Adaptive Immunity and Critical Illness

Immune System: an Overview

The primary force that has driven the evolution of the human immune system has been the need to promptly recognize and appropriately respond to danger threatening the survival of the host organism. Danger, however, can take many forms. It may be the invasion of host tissue by infectious pathogens such as bacteria, viruses, or fungi, but it also may be the disruption of tissue from traumatic injury or the neoplastic transformation of normal tissue into cancer. As such, the immune system has evolved into a complex and sophisticated network of immunologic response mechanisms that orchestrate an effective host defense.

The immune system can be conceptualized as comprising two main components: first, the innate immune system, which encompasses a limited number of germline gene products and therefore responds immediately but unspecifically to a broad variety of threats; and second, the adaptive immune system, which becomes activated more gradually as it relies on gene rearrangement, selection, and clonal expansion to produce a specific, tailored response and long-lasting immunologic memory. As crucial as the immediate activation of the immune response is the timely resolution of this response to prevent further tissue damage and organ dysfunction. Without resolution, persistent inflammation promotes deleterious tissue remodeling and organ dysfunction and can promote transformation into cancerous neoplasia.

Recognition of Foreign Molecules

The skin and mucous membranes (e.g., in the airways or in the gastrointestinal tract) are natural physical barriers that act as the first line of defense to prevent invasion of external pathogens. A surface layer of mucus prevents microbial binding to the host cell, and tight junctions between cells preclude simple passage of pathogens into deeper tissue. Numerous pathogens have developed various strategies to overcome this initial most primitive form of defense and subsequently encounter more complex defense mechanisms of the host immune system as they invade the underlying tissue ( Fig. 83.1 ).

Specific groups of invading microorganisms are recognized via pathogen recognition receptors (PRRs), which are expressed on epithelial barriers as well as by cells mainly of the innate immune system such as dendritic cells and macrophages. These PRRs act as sensors of microbes and recognize conserved macromolecular motives from microorganisms, called pathogen-associated molecular patterns (PAMPs). Examples of bacterial PAMPs include lipopolysaccharide (LPS, the main virulence factor of gram-negative bacteria), peptidoglycan, lipoteichoic acid (a cell wall component of gram-positive bacteria), flagellin, and bacterial DNA. Damage-associated molecular patterns (DAMPs) are released by damaged host cells and contribute to the activation of the overall immune response. The stimulation of a specific family of PRRs named Toll-like receptors (TLRs) or of the NOD-like receptor (NLR) family of intracellular PRRs results in the triggering of downstream signaling cascades. Depending on the particular receptor engaged, this process leads to the activation of a transcriptional response program, which includes nuclear factor κB (NF-κB), followed by the production and secretion of cytokines, chemokines, and nitric oxide (NO). Proinflammatory cytokines lead in turn to an ensuing, coordinated activation of the innate and adaptive immune response.

Innate Immune Response

Cells of the innate immune system include myeloid cells (e.g., monocytes, macrophages, dendritic cells, granulocytes [eosinophils, basophils, neutrophils]), and innate lymphoid cells (e.g., natural killer [NK] cells). These cells are present at important sites of primary pathogen exposure, such as the airways, intestinal mucosa and skin, and are crucial for the initiation of an inflammatory response. For example, recent lineage- and temporal-specific tracking studies suggest that so-called tissue-resident macrophages, which are derived from embryonic progenitor cells without contributions from bone marrow-derived monocytes, are maintained in the periphery, where they patrol the tissue for invading microbes. Once a potential threat is encountered, these cells become activated and release chemokines (most importantly CCL2, also known as monocyte chemoattractant protein-1, MCP-1), which recruit and activate blood monocyte-derived Ly6C+ macrophages and dendritic cells. Thus tissue-resident macrophages act as sentinels, which recruit and assist in the “licensing” of leukocytes. In turn, the recruited innate immune cells release an array of proinflammatory mediators including cytokines (e.g., tumor necrosis factor-α [TNF-α] interleukin-1 [IL-1], IL-6, macrophage migration inhibitory factor [MIF]), chemokines (e.g., IL-8), prostaglandins, reactive oxygen, and nitrogen species to mount a robust proinflammatory response. Specific cytokines (e.g., IL-1 and TNF-α) and chemokines (e.g., IL-8 and MCP-1) activate the vascular endothelium, increase vascular permeability, and induce site-directed chemotaxis. Cytokines also facilitate the migration of leukocytes from the vasculature to the site of injury and enable interstitial leakage of protein-rich fluid, resulting in the “tumor” of local inflammation. In addition, the upregulation of inducible NO synthase in the adjacent microvasculature leads to increased synthesis and release of NO, which results in local vasodilation. The enhanced generation of prostaglandin E ₂ (PGE ₂ ) by cyclooxygenase produces the characteristic “rubor” of local inflammation. IL-1, TNF-α, and IL-6 can act on the hypothalamus to alter the thermoregulatory set point, thereby inducing fever. IL-6 induces acute-phase reactant protein production by hepatocytes. Although all these events promote a strong proinflammatory immune response, other innate immune cell products, such as IL-10 and transforming growth factor-β (TGF-β), are released simultaneously and play an important role in the resolution of the inflammatory response and in the initiation of tissue repair. Taken together, this accumulation of events results either in the elimination of the invasive pathogen and in the subsequent downregulation of the immune response or in a more vigorous immune response by triggering the simultaneous activation of the more specific adaptive immune system.