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An overview of the immune system is provided in Chapter 182. This chapter is focused upon those aspects of inflammation, tolerance, and genetics that are particularly relevant to autoimmune disorders.

The immune system may be broadly divided into the innate immune system and the adaptive immune system. The innate immune system is distinguished by hard-wired programs to recognize patterns characteristic of pathogens, also known as pathogen-associated molecular patterns (PAMPs). The adaptive immune system consists of T-cell and B-cell functions. T cells and B cells adapt to the environment and undergo a training process to learn to distinguish foreign antigens from self-proteins. As the training process will be distinct for each individual, there is opportunity for errors. Autoimmunity arises from errors in the process of establishing self-tolerance. In contrast, defects in the regulation of innate responses lead to autoinflammatory disorders. These concepts are useful in understanding the underlying pathogenesis of autoimmune disorders, but inflammation can drive breaks in tolerance, and most such conditions are accompanied by inflammation. Thus, the clinical picture in a patient can often reflect both inflammation and autoimmunity.


Neutrophilic infiltrates accompany many autoimmune diseases of childhood. Many of the vasculitides and nearly all types of arthritis are accompanied by a neutrophilic infiltrate. These cells may be extremely destructive. Housed within granules are a multitude of proteolytic enzymes, antimicrobial peptides, and proteins, all of which typically are released into the phagosome holding the bacteria. Neutrophils also have a strategy to entrap larger pathogens in a NET (neutrophil extracellular trap). This killing pathway is favored for large pathogens and in the setting of type I interferon excess. Neutrophil NETs represent extruded granule contents enmeshed in a DNA-histone matrix. NETs have significant potential for tissue damage. Because of their destructive enzymes and reactive oxygen species, neutrophils in tissues are associated with end-organ injury, regardless of whether they were recruited for pathogen defense or as part of an inflammatory process.

Tissue macrophages represent one of the main sentinel cells in the body; others are mast cells and dendritic cells. Certain pathogens, such as mycobacteria and fungi, are resistant to neutrophil killing. In some autoimmune and autoinflammatory diseases, characterized by high levels of tumor necrosis factor (TNF), macrophages can become activated in a poorly understood process, then aggregate and form granulomas. All granulomas are comprised of activated macrophages, called epithelioid cells, but not all activated macrophages are found in granulomas. Because macrophages are dependent on γ-interferon and TNF, TNF inhibitors can effectively treat granulomatous diseases.

Natural killer (NK) cells were originally defined by their ability to kill tumor cells in vitro. NK cells kill their targets by forming a synapse and releasing cytotoxic granules into the synaptic cleft. The granules contain granzyme B, which activates apoptosis in the target cell, and perforin, which is thought to act as a pore to facilitate ...

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