Identification of possible candidate genes regulating Sjögren's syndrome-associated autoimmunity: a potential role for TNFSF4in autoimmune exocrinopathy
© Nguyen et al.; licensee BioMed Central Ltd. 2008
Received: 26 August 2008
Accepted: 25 November 2008
Published: 25 November 2008
Sjögren syndrome (SjS) is a systemic autoimmune disease in which an immunological attack primarily against the salivary and lacrimal glands results in the loss of acinar cell tissue and function, leading to stomatitis sicca and keratoconjunctivitis sicca. In recent years, two genetic regions, one on chromosome 1 (designated autoimmune exocrinopathy 2 or Aec2) and the second on chromosome 3 (designated autoimmune exocrinopathy 1 or Aec1) derived from nonobese diabetic (NOD) mice, have been shown to be necessary and sufficient to replicate SjS-like disease in nonsusceptible C57BL/6 mice.
Starting with the SjS-susceptible C57BL/6-derived mouse, referred to as C57BL/6.NOD-Aec1Aec2, we generated a large set of recombinant inbred (RI) lines containing portions of Aec2 as a means of identifying more precisely the genetic elements of chromosome 1 responsible for disease development.
Disease profiling of these RI lines has revealed that the SjS susceptibility genes of Aec2 lie within a region located at approximately 79 ± 5 cM distal to the centromere, as defined by microsatellite markers. This chromosomal region contains several sets of genes known to correlate with various immunopathological features of SjS as well as disease susceptibility genes for both type 1 diabetes and systemic lupus erythematosus in mice. One gene in particular, tumor necrosis factor (ligand) superfamily member 4 (or Ox40 ligand), encoding a product whose biological functions correlate with both physiological homeostasis and immune regulations, could be a potential candidate SjS susceptibility gene.
These new RI lines represent the first step not only in fine mapping SjS susceptibility loci but also in identifying potential candidate SjS susceptibility genes. Identification of possible candidate genes permits construction of models describing underlying molecular pathogenic mechanisms in this model of SjS and establishes a basis for construction of specific gene knockout mice.
Sjögren syndrome (SjS) is a chronic, systemic, human autoimmune disease in which an immunological attack initially against the salivary and lacrimal glands results, respectively, in dry mouth (stomatitis sicca) and dry eye (keratoconjunctivitis sicca) disease(s) [1–3]. Despite efforts to define the genetic, environmental, and immunological bases of SjS, the underlying etiology of this disease remains ill defined. In attempts to better define the nature of SjS autoimmunity, a variety of mouse models exhibiting various aspects of SjS have been studied extensively . One of the more intensively studied models of SjS is the nonobese diabetic (NOD) mouse [5–9]. Based on disease profiling of various congenic partners and gene knockout lines of NOD, we have proposed that the development and onset of SjS-like disease in these mice can be divided into at least three distinct consecutive phases [10–19]. In phase 1, a number of aberrant physiological and biochemical activities, thought to result from a genetically based retarded salivary gland organogenesis and increased acinar cell apoptosis, occur prior to and independent of detectable autoimmunity. In phase 2, believed to result from the glandular cell injury of phase 1, small numbers of macrophages and dendritic cells are attracted to the exocrine gland where these sentinel cells recruit T and B lymphocytes that form lymphocytic foci (LF), some of which histologically appear as germinal centers. In phase 3, the onset of clinical disease as defined by salivary and lacrimal gland secretory dysfunction occurs, possibly resulting first from the production of autoantibodies that interfere with the neural-acinar cell signaling pathways and then from progressive loss of acinar cell mass hastened by the action of effector T cells.
A genetic predisposition for development and onset of SjS-like disease in NOD mice has also been defined. First, SjS-like disease in these mice appears independent of or only weakly associated with major histocompatibility complex (MHC) class I and class II genes [10, 20], thus mimicking SjS in humans. This can be seen by the fact that the congenic strain, NOD.B10-H2 b , in which the NOD MHC I-Ag7Idd1 diabetes susceptibility locus was replaced by the MHC I-A b locus , continued to show SjS-like disease, including salivary and lacrimal gland dysfunction. Second, replacing Idd loci other than Idd1 (for example, Idd9, Idd10, and Idd13) resulted in the identification of Idd3 on chromosome 3 and Idd5 on chromosome 1 as critical genetic regions for development of SjS-like disease in NOD mice . In a reverse approach, introducing both Idd3 and Idd5 derived from NOD mice into SjS-nonsusceptible C57BL/6 mice resulted in a severe SjS-like disease, confirming the contributions of these two genetic loci to the development and onset of SjS . Furthermore, the preclinical nonimmune aspects manifested in phase 1 of the disease appeared to associate with the Idd5 locus (referred to as autoimmune exocrinopathy 2 or Aec2), whereas the immunological aspects of the disease manifested in phases 2 and 3 of the disease appeared to associate with Idd3 (referred to as Aec1). This recently generated mouse strain is referred to as C57BL/6.NOD-Aec1Aec2. While the pathophysiological and immunological aspects may not be linked solely to one or the other genetic region (as originally proposed ), the complete disease profile requires genes within both of these genetic loci.
