Page 791 - Clinical Immunology_ Principles and Practice ( PDFDrive )

762 Part SIX Systemic Immune Diseases

report, however, details two cases of pyomyositis initially diag- highly related glycoproteins, including IFN-α and IFN-β, that
nosed as PM. Patients presenting with disseminated pyomyositis act on the type 1 IFN receptor. In DM muscle, the IFN-Is likely
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may be difficult to distinguish clinically from those with IIM, are produced by plasmacytoid dendritic cells (pDCs). After
especially in immunosuppressed individuals, who may not mount activation of the IFN receptor, a cluster of IFN-I–inducible genes
a systemic response. 15 is transcribed, resulting in upregulation of several proteins, also
known as the IFN signature, in the muscle and peripheral blood
PATHOGENESIS of patients with DM. Well known is the myxovirus resistance
protein A (MxA), which, similar to other IFN-I–inducible proteins,
The precise mechanisms of cell damage and death in the IIMs has antiviral properties. This protein is overexpressed in both
are still unknown. T lymphocytes invading muscle fibers are the muscle and skin in DM but not in PM or IBM. Further,
predominantly lacking the costimulatory receptor CD28, indicative decreased expression of MxA mRNA in peripheral blood mono-
that they are chronically stimulated and end-differentiated. nuclear cells may correlate with decreasing muscle symptoms
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CD28 lymphocytes are found in both muscle tissue and in juvenile DM patients. Indeed, some of the IFN-induced proteins
peripheral blood. They produce proinflammatory cytokines and may sustain autoimmunity in DM. For example, retinoic acid-
release perforin and granzyme into targeted muscle cells. B cells inducible gene 1 (RIG-I) and melanoma differentiation-associated
and plasma cells are also present in myositis muscle infiltrates. gene 5 (MDA-5) are IFN-I–induced proteins that induce IFN-I
The differentiation of B cells into antibody-producing plasma production in a positive feedback fashion. Both proteins con-
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cells occurs within myositis muscle and is regulated by B cell– tribute to IFN induction in response to measles virus infection,
activating factor (BAFF). These antibodies are likely directed nurturing the suspicion for a role of viral infections in myositis.
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against autoantigens or cross-reacting viral antigens. Engel and colleagues have demonstrated several important
In addition to adaptive immune mechanisms, innate and pathological distinctions between DM and PM and have suggested
nonimmune mechanisms also may be responsible for muscle that in DM, the capillaries are the initial point of injury. A model
cell damage and death. For example, Toll-like receptor (TLR)-3 of disease has been proposed in which primarily capillaries are
and TLR-7 are expressed by infiltrating inflammatory cells and damaged and myocytes are secondarily involved. Complement
immature myoblasts in myositis muscle. TLR activation leads and immunoglobulins may be found in the capillary walls even
to production of inflammatory cytokines such as interleukin where the remainder of the muscle is normal. The membrane
(IL)-6, thereby triggering or perpetuating inflammatory responses. attack complex of complement deposits there, and endothelial
Classic apoptosis is absent in IIM biopsies, but growing evidence cells are swollen and pale. Even in unaffected regions of muscle,
suggests that autophagy could be responsible for myofiber death. special staining reveals a marked decrease in capillary numbers.
After damage, a muscle fiber, which is a syncytium, can More advanced changes include microtubular endothelial inclu-
regenerate. Initially, on light microscopy one can appreciate sions and microvacuoles. Evaluation of lymphocyte populations
loss of striations leading to a homogeneous appearance, fiber in DM shows a high percentage of B cells and macrophages in
size variation, atrophy, and centralization of the nuclei. In the the perivascular regions and an increasing frequency of CD4 T
inflammatory myopathies, cell-mediated cytotoxicity is a primary cells and pDCs toward the perimysium and endomysium. In
method of destruction. Macrophages and cytotoxic T cells invade DM, especially the juvenile-onset form, inflammation and necrosis
the myofibers. The myocyte cytoplasm close to the invaginated followed by atrophy appear in a perifascicular pattern. Perivascular
cells appears vacuolated and swollen. Other regions of the same lymphocytic infiltrates, typical of later disease, have not been
cell may show intense regeneration, as seen histologically by described as an early change. Consistent with the importance
aggregates of nuclei with prominent nucleoli and fiber splitting. of immune complexes, histological abnormalities in the DM
Thus degeneration and regeneration can coexist in the same fiber. skin are indistinguishable from the changes in lupus.
Cytokines and chemokines (Chapters 9 and 10) , which form In contrast to DM, PM and IBM do not demonstrate marked
an integrated network regulating inflammation, are produced capillary changes, the perivascular infiltrates are less pronounced,
by muscle fibers, immune cells, and endothelial cells. As an and T-cell infiltrates in the perimysial and endomysial regions
example, IL-1 is consistently found in myositis muscle. IL-1 are more pronounced. Nonnecrotic fibers may be surrounded
facilitates transmigration of leukocytes by increasing the expres- by T cells and macrophages. T cells are enriched for the CD8
sion of adhesion molecules on endothelial cells. Further, IL-1 subset. There is negligible evidence of natural killer (NK) cell
can decrease the proliferation of myoblasts. In some myositis presence. Should cytotoxic T cells prove to be the major effector
patients, treatment with anakinra, an IL-1 receptor antagonist, cells, cloned T cells could lead to relevant antigenic targets. CD8
results in improvement. This finding further supports a pathogenic T cells recognize their antigenic peptide in association with major
role of IL-1. IL-1 acts in synergy with the other proinflammatory histocompatibility complex (MHC) class I molecules. Although
cytokines, tumor necrosis factor (TNF)-α and IL-17, to induce resting normal muscle has very low class I expression, it is
the production of IL-6 and CCL20 by myoblasts. The chemokine upregulated in regenerating and degenerating fibers found in
CCL20 recruits Th17 lymphocytes and immature dendritic cells both inflammatory and noninflammatory myopathies. Interest-
into the muscle. IL-6 perpetuates inflammation by suppressing ingly, in DM, class I expression is upregulated predominantly
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FOXP3 regulatory T cells. More recently, IL-15 has been reported in the perifascicular regions, around sites of atrophy, and near
to have a pathogenic role. IL-15 is expressed in muscle cells and sites of cellular invasion. In contrast, in PM, class I expression
myoblasts derived from PM and DM patients. IL-15 regulates may be diffusely upregulated even where there is no cellular
T-cell activation and proliferation, and a higher expression of infiltrate. IBM shows a more focal class I distribution in regions
this cytokine at baseline may be associated with a poor response of T-cell invasion. The presence of focal regions of MHC class
to immunosuppressive therapy. 16 I expression in nonnecrotic fibers at the site of activated CD8
The role of type I interferons (IFN-Is) in the pathogenesis T cells is compatible with cytotoxicity as a prime mechanism of
of DM has been extensively studied. The IFN-Is are a family of myocyte necrosis in IBM and PM. A pivotal study using transgenic