MAF Shalaby Prof. Rheumatology Al Azhar University, Cairo, Egypt.

Transcription

1 MAF Shalaby Prof. Rheumatology Al Azhar University, Cairo, Egypt.

2 AUTOIMMUNE DISEASE RA SLE VASCULITIS RELAPSING POLYCHONDRITIS SS DM/PM SJOGREN S SYNDROME

3 RHEUMATOID ARTHRITIS Classically immune mediated disease have been characterized based on their predominant immunopathologic lesion

4 RA; Definition Is a chronic, inflammatory, systemic disease that produces its most prominent manifestations in the diarthrodial joints. Persistent, progressive synovitis and joint damage develops in peripheral joints causing severe disability in young people

5 RA; Etiology The initial events inciting the inflammatory response is unknown. An infectious etiology of RA has been vigorously pursued without yielding convincing evidence. Genetic & environmental factors control the progression, extent and pattern of the inflammatory response and are thereby responsible for the heterogenous clinical features

6 Pathogenesis Genetic factors Environmental factors Immune dysregulation Autoimmune disease

7 In RA autoimmune disease is mediated by innate and adaptive immunity, attacking particular tissue, the synovial membrane

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9 Pro-Inflammatory IL-1 TNF-α IL-6 GM-CSF IL-8 References Feldmann et al. (1993) Progress in Growth Factor Research 4, Feldmann et al. (1996) Annu. Rev. Immunol. 14, Anti-Inflammatory IL-1Ra p55-stnf-ri p75-stnf-rii IL-10 TGF-β

10 The target antigenic structure in RA is Synovial membrane

11 Cellular components include mainly the synoviocytes: Type A (macrophage like) and Type B ( fibroblastic like)

12 Type A & B are the primary source of cytokines in RA including : IL 1, IL 6, IL 8, IL 12, IL 15, IL 16, IL 18, IL 32 and TNF alpha, granulocyte macrohage colony stimulating factors

13 IL=interleukin; TNF=tumour necrosis factor; PMN=polymorphonuclear leucocyte Adapted from Voulgari PV. Expert Opin Emerging Drugs 2008;13:

14 In RA excess TNF is generated Macrophage This stimulates an inflammatory response that results in cartilage destruction TNF Inflammation T Cell

15 TNF α TNF α Tumour Necrosis Factor- (TNF- ) Identified in 1970s by Lloyd Old et al., as a serum factor that caused necrosis of some murine tumours. In the 1980s, studies into the role of TNF intensified TNF is a multifunctional proinflammatory mediator Induction of further cytokine production Activation or expression of adhesion molecules Growth stimulation TNF action needs to be carefully controlled by the body Figure: TNF 22 May 10 Medhat Shalaby 15

16 Cytokine in RA Stage of disease Cytokine involved Initiation of synovitis Synovial inflammation IL-1,6, TNF-α, IFNα,IFNβ Effector cell function IFNу,TGFβ,IL-4,5,10,12,15,18. Perpetuation of synovitis IFNу,TNF-α,IL-1,4,12,15,18, IL-7, and IL-17. Chronic synovitis Angiogenesis VEGF,FGF,IL-18,HGF,Ang-1, CXCL12, TNF-α, IFNα,β Cell migration MIP-1α,MIP-1βMCP-1,IL-8,ENA-78 Adhesion molecule expression on EC IL-1, TNF-α & IFNу Induction of MMP production Direct IL-1 & TNF- α Indirect IL-17,IL-18 and MIF Medhat Shalaby 16

17 RA; TNF α In RA joint, TNF α is predominantly produced by cells of macrophage lineage. While it originate as a surface molecule, Its predominant action follows its release as free molecule. This release involve the action of TNF α converting enzyme. Upon binding to the receptor, it signals transcription of molecules which are inflammatory in nature. 22 May 10 Medhat Shalaby 17

18 Pathogenesis of Joint Destruction Macrophages Proinflammatory cytokines Chemokines Increased Inflammation Endothelium Adhesion molecules Increased Cell Infiltration TNF Synoviocytes Metalloproteinase synthesis Articular Cartilage Degradation Osteoclast progenitors RANKL expression Bone Erosions 22 May 10 Medhat Shalaby 18

