Question

In autoimmune diseases, part of your immune system works against your own body.In Rheumatoid arthritis, this leads to inflammation of joints due to infiltration of immune cells. How do TNF-α and IL-1 enhance the infiltration of leukocytes into the joint space?

Answer 1

Rheumatic arthritis is an immune mediated inflammatory disease.The synovial layer is normally 1-3 cells thick. In rheumatic arthritis this lining is greatly hypertrophied (8-10 cells thick). Primary cell populations in this layer are fibroblasts and macrophages.In RA, the subintimal area of synovial joint is heavily infiltrated with inflammatory cells, including T and B lymphocytes, macrophages, mast cells, and mononuclear cells that differentiate into multinucleated osteoclasts.

The disease propagates through a T cell activation.Upon engagement of the receptors, a T cell usually becomes activated. When T cell is gets activated, they will in turn proliferate and begin to secrete additional cytokines including IL-2 which furthers their proliferation, and depending on other exposures, cytokines such as IFN-γ, TNF, and IL-4. It is the effect of these T-cell derived cytokines that additional cells become activated.Most of the damage from the disease is affected through effector cells and their products including cytokines and other mediators.  

It is the macrophage that has been seen as one of the master substances causes damage. Macrophages are rich sources and major producers of proinflammatory cytokines including TNF, IL-1, IL-6, IL-8, and GMCSF. These cytokines further stimulate the macrophage, as well as other cells in the microenvironment in a including fibroblasts and osteoclasts.

Inflammatory Mediators in RA

Cytokinins

One of the most important group of mediators in RA are cytokines. The most prominent of these are TNF, IL-1, and IL-6. These cytokines, released in the synovial microenvironment have autocrine (activating the same cell), paracrine (activating nearby cells), and endocrine (acting at distant sites) effects and accounting for many systemic manifestations of disease. There are many shared functions of TNF, IL-1, and IL-6, and these cytokines in turn upregulate the expression of the others. Among the important effects of these cytokines are:

• Induction of cytokine synthesis
• Upregulation of adhesion molecules
• Activation of osteoclasts
• Induction of other inflammatory mediators including prostaglandins, nitric oxide, mtrix metalloproteinases
• Induction of the acute phase response (e.g. C-reactive protein, increased ESR)
• Systemic features (e.g., fatigue, fever, cachexia)
• Activation of B cells (IL-6)