Info

Splenic CD4+T cells (5 x 107) were transferred into BALB.B-scid/scid mice, and the development of arthritis was inspected after 12 weeks * p <0.05 vs TNFa+/+-IL-1Ra-/- mice by x2 test ** p <0.01 vs TNFa+/+-IL-1Ra-/- mice by x2 test

Splenic CD4+T cells (5 x 107) were transferred into BALB.B-scid/scid mice, and the development of arthritis was inspected after 12 weeks * p <0.05 vs TNFa+/+-IL-1Ra-/- mice by x2 test ** p <0.01 vs TNFa+/+-IL-1Ra-/- mice by x2 test suggest that TNFa derived from both T cells and synovial lining cells is involved in the development of arthritis.

We previously showed that IL-1 plays an important role in the enhancement of T cell-APC interactions through the induction of CD40L and 0X40 on T cells (Nakae et al. 2001b). Consistently with this observation, CD40L and 0X40 expression were enhanced in T cells stimulated with antigen-bearing IL-1Ra-/- APCs in comparison to WT APCs. On the other hand, ligation of CD40 on APCs by CD40L induces 0X40L expression and TNFa production by APCs (van Kooten and Banchereau 2000; Weinberg 2002). Furthermore, we have demonstrated that TNFa induces 0X40 expression on T cells (Horai et al. 2004). Thus, upon interaction with antigens, APCs produce IL-1. IL-1, in turn, activates T cells, resulting in the induction of CD40L. The CD40L-CD40 interaction induces APCs to produce 0X40L and TNFa, resulting in the induction of 0X40 on T cells. Therefore, it is suggested that TNFa plays an important role in the sensitization of T cells and contributes to the development of autoimmunity.

It is known that TNFa-/- mice lack splenic primary B cell follicles and cannot form either organized follicular dendritic cell (DC) networks or germinal centers in the spleen and peripheral lymphatic organs (Pasparakis et al. 1996). Prolonged antibody responses are generally impaired in TNFa-/- mice, although Ig class-switching is not completely deficient. It is therefore reasonable to suppose that these functions of TNFa in the humoral immune responses may also contribute to the development of autoimmunity in IL-1Ra-/- mice. However, since we could not induce arthritis by transferring IL-1Ra-/- mouse serum into WT mice, only a weak contribution of humoral immune responses is suggested in this animal model (Horai and Nakajima, unpublished results).

0n the other hand, it is known that TNFa elicits inflammation by activating and recruiting inflammatory cells and inducing proinflamma-tory cytokines and chemokines, such as IL-1, IL-6, and CXCLIO (Pang et al. 1994; Nakae et al. 2003b). In this context, mouse models that exhibit higher amounts of TNFa protein, such as transgenic (Tg) mice carrying the TNFa gene or mice deficient for the TNFa AU-rich element (TNFaare), spontaneously develop arthritis (Keffer et al. 1991; Kontoyiannis et al. 1999). It was suggested that innate and/or stromal mechanisms rather than T cell-mediated autoimmune mechanisms are involved in the development of arthritis, because arthritis develops in RAG1-/- background, although Crohn's-like disease is induced by an immune-mediated mechanism in the same model (Kontoyiannis et al. 1999). Likewise, inflammatory cytokines, such as IL-1 and TNFa, but not IL-6, play important roles in the effector phase of the disease in the K/BxN model, although the effect of TNFa deficiency was not as strong in this model compared to that seen in the IL-1Ra-/- mice (Ji et al. 2002). Taken together, these observations suggest that TNFa plays important roles in both sensitization of T cells and elicitation of inflammation in the development of arthritis in IL-1Ra-/- mice.

