Innate Immunity and the Kidney

A Brief History of Discoveries of the Innate and Adaptive Host Immune Responses

The initial recognition of active host defense against microbial pathogens is credited to Élie Ilyich Metchnikoff, who realized amebocytes from starfish would migrate toward foreign invaders and ingest them. He reasoned that such a beneficial host defense would be passed on to higher organisms by Darwinian evolution and would likely be found in humans. He was first to confirm this fact by finding specialized cells in human blood engaged in what he coined to be “phagocytosis.” Metchnikoff gained the support of Louis Pasteur, and he spent the rest of his career at the Pasteur Institute in Paris investigating the role of phagocytic cells in innate host defense. He observed two major types of phagocytic cells: large tissue-based macrophages and smaller circulating “microphages,” now known as neutrophils. Metchnikoff's observations were first scoffed at by his peers and public. George Bernard Shaw's play “The Doctor's Dilemma” was written as a humorous satire of Metchnikoff's ideas.

While the cellular contribution of professional phagocytes to host defense was under study in Paris, a competing school of humoral immunity was championed in Germany. Behring and Kitasato of the Koch Institute in Berlin showed that immune serum from animals that survived an infection, in the absence of cells, could passively protect nonimmune animals. The protective factor, serum antibodies, were discovered in immune serum, along with series of proteins that amplified antibody activity, now recognized as the complement system. This work was conducted primarily by Paul Ehrlich et al. in Germany. Subsequent studies clearly established that humoral immune elements, myeloid cells of the innate immune system, and lymphoid cells of the adaptive immune system collaborate to defend patients from microbial invaders. Appropriately, Metchnikoff and Ehrlich shared the Nobel Prize in medicine in 1908, as recognition of their critical discoveries and as an acknowledgment of the equal importance of humoral and cellular immunity in host defense.

Recently, the Nobel Prize in Physiology and Medicine was shared by three scientists for unraveling the mysteries of innate immune sensing, pattern recognition, and Toll-like receptors (TLRs). In 2011 the Nobel Prize went to Bruce Beutler for discovering TLR4, the long sought-after cellular receptor that recognizes bacterial endotoxin. He shared the prize with Ralph Steinman for his discovery of dendritic cells and Jules Hoffman for developing the basic concepts and identity of the pattern recognition receptors in innate immune activation.

Introduction Into Innate Immunity

The innate immune response can be likened to the rapid response team found in most large hospital systems. This team consists of a specified group of healthcare workers, with a clear set of identifiable skills, and has the responsibility to immediately respond and rescue suddenly ill patients within the hospital. The code team does not know what they will find when they arrive at the patient's room. It may be a plugged endotracheal tube in a patient needing ventilator support, chest pain with a dysrhythmia, someone fallen out of bed with a bumped head, a massive gastrointestinal hemorrhage, an adverse drug reaction with anaphylactic shock, or a myriad of other crises that require immediate attention. The team members must make a rapid assessment of the problem, begin appropriate care, and call in other specialists to assist if necessary. Our innate immune system serves similar functions when our physical barriers to infection have been breached by a traumatic injury to the integument.

Any injury can pose a threat to host survival on two fronts: infection by entry of pathogens from the external environment or exsanguination with loss of the internal milieu from bleeding. The innate immune response system is called into action within minutes by danger signals sent out by sentinel macrophages and soluble pattern recognition receptors such as the mannose-binding lectin and alternative complement pathway. Local generation of chemical signals in the form of chemokines and other chemoattractants is detected by adjacent endothelial cells and circulating neutrophils and platelets to begin the delivery of phagocytic cells and antimicrobial peptides to engage and eliminate any microbial pathogens invading the tissues. Concomitantly, the clotting system is activated when exposed collagen binds to circulating von Willebrand factor (VWF), thereby creating long multimers of VWF to which platelets bind and aggregate. Simultaneously, tissue factor exposed by endothelial membrane disruption initiates the coagulation cascade with fibrin deposition. The innate immune response and coagulation systems are coactivated and coregulated to protect against excessive bleeding and infection. Innate immune sensing of danger is a highly evolved and complex network of cellular and soluble receptor molecules that recognize highly conserved molecular patterns found in essential structures for microorganisms, but not for human cells. These exogenous ligands are referred to collectively as PAMPs (pathogen-associated molecular patterns). However, innate immune signaling is not simply initiated by “self” versus “non-self” recognition. Innate immune receptor molecules also recognize endogenous human pattern molecules leaked from dead or dying cells and elements of ground substances that make up the intercellular matrix. The endogenous pattern molecules released during tissue injury are danger signals detectable by innate immune cells by the same type of pattern-recognition receptors that detect PAMPs. The danger signals from tissue injury are DAMPs, or damage-associated molecular patterns. The most widely recognized pattern recognition receptors of innate immunity are the Toll-like receptors (TLRs) but are not the only receptors that participate in the host response to pathogens. A brief summary of major ligands that make up the PAMPs, DAMPs, and their cellular receptors expressed on immune cells is found in Table 82.1 and detailed, along with the major intracellular signaling pathways, in Fig. 82.1 .

Cellular and Humoral Components of Host Innate Immune Defenses