For years, identification of candidate genes associated with autoimmune diseases such as T1D  or systemic lupus erythematosus  in animal models has been providing invaluable data on delineating the genetic components of these diseases, now translating to the human disease. These studies have formed a template for our current efforts to identify the SjS susceptibility loci and candidate genes underlying SjS which, in this respect, have lagged behind many other autoimmune diseases. Although our initial work defined the Aec1 and Aec2 genetic regions present in C57BL/6.NOD-Aec1Aec2 mice as being an approximately 48.5-cM centromeric region on chromosome 3 and an approximately 73.3-cM telomeric region on chromosome 1, respectively , the size of these regions precluded identification of candidate genes. Subsequently, we shortened Aec1 to an approximately 19.2-cM region in the first studied recombinant inbred (RI) line, C57BL/6.NOD-Aec1R01Aec2 . For the present study, we generated a set of new RI lines that further demarcate the boundaries of Aec2. These new C57BL/6.NOD-Aec1Aec2R(n) RI lines identify not only a much shorter Aec2 sublocus at position 79 cM of chromosome 1, but also potential candidate SjS susceptibility genes on which to build hypothetical models that can be tested for validating possible pathogenic molecular mechanisms of SjS-like disease.
Materials and methods
C57BL/6.NOD-Aec1Aec2R(n) and C57BL/6.NOD-Aec1R(n)Aec2R(n) mice were generated by crossing C57BL/6.NOD-Aec1Aec2 mice with C57BL/6J mice purchased from The Jackson Laboratory (Bar Harbor, ME, USA). The F1 heterozygotes were screened for the presence of crossover events within the Aec1 and/or Aec2 genetic regions by microsatellite marker genotyping. Individual mice indicating a crossover in Aec2 were bred with a C57BL/6J mouse to produce Aec2 crossover heterozygous male and female offspring that were then used to produce F2 generations. Mice of the F2 generations were screened for a male and female homozygous for the crossover chromosome. Once an appropriate homozygous recombinant founder pair was identified, the RI line was maintained via a single line of descent.
All RI lines were bred and maintained under specific pathogen-free conditions in the animal facility of Animal Care Services of the University of Florida (Gainesville, FL, USA). Both male and female mice 4 to 24 weeks of age were used in the following studies. All mice received water and food ad libitum. Blood samples were collected while the mice were anesthetized with isoflurane. Euthanasia was carried out by cervical dislocation after anesthetization with isoflurane or 100% CO2. Studies described herein were approved by the University of Florida Institutional Animal Care and Use Committee.
To determine the genetic status of each offspring, DNA was prepared using the DNeasy Tissue Kit (Qiagen Inc., Valencia, CA, USA) from a small tail snip taken between 2 and 4 weeks of age just prior to weaning. Each DNA sample was used as a template in polymerase chain reaction amplification with D1mit primers covering the Aec2 genetic region. Microsatellite markers that differentiated genes derived from NOD mice from those derived from C57BL/6J mice were chosen. Primer sequences for the microsatellite markers were based on sequences available from The Jackson Laboratory and purchased from Integrated DNA Technologies (IDT, Coralville, IA, USA).
Measurement of saliva flow rates
To measure stimulated flow rates of saliva, individual mice were weighed and given an intraperitoneal injection of 100 μL of a mixture containing isoproterenol (0.02 mg/1 mL of phosphate-buffered saline [PBS]) and pilocarpine (0.05 mg/1 mL of PBS). Saliva was collected for 10 minutes from the oral cavity of individual mice using a micropipette starting 1 minute after injection of the secretagogue. The volume of each saliva sample was measured. The saliva samples were then frozen at -80°C until analyzed.
Male and female C57BL/6.NOD-Aec1Aec2R(n) mice were euthanized at various ages as indicated in the text. Submandibular and lacrimal glands were surgically removed from each mouse and placed in 10% phosphate-buffered formalin for 24 hours. Fixed tissues were embedded in paraffin and sectioned at 5-μm thickness. Paraffin-embedded sections were de-paraffinized by immersing in xylene, followed by dehydrating in ethanol. The tissue sections were prepared and stained with hematoxylin and eosin dye (Histology Tech Services, Inc., Gainesville, FL, USA). Stained sections were observed at × 100 magnifications for glandular structure and leukocyte infiltration. To detect and determine leukocytic infiltrations in salivary and lacrimal glands, a single histological section per gland per mouse was examined by two individuals blinded to the RI lines. LF, defined as aggregates of greater than 50 leukocytes, were quantified for each section.
