sjgren 's syndrome ( sjs ) is a systemic chronic autoimmune disease that targets the exocrine glands , predominantly the salivary glands and lacrimal glands , resulting in xerostomia ( dry mouth ) and keratoconjunctivitis sicca ( dry eyes )   . the disease also presents with systemic manifestations involving the destruction of the thyroid gland , lungs , liver , and kidneys . the national arthritis data workgroup using the olmsted county , mn and 2005 us population prevalence estimates from the census bureau has estimated that the prevalence of primary sjs ( psjs ) in the usa approaches 1.3 million with a range of 0.43.1 million of the approximate 214.8 million population , with a female - to - male ratio of about 9  :  1 , indicating a probable correlation between disease development and sex hormones     . psjs affects salivary and/or lacrimal glands in the absence of other rheumatic diseases , while its more common secondary form occurs in the presence of other rheumatic diseases , such as systemic lupus erythematosus ( sle ) , rheumatoid arthritis ( ra ) , scleroderma , and primary biliary cirrhosis . the degree of glandular destruction is related to the progressive development of lymphocytic infiltrations which are composed primarily of cd4 and cd8 t cells     , b cells , macrophages , and dendritic cells     .   according to the revised european - american consensus group criteria , diagnosis of sjs includes signs of ocular and oral dryness , detection of infiltrating lymphocytes within minor salivary glands with quantification determined by histopathological evaluation , and the presence in serum of autoantibodies , specifically anti - ssa / ro , anti - ssb / la , and antinuclear antibodies   ( ana ) .   recently , considerable interest has focused attention on serological evaluations showing the presence of rheumatoid factor ( rf ) , elevated immunoglobulin levels ( hypergammaglobulinemia ) , anti--fodrin , and the presence of antibodies to the muscarinic acetylcholine receptors , especially the type 3 receptor ( m3r ) which could impair secretory function     [ 1624 ] . the precise etiology of sjs remains elusive ; however , a number of possible theories have been postulated . environmental triggers including exposure to epstein - barr virus , hepatitis c virus , and retroviruses including both human t - cell lymphocytic virus type i ( htlv-1 )   and human endogenous retrovirus ( herv - k113 ) , may initiate epithelial cell activation and a prolonged inflammatory response in genetically predisposed individuals , resulting in systemic autoimmunity . other hypotheses , including epithelial / acinar cell apoptosis , emergence of autoreactive t cells , effect of autoantibodies and neurological dysfunction , the challenge of attempting to understand the mechanism of human sjs pathogenesis is the inability to learn the biological and immunological occurrence prior to overt clinical signs . end - stage disease is often the only parameter which is used to characterize the entire disease process .   as a result therefore , animal models for sjs would permit the investigation of the full spectrum of possible etiologies from prior to during and after disease development . an ideal sjs mouse model should fulfill a range of common characteristics present in human sjs , including etiological , clinical , histological , serological , and immunobiological features as detailed in table 1 . furthermore , different models will represent sjs in either its primary or secondary form , as demonstrated in table 2 which clarifies the relevance of each mouse model . this paper will provide a comprehensive examination of many animal models of sjs that mimic fully or various pathological aspects of human sjs . the nonobese diabetic ( nod ) inbred strain of mice were developed from a cataract - prone subline ( cts ) derived from outbred icr mice . the nod strain is not cataract - prone , however , and is most commonly used as a model for human type 1 insulin - dependent diabetes mellitus ( iddm or t1d ) due to lymphocytic infiltrations ( insulitis ) which cause the destruction of pancreatic islets . onset of diabetes in highly inbred nod mice occurs between 90 and 120 days , with an incidence of 6080% in females and 2030% in males by 210 days . spontaneous onset of diabetes in nod mice presents with hyperglycemia , hypercholesterolemia , glycosuria , ketonuria , polyuria , polydipsia , and polyphagia , all common clinical features of human iddm . while insulitis develops by 4 weeks ( wks ) of age , lymphocytic infiltrations in the salivary and lacrimal glands occur at approximately 1216  wks of age with corresponding loss of secretory