Hormones In mice, castrating females and /or providing androgens or antiestrogens protects from disease, whereas castrating males and providing estrogens accelerates and worsens SLE. The metabolish of sex hormone is abnormal in some lupus patients Men and women with lupus metabolized testosterone more rapidly than normal, and estrogenic metabolites of estradiol persist longer In women Neuroendocrine system. Hyperprolactinemia, abnormalities in hypothalamic and/or pituitary function
Hormones • In mice, castrating females and /or providing androgens or antiestrogens protects from disease, whereas castrating males and providing estrogens accelerates and worsens SLE. • The metabolish of sex hormone is abnormal in some lupus patients. Men and women with lupus metabolized testosterone more rapidly than normal, and estrogenic metabolites of estradiol persist longer in women. • Neuroendocrine system. Hyperprolactinemia, abnormalities in hypothalamic and/or pituitary function
Abnormal immune system Sustained presence of autoantigens increased apoptosis, impaired clearance of apoptoSIS Hyperactivity in B and T lymphocyte Increased expression of surface molecules participating in cell activation in both B and T-cell Overproduction of certain cytokines Defective regulatory mechanisn Autoantibodies to DNA, RNA, and a host of other cell nucleus antigens Circulating immune complexes are frequently observed and these may deposit in the kidney, skin, brain, lung, and other tissues. It causes inflammation and tissue damage by a number of mechanism, notably fixation and activation of the complement system
Abnormal immune system • Sustained presence of autoantigens: increased apoptosis , impaired clearance of apoptosis • Hyperactivity in B and T lymphocyte • Increased expression of surface molecules participating in cell activation in both Band T-cell • Overproduction of certain cytokines • Defective regulatory mechanism • Autoantibodies to DNA, RNA, and a host of other cell nucleus antigens. • Circulating immune complexes are frequently observed and these may deposit in the kidney, skin, brain, lung, and other tissues. It causes inflammation and tissue damage by a number of mechanism, notably fixation and activation of the complement system
Lymphoid compartment Apoptotic TCR Tcell TYYa MHC class ll TceB-ce‖ co-operation Immune complex Kidney
The Role of Dendritic Cells(DC)and Alpha Interferon Normally, resting DC mediate tolerance, i.e., no immune response to own tissues they capture dead cells debris, and the immune system never encounters this waste Dc become activated by viral infections, producing a interferon. After viral infections resolve, a interferon disappears DC proliferate and become activated when blood cells from normal donors are cultured with sera from lupus patients IFN a identified as the primary substance responsible for this effect In lupus, the normal immune response appears altered as plasmacytoid dendritic cells(pDC) become hyperactivated by IFNa Immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG induce IFNa production in pDC Abnormal secretion of alpha interferon in lupus: the signature cytokine for the disease Dendritic cells activate B and T cells, leading to a chronic autoimmune state= lupus
The Role of Dendritic Cells (DC) and Alpha Interferon • Normally, resting DC mediate tolerance, i.e., no immune response to own tissues: they capture dead cells debris, and the immune system never encounters this waste • DC become activated by viral infections, producing interferon. After viral infections resolve, interferon disappears • DC proliferate and become activated when blood cells from normal donors are cultured with sera from lupus patients • IFN identified as the primary substance responsible for this effect • In lupus, the normal immune response appears altered as plasmacytoid dendritic cells (pDC) become hyperactivated by IFN • Immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG induce IFN production in pDC • Abnormal secretion of alpha interferon in lupus: the signature cytokine for the disease • Dendritic cells activate B and T cells, leading to a chronic autoimmune state = lupus
Cytokines involved in the sle disease process Plasmacytoid dendritic cell Myeloid dendritic cell Macrophage Innate system ※ IL-12. IL-23 IFN-a TNF IL-6 BAFF Adaptive immune CD8 CD4+ B cell system T cell TCR IFNy,L-17,儿L21 l-10,l6 Ronnblom, L& Elkon, KB(2010)Cytokines as therapeutic targets in SLE Nat Rev. rheumatol. doi: 10. 1038/nrrheum 2010 64 nature REVIEWS RHEUMATOLOGY
Cytokines involved in the SLE disease process Rönnblom, L. & Elkon, K. B. (2010) Cytokines as therapeutic targets in SLE Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2010.64