The suppression of immune system disorders by passive attrition

Abstract

Exposure to infectious diseases has an unexpected benefit of inhibiting autoimmune diseases and allergies. This is one of many fundamental fitness tradeoffs associated with immune system architecture. The immune system attacks pathogens, but also may (inappropriately) attack the host. Exposure to pathogens can suppress the deleterious response, at the price of illness and the decay of immunity to previous diseases. This "hygiene hypothesis" has been associated with several possible underlying biological mechanisms. This study focuses on physiological constraints that lead to competition for survival between immune system cell types. Competition maintains a relatively constant total number of cells within each niche. The constraint implies that adding cells conferring new immunity requires loss (passive attrition) of some cells conferring previous immunities. We consider passive attrition as a mechanism to prevent the initial proliferation of autoreactive cells, thus preventing autoimmune disease. We see that this protection is a general property of homeostatic regulation and we look specifically at both the IL-15 and IL-7 regulated niches to make quantitative predictions using a mathematical model. This mathematical model yields insight into the dynamics of the "Hygiene Hypothesis," and makes quantitative predictions for experiments testing the ability of passive attrition to suppress immune system disorders. The model also makes a prediction of an anti-correlation between prevalence of immune system disorders and passive attrition rates.

Figure 1. Illustration of the dynamics of homeostatic regulation.

Cells enter the system from either infections or through homeostatic influx , which is zero for some niches. Survival factors (S.F.) regulate the total number of cells in the niche by either inhibiting cell death or inducing cell division. The rate of stimulation by survival factor for each cell, , is a function of the total number of cells in the niche, .

Figure 2. Illustration of the effects of passive attrition.

A. Without an influx of new cells sub-populations are stable in number. B. With an influx of new cells the competition for survival factors is increased and all populations are reduced in number. This is referred to as passive attrition. C. Autoreactive cells (red) can be stimulated to divide by self-antigens. This gives them a competitive advantage over the other sub-populations in the niche. D. If the influx of new cells is large or the antigenic stimulation rate is small, the autoreactive population can experience passive attrition. In a filthy environment the influx of new cells from infections will be large, suppressing the growth of autoreactive populations. In the more sterile environment represented in C. this suppressive effect is absent.

Figure 3. Illustration of a threshold for suppression by passive attrition.

This threshold is defined by Eq. 6 separating conditions for suppression (green region) and proliferation (pink region) of autoreactive cells. The vertical axis is the influx from infection . This quantity is typically controlled by the external environment and is expected to be proportional to the infection rate. The lower portion of the figure represents cells in a more sterile environment and the upper portion of the figure a filthy one with frequent infections. The horizontal axis is the antigenic stimulation rate for a small population of autoreactive cells . Cells with antigenic stimulation rate less than (the homeostatic influx divided by the number of cells in the niche at equilibrium) are always suppressed though for some niches . No populations with (where is the apoptotic rate under high levels of competition for survival factor) can be suppressed by passive attrition because the division rates of these cells (from autoantigen exposure) are large enough to maintain the population even in the absence of survival factors.

Figure 4. Memory formation with and without passive attrition.

For both scenarios the number of antigen specific cells quickly rises during an immune response, then rapidly decreases until the total cell number is approximately at equilibrium, , as indicated by the black dashed line. The blue curve illustrates the case with no passive attrition, where , and . CD memory in a sterile environment is representative of this (blue) scenario. The red curve illustrates the scenario where new cells are frequently added to the niche shared by the specific memory, causing the number of antigen specific cells to decline over time.

Figure 5. A schematic illustration of a small population of autoreactive cells .

These cells can either be suppressed if is large enough (green line) or experience exponential growth (black dashed line). If the cell population becomes large other factors will alter the growth rate such as feedbacks from inflammation and tolerance mechanisms, illustrated schematically in red.

Figure 6. Boundaries discriminating between autoreactive cell populations that are suppressed vs those which proliferate, for humans (solid lines) and mice (dashed lines).

The condition for suppression is given by Eq. 19 and 25 and the numerical values of the parameters are found in Table 1. The features of these curves are discussed in the caption to Fig. 3. CD memory T cells belong to the IL-15 niche (red lines). The model predicts that for CD T cells which are in the IL-7 niche (black lines), all autoreactive populations with antigenic stimulation rates below are suppressed by the homeostatic influx of naive T cells. Passive attrition can not suppress autoreactive cells with .

Figure 7. Schematic of proposed experimental protocol.

Individual steps 1–5 are described in more detail in the corresponding enumerated list in the text.