function by 20  wks old     [ 35 , 36 ] . at the onset of sjs - like disease , various signature autoantibodies can also be detected , specifically , anti - ssa / ro , anti - ssb / la and anti - muscarinic receptor type iii ( m3r ) which has been demonstrated to directly contribute to the secretory dysfunction in this animal model and sjs patients . the development of t1d in the nod mouse is controlled by more than 18 chromosomal regions . early studies involving replacement of individual insulin - dependent diabetes ( idd ) susceptibility intervals such as idd3 , idd5 , idd13 , idd1 , and idd9 had minimal effect on the development of autoimmune exocrinopathy or sjs - like disease . both idd3 and idd5 are required for development of salivary and lacrimal dysfunction . when both nod - derived genetic regions were introduced to the sjs nonsusceptible c57bl/6 strain by crossing c57bl/6.nodc3 mice carrying idd3 ( autoimmune exocrinopathy 1 ( aec1 ) ) locus and c57bl/6.nodc1 t mice carrying idd5 ( aec2 ) locus , the c57bl/6.nodc3.nodc1 t or c57bl/6.nod - aec1aec2 mouse strain was produced which is homozygous for both idd3 and idd5 chromosomal intervals . this double congenic strain fully recapitulated the sjs - like disease process , exhibiting pathophysiological changes at early age , followed by lymphocytic infiltrations of the salivary   and lacrimal glands at 1216  wks of age , then accompanied by the production of autoantibodies to nuclear antigens ( ssa / ro , ssb / la ) and m3r in the absence of t1d . the lymphocytic foci ( lf ) consisted mainly of cd4   and cd8 t cells , as well as b lymphocytes with associated loss of saliva production by 20  wks of age .   due to the presence of t cells and sporadic numbers of dendritic cells and macrophages within infiltrates , an increase in the levels of proinflammatory cytokines such as interleukin-17 ( il-17 ) , il-22 , and il-23 a recombinant inbred line , known as c57bl/6.nod - aec1r1aec2 , was developed to define smaller genetic regions that contain those genes necessary to induce autoimmune exocrinopathy by narrowing the aec1 region     . the genetic region of aec1 locus was shortened from a 48.5  cm segment to a centromeric piece spanning 19.2  cm . the resultant strain exhibited more rapid sjs - like disease in males , with males developing salivary gland infiltrations at 10  wks of age compared to 19  wks in females . females presented with more severe sialadenitis and larger infiltrations in the submandibular gland by 22  wks ; however , they exhibited no dacryoadenitis whereas males exhibited significantly high levels of dacryoadenitis . furthermore , a homogeneous nuclear ana pattern was apparent in males as early as 5  wks of age but not until 10  wks in females . both sexes demonstrated a significant loss of saliva flow rate ( 3540% ) beginning at 5  wks of age , but only males displayed a loss of lacrimal gland secretory function . the lack of lacrimal gland dysfunction in females may be attributed to the loss of a necessary gene on the shortened aec1 locus which could regulate the sex dimorphism presented in sjs . interestingly , the major histocompatibility complex ( mhc ) genes have little or no relation to the development of sjs in the nod mouse . for example , the mhc class ii region , when replaced from a to a locus in nod mice , prevented the development of t1d , but the onset of ss - like disease remained unaffected     . also , the nod.h2 strain presents with exocrine gland infiltrations and compromised saliva flow without symptoms of t1d due to the replacement of the a allele with i - a , but continues to develop spontaneous thyroiditis at a low occurrence ( 5% )     [ 43 , 44 ] . the nod.b10-h2 strain also demonstrates an sjs - like phenotype with inflammatory infiltrations in the exocrine glands without the occurrence of t1d due to the replacement of the diabetogenic mhc locus with the mhc locus of c57bl/10 strain that is nonsusceptible to t1d     [ 45 , 46 ] . as a result , the nod and nod - derived animal models have been critical in elucidating the genetic basis of sjs development . the first mouse model for spontaneous sjs was the nzb / w f1 hybrid described in 1968 . by crossing the first filial generation new zealand black ( nzb ) mouse with the new zealand white ( nzw ) mouse , the nzb / w f1 hybrid was produced , which spontaneously developed disease characteristic of sjs and sle . mononuclear cell infiltrations were present in both salivary and lacrimal glands by 4 months of age , with more severe lesions in the lacrimal glands of females . epithelial cell nodules were also present , as well as edematous changes , necrosis , and