Loops 1, 2 and 4, which all include the TD node, can amplify the immune response to CS and enhance the TD outcome when they are activated. As Loop 1, 2 or 4 is necessary for COPD progression under the condition given in Table A in S1 File discussed above, we also carried out simulations to investigate whether one of these loops is sufficient for COPD when other positive feedback loops are broken. Here, k3 = 1.9×106 cell/(ml day), kI6,TD = 22.0pmol/(cell day), and KTg,I6 = 2.3 pmol/L are used for Loop 1, 2, and 4, respectively. The other parameter values are given in Table A in S1 File (dTD = 2.9×10−3/day). The results show that activation of Loop 1, 2, or 4 can lead to COPD [Fig 12(A)]. Again, Loop 3 alone is not able to drive COPD progression by modification of kI12, M1.