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20 - 22 September 2012, Opatija, Croatia
THE IMMUNOPATHOGENESIS OF RHEUMATOID ARTHRITIS
Asja Stipić Marković, Department of Clinical Immunology, Pulmology and Rheumatology, Clinic for Internal
Medicine, Medical School University of Zagreb, University Hospital Sveti Duh, Zagreb, Croatia
Rheumatoid arthritis (RA) is an autoimmune disease in which the synovial tissue transforms into a destructive pannus
leading to erosions and lost of joint functions.Why the systemic loss of immune tolerance is linked to a localized onset
of inflammation in the joint is still unclear. Distinct disease mechanisms are at play in RA pathology. The heterogeneity
is consequence of the multifactorial nature of the disease and specific combination of environmental factors with polygenetic
background. Environmental factors have a major role in developing RA as it is shown in genetically identical
twins.
Factors that facilitate autoimmunity
Proliferation of synovial, oligoclonal, antigen-specific, autoreactive CD4+T cells is key event in RA pathogenesis. Etiological
antigens are selfproteins, formed, for example, after alterations in citrullination of mucosal proteins upon influence
of environmental stressors on barrier tissues (ie, smoking on pulmonary tissue). Several citrullinated self-proteins with
neoepitopes are recognized, but most of the patients with seropositive RA have antibodies for citrullinated α-enolase
(anticyclic citrullinated peptide antibodies).That is accompanied with strong association with smoking and common
aminoacid motif (QKRAA) in HLA-DRB1*04,PTPN22 genotype. Other citrullinated self-proteins are: keratin, fibrinogen,
collagen, vimetin and fibronectin, all showing similar interactions with smoking and same risk alleles. Altered citrullination
of mucosal proteins also could be induced in periodontal disease by bacteria Porphyromonas gingivalis, microorganism
expressing PADI4 (peptidyl arginine deiminase type IV).
Other important causes facilitating autoimmunity in articular compartment are various microorganisms (bacteria, viruses)
and their products.They induce specific T response which crossreact with human antigens (mechanism named
molecular mimicry). Another mechanism in RA pathophysiology is autoantibody production against Fc portion of human
immunoglobulin, in the course of infection in which immune complexes are produced.
Furthermore, an new mechanism in autoantibody-positive RA is mediated by gastrointestinal microbiome.
Perpetuation of synovial inflammation
Specific,autoreactive CD4+Th-1 cells, which infiltrate synovial tissue, migrate from lymph nodes where they got information
about autoantigen from dendritic cells (DC). However, specific antigen induce proliferation of other T cell subsets:
Th-17 (producing IL-17A,IL-17F,TNF-α) and T regulatory cells (Tregs), Foxp3 positive (important arm of the immune
system responsible for suppression of the response). DCs, another key players in immune response, are patrolling and
scanning peripheral tissue. They take antigens and transfer it through lymphatic system to local lymph nodes. In the
lymph nodes, DCs present antigen to naive T cells and act somehow altering the morphology of subcapsular sinus floor
what divert the homing route of T lymphocites, which trafficking through
efferent lymph vessel infiltrate synovial membrane. In synovium, there is no balance (T cell homeostasis) between
Th-17 and T regs, because macrophages and DC provide a milieu supporting Th-17 differentiation. Parallely, Tregs are
blocked. Cytokines, macrophage-derived (TGF-β,IL-1β,IL-6,IL-21,IL-23,TNF-α), DC-derived (TGF-β,IL-12,IL-15,IL-18,IL-23,),
Th-17 derived (IL-17A, IL-17F,IL-21,IL-22,TNF-α), and IFN-γ, create hierarchy with TNF-α at its peak. TNF-α is essential for
persistence of the joint inflammation. Exclusive cytokine expression patterns are characteristic for distinct autoimmune
disease. IFNs, early mediators of the innate immune response, affect initiation and amplification of autoimmunity in
SLE. However, in a subgroup of patients with RA, IFN type I molecular signature is upregulated, but it could mean that
this cytokine profile is patient-specific rather than a disease-specific phenomenon. Further characteristic of this subgroup
of patients is increased activitiy of complement and coagulation cascades. IFN/STAT-1 activation in RA synovium
could be an attempt to limit inflammation. Upregulation of IFN-induced genes has been observed in peripheral blood
cells of patients with other auatoimmune disease as a common hallmark in chronic autoimmunity. Besides T cells, the
synovium in rheumatoid arthritis contains B cells, plasma cells, plasmablasts, macrophages and plasmacytoid dendritic
cells. B cells, localized in T-cell-B-cell aggregates, form humoral part of adaptive autoimmunity.A pathogenic role of B
cells is confirmed by the efficacy of rituximab. The autoantibody level is variably altered after rituximab therapy which,
with the fact that plasma cells are not targeted, suggests that these cells are not only antibody producers but have role
in autoantigen presentation and cytokine production. Plasmacytoid DCs in synovium continue presentation and T cells
activation. Macrophages,(M1 phenotype), represent innate immunity arm along with mast cells (produce vasoactive
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