connective tissue replacement of parenchyma . hypergammaglobulinemia , pulmonary vasculitis , nuclear autoantibodies , reduced complement levels , and circulating immune complexes were also presented in this mouse model . the mrl / lpr mouse was developed with a genetic mutation of the lymphoproliferation ( lpr ) gene on chromosome 19 which encodes the structural gene for the fas antigen . the mrl - lpr / lpr mouse spontaneously develops disease similar to sle   and ra , characterized by splenomegaly , arthritis , glomerulonephritis , and massive lymphadenopathy . this model develops an sjs - like phenotype beginning at 2 months of age with the onset of inflammatory infiltrations within the submandibular glands , followed by a less severe inflammation in the parotid and sublingual glands . although an early report suggested that mrl mice do not synthesize anti - ssa / ro and anti - ssb / la auto - antibodies , more recent reports indicate that nearly 30% of mice develop anti-52  kda ssa / ro antibodies , 6% develop anti-60  kda ssa / ro antibodies , and 6% develop anti - ssb / la antibodies , but not ssa / ro .   due to the defect in the fas antigen which controls apoptosis , the mrl / lpr mice develop aggressive autoimmune lymphoproliferation contributed by the autoreactive lpr t cells which have escaped thymic selection . the nfs / sld mouse bears a mutation in the sublingual gland differentiation arrest ( sld ) gene which affects acinar cell differentiation into mucous - secreting cells in the sublingual gland . at three days of age , the nfs / sld mice are thymectomized without any prior immunization ; these mice develop a spontaneous psjs - like disease . severe inflammatory infiltrations develop after 4 wks of age in both salivary and lacrimal glands that are composed mainly of cd3 and cd4 t cells with a lesser number of cd8 t cells and b220 b cells . nfs / sld mice which developed infiltrations in the glands had significant levels of igg autoantibodies in sera . the organ - specific 120-kilodalton -fodrin autoantigen which has high sequence homology with the human cytoskeleton protein -fodrin was found within the salivary glands of nfs / sld mutant mice , indicating a potential role in the development of sialadenitis and dacryoadenitis     . the early accumulation of -fodrin within the salivary glands may lead to   the observed loss of secretory function by 18 wks ; however , this is most likely due to aging rather than sjs - like disease phenotype   . the iqi / jic mouse is an inbred strain established from the imprinting control region ( icr ) mouse strain similar to nod . the strain is marked by an increase in the number of b cells within the thymus of aged females , as well as the presence of mononuclear cell infiltrations within the salivary and lacrimal glands . the major composition of inflammatory infiltrations is reportedly b220 b cells , with a lesser numbers of cd4 t cells . however , small foci consist primarily of cd4 cells , indicating that b cells continuously invade the affected organs as the disease progresses . sialadenitis is present in 80% of female mice with lesions beginning at 6 months of age , and one - third of the animals produce speckled - type igg antinuclear autoantibody by 15 months of age . neither anti - ssa / ro nor anti - ssb / la autoantibodies were detected . expression of mhc class ii antigen is apparent in the ductal epithelial cells surrounding lf . additionally , lymphocytic infiltrations are also observed in the pancreas , kidneys , and lungs as the iqi / jic mice aged . enhanced expression of kallikrein-13 ( klk-13 ) has been detected in salivary glands , suggesting that klk-13 may be a candidate autoantigen in sjs that could contribute to the development of sialadenitis due to increased t cell response to organs expressing klk-13     . the aly / aly mouse possesses the homozygous autosomal recessive mutation alymphoplasia ( aly ) gene , resulting in loss of lymph nodes and peyer 's patches     . subsequently , aly / aly mice readily accept allogenic skin grafts and demonstrate impaired response to t cell - dependent antigens due to absence of germinal center formation . these mice spontaneously develop an sjs - like phenotype by 14  wks of age , with worsening disease as they aged , presenting with chronic salivary and lacrimal gland inflammation as well as inflammation of the exocrine glands of the pancreas . both lung and exocrine gland infiltrations are apparent , with infiltrating cells being primarily cd4cd8 t cells . both salivary and lacrimal glands demonstrate lymphocytic accumulation within periductal areas spanning to the lobules , and lacrimal glands