Sjögren's autoimmunity: how perturbation of recognition in endomembrane traffic may provoke pathological recognition at the cell surface

Abstract

CD4 T cell antigen recognition requires presentation by major histocompatibility complex Class II molecules (MHC II). B cell surface immunoglobulins recognize antigens independently of MHC II, but activation typically requires CD4 cell cytokines as accessory signals. Plasma membrane-endomembrane traffic in lacrimal gland acinar cells, targets of autoimmune activity in Sjögren's syndrome, may satisfy both requirements. The Golgi protein galactosyltransferase and the lysosomal proteins cathepsin B and cathepsin D appear at the plasma membranes during sustained secretomotor stimulation. The RNA transcription termination factor La, a frequent target of Sjögren's autoantibodies, appears in the acinar cell cytoplasm and plasma membranes during viral infection and during in vitro exposure to cytokines. MHC II cycle through endomembrane compartments which contain La, galactosyltransferase, cathepsin B and cathepsin D and which are sites of proteolysis. This traffic may permit trilateral interactions in which B cells recognize autoantigens at the surface membranes, CD4 T cells recognize peptides presented by MHC II, B cells provide accessory signals to CD4 T cells, and CD4 T cells provide cytokines that activate B cells. Acinar cells stimulate lymphocyte proliferation in autologous mixed cell reactions, confirming that they are capable of provoking autoimmune responses.

Use of nucleofection to efficiently transfect primary rabbit lacrimal gland acinar cells

“…Many studies investigating the mechanisms associated with the development of dry eye disorders and the autoimmune disease, SjS, utilize rabbit LGAC cultures (Jerdeva et al 2005;Marchelletta et al 2008;Mircheff et al 1998;Xie et al 2002) while others use rat and mouse LGAC (Chen et al 1998;da Costa et al 2006;Hodges et al 2004;Rios et al 2005;Sanghi et al 2000;Zoukhri and Kublin 2002). Primary cultured LGAC have previously exhibited very low transfection efficiency using non-viral, lipid-based methods, thus significantly limiting the types of experiments that may be conducted.…”

Regenerative Medicine - from Protocol to Patient

“…However, in the presence of infl ammatory signals, these lymphocytes become activated and secrete pro-infl ammatory cytokines, which cause homing of additional T cells to the tissue and an increase in the level of infl ammation thereby aggravating the existing condition and forming a vicious loop of infl ammation (Gao et al 1998 ). Any condition that results in hyper activity of the functional unit can also initiate infl ammatory response within the lacrimal glands resulting in antigen presentation and cytokine secretion by the epithelial cells of the gland (Meggs 1993 ;Mircheff et al 1998 ). These pro-infl ammatory mediators cause epithelial cell death by apoptosis and also loss of conjunctival goblet cells -a combinatorial assault that leads to worsening of the existing condition.…”