Self RegulationSelf Recognition and Self RegulationMemory and Self RegulationConclusionsComplexity in the Immune SystemEmily HagerOften in this class we’ve run up against the question of whether any of the results from studying dynamical systems, chaos, or bifurcations can be usefully applied to real systems, and whether they can give testable predictions. I chose to study the immune system, partly in hopes that it is a model system where this problem has been confronted. The idea of the immune system as network was first proposed more than 30 years ago, and since then major discoveries have been made. The network theory of immunology was conceptually useful for several years, until memory cells were found. Now it is coming back into study, both for modeling purposes and because of its applications in the computer realm. The immune system is interesting in that it stores information in a crowd of interacting molecules – unlike most non-biological networks. There is no one unified network model of the immune system that answers all the questions about immune function. Here, I’d like to go into some of the models that are floating around, and what they’re good for. There are three key aspects of the immune system that network models have tried to account for: self regulation (ie immune responses usually do not explode), memory (immune systems are able to recognize and respond more quickly to pathogens they’ve seen before), and self-recognition (immune systems don’t attack cells in the body they’re part of). As it turns out, all three of these properties can emerge from network models or cellular automata – but not necessarily in a biologically relevant way.Self RegulationAny useful model of immune responses must include self regulation at least in some domains. Otherwise, the system will blow up and it will not tell us much.Self Recognition and Self RegulationThe Varela model (differential equations and networks):This model depends on the idea that B cells have both antibodies and antigens thatcan be recognized by other antibodies – and therefore that the B cells and lymphocytes form a regulating network. It is true that B cells can interact with T cells and TH cells in ways that influence their antibody production. So far so good. They represent the concentrations of the antibodies and B cell clones that produce them by a series of coupled differential equations. The concentration of each antibody is increased by production from B cells and decreased by inactivation, denaturation, and complexing with other antibodies. The B cell concentration is decreased by a rate of celldeath proportional to the population size, increased by a constant factor (production in thebone marrow), and increased by a function of the concentration of the related antibody. They model the existence of “self” antigens by setting a few of the concentrations constant (regardless of the number of related antibodies produced). This represents the constantly replenished antigens in the body, which unlike an invader, do not fall off over time when attacked. They found that for linearly connected networks and for fewer than 3 nodes, the presence of this “self” antigen pushed the system into chaos. But for a 3 node, looped network, the system was able to stabilize with low concentrations of the antibodiestargeted at the constant antigen. The authors also propose that similar network dynamics can explain the effectiveness of certain strategies of treatement for autoimmune disease, like injecting the patient with certain antibodies. This change in concentration would affect (and stabilize) the network dynamics.Memory and Self RegulationThe BSP III model (cellular automata): This model is a simplified version of the original BSP model, which was proposedby Stauffer and Weisbuch in 1992. In the BSP III, the network is a lattice in n-dimensional “shape space” (where each dimension corresponds to a property that influences the ability of antigen determinants to bind to antibodies). Each node (which corresponds to a B cell) is given a value: 0 for “virgin” or as yet unactivated cells, 1 for suppressed cells, and 2 for active or immune cells (producing antibodies). It loses some ofthe fine detail of the original BSP model, which gave B cells values corresponding to the concentration of antibodies they produced, but is easier to model. Each cell at the point r interacts with the point at –r and with that point’s nearest neighbors (to model a system ofinterlocking “shapes”). Each cell’s status is changed based on the activation state of the influencing cells, in such a way that activation below a certain level induces no change and activation above a certain level saturates. To study the dynamics of the system, Bernandes and Zorzenon dos Santos plotted the percentage of nodes in each of the states (0,1,2) as the system progressed. To model invasion, they changed clusters across the system suddenly to the 2 (active/high concentration) state. They found that increasing activated levels above a certain threshold led to explosive behavior, where most of the cells would remain in the active state. But in a certain range of activation, there would be a spike of activity followed by a return to almost resting. In their results, they claim to see immune “memory” in the following way.Each pathogen has a set of antigen determinants. To model this, they perturbed several clusters in the lattice each run. Some small number of the clusters (~20%) would remain in the “active” state even long after the initial response had decayed. They would then perturb the model again in an identical way, and the initial response was faster, andmore of the clusters persisted. So in this model, the network stores the “memory” of each infection because the cells corresponding to certain parts of the antigen signature remain active. This is very different from the “memory cell” concept, where activated cells end up as long-lived memory cells, which can quickly differentiate into active cells on reinfection. Unfortunately for them, memory cells do in fact exist. However, it would be interesting to see whether their limits for the percentage of cells that can be activated before causing an autoimmune reaction bear any resemblance to the real world. Also these findings may be interesting for other systems that are capable of “storing” information. ConclusionsNetworks have been proposed as a