show significant degeneration of acinar cells surrounding infiltrations . tissue damage is minor or absent in salivary glands of aged mice , and the liver shows mild lymphoid cell infiltration . no autoantibodies to self - antigens or nuclear components are apparent , likely due to extreme defects in humoral immunity . human t - cell leukemia virus 1 ( htlv-1 ) is a retrovirus involved in adult t - cell leukemia as well as in the pathogenesis of autoimmune diseases such as sjs , ra , and possibly multiple sclerosis ( ms ) . transgenic mice containing the htlv-1 tax gene under the control of the viral long terminal repeat ( ltr ) acquires an autoimmune phenotype which targeted the exocrine glands . at early age , htlv-1 tax transgenic mice have rapid proliferation of epithelial cells with subsequent ductal proliferation , causing distortion of the salivary gland architecture . however , lacrimal glands develop less severe infiltrations with onset occurring much later than in the salivary glands . massive lf develop between 68 months of age with subsequent destruction of acinar tissues . the degree of destruction corresponds with the level of tax gene expression in the ductal epithelium , suggesting that htlv-1 may be tropic for ductal epithelial cells in the exocrine glands . therefore , it is postulated that htlv-1 may trigger the viral induction of inflammatory lesions via initiation of proliferation and lymphocytic infiltrations . however , disease etiology in this mouse model is likely different from that in human psjs in which lymphocytic infiltration occurs before proliferation of ductal cells . interleukin-6 is a cytokine that influences the immune response , participating in autoimmune disease development and pathogenesis of liver disease . using a murine graft - versus - host reaction ( gvhr ) model with mhc class ii disparity , the amount of autoimmune - like lesions were examined to observe a difference in transgenic mice with high il-6 concentrations . the gvhr il-6 transgenic mice had increased il-6 serum levels and antimitochondrial antibodies ( ama ) , larger spleen indexes , and weakened autoimmune - like lesions of the liver , pancreas , and salivary glands when compared to controls . there is a discrepancy between ama titers and histological features in il-6 tg mice , indicating that ama production may be a result of polyclonal activation of b cells upon stimulation by il-6 . interleukin-10 ( il-10 ) is a cytokine that may contribute to inflammation and pathogenesis in various autoimmune diseases , due to its function in regulating the proliferation and differentiation of b cells and in enhancing mhc class ii antigen expression . il-10 has also been shown to induce expression of cell adhesion molecules on endothelial cells and to trigger apoptotic cell death . il-10 tg mice were generated by using the human salivary amylase promoter to regulate il-10 gene expression . histological examination confirmed the presence of inflammatory lesions within the exocrine glands in 8  wks old mice , with concomitant decreased salivary and lacrimal fluid secretion . staining of lymphocytic infiltrates demonstrated that the cell population was predominantly cd4 with a lesser portion ( < 10% ) of cd8 cells . , no significant difference was observed between igg1 levels in wild - type control and transgenic mice and no autoantibodies were detected . interestingly , cd4 t cells in il-10 tg mice expressed fasl , suggesting that il-10 may play a part in fasl activation of nonspecific bystander t cells , which coincides with fas / fasl - mediated apoptosis in the destruction of acinar tissue . interleukin-12 ( il-12 ) is a heterodimeric cytokine produced mainly by activated macrophages , dendritic cells , and granulocytes which functions in the activation of nk cells and induces cd4 t cell differentiation from a th0 to th1 cell phenotype     [ 69 , 70 ] . il-12 sjl transgenic mice were made by expressing il-12 p70 under the transcriptional control of the thyroglobulin promoter , resulting in il-12 overexpression in the thyroid organ . histopathological analysis showed an increase in mononuclear infiltrates within salivary and lacrimal glands when compared with wild - type mice . lf consist primarily of b220 b lymphocytes with a lesser amount of cd4 t lymphocytes . sex - dependent growth retardation was observed in female , but not male mice , suggesting a sex - specific effect of il-12 overexpression     . a significant decrease in saliva flow rate was evident in both sexes ; however , in males the decrease was age dependent while in females the change was neither age nor gene dose dependent . increased levels of ana