Page 737 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 52 Rheumatoid Arthritis 709

regulate T-cell activation, differentiation, and persistence. Besides N mice indicates that enhanced vasopermeability at sites destined
HLA and PADI4, which influence the molecular determinants to become arthritic is a crucial early event, at least in antibody-
of T-cell “input signals,” these include CD28, CTLA-4, and induced disease. This process is dependent on mast cells
CD2-CD58 (regulation of T-cell costimulation); CD247, PTPN22, and neutrophils and on the release of the vasoactive amines
PRKCQ, TAGAP, and REL (transducer modules of TCR signaling); histamine and serotonin, which contribute to heightened vascular
STAT4 and TNFRSF14 (inducers of lineage-specific cytokine gene permeability.
expression and persistence of memory T cells); and REL, IL2-IL-21, Neovascularization further promotes influx of inflammatory
IL2RA, and IL2RB (regulators of IL-2 gene expression and IL-2R cells. To what extent this is driven by the hypoxic environment
signaling). Notable overlap with these and other allelic variants is not entirely clear, but angiogenic growth factors such as vascular
has been reported in other autoimmune diseases, indicating that endothelial growth factor (VEGF), angiopoietin, Tie-2, and
susceptibility to RA is linked to fundamental perturbations of hypoxia inducible factor (HIF), as well as lymphangiogenic factors
immune tolerance. Variants mapping to cell surface receptors VEGF-C and VEGF-R3, make important contributions. It has
(IL6R, CCR6, CD40, CD5, FCGR2A) and intracellular signaling been proposed that influx of inflammatory lymphocytes and
intermediates (TNFAIP3, TYK2, TRAF1, TRAF6, RASGRP1, BLK) cells of monocytic lineage far outweighs the egress of cells from
are well represented, as are transcription factors linked to cell synovial tissue, likely due to chemokine gradients and engagement
differentiation and effector function (GATA3, IRF5, IRF8, IKZF3, of sphingosine 1 phosphate receptor 1 (S1P1) by CD69 expressed
RBPJ, RUNX1). Perturbations in expression or function of these on activated lymphocytes. This leads to downregulation of S1P1
genes will influence the function of a broad range of immune and retention of cells in tissues. Once in the synovium, egress
cell subsets. may be promoted by specific mediators such as sphingosine 1
phosphate, which actively regulates cellular egress, or blocked
Synovial Pathology through integrin/adhesion molecule interactions, e.g., between
RA targets diarthrodial joints, structures characterized by hyaline antigen-specific T cells and dendritic cells/APC, through TCR-
cartilage lining opposing articulating surfaces and a cavity of dependent “stop” signals, or perhaps through highly selective
viscous synovial fluid lined by synovial membrane lacking a and specific inactivation of chemokines by proteolysis, e.g., stromal
basement membrane, but encased by a fibrous joint capsule. derived factor (SDF)-1 cleavage by cell surface dipeptidyl peptidase
Normal synovial tissue comprises a lining layer, no more than CD26. The abundance of lymphatic vessels in inflamed synovium,
a few cells in depth, of stromal fibroblast-like synoviocytes suggested by expression of podoplanin and CD31 in situ, suggests
(FLSs—also known as type B synoviocytes) and sublining that active lymphangiogenesis exists that may promote efflux of
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macrophages (type A synoviocytes). The synovium serves to line cells and fluid from the synovium. Interestingly, enhanced
noncartilaginous surfaces, and although blood vessels are sparse, proliferation of lymphatic vessels and increased lymphatic
it functions to provide essential nutrients to avascular structures drainage have been documented after tumor necrosis factor
including cartilage, tendons, and bursae. Recent insights from (TNF) blockade. Lymphatic growth factors such as VEGF-C
synovial biopsies of “at-risk” subjects who have both joint pain (which signal through VEGFR-3/Flt-4) have been implicated in
(arthralgia) and serum RA-associated autoantibodies (i.e., systemic promoting this joint-protective effect.
autoimmunity) suggest that the transition from “normal” to
inflamed synovium may occur over a period of only a few weeks Organization of Lymphoid Tertiary Microstructures
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or months. Subtle T-cell infiltration was detected in those Tissue microstructure both dictates and facilitates immune
subjects who went on to develop clinically apparent synovitis. responses in secondary lymphoid organs and mucosa-associated
lymphoreticular tissues (MALTs). These structures have evolved
Increased Vascularity and Cell Migration to coordinate responses to pathogens and to direct lymphocyte
The range of pathology observed in patients with RA perhaps recirculation, and although their role in immune homeostasis
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most convincingly underscores the heterogeneity of the disease. is established, quite how they contribute to pathological states
The earliest changes observed relate to increases in vascularity is less well understood. Thus the inflamed synovium appears to
characterized by vascular congestion and thrombosis with be uniquely suited to supporting distinct patterns of cellular
obliteration of small vessels in association with perivascular infiltrates—noncapsulated, as opposed to capsulated—inducible
inflammatory infiltrates. Hyperplasia of the synovial lining layer lymphoid structures, that could play a role in pathways of cell
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is another typical early finding. These changes are rather non- activation, differentiation, and survival. These include diffuse,
specific and certainly not diagnostic. rather disorganized lymphocytic infiltrates which comprise the
A key checkpoint defining the switch from acute to chronic most common form of synovitis, occurring in ~30% in prospective
persistent inflammation is the sustained activation of microvascular cohort studies; up to 70% has been described in late-stage disease
endothelium, phenotypic changes in the high endothelial venules (at arthroscopy, joint replacement surgery). In 40–50% of patients
(reminiscent of tissue injury), and the concomitant upregulation more organized follicular structures may exist (Fig. 52.2). Based
of adhesion molecules such as intercellular adhesion molecule on immunohistochemical analysis, approximately 25% of these
(ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 (Chapter follicular structures include organized germinal centers in which
11). According to current thinking, the expression of chemoat- there are zones of proliferating B cells with affinity maturation,
tractants derived from synovial stromal cells heralds the rolling, in addition to a distinct T-cell zone. In aggregates lacking germinal
adhesion, and transmigration of mononuclear cells through centers, follicular dendritic cells (DCs) are absent.
endothelial barriers into the synovial membrane. It also contributes A fourth histological pattern, characterized by granulomatous
to the progressive synovial hypertrophy and hyperplasia, sometimes reactions, has been described in a much smaller subset of patients.
with villous-like projections more typical of chronic, established The cellular and molecular determinants of these structures include
inflammation. Intravital imaging of synovial joints of mice injected the homeostatic lymphoid chemokines CXCL13 and the CCR7
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with arthritogenic antibodies derived from the serum of K/B × ligands CCL21 and CCL19, VCAM-1 ICAM-1 LTβR mesenchymal