IntroductionTransforming growth factor beta (TGF-␤) is recognized as a highly pleiotropic family of growth factors involved in the regulation of numerous physiologic processes including development, hematopoiesis, wound healing, and immune response. The 3 isoforms of this growth factor that have been identified in mammals (TGF-␤1, -␤2, and -␤3) are encoded by distinct genetic loci and share a high level of homology. They act on virtually all cell types and mediate similar cellular responses in vitro, like regulation of proliferation, differentiation, apoptosis, and extracellular matrix synthesis. [1][2][3] In vivo, however, they demonstrate partly unique sets of physiologic functions due to different tissue distribution and temporal expression during development. [4][5][6] The TGF-␤ isoforms exert all their cellular functions through formation of a tetrameric complex with the 2 cell surface receptors T␤RI and T␤RII. Complex formation leads to phosphorylation of T␤RI on serine/threonine residues and propagation of the intracellular signal to the nucleus through a chain of phosphorylations of Smads, which regulate gene expression in cooperation with other transcription factors. 7 A growing body of evidence suggests TGF-␤ to be one of the major regulators of immune function, acting both by suppressive and stimulatory mechanisms on leukocytes to achieve a balanced immune response. [8][9][10] The suppressive mode of action has been highlighted by studies demonstrating inhibition of interleukin 1 (IL-1)-, IL-2-, and IL-7-dependent thymocyte proliferation by TGF-␤ 11-16 through autocrine and paracrine mechanisms, 13,17,18 whereas immunostimulatory functions were suggested by the capacity of TGF-␤ to induce cytokine expression in T cells and to promote effector expansion by inhibition of apoptosis. [19][20][21] Moreover, the influence of TGF-␤ on the development and function of other cells of the immune system, such as B cells, macrophages, and dendritic cells, has been reported. 10 Striking evidence for the importance of TGF-␤ in immune regulation was reported from studies on TGF-␤-null animals that demonstrated postnatal lethality and massive multifocal inflammation affecting multiple organs. 9,22,23 The uncontrolled inflammatory reaction has been ascribed to autoimmune mechanisms including autoantibodies and autoreactive T cells. [24][25][26][27] However, attempts to develop the phenotype by transplanting TGF-␤1-null bone marrow to healthy recipient mice unexpectedly resulted in minute inflammatory signs that did not cause clinical symptoms. 25 This raised the possibility that the presence of immune cells deficient for TGF-␤1 is not sufficient to cause the inflammatory phenotype. Alternatively, TGF-␤1-deficient donor cells may be responsive to endocrine or paracrine sources of TGF-␤1 produced by recipient tissues.Further evidence strongly suggests a role of TGF-␤ in the regulation of inflammation using dominant-negative transgenic For personal use only. on May 12, 2018. by guest www.bloodjournal.org From mouse models...

The nonobese diabetic (NOD) mouse spontaneously develops autoimmune‐mediated diseases such as diabetes and Sjögren′s syndrome. To investigate whether NOD genes also promote autoimmune‐mediatedarthritis we established a NOD strain with an MHC class II fragment containing the Aq class II gene predisposing for collagen induced arthritis (NOD.Q). However, this mouse was resistant to arthritis in contrast to other Aq expressing strains such as B10.Q and DBA/1. To determine the major resistance factor/s, a genetic analysis was performed. (NOD.Q×B10.Q)F1 mice were resistant, whereas 27% of the (NOD.Q×B10.Q)F2 mice developed severe arthritis. Genetic mapping of 353 F2 mice revealed two loci associated with arthritis. One locus was found on chromosome 2 (LOD score 9.8), at the location of the complement factor 5 (C5) gene. The susceptibility allele was from B10.Q, which contains a productive C5 encoding gene in contrast to NOD.Q. The other significant locus was found on chromosome 1 (LOD score 5.6) close to the Fc‐gamma receptor IIb gene, where NOD carried the susceptible allele. An interaction between the two loci was observed, indicating that they operate on the same or on interacting pathways. The genetic control of arthritis is unique in comparison to diabetes, since none of these loci have been identified in analysis of diabetes susceptibility.

The non‐obese diabetic (NOD) mouse spontaneously develops diabetes and sialadenitis. The sialadenitis is characterized by histopathological changes in salivary glands and functional deficit similar to Sjögren's syndrome. In humans, Sjögren's syndrome could be associated with other connective tissue disorders, such as rheumatoid arthritis. In the present study the genetic control of sialadenitis in mice was compared to that of arthritis. We have previously reported a NOD locus, identified in an F2 cross with the H2q congenic NOD (NOD.Q) and C57BL/10.Q (B10.Q) strains, that promoted susceptibility to collagen‐induced arthritis. The sialadenitis in NOD.Q showed a similar histological phenotype as in NOD, whereas no submandibular gland infiltration wasfound in B10.Q. The development of sialadenitis was independent of immunization with type II collagen and established arthritis. To identify the genetic control of sialadenitis, a gene segregation experiment was performed on an (NOD.Q×B10.Q)F2 cross and genetic mapping of 353 F2 mice revealed one significant locus associated with sialadenitis on chromosome 4, LOD score 4.7. The NOD.Q allele‐mediated susceptibility under a recessive inheritance pattern. The genetic control of sialadenitis seemed to be unique in comparison to diabetes and arthritis, as no loci associated with these diseases have been identified at the same location.

We investigated the role of the major histocompatibility complex (MHC) region in the specificity of autoimmunity by analysing specifically the development of sialadenitis, but also insulitis, nephritis and autoantibody production in autoimmune-prone nonobese diabetic (NOD) mice where the MHC H2 g7 haplotype had been exchanged for the H2 q (NOD.Q) or H2 p (NOD.P) haplotype. The exchange of H2 haplotype did not affect the frequency of sialadenitis because the H2 q and H2 p congenic NOD strains developed sialadenitis with the same incidence as NOD. However, the severity of sialadenitis varied among the strains, as NOD.Q > NOD > NOD.P. At 11-13 weeks of age, the NOD.Q (H2 q ) female mice developed more severe sialadenitis compared to NOD.P (H2 p ) (P ¼ 0.038). At 20 weeks, the NOD (H2 g7 ) female mice showed more severe sialadenitis than NOD.P (P ¼ 0.049). This is in contrast to the development of insulitis in the present strains, because the incidence of insulitis was almost completely inhibited by the replacement of the H2 g7 haplotype of NOD. The incidence of insulitis in NOD.Q was 11-22%, compared to 75% in NOD, which correlated well with lower titres of anti-glutamic acid decarboxylase (anti-GAD) antibodies in NOD.Q compared to NOD (P ¼ 0.009). However, the introduction of the H2 q haplotype into the NOD strain instead directed the autoimmune response towards the production of lupus types of autoantibodies, because the incidence of antinuclear antibodies (ANA) in NOD.Q was 89% compared with 11% in NOD.P and 12% in NOD mice, which in turn correlated with a high incidence of nephritis in NOD.Q compared to NOD. Consequently, we show that different haplotypes of MHC are instrumental in directing the specificity of the spontaneous autoimmune inflammation.