Lecture 13 - biologics in arthropathies Flashcards
what is involved in the susceptibility of rheumatoid arthritis?
1) genetic susceptibility,
2) a primary exogenous arthritogen,
3) an autoimmune reaction to joint components,
4) expression/production of mediators of joint damage.
describe the immunopathogensis of ehramotid arthritis
Initial Trigger: The process starts with an antigen, possibly a microbe, which activates CD4+ T-cells.
Activation of Immune Cells: These T-cells then produce cytokines that activate other immune cells, including B-cells and macrophages.
B-cell Activation: Activated B-cells produce rheumatoid factor, leading to the formation and deposition of immune complexes in joints.
Macrophage Activation: Macrophages release tumor necrosis factor (TNF) and other cytokines, which stimulate fibroblasts, chondrocytes, and synovial cells.
Tissue Destruction: The stimulated cells release destructive enzymes (like collagenase, stromelysin, and elastase) and inflammatory mediators (like PGE2), which contribute to joint injury and the formation of pannus (inflammatory exudate).
Endothelial Activation: TNF also activates endothelial cells, leading to the expression of adhesion molecules.
Inflammatory Infiltration: The expression of adhesion molecules facilitates the accumulation of inflammatory cells in the joint area.
Chronic Inflammation and Damage: Chronic inflammation leads to the destruction of bone and cartilage, and can result in fibrosis and ankylosis (joint stiffness).
what are clinical features of early rheumatoid arthritis?
Symptoms
- Joint pain/swelling
- Stiffness following inactivity
- Systemic ‘flu-like’ features
Signs
- Synovitis
- Joint swelling/tenderness
- Extra-articular features
describe TNFA
tnfa is a critical mediator
TNFa is a multifunctional pro-inflammatory mediator
a. Induction of further cytokine production
b. Activation or expression of adhesion molecules
c. Growth stimulation
TNFa action needs to be carefully controlled by
the body
Mediates key roles in;
acute and chronic inflammation
anti-tumour responses
infection
Overproduction of TNF is associated with a wide range of pathological conditions.
Effort to find ways to down-regulate production or inhibit its effects.
what are the 2 forms of TNFa?
- membrane bound TNFa (26Da)
- Soluble TNFa (17kDa)
TACE is a TNFa converting enzyme
describe the two tnfa receptors.
TNFR1 and TNFR2 share structural similarity in extracellular domain. they have intracellular differences and different signalling pathway.
decried TNFR1
55-60 kDa TNF receptor type 1 (TNFR1) constitutively expressed in nearly all tissue
Capable of inducing cell death through a ‘death domain’ of the intracellular portion of the receptor
Binds TNF, is internalised, recruits TRADD (a death domain-containing signal transduction adapter molecule), which leads to DNA degradation and cell death (apoptosis).
describe TNFR2
75-80 kDa protein
No death domain – cannot induce apoptosis
Recruitment of TRAF2 leads to activation of the NFB pathway, production of cytokines, inhibitors of apoptosis
Differential expression of TNFR1 and TNFR2
what are TNFa signal transduction and effector mechanisms?
TNFα can signal through two different receptors, TNFR-1 and TNFR-2, which are present on the cell surface.
With TNFR2 the signalling pathway recruits TRAF2 which can allow signalling to activate the NFκB pathway.
NFκB is typically held inactive in the cytoplasm by IκB but upon activation translocates into the nucleus.
Once in the nucleus, NFκB can induce the transcription of various genes.
TNFα signaling through TNFR-1 can also lead to apoptosis.
what are the transcription products of TNFa signalling?
pro-inflammatory
TNFa
IL-1B
Upregulation of adhesion molecules (ICAM-1, VCAM-1)
Cytokines that further enhance the immune response (e.g. Il-6)
Activators of inflammatory pathways (arachidonic acid metabolites, superoxides and nitric oxide)
describe the different lines of therapy for the treatment of rheamotid arthritis
diet
NSAIDS
steroids
immunosuppressive drugs or DMARDS
biologics
what do biologics do in the immune system to help combat rheumatoid arthritis
biologics are used for the treatment of patients with rheumatoid arthritis who have been unresponsive with the treatment of DMARDS. biologics inhibit the TNFa inflammotry mediators. main anti-TNFa biologics are:
infliximab. it is a chimeric mAb. IV delivery
etancercept. it is a TNFa mimetic, not mAb, but has Ab Fc structural component. it is injected at home
adalimumab. human recombinant protein, injected at home.
golimumab. humanised mAb. injected at home.
what are biologics ie how t they work?
Biologics are antibody-like molecules. Antibodies are produced by B-lymphocytes as part of the body’s immune response to fight infections. antibodies are made in autoimmuen disease and atatck self proteins as if they are foreign or non self. antibodies are made in autoimmuen diseases and atatck self proteisn as it they are foreign or non self. Antibody producing cells are short lived
describe the structure of an antibody
variable region at top, content region at bottom half.
three globular regions of the protein form a Y shape
the two antigen binding sites are at the tips of the arms
composed two protein chains; heavy chains and light chains
what is infliximab ?
infliximab is a recombinant antibody produced and secreted from mouse myeloma cells. It is a chimeric antibody 25% mouse derived and 75% human protein. It is generated and manufactured under sterile conditions.
The antibody is manufactured by continuous perfusion cell culture. The collected harvests are clarified by filtration before further purification.
