells were also included which would down-regulate the Th1 cells that stimulate inflammation.

Figure 1
Figure 1

 

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