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290 Part III Immunologic Basis of Hematology

Depending on the context, only certain effector functions will effec- [TGF]-β, and IL-35), competition for survival factors (costimulation
tively eliminate certain pathogens. For example, antibodies will not and cytokines), and by direct cell–cell contact. Thus regulatory T cells
be effective against intracellular pathogens. By analogy, only certain represent a major peripheral tolerance mechanism to prevent aberrant
effector functions may cause autoimmune disease, depending on the autoreactive T-cell activation.
circumstances. Based on their cytokine secreting profile, T-helper
(Th) cell responses can be divided into multiple subsets including
Th1, Th2, and Th17 cells that in turn lead to very different effec- BREAKDOWN OF SELF-TOLERANCE IN
tor functions (see Fig. 25.2). The propensity to make these various AUTOIMMUNE DISEASES
types of responses depends on a number of factors including the
cytokine milieu, costimulation, genetics, route of antigen exposure, Presumably, for autoimmune diseases and autoantibody production
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and dose of antigen. Intriguingly, in certain murine models of to occur, one or more of the multilayered mechanisms to prevent
autoimmunity such as the nonobese diabetic (NOD) model, experi- autoimmunity must fail. Surprisingly, the precise nature of these
mental manipulations that shift responses away from Th1 and toward failures is not well understood. The mechanisms of failure are
Th2 are highly protective against disease. This is also relevant to likely different for the various autoimmune diseases and perhaps
B-cell autoimmunity per se because, through the use of different even for different patients with similar syndromes. Moreover, it
isotypes of Ig, different effector functions can occur. The cytokines seems likely both from phenomenologic and genetic studies that
secreted by Th1 and Th2 cells have profound effects on the isotypes failures at several levels are required to generate clinically significant
of immunoglobulins that are produced during a response. Thus, autoimmunity.
not only is the T-cell component of the response channeled in this This chapter is not meant to review the nature of autoimmune
way, but the humoral response is also influenced. Th17 cells, which diseases; however, before considering the likely points at which self-
are important for responses to extracellular bacteria as well, have tolerance mechanisms break down, it is useful to review some basic
been recognized as important pathogenic cells in several autoimmune concepts about these diseases. Grossly, autoimmune diseases have
diseases. These include mouse models of multiple sclerosis, collagen- often been divided into organ-specific and systemic autoimmune
induced arthritis, and inflammatory bowel disease. Thus genetic syndromes. This classification is useful, but as these diseases are
predisposition or environmental factors that drive Th-cell differentia- becoming better understood, the dividing lines are blurring; patho-
tion to a particular Th subset may enhance the chances of developing geneses of all these diseases are likely to have much in common.
certain autoimmune diseases that are associated with that type of In particular, systemic autoimmune diseases are actually much
response. more specific in their antigenic targets than is commonly realized.
Table 25.1 shows the types of autoantibodies commonly found
Control of Self-Reactive Lymphocytes: in several systemic autoimmune diseases. Certain autoantibodies
are diagnostic for specific autoimmune diseases, such as anti-Sm
Regulatory T Cells in SLE. Thus Sm is a specific target in SLE, but patients with
autoimmune diseases, such as rheumatoid arthritis (RA), do not
As described earlier, one fate of a developing thymocyte that binds respond to this autoantigen. In fact, only 30% of all patients with
too strongly to a self-MHC−peptide complex in the thymus, is its SLE make anti-Sm, meaning that the other 70% are tolerant of their
elimination by negative selection. An alternative fate for such a T cell own Sm despite having a systemic autoimmune disease. Another
is the adoption of a suppressive phenotype and differentiation into a salient feature of most human autoimmune diseases is adult onset.
specialized subset called regulatory T cells, which dampen immune Both the selective nature of disease and its late onset argue against
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responses (see Fig. 25.2). As they are selected by recognition of gross defects in the basic central tolerance mechanisms as being
self-peptide−MHC complexes in the thymus, thymically derived the cause.
regulatory T cells are activated upon encounter with their self-derived Instead, these considerations suggest that most clinical auto-
cognate antigen in the periphery and can subsequently inhibit auto- immune diseases are likely to arise from defects in the later stages
reactive immune responses. Regulatory T cells are characterized by
their expression of the lineage-determining transcription factor Foxp3
and the high-affinity IL-2 receptor CD25. In the most extreme
case, the importance of these cells is underscored by a rare and TABLE Patterns of Autoantibody Expression in Systemic
fatal inherited autoimmune disorder, IPEX (immune dysregulation, 25.1 Autoimmune Diseases
polyendocrinopathy, enteropathy, and X-linked inheritance), that Autoantigen/
lacks functional Foxp3 and hence regulatory T cells. The absence Autoimmune
of functional regulatory T cells in these patients leads to a fatal Diseases (% of Systemic
systemic autoimmune syndrome within 1 year of age, unless bone Patients With Lupus Rheumatoid Sjögren
marrow transplantation is performed. Similar observations have been Autoantibody) Erythematosus Arthritis Scleroderma Syndrome
made in Scurfy mice and in mice genetically engineered to lack dsDNA 40
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Foxp3. Interestingly, the autoimmune syndrome that develops in
patients lacking Aire (APECED, as described earlier) likely involves ssDNA 70
defective regulatory T-cell generation, because the adoptive transfer Histones 70
of specific regulatory T cells prevents the onset of autoimmunity in Sm 30
Aire-deficient mouse models. nRNP 30
In cases that are less extreme than Foxp3 or Aire deficiency,
perturbance in the homeostasis, development, or expansion of regula- Ro (SS-A) 35 60
tory T cells could still predispose individuals to develop autoimmune La (SS-B) 15 40
diseases. Increasing regulatory T cells in patients with autoimmune IgG (RF) 20 90 10−20
diseases could be therapeutically beneficial, as expansion of regulatory
T cells have been shown to prevent autoimmune syndromes such Scl-70 (Topo I) 70
as inflammatory bowel disease, type I diabetes, and autoimmune Centromere 70
encephalomyelitis in murine models. Furthermore, they can also dsDNA, Double-stranded DNA; nRNP, native ribonucleoprotein; Scl-70,
be used to prevent transplantation rejection and bone marrow scleroderma 70-kDa antigen (topoisomerase I); Sm, Smith ribonucleoprotein;
transplant-associated GVHD. Regulatory T cells inhibit the activa- ssDNA, single-stranded DNA. Blank space indicates rarely or never detected.
tion of other T cells through multiple mechanisms including the From Tan EM: Antinuclear antibodies: Diagnostic markers for autoimmune
diseases and probes for cell biology. Adv Immunol 44:93, 1989.
secretion of suppressive cytokines (IL-10, transforming growth factor