19 Activation Activated T-cell Activated Macrophage Fibroblast Activated B-cell TNF IL 6 MMPs Autoantibodies, e.g. RF Inflammation & Joint Destruction

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21 APC MHC TCR T-cell CD80/86 CD28 Abatacept CD80/86 (B7 1 or B7 2)

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23 B Lymphocyte depletion therapy in RA Although a great interest was made as regards to the role of T lymphocytes in RA, Stastny in 1975, reported the link of RA to HLA DR4, which mediates interaction with T cells, although it is carried on B cells

24 B Lymphocyte depletion therapy with rituximab in RA However, by the 1990s, the importance of T cells seemed less clear and the local dominance of T cells was found to be general to inflammation And synovial hyperplasia proved to be largely intimal macrophage activation, which preceded T cell influx and was not of the pattern expected from T cells, Evidence of autoreactive T cells was unconvincing

25 B Lymphocyte depletion therapy with rituximab in RA What remained unusual about RA synovium : It was noticed the presence of germinal centers (dividing B lymphocytes) and its ability to survive

26 B Lymphocyte depletion therapy with rituximab in RA B cell survival depends on fibroblastic cells as well as signals from immune complex and T cells, so, the roles of autoantibodies in the mediation of inflammation and the underlying immune response in RA was readdressed

27 B Lymphocyte depletion therapy with rituximab in RA B cell survival depends on fibroblastic cells as well as signals from immune complex and T cells, so, the roles of autoantibodies in the mediation of inflammation and the underlying immune response in RA was readdressed

28 B Lymphocyte depletion therapy with rituximab in RA Abrahams (2002) studies indicated that both articular and extraarticular features of RA were compatible with the effects circulating complexes generating TNF specifically through IgG Fc receptor with local amplification mechanisms in the synovial environment and bone marrow. The ability of complex forming antibodies to generate arthritis in this way has been supported by Matsumoto, 2002

29 B Lymphocyte depletion therapy with rituximab in RA Removing of B cells would interrupt interaction with these T cells blockage antigen presentation interrupting antibody production Also, the concept that RA driven by selfperpetuating B cells assisted by blameless T cells has the great attraction that it might be amenable to the induction of long time remission, if relevant B cells clones could be ablated

30 The role of B lymphocyte in RA is

31 Role of B cells in RA: (1) antigen presentation leading to T cell activation B cells are highly efficient antigen presenting cells (APCs) Antigen presentation leads to T cell activation Activated T cells produce cytokines that activate macrophages to produce pro inflammatory cytokines Results in inflammation and joint destruction (Lanzavecchia, 1990; Lund et al, 2005; O Neill et al, 2005; Roosnek & Lanzavecchia, 1991; Silverman & Carson, 2003)

32 Role of B cells in RA: (2) autoantibody production Autoreactive B cells produce autoantibodies, including Rheumatoid Factor (RF) Formation of RF immune complexes in the synovium leads to production of pro inflammatory cytokines through: Complement activation Macrophage activation (Abrahams et al, 2000; Silverman & Carson, 2003; Sutton et al, 2000)

33 Role of B cells in RA: (3) cytokine production Activated B cells produce cytokines (e.g. TNF α, interleukin [IL] 6, lymphotoxin α) which are known to promote inflammation and joint damage in RA Lymphotoxin promotes the formation of new lymphoid structures in the synovium, thus helping to perpetuate autoimmune reactions (Duddy et al, 2004; Lund et al, 2005)

34 B Cell Roles In RA Secretion of Cytokines Antigen Presentation & T cell activation Autoantibody production; Self perpetuation Roche core set IL -6 I L - 6 B cell TN F- IL- 10 Macroph age TN F- IL- 10 Dendriti c cell B cell TNF - Inflammatory damage Cartilage loss T cell B cell R F Fix compleme nt Plas ma cell R F R F R F R F Inflame d synovi a

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