were observed at 13 wks , and age - dependent increase in anti - ssb / la autoantibody was also presented ; however , no significant difference in anti - ssa / ro autoantibody was seen when compared with wild - type controls . morphological changes included an increase in acinar cell volume and a decrease in cell number per acinus in the salivary glands     . this mouse model tends to develop autoimmune thyroid disease , indicating the il-12 tg mouse is   a candidate animal model for secondary sjs . interleukin-14 ( il-14 ) is a cytokine produced mainly by t cells and acts as a b cell growth factor . increased levels of il-14 are present in the peripheral blood leukocytes of both psjs and secondary sjs patients with sle     . il-14 tg mice develop hypergammaglobulinemia involving igg , iga , and igm autoantibodies , parotid gland lymphocytic infiltrations , deposits of igm in the kidneys , and mild renal disease . these features are characteristic of human sjs , but also reflect a sle - like phenotype     . development of large b cell lymphomas in aged il-14 tg mice occurs as a result of dysregulation of il-14 which regulates b lymphocyte growth , a common clinical manifestation in both sjs and sle patients     . il-14 tg mice also demonstrate enhanced antibody responses to vaccinations with t - independent and t - dependent antigens . decreased saliva secretion occurs prior to lymphocytic infiltrations of the salivary glands . tear flow has not been fully defined , although lymphocytic infiltrations do occur in the lacrimal glands . less than 25% of il-14 tg mice test positive for anti - ssa / ro and anti - ssb / la which are detected at 12 months of age in the salivary glands , suggesting that other autoantibodies may contribute to the initial phase of sjs development which remains to be determined     . b - cell activating factor ( baff ) is a ligand in the tumor necrosis factor ( tnf ) family which acts as a powerful modulator of b cell activity     . baff is produced by myeloid cells and acts to induce the polyclonal maturation of resting immature b cells to resting mature b cells without stimulating proliferation . several autoimmune diseases , including sle and sjs , have increased blood levels of baff , and neutralization of baff results in disease prevention . mice transgenic for baff develop an sle phenotype , presenting with hyperproliferation of b lymphocytes and elevated levels of rf and anti - dna autoantibodies     . as the baff tg mice age , they develop a secondary sjs - like phenotype by 13 months of age with reduced saliva flow , presenting with enlarged salivary glands and corresponding b220 cells lymphocytic infiltrations with destruction of ductal and acinar cells     . baff tg mice also had severe hypergammaglobulinemia with high levels of immunoglobulins , specifically igg , igm , iga , and ige isotypes ; however , neither anti - ssa / ro or anti - ssb / la autoantibodies were detected     . summarized data for spontaneous and transgenic mouse models is presented   in table 3 . inhibitor of differentiation 3 ( id3 ) is a nuclear protein which inhibits the dna binding of basic - helix - loop - helix ( bhlh ) transcription factors and is involved in both negative and positive regulations of cell growth and differentiation     . id3 is also influential in tcr - mediated t cell selection during t cell development     . id3 null mutants develop lymphocytic infiltrations within the salivary and lacrimal glands by 2 months of age , corresponding with a loss in secretory function . both autoantibodies , anti - ssa / ro and anti - ssb / la , were shown to be present at significant levels after 1 year of age . neonatal 3 day thymectomization or genetic ablation of t cells resulted in an improvement in disease condition , implying that autoimmune t cells are of thymic origin . b cells were observed to behave in cooperation with t cells in the suppression of exocrine function . the phosphoinositide 3-kinase ( pi3k ) enzymes produce 3-phosphorylated phosphoinositides which function as second messengers downstream of multiple receptor types . to create a null mutant for pi3k , a strain with a floxed allele of pik3r1 and a null allele of pik3r2 was crossed with lck - cre transgenic mice , producing the r1t / r2n strain     . the resulting knockout mouse develops an sjs - like autoimmunity , with lymphocytic infiltration of the lacrimal glands and acinar cell atrophy and destruction . infiltrations in the lacrimal glands consist primarily of cd4 t cells with a lesser portions of cd8 t cells and b220 b cells . infiltrations also occur within the lungs , liver , and intestines , with no inflammation in