8.2.3 The Role of IL-17 in the Development of Arthritis

IL-17 levels in IL-1Ra-/- mouse joints were elevated from the levels seen in wild-type mice. After stimulation with CD3, IL-17 production was greatly enhanced in IL-1Ra-/- T cells (Nakae et al. 2003d). In our examination of the development of arthritis in IL-17-/- mice, we demonstrated that IL-17-deficiency completely suppressed the onset of disease in IL-1Ra-/- mice (Nakae et al. 2003d). Joint inflammation was also suppressed in IL-17-/--human T cell leukemia virus type I (HTLV-I) Tg mice carrying the HTLV-I tax gene, another RA model in which arthritis develops spontaneously (Iwakura et al. 1991; unpublished observation). An important role for IL-17 was also indicated in the CIA model (Nakae et al. 2003c). We have shown that, upon stimulation with ovalbumin (OVA), OVA-specific T cell proliferation was low in T cells from IL-17-/--DO11.10 mice (Nakae et al. 2002, 2003d), mice carrying an OVA-specific T cell receptor transgene. These results suggest that IL-17 is involved in T cell priming. Consistent with this notion, we demonstrated that the sensitization of T cells following immunization with type II collagen was significantly reduced in IL-17-/- mice (Nakae et al. 2003c). Nonetheless, since both the incidence and the severity score were reduced in IL-17-/- mice in CIA, IL-17 may function not only at the sensitization phase but also the elicitation phase.

As mentioned above, IL-1Ra production by T cells is critical in the regulation of T cell activity by acting on T cells in an autocrine manner

(Horai et al. 2004). It is known that IL-1 induces CD40L on T cells, and CD40 signaling activates TNFa expression in APCs (van Kooten and Banchereau 2000; Nakae et al. 2001b). Since the TNFa induces 0X40 expression on T cells (Horai et al. 2004) and IL-17 production by T cells was induced by 0X40 activation (Nakae et al. 2003d), TNFa-mediated induction of 0X40 expression in T cells may induce production of IL-17, resulting in the exacerbation of inflammation. Thus, it was suggested that both CD40L-CD40 and 0X40L-0X40 play important roles in the development of autoimmunity. In agreement with this notion, blockade of the CD40L-CD40 or 0X40-0X40L interaction inhibited arthritis development in IL-1Ra-/- mice (Horai et al. 2004). These observations suggest that T cell-dependent autoimmu-nity is induced in IL-1Ra-/- mice through the induction of TNFa and IL-17, as the downstream mediators of the IL-1 action, and these cytokines also play important roles in the elicitation phase of inflammation (Fig. 3).

Fig. 3. Crucial roles for IL-17 and TNFa, downstream of IL-1 signaling, in the pathogenesis of arthritis

8.3 The Roles of TNFa and IL-17 in the Development of Aortitis

8.3.1 Development of Aortitis in IL-1Ra-/- Mice

IL-1Ra-/- mice on the BALB/c background spontaneously developed arterial inflammation at 4 weeks of age. Approximately 50% of the mice were affected by 12 weeks (Matsuki et al. 2005). A similar observation was reported in IL-1Ra-/- mice on the 129/Ola x MF1 background (Nicklin et al. 2000). On the C57BL/6 background, however, there were no signs of arterial inflammation, suggesting the significant involvement of background genes in the development of aortitis, a similar observation that has been made for arthritis (Horai et al. 2000). In F2 hybrids of BALB/c- and C57BL/6-IL-1Ra-/- mice, arthritis was rare but aortic inflammation was common, indicating that the sets of background modifier genes that cause susceptibility to each disease are not fully overlapping (Shepherd et al. 2004).

Inflammation of the cardiovascular system was observed preferentially at the aortic root of IL-1Ra-/- mice (Fig. 4) (Matsuki et al. 2005). The infiltration of monocytes and occasionally neutrophils was observed in the aorta and aortic valve. A loss of elastic lamellae in the aortic media could be observed by histological examinations. Mono-cytes/macrophages and some neutrophils had infiltrated the inflammatory sites within the aortic sinus. Thus, the aortic inflammation in these animals may have characteristics of both acute and chronic phases of disease. We identified numerous examples of neovascularization within severe lesions. Chondrocyte-like cells were observed in the majority of IL-1Ra-/- mouse aortas; no such cells could be observed in the aortas of WT mice. Calcification of the media of the aorta was observed in a subset of IL-1Ra-/- mice. As calcification of the media, involving the degradation of smooth muscle cells, is a sign of degenerative processes (Tanimura et al. 1986a, 1986b), this result suggests the involvement of an immune response in this pathology. These mice suffered from mild aortic stenosis and hyperplasia of the interventricular septum and left ventricular posterior walls. In agreement with previous reports, these pathological findings resemble aspects of Takayasu arteritis or polyarteritis nodosa in humans (Nicklin et al. 2000).

