Page 738 - Clinical Immunology_ Principles and Practice ( PDFDrive )

710 Part SIX Systemic Immune Diseases

further evidence of disease heterogeneity. This strategy assumes
that each disease phenotype should be represented in gene
expression signatures of multiple genes. Remarkable variation
in gene expression signatures has been observed, and initial
reports seemed to suggest that these signatures could be divided
23
broadly into two groups. The first is characterized by upregula-
tion of immune response and inflammatory genes; these tissues
are enriched for MHC and immunoglobulin gene products. In
some tissues this signature may resemble an antiviral response
consistent with prior infectious insult and, more specifically, a
signal transducer and activator of transcription 1 (STAT1)–depen-
dent gene signature (promoting protective or proinflammatory
23
effects). This has also been observed in peripheral blood
lymphocytes (PBL) from patients. The second group is more
indicative of tissue remodeling, more reminiscent of that seen
in osteoarthritis. Most interestingly, distinct fibroblast-like
synoviocytes (FLSs), genotypes, and phenotypes match the type
FIG 52.2 Lymphoid Follicular Structures in Inflamed Rheu- of RA tissue from which they derived. For example, FLS signatures
matoid Arthritis Synovial Tissue. A characteristic hematoxylin from high-intensity inflammatory tissue resemble signatures of
and eosin–stained tissue section from a patient with active RA transforming growth factor (TGF)-β/activin-A–induced expres-
showing a large follicular-like structure (original magnification sion profiles in myofibroblasts, whereas growth factors such as
×100). This section is also stained with monoclonal antibodies insulin-like growth factor 2 and insulin-like growth factor binding
to CD3ε, followed by a three-step immunoperoxidase staining protein 5 characterize FLSs from tissues with low-intensity
+
protocol (CD3 T cells stained dark red). (Courtesy Tak, et al. inflammation. These data support the notion of RA heterogeneity
Arthritis Rheum 1996;39:1077, with permission from J. Wiley being reflected in FLSs as a stable, if not transformed, trait. They
and Sons, Inc.) would also be consistent with a model in which there is a transi-
tion from an antigen-driven phase of disease to a relatively
antigen-independent process, characterized by autonomous,
+
+
−
organizer cells, and hematopoietic-derived CD3 CD4 IL-7R R invasive, and aggressive FLSs and manifested as persistence of
+
ANK lymphoid inducer cells. Lymphoid tissue inducer cells the inflammatory state. Subsequent disease flares might arise as
produce LT-β, which is required for high endothelial venule dif- a consequence of repeated exposure of lymphocytes to antigen
ferentiation, amplification of chemokine expression, and develop- after infectious or mechanical insult.
ment of the stromal architecture. The mechanisms that sustain Gene expression signatures have clinical utility. For example,
these lymphoid structures over time are not fully characterized a type I IFN signature in peripheral blood cells negatively predicts
but could involve persistence of antigen and augmented antigen- the response to B-cell–depleting therapy rituximab, but its
presenting function through the differentiation of follicular DCs, detection in neutrophils predicts a good response to
localized and autonomous expression of cytokines and growth anti-tumor necrosis factor (TNF) therapy. Enrichment of TNF-
factors, chemokine gradients favoring cellular interactions, and induced genes in early RA synovial biopsies is associated with
dysregulation of leukocyte homing and/or egress. Documentation higher disease activity and predicts poor response to first-line
of class-switch recombination and somatic mutation of immu- therapy, regardless of the drug therapy, while enrichment of
noglobulin genes in situ is further evidence of active adaptive synovial myeloid, but not lymphoid, gene expression signatures
immunity within synovial lymphoid follicles, and suggests that at baseline is associated with good clinical responses to TNF
supporting in situ production of pathogenic antibodies is of blockade at 16 weeks.
considerable pathobiological importance. Aberrant expression of microRNA (miRNA) in cells or plasma
24
Cross-sectional studies have indicated that, from a clinical of patients with RA has been widely reported, with circulating
standpoint, these distinct patterns reflect not only the heterogene- miRNA, such as miR-223 and MiR-16, correlating with disease
ity of the disease but also a spectrum of disease severity, with activity. This is of particular relevance because of the unique
each pattern requiring a distinct targeted approach to therapy. role for miRNA in regulating expression of multiple gene sets.
More recent prospective studies, however, seem to indicate that A recent report indicates that baseline expression of miR-125b
the presence of lymphoid aggregates is one aspect of a rather in peripheral blood mononuclear cells of drug-naïve early RA
dynamic process. Although the lymphoid aggregates are associated patients predicts response to therapy at 3 months.
with the degree of synovial tissue cellularity and vascularity, they
are neither diagnostic for RA nor predictive of radiographic Immunobiology of RA
outcome such as joint erosions. The dynamic nature of these Initiation of the Immune Response
lymphoid structures is supported by their dissolution after therapy Synovial fibroblasts are exquisitely sensitive to inflammatory
with rituximab (anti-CD20) and TNF inhibitors, in the latter cytokines such as IL-1, TNF-α, and IL-6. Accumulating evidence
case enhancing lymphatic flow. indicates that FLSs also express a range of toll-like receptors
(TLRs) that can respond to exogenous, pathogen-associated
Gene Expression Signatures molecular patterns (PAMPs) or indeed a growing range of self-
Gene array technology has permitted unbiased and systematic tissue proteins, some of which could be considered damage
analysis of synovial tissue at the whole-genome level and, as associated molecular patterns (DAMPS). Endogenous ligands
with genetic, serological, and histological analysis, has provided especially relevant to inflammatory arthritis include heat shock