the kidney , supporting a primary sjs disease . the multifunctional cytokine , transforming growth factor beta 1 ( tgf-1 ) , is produced mainly by lymphocytes , macrophages , and dendritic cells and is involved in immunoregulation , embryonic development , hematopoiesis , wound healing , fibrosis , and tumorgenesis     [ 8589 ] . homozygous mutants of the tgf-1 gene experience a rapid onset of severe systemic inflammation which predominantly targets the salivary glands , eyes , heart , skeletal muscle , lungs , liver , stomach , pancreas , and brain     . inflammatory infiltrates vary in cellular compositions across the spectrum of affected organs , from primarily lymphocytic in the brain to primarily neutrophilic in the stomach . salivary gland infiltrations appear at 1  wk of age and increase in severity with age     . mononuclear lymphocytic infiltration in the salivary gland causes rapid atrophy of acinar tissues and high deposition levels of igg , tnf- , ifn- , il-1 , il-4 , il-6 , and il-10 in the lesions . saliva production is significantly affected in tgf-1 ko mice when compared to wild - type controls . peripheral blood analysis of tgf- 1 ko mice revealed the presence of anti - ssdna , anti - dsdna , ana , and glomerular immune complex deposits     . tgf-1 also affects thymocytes differentiation by inhibition of precursor cd4cd8 thymocytes differentiation into mature cd4cd8 thymocytes . thrombospondin-1 ( tsp-1 ) is a matricellular protein which regulates both in vitro and in vivo activation of latent tgf-     [ 92 , 93 ] . relying on the   precise pathogenic effect that tgf- exerts on the autoimmune process of sjs , a tsp-1 deficient mouse strain was created ; however , the deficient mice   presented with less severe inflammation when compared with the tgf- ko mouse . inflammatory infiltrates within the lacrimal glands were first observed at 24  wks of age , consisting primarily of cd4 t cells with a lesser amount of cd8 t cells . tsp-1-deficient mice also demonstrate reduced eye size which occasionally leads to complete closure and loss of eyes . damage to the corneal epithelial barrier is apparent , occurring in conjunction with corneal edema in aged mice . both anti - ssa / ro and anti - ssb / la autoantibodies are detected at elevated levels in the sera , and a significant loss of lacrimal gland secretory function is evident . a twofold increase in il-17a cells was observed in splenocytes , and increased apoptosis and transcriptional levels of il-6 and ifn- were seen in the lacrimal glands of 8-week- old mice . also , a considerable increase in il-17acd4 peripheral t cells was apparent in 24 wks old tsp-1-deficient mice ,   concurrent with reduced levels of ifn-. currently , it is unknown whether this mouse model develops sialadenitis and secretory dysfunction in the salivary glands . the aromatase gene controls activation of estrogen production     . to determine whether estrogen levels may contribute to sjs disease pathogenesis male and female arko mice over 12 months old present with mild splenomegaly , lymphadenopathy , and hypercellularity in the bone marrow , with no apparent lymphocytic infiltrations occurring within the lungs and liver . peripheral blood analysis revealed a 1.5- to 2-fold increase in leukocyte population with a significant increase in the number of b220 b lymphocytes , but no change in the number of t cell antigen receptor- t cells . mild proteinuria and massive lymphocyte infiltration within the kidneys suggest renal dysfunction in the arko mice . in aged arko mice ( 1217 months ) , enlarged salivary glands with massive lymphocytic infiltrations were observed , with severe acinar tissue destruction . sera analysis revealed the presence of anti--fodrin autoantibodies , and analysis of infiltrates in salivary glands showed evidence of proteolytic fragments of -fodrin , indicative of tissue destruction often present in psjs . the arko mice were negative for ana and manifested long - term estrogen deprivation resulting in autoimmune exocrinopathy and occasionally renal failure . frequently , antibodies to carbonic anhydrase ii ( caii ) , a basic zinc metalloenzyme involved in the catalysis of a reversible hydration of carbon dioxide , are characteristic of autoimmune pancreatitis     [ 97 , 98 ] . however , recent findings suggest their presence in other autoimmune diseases such as sjs as well as connective tissue diseases     . autoimmune sialadenitis was induced in pl / j(h-2 ) mice by immunization with human carbonic anhydrase ii ( caii )   . mice immunized with caii developed an increase in the size and focus score in the salivary and lacrimal glands . in addition the animals