Aromatase-deficient mice spontaneously develop a lymphoproliferative autoimmune disease resembling Sjögren's syndrome

Abstract

Sjögren's syndrome (SS) is an incurable, autoimmune exocrinopathy that predominantly affects females and whose pathogenesis remains unknown. Like rheumatoid arthritis, its severity increases after menopause, and estrogen deficiency has been implicated. We have reported that estrogen receptor-α and -β-knockout mice develop autoimmune nephritis and myeloid leukemia, respectively, but neither develops SS. One model of estrogen deficiency in rodents is the aromatase-knockout (ArKO) mouse. In these animals, there is elevated B lymphopoiesis in bone marrow. We now report that ArKO mice develop severe autoimmune exocrinopathy resembling SS. By 1 year of age, there is B cell hyperplasia in the bone marrow, spleen, and blood of ArKO mice and spontaneous autoimmune manifestations such as proteinuria and severe leukocyte infiltration in the salivary glands and kidney. Also, as is typically found in human SS, there were proteolytic fragments of α-fodrin in the salivary glands and anti-α-fodrin antibodies in the serum of both female and male ArKO mice. When mice were raised on a phytoestrogen-free diet, there was a mild but significant incidence of infiltration of B lymphocytes in WT mice and severe destructive autoimmune lesions in ArKO mice. In age-matched WT mice fed a diet containing normal levels of phytoestrogen, there were no autoimmune lesions. These results reveal that estrogen deficiency results in a lymphoproliferative autoimmune disease resembling SS and suggest that estrogen might have clinical value in the prevention or treatment of this disease.

Arthralgia Associated with Autoimmune Abnormalities under Aromatase Inhibitor Therapy: Outcome after Cessation of Treatment

“…We considered that this pain was not related only to the estrogen deprivation resulting from AI therapy, but was secondary to autoimmune abnormalities probably induced or promoted by the AI therapy and/or the cancer. An aromatase knockout mouse model, which spontaneously develops renal and salivary gland lesions similar to those described in Sjögren syndrome, could confirm this hypothesis 4 . Other authors have since reported cases of rheumatoid arthritis or Sjögren syndrome occurring with AI therapy 5,6 .…”

Estrogen receptor β-deficient female mice develop a bladder phenotype resembling human interstitial cystitis

“…Previous studies demonstrated that 28% of IC patients develop autoimmune exocrinopathy, Sjogren's syndrome (SS) (25). Our studies show that ArKO mice, which have complete loss of estrogen, spontaneously develop signs of lymphoproliferative autoimmunity, which particularly resembles SS (7).…”

“…The discovery of the second ER, ER␤, provided an explanation for the effects of estrogen in several ER␣-negative tissues such as the prostate, intestine, and lung, where ER␤ serves as a modulator of terminal differentiation of epithelium (3)(4)(5)(6)(7). ER␤ and ER␣ knockout mice (ER␤ Ϫ/Ϫ and ER␣ Ϫ/Ϫ ) have been invaluable in analyzing and dissecting the functions of ER␤ and ER␣ (8,9).…”

Establishment of NOD-Pdcd1-/-mice as an efficient animal model of type I diabetes

“…Briefly, grade 1 represents periinsulitis with mononuclear cell infiltration in Ͻ20% of the area of each islet, grade 2 represents moderate insulitis with mononuclear cell infiltration in 20-50% of the area of each islet, and grade 3 represents severe insulitis with mononuclear cell infiltration in Ͼ50% of the area of each islet. Sialoadenitis was scored accord-ing to the published criteria (15). Briefly, grade 1 represents the presence of one to five foci of mononuclear cells (Ͼ20 cells per focus), grade 2 represents the presence of more than five foci of mononuclear cells but without significant parenchymal destruction, grade 3 represents the presence of multiple confluent foci with moderate parenchymal degeneration, and grade 4 represents the presence of extensive infiltration with extensive parenchymal destruction.…”

“…The NOD (nonobese diabetic) mouse, an animal model of type I diabetes, greatly contributed to the understanding of the genetic basis of type I diabetes (4-6). So far, 28 susceptible loci 4.1, 4.2, 5.1, 5.2,[6][7][8] 9.1, 9.2, 9.3,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] have been identified on the NOD chromosomes by several different crosses and generation of congenic mice.Although many diabetes-susceptible loci have been identified by using NOD mice, the identification of their responsible genes and͞or the analyses of the immunological function of each locus have not been carried out smoothly. The difficulty is likely due in part to the late onset and the low penetrance of type I diabetes in NOD mice (40-70% and 20-40% at 30 weeks of age for females and males, respectively) and also to the involvement of many genes.…”