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The Biochemistry of Rheumatoid Arthritis

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1 The Biochemistry of Rheumatoid Arthritis
PHM 142 Yunfan Zhang, Jingyi Qiu, Jeffrey Lai, Yifan Zhou PHM Fall 2016 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2 Clinical representation of rheumatoid arthritis
Incidence of RA is 0.05% per year and prevalence is 1% of the adult population Woman 3x > man in frequency Onset: 40-50yrs Systemic autoimmune disease Number of actively inflamed/swollen joints Estrogen effect on bones development Onset can also be any age stiffness Ref:

3 Diagnosis Swelling and stiffness of small joints -- refer to specialist within 3 months Raynaud’s phenomenon -- burning feel when exposed to cold environment (possible) Swan-neck deformity of fingers, fixation of joints International used classification: 1987 ACR (American Rheumatism Association) Morning stiffness Arthritis (swelling) Symmetric arthritis Arthritis of Hand joints (wrists) Rheumatoid nodules Rheumatoid factor Radiographic changes If 4/7 are met, the diagnosis can be made Serum rheumatoid factor test (ELISA) Take a venous blood sample Not usually seen in normal individuals AutoAntibody against IgG The more positive, the worse the joint destruction and systemic involvement False positive can occur in 5% healthy individuals

4 Rheumatoid Factors Rheumatoid Factors (RFs)
RFs are autoimmune antibodies produced by the activated B cells (plasma cells) They are directed against the Fc domain on the immunoglobulins G (IgG) They are present in 75% of rheumatoid arthritis patients Anti-Citrullinated Peptide Antibody (ACPA) ACPAs are a special type of RF that recognize citrullinated proteins They are more specific in diagnosing rheumatoid arthritis

5 Pathogenesis Overview
In normal joint, Synovium → synovial membrane and loose connective tissue The lining cells are either Type A (macrophages- like synoviocytes) or Type B (fibroblast-like synoviocytes) In early rheumatoid arthritis, Thickened synovial membrane Formation of blood vessel network in synovium T cells and B cells into synovial membrane and present in synovial fluid with neutrophils Synovial membrane invades cartilage In established rheumatoid arthritis, Synovial membrane becomes the pannus (an inflammatory tissue) Pannus continues invading and destroying cartilage and bone Ref: Ernest H. et al (2001)

6 Rheumatoid Arthritis Pathways
CD4+ T cells activate monocytes, macrophages, synovial fibroblasts, chondrocytes, and osteoclasts Secretion of interleukin-1(IL-1), and interleukin-6 (IL-6), Tumor Necrosis Factor (TNF-α),and matrix metalloproteinases (MMPs) Stimulation of angiogenesis, forming blood vessels in synovium Synovium endothelial cells express adhesion molecules, recruiting inflammatory cells Activated CD4+ T cells induce B cells to produce immunoglobulin, including rheumatoid factor which involves in the immune complexes formation. CD4+ T cells express osteoprotegerin ligands to stimulate osteoclastogenesis Synovial inflammation caused by TNF-α, IL-1 and IL-6. Joint damage caused by MMPs and osteoclastogenesis. Ref: Ernest H. et al (2001)

7 Key Mediators Interleukin-1
Produced mostly by monocytes and macrophages, but also by endothelial cell, B cell, and activated T cells In normal conditions, two mechanisms to regulate interleukin-1 activities: a. Compete for Type I and Type II receptors b. Natural occurring antagonist for receptors Activate leukocytes, endothelial cells and synovial fibroblasts. Induce matrix-enzyme production by chondrocytes Interleukin-6 Produced by T cells, monocytes, macrophages, and synovial fibroblasts Induce the B cell differentiation and maturation Activate T cells, leukocytes and osteoclasts Involve in acute phase response Stimulate the proliferation of synovial fibroblasts Tumor Necrosis Factor (TNF-α) Promote inflammation by inducing inflammatory cytokines and fibroblast Suppress functions of regulatory T-cell Activate resorption of bone and cartilage by osteoclasts TNF-α is the main cytokine involved in the inflammatory response of RA Cartilage and bone destruction is mostly directed by IL1 This cytokine, produced by a variety of cells, mainly activated macrophages and FLS, has both pro- and anti-inflammatory properties. High levels of IL6 have been detected both in the circulation and SF of RA patients Eck, M.J., Sprang, S.R. (1989) Protein Data Bank (2008) Somers, W., Stahl, M., Seehra, J.S. (1997)

