SpeakersLawrence Steinman, M.D.
"The Long and Winding Road to Antigen Specific Therapy of Autoimmunity"
Samia Khoury, M.D.
"Immune Intervention in MS From Bench to Bedside"
The animal model for the study of MS is experimental autoimmune encephalomyelitis (EAE). EAE can be induced in a number of species by immunization with myelin antigen and adjuvant. Studies in EAE have helped our understanding of the immune response in multiple sclerosis and many therapies available to patients are first tested in EAE. The past decade has provided a rich interaction between the fields of neurology and immunology. This has given rise to improved understanding of the pathogenesis of multiple sclerosis and the development of new therapies that target specific immune pathways. The demyelinating process in multiple sclerosis (MS) involves T-cells, immunoglobulins and complement, but recent evidence shows that cytokines, chemokines, adhesion molecules, metalloproteinases, nitric oxide and oxygen metabolites, all participate in the effector stages of the disease, and can therefore be potential therapeutic targets. Peter Mannon, M.D.
"Experimental Immunomodulation in Inflammatory Bowel Diseases"
Peter Lipsky, M.D.
"B cell Dysfunction in Human Autoimmunity"
Cornelia Weyand, M.D., Ph.D.
T Cell Aging and Autoimmunity
The risk to develop rheumatoid arthritis is age-dependent and is highest in postmenopausal women during the 7th and 8th decade of life. With age emerging as the strongest susceptibility factor it is difficult to envisage the underlying defect in RA as an adaptive immune response to antigen. Adaptive immunity degenerates with age, particularly after the age of 40-50 when thymic T cell production becomes minimal. Defective T cell responses in the elderly are considered the major mechanisms leading to immunosenescence, a state of the immune system characterized by impaired responses to vaccines, infections and tumors. Studies in RA patients have shown that the aging process of the immune system is accelerated by 20 to 30 years and have given rise to the model that premature immunosenescence predisposes to autoimmunity. RA patients accumulate CD4 T cells that have entered the cellular senescence program. T-cell precursors have excessively proliferated; naive T cells have restrictions in clonal burst. Memory CD4 T cells in RA display a number of phenotypic and functional changes that qualify them as proinflammatory cells. Specifically, RA patients have high frequencies of CD4+CD28- T cells in the blood and in the tissue. These CD4+CD28- T cells show de novo expression of immunoregulatory receptors, such as NKG2D and killer immunoglobuline-like receptors (KIR). They utilize KIRs to kill target cells, even in the absence of T-cell receptor triggering. Cross-linking of KIRs enhances IFN-g production. CD4+CD28- T cells also acquire expression of CX3CR1, the receptor for fractalkine. Fractalkine is abundantly produced by synovial fibroblasts. Membrane-anchored fractalkine enhances T-cell adhesion, co-stimulates IFN- production by CD4+CD28- T cells, and provides survival signals for interacting CD4+CD28- T cells. In essence, memory CD4 T cells in RA are characterized by a panel of novel immunoregulatory receptors through which they obtain a multitude of co-stimulatory signals. Ligands for such co-stimulatory molecules are abundant in the synovial microenvironment, creating a unique niche for senescent CD4+CD28- T cells. Environmental cues different from antigens, such as KIR-binding ligands and fractalkine, can modulate T-cell activation in the lesion and determine outcome of immune responses in this tissue site. In summary, aged T cells are functionally distinct from young T cells and are characterized by the expression of regulatory receptors driving their activation in the peripheral tissue. This process provides a mechanistic link between accelerated immunosenescence and chronic inflammatory disease in RA. |