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Mechanisms of Autoimmunity

Brendan Antiochos, Antony Rosen

Human autoimmune diseases occur frequently (affecting in KEY CONCEPTS
aggregate >5% of the population worldwide) and impose a
significant burden of morbidity and mortality on the human Autoantibodies in Autoimmune Diseases
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population. Autoimmune diseases are defined as diseases in • Some autoantibodies precede the development of any symptoms by
which immune responses to specific self antigens contribute to years (e.g., antinuclear antibodies and antiphospholipid antibodies in
the ongoing tissue damage occurring in the disease. Both the systemic lupus erythematosus [SLE], anti– cyclic citrullinated peptide
specificity of the immune response and its role in tissue damage [CCP] in rheumatoid arthritis [RA]).
are central components of the definition. Autoimmune diseases • Some autoantibodies only occur at around the time of onset of disease
manifestations (e.g., anti-Sm and anti-ribonucleic protein [RNP] in SLE).
can be either tissue specific (e.g., thyroid, β-cells of the pancreas), • There is a striking association of specific autoantibodies with distinct
where unique tissue-specific antigens are targeted, or can be more clinical phenotypes (e.g., antitopoisomerase-1 with diffuse scleroderma
systemic, in which multiple tissues are affected and a variety of and interstitial lung disease).
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apparently ubiquitously expressed autoantigens are targeted.
Although the definition appears relatively simple in concept,
the complexity of this spectrum of disorders is enormous and
has greatly challenged elucidation of simple shared mechanisms. THE DISTINCT PHASES IN THE DEVELOPMENT
This complexity affects almost every domain, including genetics, OF AUTOIMMUNITY
phenotypic expression, and kinetics. In the last case, there is
frequently a prolonged period (weeks to months) between initial A major barrier to understanding mechanisms of autoimmunity
onset of symptoms and development of the diagnostic phenotype, comes from difficulty in defining early events in these diseases.
and the expression of disease may vary within the same individual Since diseases are only recognizable after development of the
over time. However, despite this enormous complexity, there is a diagnostic phenotype, there has been a tendency to interpret
striking association of the clinical phenotype with the targets of findings at the time of disease diagnosis with events present
the autoimmune response. This association is, in fact, so strong at disease initiation. Significant recent data from studies of
that autoantibodies have been used for diagnosis and prognosis the development of autoantibodies over time in patients who
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in the human autoimmune diseases. For example, autoantibod- subsequently manifest an autoimmune disease have demonstrated
ies recognizing thyroid peroxidase are found in patients with that the onset of an autoimmune response and the development
autoimmune thyroiditis, autoantibodies to the Sm splicing of clinical symptoms are generally separated in time. In the case of
ribonucleoprotein (RNP) complex are diagnostic of systemic type I diabetes, development of islet cell autoantibodies frequently
lupus erythematosus (SLE), and autoantibodies recognizing precedes diabetes, and additional islet cell autoantibodies accrue
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topoisomerase-1 are found in patients with the diffuse form over time. Similarly, autoantibodies recognizing citrullinated
of scleroderma. The immune response in autoimmune diseases proteins (rheumatoid arthritis [RA]–specific autoantibodies;
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has features of an adaptive immune response (usually directed see below) frequently precede the development of RA. These
against exogenous antigens), but its targets are autoantigens. Since findings indicate that either a threshold needs to be exceeded
the adaptive immune response is initiated when suprathreshold in terms of tissue damage before symptoms manifest, or that
concentrations of molecules with structures not previously there are two distinct phases in disease development, one marked
tolerized by the host are encountered in a proimmune context, by production of a group of autoantibodies and the second
the association of specific autoantibodies with distinct clinical by autoamplifying tissue damage. In a landmark study in SLE,
5
phenotypes provides critical clues to understanding the initiation Arbuckle et al. have provided important insights into this issue.
and propagation of autoimmune diseases. They analyzed sera collected from patients from the US military,
This chapter highlights some of the mechanistic principles who subsequently developed SLE. Strikingly, autoantibodies in
that underlie autoimmune diseases. The extraordinary breadth SLE could be divided into two groups: (i) those that precede the
and complexity of this disease spectrum means that the areas diagnosis of SLE by several years—these included antinuclear
included cannot nearly encompass everything relevant. and antiphospholipid antibodies; and (ii) those that occurred

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