Detection of anti-nuclear autoantibodies in the sera
Anti-nuclear autoantibodies (ANAs) in the sera of mice were detected using an ANA screening kit (Immuno Concepts, Sacramento, CA, USA). Sera were tested at dilutions of 1:40, 1:80, and 1:160. Presented in this paper, however, are data from testing sera at 1:40 dilutions. In brief, HEp-2 fixed substrate slides were overlaid with the appropriate mouse serum. Slides were incubated for 30 minutes at room temperature in a humidified chamber. After three washes for 5 minutes with PBS, the substrate slides were covered with Alexa 594-conjugated goat anti-mouse IgG (H/L) (Invitrogen Corporation, Carlsbad, CA, USA) diluted 1:50 for 30 minutes at room temperature. After three washes, nuclear fluorescence was detected by fluorescence microscopy at × 100 magnification.
Modeling of biological pathways using Pathway Studio
To model biological pathways from selected genes located within the redefined Aec2 genetic region, Pathway Studio version 5.0 software (Ariadne Genomics, Rockville, MD, USA) and the ResNet mammalian database were used. Functions of selected genes within the two genetic regions and known SjS-related genes were first verified from the ResNet mammalian database and then imported into Pathway Studio to visually construct molecular and biological interactions or relationships among the inputted genes.
For this study, we have standardized both saliva and tear collections based on the body weight of the individual mice in an attempt to better control comparisons. We have incorporated this for mice of the C57BL/6 genetic background because, first, disease tends to occur in the C57BL/6 genetic background strains at an earlier age, often necessitating collections of saliva and tears when the mice are as young as 4 to 6 weeks of age and are less than half the size of adult mice, and, second, there are greater size differences between male and female mice during the time course studied. Statistical evaluations between saliva collections were determined by using the unpaired t test generated by GraphPad InStat software (GraphPad Software, Inc., San Diego, CA, USA). A two-tailed P value of less than 0.05 was considered significant.
Genetic profiling of the recombinant inbred lines
Disease profiling of the recombinant inbred lines
SjS-like disease in our NOD-derived mouse lines, including C57BL/6.NOD-Aec1Aec2, is characterized generally by three criteria , reflecting the objective criteria used to identify SjS in humans . These are (a) the loss of saliva and tear flow rates over time, (b) the presence of LF in the salivary and lacrimal glands, and (c) the presence of ANAs in sera. To determine which of the RI C57BL/6.NOD-Aec1Aec2R(n) mice develop salivary gland dysfunction, temporal changes in saliva flow rates were determined for both male and female mice at an early age (7 ± 1 weeks) and then at a later age (22 ± 2 weeks). The number of mice examined for each new RI line was dependent on the number of offspring produced in the first few pregnancies following inbreeding.
Quantification of lymphocytic foci in the salivary and lacrimal glands of mice from several representative C57BL/6.NOD-Aec1Aec2R(n) recombinant inbred lines
Number of mice
Average number of LF
Number of mice
Average number of LF
Male and female
Male and female
20 and 24
1.0 ± 0.0
1.7 ± 0.4
20 and 24
0.0 ± 0.0
1.5 ± 0.3
4.0 ± 1.7
5.8 ± 4.1
21 and 22
3.0 ± 0.6
2.8 ± 0.7
2.4 ± 0.7
2.8 ± 0.6
20 and 21
2.2 ± 1.0
6.5 ± 4.5
Redefining the Sjögren syndrome susceptibility Aec2genetic region
In the present study, in which the specific goal was to redefine (and narrow) the boundaries of the Aec2 genetic region on chromosome 1 known to predispose NOD and NOD-derived lines of mice to SjS, we generated a large set of new RI lines (n = 39) and examined each line for its SjS-like disease profile. Disease profiles obtained with the C57BL/6.NOD-Aec1Aec2R(n) RI lines indicate that the Aec2 genetic region of C57BL/6.NOD-Aec1Aec2 mice, postulated to regulate primarily the pathophysiological and biochemical abnormalities that subsequently result in the activation of the autoimmune attack against the submandibular and lacrimal glands , is a single subregion mapping to the telomeric portion of chromosome 1 located at approximately 79 ± 5 cM. However, penetrance and severity of SjS-like disease may be further influenced by genes located within a few centimorgans on the centromeric side of this region, possibly pointing to SjS-associated quantitative trait loci (QTL) genes. Although the size of the redefined Aec2 region remains relatively large for identification of individual candidate SjS susceptibility genes, the genes residing within this subregion can be grouped into four functionally clustered sets, each suspected previously of involvement in SjS susceptibility. These are (a) endogenous viruses and oncogenic genes, (b) Fas/FasL-associated apoptosis, (c) TH17-associated activities, and (d) fatty acid, lipid, lipoprotein, and cholesterol homeostasis. However, perhaps the most obvious aspect is the fact that this redefined Aec2 region contains the QTL-Ath1 region containing some 10 genes, including tumor necrosis factor ligand superfamily member 4 (Tnfsf4 or Ox40L) and Tnfsf6 (Fasl).
