A detailed overview of the immune
system is provided in Chapter 186. This chapter
is focused upon those aspects of inflammation, tolerance, and genetics
that are particularly relevant to autoimmune disorders.
The immune system exists to defend against infection and it has
developed a beautiful yet complex system to distinguish the “self” from foreign
moieties that are considered a threat. 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 distinguish 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.
Accordingly, most autoimmune disorders are thought to arise from
errors in the process of establishing self-tolerance. In contrast,
defects in the regulation of innate responses lead to autoinflammatory disorders.
The distinction is based on the finding of autoreactive B cells
and T cells in autoimmune disorders, as opposed to autoinflammatory
diseases, which are associated with considerable inflammatory changes
but an absence of autoreactive cells.
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, although they are ideally suited for eliminating
bacteria. Housed within granules are a multitude of proteolytic
enzymes, antimicrobial peptides, and proteins, which are released
into the phagosome holding the bacteria. Of relevance to immune and
inflammatory diseases is the potential for neutrophils to damage
healthy tissue in a bystander phenomenon. Recurrent infections lead to
end organ damage as a consequence of neutrophil release of granule
material into the tissue. In autoimmune or autoinflammatory disorders,
the neutrophils are recruited inappropriately but similarly cause
substantial damage to tissues over time.
Tissue macrophages represent one of the main sentinel cells in
the body; others are mast cells and dendritic cells. Certain pathogens
are resistant to neutrophil killing, such as mycobacteria and fungi.
In some autoimmune and autoimflammatory disease, characterized by
high levels of TNF-α, macrophages can become activated
in a poorly understood process, then aggregate and form granulomas.6,7 All
granulomas are comprised of activated macrophages, called epithelioid
cells, but not all activated macrophages are found in granulomas.
These disorders are effectively treated with TNF-α inhibitors.
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.10 The
granules contain granzyme B, which activates apoptosis in the target
cell, and perforin, which is thought to act as a pore to facilitate
entry of granzyme B. The role of the NK cell is ...