Page 775 - Clinical Immunology_ Principles and Practice ( PDFDrive )

746 Part SIX Systemic Immune Diseases

where they secrete proinflammatory and profibrotic mediators, is a fundamental pathogenetic alteration underlying fibrosis
including transforming growth factor-β (TGF-β), cytokines, and in SSc.
chemokines. These molecules can activate fibroblasts as well as Fibroblasts explanted from lesional SSc tissues continue to
endothelial cells, recruit further inflammatory cells, and initiate display an abnormal phenotype when propagated ex vivo, with
the fibrotic response. Because TGF-β, in particular, can induce enhanced rate of synthesis of collagen and other ECM molecules,
its own production as well as that of other profibrotic growth expression of α smooth muscle actin and cell surface adhesion
factors, such as connective tissue growth factor (CTGF) and molecules, and spontaneous generation of ROS through the
platelet-derived growth factor (PDGF), an initial cytokine burst nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
could result in amplified cytokine production and sustained complex pathway as well as from mitochondrial respiration.
autocrine and paracrine signaling. Additionally, as the extracellular Additionally, explanted SSc fibroblasts show hallmarks of
matrix (ECM) undergoes remodeling, it loses compliance and senescence. The persistent activated scleroderma phenotype is
increases its stiffness, which, in itself, triggers biomechanical likely to reflect epigenetic modifications caused by chromatin
activation of resident stromal cells, in part by liberating and remodeling, DNA methylation, or altered expression of noncoding
activating latent matrix-bound latent TGF-β. Alterations in regulatory RNAs, including microRNA and long noncoding
the relative proportions and function of regulatory T cells RNAs.
(Tregs) and T-helper 17 (Th17) cells, and innate lymphoid cells TGF-β is a pleiotropic cytokine and a pivotal regulator of
(ILCs), have been documented and may play important roles tissue repair and fibrosis (Chapter 9). Multiple abnormalities in
in pathogenesis. TGF-β pathways have been identified in SSc, indicating a key
Virtually all patients with SSc have antinuclear and other role in pathogenesis. Lesional fibroblasts secrete TGF-β and
autoantibodies in serum. These autoantibodies are generally exhibit TGF-β hyperresponsiveness caused by elevated expression
highly specific for SSc and tend to be mutually exclusive (see of TGF-β surface receptors, and integrin-mediated activation of
below). Moreover, SSc-specific autoantibodies show strong latent TGF-β. Furthermore, SSc fibroblasts show evidence of
association with individual disease subphenotypes, and their constitutive phosphorylation of Smad transcription factors and
titers can fluctuate with disease activity. Multiple mechanisms other key intracellular signaling pathways that, together with
have been proposed to account for autoantibody generation in deficiencies in endogenous antifibrotic mechanisms, might
10
SSc. In patients with SSc, B cells overexpress the surface receptor contribute to the persistence and progression of fibrosis.
8
CD19, resulting in hyperresponsives. Additionally, specific Therapies that selectively or nonselectively block growth factor
self antigens undergo posttranslational modifications, such as signaling and abrogate fibrogenic pathways triggered by growth
proteolytic cleavage, increased expression or misdirected subcel- factors, chemokines, PDGF, Wnt, and CTGF are currently under
lular localization that create neoepitopes recognized as nonself development.
by the immune system. Although SSc-associated autoantibodies
have well-established clinical utility as diagnostic and prognostic CLINICAL FEATURES
markers, their direct role in SSc-associated tissue damage remains
9
uncertain. Recent studies have indicated that patients with SSc Overview
also commonly have functional antibodies that are directed against The term “scleroderma” is used to describe both systemic scle-
fibroblasts and endothelial cells; the PDGF receptor; vascular rosis and localized scleroderma, a disorder generally limited to
receptors, such as endothelin-1 and angiotensin II receptors; skin. SSc is highly variable in its clinical expression and thus
and matrix metalloproteinases (MMPs). represents a broad spectrum of disease. The disease process
can target skin, blood vessels, and the lungs, heart, GI tract,
Fibrosis: Cellular and Molecular Components kidneys, and musculoskeletal system, subsets of patients exist
Interstitial and vascular fibrosis, the hallmarks of SSc, is character- with unique clinical features and distinct clinical outcomes.
ized by replacement of normal tissue architecture with dense Raynaud phenomenon is virtually universal in SSc, suggesting
and noncompliant connective tissue. Although isolated organ that perturbation of the terminal arteries of the circulation is
fibrosis is a generalized and frequent sequel to any form of chronic a fundamental process that links the different subsets of the
or recurrent tissue injury, fibrosis concurrently affecting multiple disease. Thickening of the skin distinguishes SSc from other
organs is unique to SSc. Fibroblasts and related stromal cells of rheumatic diseases (Table 55.3); scleroderma (hard skin) is the
mesenchymal origin are key effector cells responsible for the most specific and prominent physical finding. Patients vary in
development of fibrosis. In response to extracellular signals, such the expression of the skin changes and are classified into two
as TGF-β, CTGF, PDGF, Wnt, chemokines, endothelin-1, lyso- major subsets defined by the degree of clinically involved skin.
phosphatidic acid (LPA1), reactive oxygen species (ROS), and In the diffuse skin variant called diffuse cutaneous SSc (dcSSc),
hypoxia, as well as integrin-mediated biomechanical signals from fibrosis of skin is widespread, and the illness is more violent
a stiff ECM, these cells proliferate; migrate; produce a broad in expression, with rapid onset and increased risk of serious
array of matrix macromolecules; adhere to and remodel con- and internal organ disease. In contrast, the limited skin variant
nective tissue; secrete growth factors, cytokines, and chemokines called limited cutaneous SSc (lcSSc) presents with long-standing
and express surface receptors for them; and undergo transdif- Raynaud phenomenon, skin fibrosis limited to the fingers or
ferentiation into apoptosis-resistant contractile myofibroblasts. distal limbs, and a generally indolent disease course. Limited SSc
Under physiological conditions, the fibroblast repair program is less likely to be associated with organ failure or shortened life
is tightly regulated and self-limiting to enable tissue regeneration, expectancy. Predictors of elevated mortality rates among patients
whereas under pathological conditions, fibroblast activation is with SSc include diffuse skin disease with a rapid rate of skin
sustained and amplified, resulting in exaggerated matrix deposi- progression and internal organ involvement (especially the lungs
tion and disruption of tissue architecture. Uncontrolled activation or the kidneys, resulting in an SRC), male gender, black race,
of fibroblasts, combined with their relative resistance to apoptosis, and later age of disease onset. 11,12