Page 742 - Clinical Immunology_ Principles and Practice ( PDFDrive )

714 Part SIX Systemic Immune Diseases

Lymphocyte Biology TNF IL-6 IL-1 –rich synovial environment is capable of sup-
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Flow cytometric analysis of dissociated synovial mononuclear porting the differentiation of Th17 cells. Sustained IL-17 expres-
cell cultures indicates that infiltrating T lymphocytes make up sion and stimulation of IL-17R–expressing stromal cells,
approximately 10–35% of cells in inflamed tissue. The ratio of macrophages, chondrocytes, and osteoclast precursors are
CD4 to CD8 T cells seen in peripheral blood is skewed in favor implicated in promoting local tissue responses. These include
of the CD4 subset. Much of the information relating to phenotype induction of chemokines, matrix metalloproteinases, nitric oxide,
and function is derived from detailed analyses of synovial fluid and cyclooxygenase and promotion of osteoclastogenesis, which
and, to a lesser extent, synovial tissue subsets. Similar enrichment are key mechanisms underpinning pathways of cartilage destruc-
of these subsets is commonly detected in PBL. Synovial T cells tion and bone erosion.
express phenotypic markers of antigen experienced, terminally
differentiated T cells with enhanced migratory capacity. Thus Molecular Basis of Persistence
synovial T cells typically carry cell surface markers such as Understanding the molecular basis of persistence is of major
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HLA-DR , LFA-1 , VLA-1 , CXCR3, CD69 , CD45RO , CD45RA , importance in diseases such as RA. It is now well established
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CD45RB , CD29 bright , CD27 , and CD25 . Recent analysis of that enhanced expression of inflammatory cytokines is one of
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citrulline-reactive B cells from RA patients indicate that they the hallmarks of chronic inflammatory diseases such as RA.
display markers of class-switched memory B cells and plasmablasts With few exceptions most cytokines are expressed in inflamed
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(CD20 CD27 IgD ). Analysis of the variable (V) regions of the synovium at mRNA or protein levels. For example, unlike PBL
immunoglobulin heavy and light chains confirm that antigen- from healthy donors, explants of synovial mononuclear cells
specific activation and differentiation of B cells into plasma cells constitutively express IL-1, IL-6, IL-8, granulocyte macrophage–
takes place in draining lymph nodes as well as in the chronically colony-stimulating factor (GM-CSF), and a vast array of che-
inflamed synovial tissue of patients with RA. Likewise, analysis mokines as well as growth factors including FGF, VEGF, and
of the T-cell repertoire indicates that the synovium provides a PDGF (Fig. 52.3). Although antiinflammatory or immunoregula-
niche for supporting expansion of specific T cells, whose clonality tory cytokines, including IL-4, IL-10, IL-11, and TGF-β, as well
is shared between different joints from the same patient, but not as specific inhibitors of IL-1α/β (IL-1Ra) and TNF-α (soluble
substantially with clones from paired blood samples. 32 TNF-R) may also be detected, functional bioassays suggest that
Analysis of synovial T cells reveals that expression of the TCR levels of these naturally occurring inhibitors may be deficient
invariant chain subunits CD3ε and TCRζ is found at lower density in relative terms. Indeed, levels of IL-1Ra and soluble TNF-R
than that found in corresponding peripheral blood T cells, are significantly upregulated in synovial fluid compared with
evidence of prior antigen engagement. While synovial fluid T serum from patients with RA, and yet IL-1 and TNF bioactivity
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cells are also FasL , Bcl2 , Bax bright , favoring a proapoptotic state, persists in spite of this, suggesting that attempts to suppress
it is thought that environmental cues transduced through common cytokine bioactivity are insufficient. The specific activity of
γ chain receptor signaling cytokines such as IL-2, IL-7, and IL-15, cytokine subsets, their networks, and their contribution to RA
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as well as type I interferons, prevent apoptosis of T cells in situ. are illustrated in Fig. 52.3. In many cases, the pathogenic roles
Synovial tissue–derived lymphocytes may be different. Consistent of cytokines have been established in rodent models, either by
with their state of terminal differentiation, a subset of synovial selectively blocking their function (e.g., with specific monoclonal
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T cells are CD28 , while at the same time expressing a range of antibodies or soluble receptor fusion proteins), by gene-targeting
natural killer (NK) cell surface receptors that are thought to approaches, or by transgenesis.
contribute to effector function independently of cognate antigen.
For over a decade it has been known that one of the dominant Immune Regulation
cytokines expressed in synovial T cells from patients with Investigation of regulatory cell subsets and their antiinflam-
established disease is IFN-γ. Somewhat surprisingly, a significant matory properties has perhaps more firmly established the
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proportion of IFN-γ cells also express IL-10. Recent data support concept that failure of the host’s intrinsic mechanisms of
a model in which there exists, during differentiation, a transition immune regulation can underpin autoimmune diseases. Experi-
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from IFN-γ Th1 T cells through an IFN-γ IL-10 double-positive ments in gene-deficient mice (e.g., Foxp3, IL-2, IL-2R, IL-2R
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stage to a single-positive IL-10 stage. This last phase could signaling, STAT5, IL-10, TGF-β) lend support to this concept.
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represent part of the normal lifecycle of an effector T cell, where In RA the data remain less clear. For example, there is in vitro
IL-10 expression promotes the resolution of the adaptive immune evidence for a relative deficiency of constitutive IL-10 expression
response, attenuating the function of DCs. Interestingly data in synovial cell cultures, and yet clinical trials of IL-10 have
indicate that this Th1 lifecycle involving a switch from IFN-γ to been disappointing. These results may reflect the complex role
IL-10 production may be defective in patients with active RA, of these cytokines in disease pathogenesis. The identification
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providing an important mechanism for persistence of effector of defective numbers and/or function of CD4 CD25 bright Tregs
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responses in vivo. Treatment of RA patients with anti-TNF has been suggested by several investigators, but reports are
appears to restore IL-10 production through induction of specific conflicting. 37,38 Some studies have shown clear reductions in
transcription factors. 35 numbers of peripheral blood Tregs in patients with RA, whereas
Emerging evidence, supported by preclinical models, points others have shown no difference; interestingly, Tregs appear
to a role for IL-17 in the pathogenesis of inflammatory arthritis. deficient in cell number in subsets of children with juvenile
Immunohistochemistry of RA synovium indicates that the idiopathic arthritis (JIA) whose disease tends to progress. In
dominant source is CD4 T cells, although γδ T cells, NK cells, synovial joints, the data are more consistent, with many reports
and mast cells also contribute. Flow cytometric analysis reveals showing substantial increases in Treg numbers in synovial tissue
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that the frequency of IL-17 T cells is less than that of IFN-γ T and fluid compared with paired PB. However, some studies
cells and that a subset expresses both IL-17 and IFN-γ. The have reported normal function at a cellular level, whereas others