Page 704 - Clinical Immunology_ Principles and Practice ( PDFDrive )

678 ParT Six Systemic Immune Diseases

around the time of onset of symptoms—these included anti-Sm, Susceptibility Initiation Propagation (Resolution)
anti-RNP, and to a lesser extent anti-DNA. The observation that B D
one group of autoantibodies precedes symptoms in SLE and that
another group appears coincident with the phenotype strongly A
suggests that the groups mark distinct events in the development Normal host
of autoimmune disease. Members of the first group are likely
markers of disease initiation; members of the second group are
likely markers of disease propagation. The antigens targeted by
the immune system in this latter phase (i.e., associated with
clinical disease) are more likely to have some function in disease
‘Free energy’
propagation, possibly through their possession of proinflamma-
tory or adjuvant functions (see below). 6 Autoimmune host

KEY CONCEPTS
Barriers to Defining Mechanisms of Human
Autoimmune Disease

• Genetic and phenotypic complexity
• Interval between initiating events and development of diagnostic
phenotype
• Challenges in quantifying human immune responses
C
It is therefore useful to examine the development of auto-
immune diseases in four phases (Fig. 50.1): Time
1. Susceptibility phase—before disease, but where one or several A Susceptibility
preconditions for later initiation are satisfied. This would
include impaired tolerance induction or altered immune • Impaired tolerance induction
• Impaired production of regulatory T cells
signaling thresholds. The susceptibility phase could either be • Altered immune signaling thresholds
inherited or acquired and permanent or transient.
2. Initiation phase—before onset of clinical disease, but marked B Initiation
by the presence of an autoimmune response (e.g., in the case • Suprathreshold concentration of autoantigens
of SLE—antiphospholipid antibodies). • Non-tolerized structure
3. Propagation phase—this corresponds with the onset of clinical • Pro-immune context – infection, malignancy, exposure to adjuvants
disease, marked by propagation-specific immune responses C Propagation
(e.g., in the case of SLE—anti-Sm antibodies). • Acquisition of adjuvant properties by disease specific autoantigens
4. Regulation/resolution phase—it should also be noted that in • Increased autoantigen expression in the target tissue
many cases during disease propagation, immunoregulatory • Immune effector pathways generate/expose autoantigen, which further
pathways are also activated, which may result in natural drives the immune response
inhibition of clinical disease over time. In rare cases, these FiG 50.1 Mechanisms of Autoimmunity. Autoimmune diseases
inhibitory pathways can lead to permanent resolution. This result from a complex interplay of pathways and events that
resolution phase will not be discussed further here, but its allow autoreactivity to manifest, and cause self-sustaining tissue
existence provides important evidence that homeostasis damage. Mechanistically, it is useful to divide the process into
can be reestablished even after the amplified phenotype three phases: (1) susceptibility phase—this is present before
develops. disease and is the phase in which one or several preconditions
for later initiation are satisfied; (2) initiation phase—this is marked
PHASE I: SUSCEPTIBILITY by the presence of autoimmunity, but precedes the diagnostic
clinical phenotype; (3) propagation phase—this is marked by
Although autoimmune diseases in humans are genetically autoimmunity and tissue damage, in which immune effector
complex, significant advances in understanding have occurred pathways cause damage and provide antigen to drive the ongoing
over the past several years. In some cases, advances have come immune response.
from the study of autoimmunity with mendelian patterns of
inheritance (e.g., autoimmune polyendocrinopathy with candi-
diasis and ectodermal dysplasia [APECED], immune dysfunction/
polyendocrinopathy/enteropathy/X-linked [IPEX] syndrome,
C1q deficiency). Advances have also come from genetic association Incomplete Thymic Tolerance Induction Predisposes
studies of various autoimmune phenotypes (e.g., SLE, type I to Autoimmunity
diabetes mellitus [DM]). There have also been important advances Significant insights into basic mechanisms can derive from
in the genetics of autoimmunity in several mouse models. These the study of rare human phenotypes. This has been true for
studies highlight a critical role for pathways of tolerance induction, autoimmunity, where several monogenic disorders have defined
immunoregulation, and setpoints/thresholds for immune signaling important pathogenic principles. Autoimmune polyendocri-
in avoiding emergence of autoimmunity. nopathy syndrome type 1 (APS-1;also called APECED) is a