Glassy Dynamics in the Adaptive Immune Response Prevents Autoimmune Disease

The immune system normally protects the human host against death by infection. However, when an immune response is mistakenly directed at self-antigens, autoimmune disease can occur. We describe a model of protein evolution to simulate the dynamics of the adaptive immune response to antigens. Computer simulations of the dynamics of antibody evolution show that different evolutionary mechanisms, namely, gene segment swapping and point mutation, lead to different evolved antibody binding affinities. Although a combination of gene segment swapping and point mutation can yield a greater affinity to a specific antigen than point mutation alone, the antibodies so evolved are highly cross reactive and would cause autoimmune disease, and this is not the chosen dynamics of the immune system. We suggest that in the immune system’s search for antibodies, a balance has evolved between binding affinity and specificity.

Figure 1

Evolution of the affinity energy for the cases of point mutation (PM) only and gene segment swapping (GSS) plus PM as a function of the number of rounds of mutation and selection used to evolve the population of antibodies. Energies evolved at larger number of rounds shown in inset.

Figure 2

Affinity of memory antibody sequences after a primary immune response for the two different immune system strategies (PM and $\mathrm{GSS}+\mathrm{PM}$) to altered antigens. The binding constant is $K$, and the antigenic distance of the new altered antigen from the original antigen is $p$. Cross-reactivity ceases at larger distances in the $\mathrm{GSS}+\mathrm{PM}$ case (no cross reactivity for $p>0.472$) than in the PM only case (no cross reactivity for $p>0.368$).

Figure 3

The number of possible epitopes that are an antigenic distance of $p$ from another epitope. The epitopes are assumed to be 20 amino acids in length. The plot is normalized, so that $\sum _{p}N(p)={20}^{20}$.