8 Inflammatory Mediators
Activated T cells and macrophages produce important inflammatory mediators Tumour necrosis factor alpha (TNF-α) Interleukin-1 (IL-1) IL-6 IL-17 Highlights of IL-6, IL-1 and TNF-α functions IL-6 and TNF-α stimulate macrophage-like synoviocytes to produce metalloproteinases (MMPs) which degrades proteins within synovium → destruction TNF-α binds to TNF-α receptor on the osteoclast precursor cells and stimulate their differentiation. IL-1 induces accumulation of leukocytes in the synovium, causing inflammation and increases collagenases in extracellular space, damaging the cartilage IL-1, 6, 17 and TNF-α induce osteoclast precursor cells to differentiate into osteoclasts

9 Osteoclastogenesis mechanism
Osteoclast is bone resorptive cell Three main regulators RANK, RANKL, OPG RANK is expressed on osteoclast precursor and mature osteoclast RANKL binds to RANK leading to osteoclast maturation and activation Cytokines e.g. IL1 and TNFα induces the expression of RANKL RANKL binds to RANK leading to osteoclasts maturation and activation OPG (osteoprotegerin) is competitive inhibitor of RANKL Osteoclasts are multinucleated bone resorptive cells deriving from the hematopoietic progenitors of the monocytemacrophage lineage. osteoclastic cells appear on the bone surface and resorb the mineral components of bone by an acid extracellular mechanism RANK, RANKL and OPD are three main factors that modulates osteoclasts under control by cytokines, humoral factors and hormones e.g. IL1, IL6 OPG and RANKL are synthesized by stromal cells/osteoblasts RANK is on the cell surface of mature osteoclasts and osteoclastic precursors RANK is expressed on osteoclast precursors and mature osteoclast RANKL is the ligand of RANK Binding of RANKL to RANK stimulates osteoclastic precursors to differentiate into mature osteoclasts Binding also activates of mature osteoclast OPG is a competitive inhibitor of RANKL

10 Chronic Inflammation and Citrullinated Proteins
Initially Initial inflammatory response of the body brings in inflammatory cells (granulocytes, monocytes, T cells, B cells etc) into the synovial joint. Most of these inflammatory cells have PAD (protein arginine deaminases) enzymes that converts the arginine on a protein into another a citrulline. When these cells die, and there is insufficient phagocytosis removal, they release citrullinated proteins and activated-PADs Citrullinated Proteins and MHC Specific MHC (major histocompatibility complex) such as HLA-DR4 recognizes the citrullinated proteins and present them This elicits a citrulline-specific T cell response, which in turn activates B cells Activated B cells differentiate into plasma cells, producing autoantibodies, anti-citrullinated protein antibodies (ACPAs), that can form immune complexes against the joint, causing chronic inflammation

11 Inflammation potentiates osteoclastogenesis
TNF∂, IL1, IL6 are inflammatory cytokines RANKL–RANK signalling pathway is not the only pathway leading to osteoclastogenesis Ref: Steeve K.T. (2004)

12 DKK1 expression modulates bone formation and resorption
Bone formation is uncoupled from bone resorption in RA TNFα is an inducer of DKK1 DKK1 is the major contributor to bone loss in inflammatory tissue, by impairing bone formation DKK1 interferes Wnt signalling Wnt induces OPG expression Bone formation and resorption usually happen simultaneously, but TNF∂ induces DKK1 protein DKK1 directly impairs bone formation and indirectly inhibits OPG expression Figure A: normal tissue, bone formation is balanced with bone resorption Figure B: arthritic tissue, bone resorption is uncontrolled, due to a change DKK1 and wnt signalling Ref: Diarra D. (2007)