manifested disintegration and atrophy of surrounding acinar cells . a small percentage of caii - immunized mice demonstrated smaller lf within the pancreas and kidney , similar to human sjs patients who develop chronic pancreatitis and renal tubular acidosis     [ 100 , 101 ] . serum antibody reactive to caii has been reported in several autoimmune diseases , including sjs , chronic pancreatitis ( cp ) , and autoimmune cholangitis . however , no proliferative responses of peripheral blood mononuclear cells ( pbmc ) to caii were observed , indicating caii is probably not a key target antigen for the immune response in the origination and development of sjs and cp     . anti - ssa / ro autoantibody is present at a significantly high level in patients with severe autoimmune diseases and serves as a standard diagnostic biomarker for   sjs and sle . balb / c mice immunized with short peptides from the 60-kda ro ( ssa ) antigen , known to induce epitope spreading , develop an immune response to the ro / la ribonucleoprotein particle . ro immunized mice present with lymphocytic infiltrations within the salivary glands composed primarily of cd4 ( 45% ) and cd8 ( 18% ) t cells and cd19 ( 35% ) b lymphocytes , concurrent with a significant decrease in saliva flow rate . intermolecular epitopes spreading can be prevented by oral administration of the ro 60 autoantigen to ro immunized mice , inhibiting salivary gland lymphocytic infiltrations and increasing salivary flow rate ; however , epitope spreading is indicative of minimal tolerance to ro and la in the b cell and t cell compartments      [ 106110 ] . this model however requires repeated immunizations with ro peptide emulsified in freund 's adjuvant over the course of several wks , with disease development not occurring until 4 months , raising the issue of a completely different etiological scenario than is seen in human sjs patients     . the role of anti - ssa / ro is not well understood in either sjs mouse models or in human sjs patients ; therefore , further study is needed to examine the pathogenic role of ro antigen . environmental triggers have been postulated to be capable of inducing autoimmunity in genetically predisposed individuals . several viruses including epstein - barr virus ( ebv ) , hepatitis c virus , and cytomegalovirus ( cmv ) have been associated with the development of sjs . frequently , individuals who are immunocompromised develop sialadenitis upon cmv infection due to viral replication which occurs primarily within the ductal epithelium of the salivary glands     . in mice , however , murine cmv ( mcmv ) instead replicates within the serous acinar epithelial cells of the submandibular gland     [ 113115 ] . salivary gland infection in mice produces an extended inflammatory immune response which leads to epithelial cell death and regeneration . four different strains of mice ( c57bl/6 [ b6]-+/+ , fas - deficient b6-lpr / lpr , tnfri - deficient b6-tnfr1 , and b6-tnfr1-lpr / lpr ) infected with murine cmv ( mcmv ) were shown to manifest certain phenotypes of sjs - like disease . for instance , fas - deficient b6-lpr / lpr mice infected with murine cmv ( mcmv ) developed anti - ro and anti - la autoantibodies and persistent severe lymphocytic infiltrations within the salivary glands that remained 100 days postinfection even after viral clearance . neither c57bl/6 [ b6]-+/+ nor tnfri - deficient b6-tnfr mice infected with mcmv had inflammation in the salivary glands at 100 days postinfection , although infiltrations were observed in both strains at 28 days postinfection . in mcmv - infected b6-tnfr1-lpr / lpr mice , identical salivary gland inflammation to mcmv - infected b6-lpr / lpr mice was observed at 28 days , and no inflammation was apparent in uninfected b6-lpr / lpr controls . all mice developed sialadenitis by 28 days which was still present at 100 days postinfection . autoimmune - prone nzm2328 mice infected with mcmv are also capable of recapitulating certain phenotypes of sjs - like disease     . infected female nzm2328 mice have severe chronic lymphocytic infiltrations in the exocrine glands composed of cd4 t cells and b220 b cells . severe local inflammations coincide with presence of organ - targeted autoantibodies against glandular antigens as well as reduced saliva volumes . anti - ro / ssa or anti - la / ssb is not detected in virus - infected animals . however , both infected male nzm2328 mice and female b6-lpr mice have significantly less severe glandular infiltrations . interestingly , animal models of mcmv - induced sjs only require a single exposure to the virus which could serve as an ideal animal model examining the