The enlarged mLN in animals with chronic intestinal worms results over time in a loss of lymphocytes from skin-draining LN.

There is a negative correlation between the size of iLN and mLN in H. polygyrus infected mice (A) indicating a restriction in the number of lymphocytes available and re-distribution of lymphocytes in animals with chronic worm infection (graph generated from data in S1B Fig). Assuming that the circulating pool of lymphocytes is constant and that the spleen size/cellularity is normal in chronic H. polygyrus infection, a model of lymphocyte distribution between the reactive mLN and skin-draining LN in animals infected with worms is proposed (B): 1. During “steady state”, in a non-infected mouse, circulating lymphocytes distributes amongst LN proportional to the existing LN cellularity (the outermost yellow circle represents the total skin-draining LN and the pink circle represents mLN, the widths of the lines symbolize the relative sizes of LN). 2. Following H. polygyrus infection, lymphocytes are recruited from the blood (red inner circle) to the reactive mLN, where they are retained. As lymphocytes are activated and go through clonal expansion the mLN expand further. Since the lymphocyte pool is restricted, the increase in mLN size per se will facilitate a re-distribution of circulating cells: When a larger proportion of circulating cells are trapped in the mLN (indicated by a larger arrow going from the blood to the mLN), the lymphocytes in non-draining skin LN will not be replaced at the same rate as they are lost. Given enough time the skin-draining LN become atrophic. 3. Chronic H. polygyrus infection maintains enlarged mLN. Since lymphocytes distribute proportional to LN cellularity, more cells distribute to the enlarged mLN and fewer cells enter the smaller skin-draining skin LN (indicated by the sizes of arrows from the blood to the respective LN). This new “equilibrium” maintains a lower cellularity in skin-draining LN for as long as the intestinal worm infection persists. Upon a secondary infection in the skin, as an effect of that fewer cells are present in the skin-draining LN, the magnitude of the 2nd immune responses will be reduced in worm infected animals (indicated by the smaller size of the green box.) 4. Following de-worming the worms are rapidly removed. The LN draining the site of infection, however, regress slowly in cellularity and remain enlarged for several weeks. Likewise, non-draining LN slowly recover in size to revert to the size of an uninfected animal. Independent of antigen persistence or not, LN size and distribution of circulating lymphocytes according to LN size can explain why recovery takes time.