Lymphoid Cell Accumulation in Salivary Glands of Autoimmune MRL Mice Can be Due to Impaired Apoptosis

Abstract

MRL-lpr mice and the congenic strain MRL þ/þ exhibit pathological abnormalities in the salivary glands similar to Sjögren's syndrome in humans. The lpr genotype has been identified as a mutation in the gene encoding Fas which is a cell surface protein that mediates apoptosis. The mutation is leaky, allowing for low levels of the APO-1/Fas (CD95) receptor and partial activity of Fas/Fas ligand-mediated programmed cell death in this strain. To examine the expression of Fas in situ, the authors analysed thymus, lymph node and salivary gland tissue from BALB/c, MRL þ/þ and MRL-lpr mice by an immunohistochemical technique (ABC-immunoperoxidase) using an anti-Fas (Jo2) antibody. For detection of apoptotic cells the authors used the terminal deoxynucleotidyl-transferase-mediated dUTP-digoxigenin nick end labelling (TUNEL) method. Thymus from MRL þ/þ and normal BALB/c mice showed a higher frequency of Fas expression than was seen in the lpr mice, but the þ/þ mice had similar expression of Fas in lymph nodes as lpr mice. The Fas protein was detected among infiltrating mononuclear cells in the salivary glands of both lpr and þ/þ mice. Apoptotic cells were found in the thymus with similar frequency in all three strains, while in the lymph nodes only BALB/c mice showed apoptosis. There was no, or very low, frequency of apoptosis among infiltrating mononuclear cells in salivary glands of both MRL strains. In conclusion, despite mutation of the Fas gene in the MRL-lpr strain, there was nevertheless an expression of the apoptosis-related Fas protein in lymphoid tissue and salivary glands of these mice. Based on analysis of apoptotic activity, the impaired Fas in autoimmune MRL mice seems to affect primarily the peripheral organs.

Transfer of human serum IgG to nonobese diabetic Igμ null mice reveals a role for autoantibodies in the loss of secretory function of exocrine tissues in Sjögren’s syndrome

“…The use of isolated IgG fractions to produce salivary gland dysfunction in immunodeficient mice suggests that this component of the immune system is a critical mediator for clinical presentation of sicca complex. Autoimmune exocrinopathy often is thought to result from cytotoxic effects of activated T lymphocytes or cytokines in response to programmed cell death occurring in the glandular epithelial cells (2,(22)(23)(24). However, the present results indicate that although T cells may be involved in the pathology of the exocrine tissue in NOD mice, the B cell effector arm appears to induce the full loss of exocrine tissue secretory function.…”

IL‐4‐Dependent Effector Phase in Autoimmune Exocrinopathy as Defined by the NOD.IL‐4‐Gene Knockout Mouse Model of Sjögren's Syndrome

“…In support of this concept are the observations that the Fas expression is induced in exocrine epithelial cells [30], that the bax and caspase-3 are activated [29], that the cysteine protease activity is elevated in both saliva and salivary gland homogenates [24], and that the increasing numbers of gland cells stain positive using TUNEL staining [24]. In order to determine the levels of apoptosis in the exocrine glands of NOD.IL-4 2/2 mice, the number of TUNEL-positive acinar cells per 4 mm 2 of histological sections of submandibular glands from 12 and 20-week-old mice were quantified.…”

Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension

“…The resulting pellet was counted in a γ counter (Cobra-II; GMI Inc., Albertville, Minnesota, USA) for 1 min. Specific binding was calculated as the difference between total and nonspecific binding according to Scatchard (24) by using the program Origin (1994 version; Microcal Software, Northampton, Massachusetts, USA) (25). Cell proliferation.…”