Understanding immune responsiveness will benefit from accepting the multidimensionality and quantitative nature of immunological phenomena 
. Here, we have engaged this precept to investigate immune-inflammatory responses following repeated HDM exposure in mice. The computational analysis we have performed allows for the identification of rules and parameters that define the system. Principal rules are that relationships between time and infiltrating total cells, as well as mononuclear cells and neutrophils, and serum immunoglobulins follow a logistic-like curve; in sharp contrast, the eosinophil response over time follows a bell shaped-like curve. These rules presuppose a dynamic behavior with at least one significant implication: the lung cellular effector profile quite drastically changes depending on dose and length of exposure to allergen. These multiple possible outcomes may be mathematically viewed as a demonstration of heterogeneity.
The distinct behavior of eosinophils is intriguing. The underlying immunological explanation is unknown at this time; however, it seems intuitive that if allergen exposure is considered as an input, persistent deliverance of such an input will stress the system and instigate reactive responses. From this perspective, the decrease of eosinophils and the increase in mononuclear cells are likely to be mechanistically related. Flow cytometric analysis delineating the changes in the dynamics of subsets of mononuclear cells (T cells and monocyte/macrophages) over the entire protocol will be informative and suggest future venues of research.
Several parameters define the behavior of the system. First, we have identified a threshold dose at approximately 0.5 µg of HDM for sensitization and 2 µg for inflammation. In fact, exposure to 2.5 µg of HDM elicits a detectable eosinophilic inflammatory response (data not shown). Second, responsiveness for all constituents is dependent on the strength of the initial dose of allergen; moreover, the greater the input, the steeper the initial slope of the response. Third, the system has an inherently limited capacity to respond, at least to the same allergen. This maximal responsiveness is achieved at a dose between 10 and 15 µg, and further increases in dose or length of exposure do not result in greater responses. Fourth, there is an entire range of responses between the threshold and the maximum; mathematically, however, the model reveals that the distribution of responses is non-linear. Lastly, a comparative analysis of inflammation and sensitization outputs reveals that the development of the latter is more sensitive to allergen than the induction of airway inflammation. That the relationships between exposure and either sensitization or inflammation are non-linear intimates that the relationship between sensitization and inflammation is non-linear as well. It is tempting to speculate that these findings may contribute to explain the difference between the prevalence of atopy (~40%) and asthma (5–10%) in humans 
The question of how the concentrations of allergen used here compare to human exposure is elusive because the terms of reference are precarious (reviewed in 
). Many studies have examined the amount of mite allergen present in homes. However, the numbers vary extraordinarily. Not only is there a plethora of environmental variables influencing the concentration of mite allergens in the household but there are also several collection and measurement techniques 
. In addition, the relationship between the micrograms of allergen measured in a dust sample and the amount of allergen that is airborne, inspired, and reaches the lower airway is enigmatic. Indeed, the inability to precisely determine mucosal HDM exposure in humans frustrates the justifiable desire to formulate a rigorous interspecies comparison of exposures. Perhaps such a straightforward comparison is an ill-conceived goal; arguably, numbers may not be translated between species but behaviors likely can.
Many issues have not been addressed here. For example, experiments were conducted in BALB/C mice. While we know that C57BL/6 mice respond to HDM even more vigorously in terms of inflammation, it definitely cannot be assumed that the behavior of these two strains, or others, is identical. Similarly, these experiments were performed in female mice and, thus, a direct application to male mice is unadvisable. In addition, we cannot presume that the behaviors described for HDM apply to other aeroallergens. With these limitations, our research furnishes a conceptual foundation and operating tools for the evaluation of other variables or system perturbations of a pharmacological, environmental or genetic nature. Based on the present research, future analysis of immune responses exploring these variables may not require the generation of entire data sets but of selected experiments to generate comparative algorithms to re-define the overall behavior of the system.
There has been a considerable interest by engineers, mathematicians and computer scientists in the application of their skills to modeling biological processes. Over the last few years, biologists have shown an increasing attraction to join in this enterprise. Arguably, the catalyst underlying this initiative has been the recognition that biological processes are, formally, complex processes. As such, efforts to incorporate new conceptual and experimental stratagems must be made to better comprehend them. The development of mathematical modeling based upon research, primarily in vitro
, examining hemopoiesis and stem cell renewal 
, models of virus-immune dynamics 
and cancer cell propagation 
typify these efforts. Particularly in the area of inflammation, agent-based and equation-based models have been established to provide insight into the complex dynamics of this process 
. However, the research presented in this manuscript is, to our knowledge, the first to investigate the interaction between aeroallergens and the immune system in vivo
from a computational perspective.