Page 708 - Clinical Immunology_ Principles and Practice ( PDFDrive )

682 ParT Six Systemic Immune Diseases

are very significant, as effective anticancer immunity may be antigens, and to spread the response to additional antigens in
phenotypically silent, and convenient technologies to quantify that tissue, greatly reduces the stringency that must be met to
somatic mutation and specific immune responses in normal keep the process going.
individuals will be needed to draw conclusions of causality.
PHASE III: PROPAGATION
Antigen Mimicry
The process of antigen mimicry (see below) has frequently been Principles of Amplification
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proposed as a potential initiator of autoimmune diseases. This One of the central features of human autoimmunity is the
mechanism, particularly when isolated, is only likely relevant to tendency of the process to amplify progressively with the accu-
those autoimmune processes clearly associated with antecedent mulation of significant immune-mediated tissue damage. Fur-
infections, particularly infections that resolve spontaneously and thermore, in the vast majority of cases, once such amplification
subsequently recur upon reexposure to the offending agent. The begins, the process is very unlikely to resolve spontaneously.
mechanism may, however, also play a role in initiation of the Autoantigens themselves can be very important in this phase,
autoimmune response in self-sustaining autoimmune processes in terms of both acquisition of adjuvant properties and regulation
but, in this case, requires that T-cell responses to the cross-reacting of levels of expression. The essential features of amplification
self antigen are initiated. are a substrate cycle, in which antigen expression and adjuvant
Foreign antigens, which often differ from their homologous properties induce an immune response, which, in turn, induces
self antigens in some areas, may, nevertheless, bear significant increased antigen expression and tissue damage—and further
structural similarity to self antigens in other regions. Initiation drives the immune response. The importance of tissue-specific
of an immune response to the foreign antigen may generate a autoantigen expression in focusing such immune responses is
cross-reactive antibody response that also recognizes the self only beginning to be recognized.
protein (antigen mimicry). When the antigen is a cell surface
molecule, antibody-mediated effector pathways can lead to host Acquisition of Adjuvant Properties by
tissue damage. Although the antibody response is cross-reactive Disease-Specific Autoantigens
with self molecules, the T cells that drive this response are gener- In spite of the fact that tens of thousands of molecules could be
ally directed at the foreign antigen, at least initially (see below). targeted by the immune system in autoimmunity, the number
Diseases involving this sort of “antigen mimicry,” therefore, tend of molecules that are frequently targeted in the different phe-
to be self-limiting, although they can recur upon reexposure to the notypes are markedly restricted—limited perhaps to 100 or so.
offending antigen. It is important to realize that antigen mimicry This has led to the proposal that frequently targeted autoantigens
alone cannot explain self-sustaining autoimmune diseases, which may themselves have properties that make them proimmune.
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are driven by self antigens and autoreactive T cells. In these Work by Howard and associates (reviewed in Plotz ) provided
cases, there is a requirement for overcoming T-cell tolerance important initial support for this proposal. They observed that
to the self protein. The central issues in this regard are (i) how the autoantigenic histidyl aminoacyl tRNA synthetase (HRS),
T-cell tolerance to self antigens might initially be broken, and which is targeted in autoimmune myositis (but not non–
(ii) once this has occurred, why these antigens continue to drive autoantigenic lysyl- and aspartyl-aminoacyl transfer RNA [tRNA]
the immune response to self. The simultaneous liberation of self synthetases), is a chemoattractant to immature DCs and other
antigen in the presence of the cross-reactive antibody response has leukocytes. The authors suggested that the selection of a self
been proposed to play critical roles in this regard. For example, molecule as a target for an autoantibody response may be a
several studies have suggested that when a humoral response consequence of proinflammatory properties of the molecule
to a foreign protein is induced that cross-reacts with the self itself. They further suggested that modification of autoantigen
antigen, a strong Th-cell response specific for the self antigen structure during processes of cell damage or death may be critical
can occur. The simultaneous liberation of significant amounts of in recruiting these additional functions of autoantigens.
self antigen in the setting of a cross-reactive antibody response
may allow for effective presentation of cryptic epitopes in the self Role of Innate Immune Receptors in Amplification
antigen to autoreactive T cells by activated cross-reactive B cells. Several innate immune receptor systems that sense and transduce
If continued release of self antigen occurs, a specific, adaptive the signals from pathogen-associated molecular patterns (PAMPs)
immune response to self will be sustained. Antigen release from (e.g., receptors of the Toll-like receptor [TLR] and retinoic acid-
tissues likely plays a critical role in driving this autoimmune inducible gene I [RIG-I]–like receptor [RLR] families) may also
process. Understanding the mechanisms of ongoing antigen play roles in transducing the proinflammatory properties of
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release at sites of tissue damage in autoimmune disease (e.g., autoantigens. Ligands for TLRs include both microbial and
unique pathways of cell injury and death) is a high priority for endogenous molecules, the latter group being particularly relevant
future work, as it provides a novel target for therapy (see below). to autoimmunity (see below). Microbial ligands include com-
It is clear from the above discussion that extraordinary ponents of gram-positive bacteria, gram-negative bacteria, yeasts,
complexity is operative in initiation of the human autoimmune and protozoans. For example, lipoteichoic acid and fungal
diseases. The patient population is genetically heterogeneous, products (e.g., zymosan) signal through TLR2, lipopolysaccharide
the human immune system is complex and extremely plastic, activates TLR4 signaling, dsRNA signals through TLR3, flagellin
and it interacts with a plethora of environmental stimuli and through TLR5, single-strand RNA (ssRNA) through TLR7 and
stochastic events. The simultaneous confluence of susceptibility TLR8, bacterial or viral DNA through TLR9, and Toxoplasma
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factors and initiation forces to set off the self-sustained and profilin through TLR11. Although viral and bacterial nucleic
autoamplifying process is, therefore, a rare occurrence. In contrast, acids are the most likely ligands for TLRs, accumulating data
once activation of autoreactive T cells has occurred, the ability demonstrate that complexes containing endogenous nucleic acids
of the immune system to vigorously respond to low concentrations are able to signal through TLRs. The exact nature and source of
of antigen, to amplify the specific effector response to those endogenous ligands for TLRs in vivo remains unclear; however,