Within the first set, several viral/oncogenic genes, such as Emv38 (endogenous ecotropic MuLV-38), Kras-2-rs1 (Kirsten rat sarcoma oncogene-2, related sequence-1), Xpr1 (xenotropic/polytropic retrovirus receptor-1), and Abl2 (Abelson murine leukemia viral oncogene-2), are found in this redefined Aec2 subregion. In our earlier studies with NOD mice , we observed that high levels of interferon-gamma (INF-γ) were present in the salivary glands of neonate mice, suggesting an important role for INF-γ in the delayed development/proliferation of acinar tissue observed in the salivary glands of neonate NOD mice. While it is logical to conclude that induction of INF-γ may be a result of short-term viral infection during the preterm and early postpartum periods, what might cause a viral outbreak at this time point remains unknown. It could be hypothesized that this occurs due to the changes in maternal hormone levels at this time. Perhaps more interesting, however, this region contains the gene Tnfsf6 encoding the proapoptotic protein FasL. FasL has numerous functions but is mainly involved in regulating immune responses, apoptosis, and retinal cell programmed death . During the early phase 1 period of SjS-like disease in NOD mice, both FasL and Fas are upregulated at both the gene and protein levels, and this increased expression of Fas/FasL corresponds to the observed increase in acinar cell apoptosis within the glands . However, it remains speculative whether there might be an association between endogenous/exogenous viral infection and Fas/FasL activity in the salivary and lacrimal glands.
The redefined Aec2 subregion also contains several genes involved in autoimmunity and/or tumorgenesis, the latter being one clinical manifestation of SjS that occurs in a small subset of patients. Of interest, but not thought to be directly involved in the development and onset of SjS, is the presence of genes specific to the ocular/lacrimal gland etiology (for example, Pdc [phosducin], which is a protein of the retinal photoreceptors cells , and Myoc [myocilin], whose product interacts with olfactemedin involved in glaucoma ). However, whether any of these genes are related to SjS susceptibility and lacrimal gland disease or merely influence the secondary disease phenotypes often associated with SjS remains unknown. In contrast, one genetic element in this region that has a direct association with the immunopathology of SjS is the QTL gene Cypr2 (cytokine production 2) . CYPR-2 is known to regulate levels of interleukin-10 (IL-10), an important cytokine that enhances the activity of B lymphocytes, and at the same time to regulate the functions of TH1 and TH17 cells . Our recent microarray studies indicate that Il10 is not upregulated during the development of SjS in the C57BL/6.NOD-Aec1Aec2 mouse model , possibly indicating a lack of immune regulation by regulatory T (Treg) cells. If so, this lack of regulation by IL-10 would be consistent with the results of gene therapy studies in which injections of vectors expressing recombinant IL-10 reduced or suppressed clinical manifestations of SjS-like disease in both salivary and lacrimal glands of mice [37, 38].
Identifying gene products that are differentially expressed in the Aec2 SjS susceptibility subregion defined by the new RI lines is moving us closer to identifying specific candidate genes involved in the onset and development of SjS-like disease. Based on our current data, our focus is turning to Ox40L as an effective candidate gene for the development of SjS. The future application of genetic knockout mice and/or short interfering RNA will permit us to further our understanding of the potential role of Ox40L in SjS and, more importantly, to translate its relevancy to human SjS.
major histocompatibility complex
quantitative trait loci
retinoic acid receptor
retinoid × receptor
tumor necrosis factor ligand superfamily member 4
We thank Robert Haynes for the countless hours spent in caring for and maintaining precise records of these RI lines and Sung Kim for his help in analyzing the function and pathway associations of selected genes. This work was supported in part by Public Health Service (PHS) grant DE014344 from the National Institutes of Health (to ABP) and by the Center for Orphaned Autoimmune Disorders at the University of Florida. CQN was supported by a postdoctoral fellowship from PHS grant T32 DE07200.
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