13 In summary, Diagnosis: 1987 ACR is the most commonly used criteria
Diagnostic test: ELISA for serum RF or ACPA: positive = systemic involvement Rheumatoid arthritis is a systemic autoimmune disease that is characterized by chronic inflammation of the synovial joint and progressive joint destruction. Activated T cells stimulate inflammatory cells such as macrophages to produce IL-1, IL-6, and TNF-α They lead to increased osteoclasts and MMP production, causing joint inflammation. RFs are autoantibodies targeting IgG; ACPAs are a specific type that target citrullinated proteins. ACPAs are more specific in diagnosing rheumatoid arthritis.

14 References Silman AJ. The 1987 Revised American Rheumatism Association Criteria For Rheumatoid Arthritis. Rheumatology. 1988;27(5):341–3. Aletaha D , Neogi T , Silman AJ , et al: 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62(9): Choy, Ernest H. S., and Gabriel S. Panayi. "Cytokine Pathways and Joint Inflammation in Rheumatoid Arthritis." N Engl J Med (2001): Massachusetts Medical Society. Alam, Javaid, et al. “Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy.” Biomedicine & Pharmacotherapy, vol. 92, 2017, pp. 615–633., doi: /j.biopha Steeve, Kwan Tat, et al. “IL-6, RANKL, TNF-Alpha/IL-1: interrelations in bone resorption pathophysiology.” Cytokine & Growth Factor Reviews, vol. 15, no. 1, 2004, pp. 49–60., doi: /j.cytogfr Diarra, Danielle, et al. “Dickkopf-1 is a master regulator of joint remodeling.” Nature Medicine, vol. 13, no. 2, 2007, pp. 156–163., doi: /nm1538. Karsdal, Morten A., et al. "Biochemical markers of ongoing joint damage in rheumatoid arthritis-current and future applications, limitations and opportunities." Arthritis research & therapy 13.2 (2011): 215. Nijenhuis, Suzanne, et al. "Autoantibodies to citrullinated proteins in rheumatoid arthritis: clinical performance and biochemical aspects of an RA- specific marker." Clinica Chimica Acta (2004): Stanaszek, Walter F., and Bruce C. Carlstedt. "Rheumatoid Arthritis: Pathophysiology." Journal of Pharmacy Practice 12.4 (1999): De Clerck, L. S. "B lymphocytes and humoral immune responses in rheumatoid arthritis." Clinical rheumatology 14.2 (1995): Fournier, Catherine. "Where do T cells stand in rheumatoid arthritis?." Joint Bone Spine 72.6 (2005): Aletaha, Daniel, et al. "2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative." Arthritis & Rheumatology 62.9 (2010): Cantagrel, Alain, et al. "Le TNF-α, l’interleukine-6 et l’interleukine-1: trois cytokines centrales de la polyarthrite rhumatoïde." Revue du Rhumatisme Monographies 84.4 (2017):

15 Karsdal, Morten A., et al. "Biochemical markers of ongoing joint damage in rheumatoid arthritis-current and future applications, limitations and opportunities." Arthritis research & therapy 13.2 (2011): 215. Nijenhuis, Suzanne, et al. "Autoantibodies to citrullinated proteins in rheumatoid arthritis: clinical performance and biochemical aspects of an RA-specific marker." Clinica Chimica Acta (2004): Stanaszek, Walter F., and Bruce C. Carlstedt. "Rheumatoid Arthritis: Pathophysiology." Journal of Pharmacy Practice 12.4 (1999): De Clerck, L. S. "B lymphocytes and humoral immune responses in rheumatoid arthritis." Clinical rheumatology 14.2 (1995): Fournier, Catherine. "Where do T cells stand in rheumatoid arthritis?." Joint Bone Spine 72.6 (2005): Aletaha, Daniel, et al. "2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative." Arthritis & Rheumatology 62.9 (2010): Cantagrel, Alain, et al. "Le TNF-α, l’interleukine-6 et l’interleukine-1: trois cytokines centrales de la polyarthrite rhumatoïde." Revue du Rhumatisme Monographies 84.4 (2017):


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