Rheumatoid Arthritis Flashcards
RA is a complex dz involving numerous cell types, name them.
Macrophages, T cells, B cells, fibroblasts, chondrocytes, neutrophils, mast cells, and dendritic cells
Several genes are implicated in the susceptibility to RA and severity of dz including what?
Class II major histocompatibility complex genes, PTPN22, and peptidylarginine deiminases
What can be present for many years before the onset of clinical arthritis?
Evidence of AI, including high serum levels of auto antibodies such as RH factor and anticitrullinated protein antibodies
T/F: Adaptive and innate immune responses in the synovium have been implicated in the pathogenesis of RA.
True
Cytokine networks involving TNF, IL-6, and many other factors participate in disease perpetuation, what does this mean?
They can be targets for therapeutic agents
Bone and cartilage destruction are primarily mediated by?
Osteoclasts and fibroblast-like synoviocytes, respectively
Do genes play a key role in susceptibility to RA as well as dz severity?
Yup, you betcha
Class II major histiocompatibility genes, especially ones containing a specific 5 AA seqyence in the hypervariable region of what are the most prominent genetic association for RA?
HLA-DR4
What are the two new defined genetic associations that suggest that the associations in RA are complex and involve many genes?
PTPNN22 and PAD14
Is there an etiologic link between viruses, retroviruses, bacteria, and mycoplasma with RA?
No but they have been associated (not linked)
Is a single specific RA pathogen?
Probs not
Repeated inflammatory stress, especially through specialized receptors that recognize common molecules produced by pathogens, in a genetically susceptible individual might contribute to what?
Breakdown of tolerance and subsequent autoimmunity
Can evidence of AI be present in RA many years before the onset of clinical RA
Yes
Autoantibodies such as RFs and anticitrullinated protein ABs are commonly associated with?
RA
Autoantibodies in RA can do what?
Recognize joint antigens such as T II collagen or systemic antigens such as glucose phosphate isomerase
Autoantibodies can potentially contribute to synovial inflammation through several mechanisms, including what?
Local activation of complement
The synovium in RA is marked by what? what cells will be there?
Intimal lining hyperplasia and sublining infiltration with mononuclear cells especially CD4+ T cells, macrophages, and B cells
What does intimal lining FLS display?
Unusually aggressive features
Macrophages in the intimal lining are what?
Highly activated and produce many cytokines
Lymphocytes can do what two things in RA?
Diffusely infiltrate the subliming or form lymphoid aggregates with germinal centers
Sublining CD4+ T cells may display what?
The memory cell pheno type
Synovial B cells and plasma cells in RA exhibit evidence of what?
Antigen driven maturation and antibody protection
Dendritic cells can potentially present antigens to T cells, where does this happen?
Synovial germinal centers
Mast cells produce what?
Small molecule mediators of inflammation
Neutrophils are rarely present in RA synovium but can be abundant where?
Synovial effusions
RA synovial effusions contain what?
Neutrophils and mononuclear cells
Immune complexes that contain autoantibodies such as and what can they do?
RFs or anticitrullinated protein antibodies that can fix complement, leading to the generation of chemoattractants
Small molecule mediators of inflammation such as what are present in RA synovial fluid?
Prostaglandins and leukotrienes
What has been implicated in the pathogenesis of RA?
Several subsets of T cells
High or low levels of T cell cytokines are present in RA synovium?
Low
Name a few T cell cytokines that are present in RA synovium and how do they get there?
IFN gamma, IL17; produced by TH1 and TH17 cells
Regulatory T cell function might be low in RA synovium, what does this mean?
uncontrolled activation of other T cells
Contribution of T cells to synovial inflammation can be through what?
Antigen-independent mechanisms such as direct cell-cell contact with macrophages
Macrophage and fibroblast cytokines are abundant where in RA?
RA synovium
Cytokine networks include what proinflammatory cytokines that can help perpetuate synovial inflammation?
IL1, TNF, IL6, IL15, IL18, GMCSF, and IL33
Chemokines that recruit inflammatory cells into the joint are commonly produced by what?
Macrophages and fibroblasts
Antiinflammatory cytokines such as IL-1Ra and IL10 are produced where, what is the problem with this?
Produced in rheumatoid synovium, amounts may be insufficient to suppress proinflammatory cytokine function or production
Complex intracellular signaling mechanisms regulate what in RA synovium?
Cytokine production and actions
What are the pathways that may be therapeutic targets for RA tx?
NFkB, MAP kinase, AP1, JAK, Syk + more
What reactive species can contribute to the toxic environment that damages cells and increases inflammation in RA?
Reactive oxygen and nitrogen
Deficiencies in what cell processes can contribute to the accumulation of cells in rheumatoid synovium?
Cell death and apoptosis
Abnormalities of what key regulatory gene can enhance accumulation of cells in a joint?
p53 TSG
Inducing apoptosis can potentially do what?
Suppress synovial inflammation and joint destruction
Angiogenesis is what kind of process in RA that does what?
Dynamic process that provides nutrients to expanding synovium
Angiogenic factors such as IL8, FGF, and VEGF does what?
Can enhance blood vessel proliferation in the synovium
Microvascular endothelium in the synovium expresses what?
Adhesion molecules that guide circulating cells into the joint under the influence of chemoattractants
Cartilage degradation and bone destruction in RA are mediated by what? (simple answer)
Distinct mechanisms and cell types
Several classes of proteases including what are produced by intimal lining cells in RA, especially FLS
MMPs, Serine proteases, cathepsins, and aggrecanases
What can invade and damage the cartilage in RA?
Synovial lining cells, especially FLS
Bone destruction is mediated by osteoclasts that are activated under the influence of what?
RANKL and other cytokines produced by RA synovium