early phase of human sjs development . autoimmunity resembling a sjs phenotype can be induced in hybrid mice upon transplantation of leukocytes from a parental strain to nonirradiated f1 recipients , generating a chronic graft - versus - host reaction ( gvhr )     [ 119121 ] . haematopoietic transplantation chimeras were produced by transplantation of spleen cells from balb / c donors to nonirradiated f1-hybrids of balb / c and cba / h - t6 mice   . both male and female chimeras were shown to subsequently develop a sjs - like phenotype with enlarged lymph nodes and nodulated contorted spleens at 7 months after transplantation . males manifested a more severe disease phenotype found in the lymph nodes and spleen when compared to both female chimeras and wild type controls . sera were negative for autoantibodies against dna , but positive ana with a nucleolar pattern was observed in most chimeric mice . raised levels of albumin in the urine of both males and females were found , with higher levels in males . kidneys in both sexes demonstrated lymphocyte  cuffs  with plasma cells surrounding the vessels and no igg , iga , or igm deposits were found in glomeruli . mononuclear cell infiltrates were apparent in both the salivary and lacrimal glands of male and female chimeras with no difference in severity between sexes . the spleens showed ordinary size and distribution of red pulp , but diminished or absent white pulp . the rim of lymphocytes was absent , and cells were enlarged within the germinal centers . the nodules in the spleen indicate that donor spleen colony - forming units have invaded the recipient spleen , resulting in competition with lymphohaematopoietic cells . the chimeric animals   showed the absence of typical clinical phenotypes of   sjs , including splenomegaly , hepatomegaly , high albuminuria , anti - dsdna autoantibodies , ascites formation , and immune complex glomerulonephritis . summarized data for knockout , immunization , infection , and transplantation chimera mouse models is presented in table 4 . as demonstrated by the vast range of available mouse models , sjs is a highly complex disease whose etiology is still not well understood . it is likely that sjs pathogenesis involves an intricate relationship between genetics and environmental factors which can provoke both innate and adaptive immunity , hormone secretion , and the autonomic nervous system into triggering the initiation and progression of the disease . animal models demonstrate a variety of potential pathologies for the disease , ranging from overproduction of inflammatory cytokines to exposure by exocrine gland - targeting viruses . therefore , these animal models provide a useful tool in observing the different stages in the glandular pathophysiological abnormality to the loss of immune tolerance and eventually to the onset of overt or clinical disease . in addition , they can serve as great tools in designing diagnoses , as well as in prevention and treatment therapies . each mouse model possesses its own advantages , as well as pitfalls , and no ideal model for the study of sjs currently exists . spontaneous models naturally develop sjs and appear most similar to the human sjs disease , but still have their drawbacks . knock - out animal models can also be useful , allowing observation of the importance a particular protein , regulatory mechanism , or cell type has in disease development , leading to improved treatment options . however , no sjs mouse model fulfills all of the necessary characteristics of the human disease , and such discrepancies may cause progress in the field to come to a standstill .
sjgren 's syndrome ( sjs ) is a complex chronic autoimmune disease of unknown etiology which primarily targets the exocrine glands , resulting in eventual loss of secretory function . 
 the disease can present as either primary sjs or secondary sjs , the latter of which occurs concomitantly with another autoimmune disease such as rheumatoid arthritis , systemic lupus erythematosus , scleroderma , or primary biliary cirrhosis . 
 current advancements in therapeutic prevention and treatment for sjs are impeded by lack of understanding in the pathophysiological and clinical progression of the disease . 
 development of appropriate mouse models for both primary and secondary sjs is needed in order to advance knowledge of this disease . 
 this paper details important features , advantages , and pitfalls of current animal models of sjs , including spontaneous , transgenic , knockout , immunization , and transplantation chimera mouse models , and emphasizes the need for a better model in representing the human sjs phenotype .