Early and late inflammatory responses.

Classical immunology teaches that the initial response to infection or injury, e.g., acute inflammation, is mediated by components of the innate host defense, such as neutrophils and macrophages. If the insult is not cleared within days, it is widely believed that a chronic inflammatory response is enabled by the persistent activation of the acquired immune response driven by T lymphocytes. Recently these traditional images of acute versus chronic inflammation are being replaced by models focused on the kinetics of the immune response, changes which may lead to epitope spreading, immune deviation and clonal exhaustion (1). We therefore propose an alternate paradigm for describing and evaluating the immunologic mediators, cells and processes that initiate, perpetuate and modulate chronic inflammatory diseases. Here we introduce the hypothesis that chronic inflammatory diseases are typified by an early phase mediated by a classic series of immunologic events that include antigen processing and presentation by dendritic cells, macrophages, or B cells, leading to activation of naïve CD4 T cells in the draining lymph nodes. However, as the disease evolves, local and environmental parameters dramatically influence the progression and character of the inflammatory response, leading to a unique late phase of disease stylized for an individual infectious agent or tissue. Evidence for an evolving immune response in chronic disease has been reported for years in models of bacterial infection, viral infection, parasite infestation, allergy, asthma and arthritis (see references in 3). Our inability as a community of investigators to appreciate the significance of these changes may be reflected by the previously underdeveloped understanding of innate host defense. Recent advances have demonstrated an intricate and highly effective network of extracellular and intracellular pattern recognition receptors (2), which coordinate both the classic acute and chronic inflammatory response. Furthermore, an acquired immune response, while orchestrated by the CD4 T cells, is fully dependent on innate effector function. Thus, we are exploring the possibility that during the late phase of inflammatory diseases we no longer have an acquired immune response, but rather dysfunctional innate immunity in which the balance of effector and suppressor T cells is disrupted. The loss of the highly evolved regulatory network for initiating and terminating adaptive immunity may trigger a state of “immune bedlam,” which we define as the late phase of a chronic inflammatory response. Inflammatory bowel disease (IBD) is no exception to the parameters of early and late disease just delineated. In one particular murine model of IBD in which the gene coding for interleukin 10 (IL-10) is disrupted, mice develop colitis anywhere from 5 to 10 weeks of age, depending on their genetic background and the luminal bacterial microbiota unique to each institution’s animal housing facility. At our institution, IL-10-deficient mice on a C57BL/10 background show histologic and clinical signs of colitis at 10 weeks of age. The disease progressively worsens until maximal inflammation and intestinal damage are observed and maintained beyond 24 weeks of age. However, the immunologic mediators responsible for colitis in a 15-week-old mouse are quite different from those expressed in a 35-week-old mouse (3). As shown in Figure 1, when the production of two traditionally opposing cytokines, IL-4 and interferon (IFN), by colonic mononuclear cells is compared, IFNlevels dominate in early disease, yet the relative concentration of these two cytokines normalizes to control amounts in late disease. Given these findings, it is not surprising that biologic treatments which disrupt