Fig. 4. Attenuation of the development of aortitis in IL-1Ra-//- mice by IL-17 deficiency. Sections of the aorta were examined by staining with (A-C) hematoxylin and eosin and (D-F) Masson's trichrome (Isoda et al. 2002). A, D Sections of the aortic valve (score 0) from a 20-week-old unaffected IL-17+/--IL-1Ra-'- mouse. B, E Sections from a 20-week-old affected IL- 17+/--IL-1Ra-//- mouse. Severe inflammatory cell infiltration and loss of elastic lamellae over greater than two-thirds of the media of the aortic sinus are observed (score 3). C, F Sections from an 20-week-old IL-17-/--IL-1Ra-/- mice. Mild inflammatory cell infiltration and loss of elastic lamellae are observed (score 2)

Fig. 4. Attenuation of the development of aortitis in IL-1Ra-//- mice by IL-17 deficiency. Sections of the aorta were examined by staining with (A-C) hematoxylin and eosin and (D-F) Masson's trichrome (Isoda et al. 2002). A, D Sections of the aortic valve (score 0) from a 20-week-old unaffected IL-17+/--IL-1Ra-'- mouse. B, E Sections from a 20-week-old affected IL- 17+/--IL-1Ra-//- mouse. Severe inflammatory cell infiltration and loss of elastic lamellae over greater than two-thirds of the media of the aortic sinus are observed (score 3). C, F Sections from an 20-week-old IL-17-/--IL-1Ra-/- mice. Mild inflammatory cell infiltration and loss of elastic lamellae are observed (score 2)

Using peripheral T cell transplantation, we also examined the role of T cells in the development of aortitis (Matsuki et al. 2005). Purified T cells from the spleens and lymph nodes of 6- to 8-week-old IL-1Ra-/-mice were transplanted into BALB/c-nu/nu mice, and the development of aortitis in the recipient mice was analyzed 10 weeks after transplantation. Twelve of the 13 recipient mice developed aortitis, indicating that T cells are crucial in the pathogenesis of aortitis. As arthritis is also induced by IL-1Ra-/- T cell transplantation, the pathogenesis of aortitis likely utilizes a similar mechanism as that seen in arthritis, in which T cell-mediated autoimmunity caused by excess IL-1 signaling is involved.

8.3.2 The Roles of TNFa and IL-17 in the Development of Aortitis

We examined the roles of TNFa and IL-17 in the development of aortitis by intercrossing these cytokine-deficient mice to IL-1Ra-/- mice. The aortic valves of these cytokine-deficient IL-1Ra-/- mice were analyzed histologically. Interestingly, TNFa-/- -IL-1Ra-/- mice showed no signs of arterial inflammation at 8 and 14 weeks of age, while approximately 50% of the TNFa+/+-IL-1Ra-/- mice developed aortitis at these ages (Matsuki et al. 2005). The incidence of aortitis in IL-17-/--IL-1Ra-/-mice was similar to IL-17+/--IL-1Ra-/- mice at 20-28 weeks of age (Table 2). The disease severity score, however, was significantly reduced in these IL17-/--IL-1Ra-/- mice (Fig. 4). Thus, in IL-1Ra-/- mice, TNFa is crucial for the development of aortitis. While IL-17 is not essential for aortitis development, it aggravates the disease, appearing to function at both the elicitation of inflammation and the sensitization of T cells.

As mentioned already, we have demonstrated that T cell-derived TNFa plays an important role for the sensitization of T cells in the development of autoimmunity in IL-1Ra-/- mice (Horai et al. 2004). Other investigators have also reported the production of TNFa in T cells (Ramshaw et al. 1994; Sakaguchi et al. 1995) and the presence of TNF receptors in aortic smooth muscle and endothelial cells (Field et al. 1997). Thus, upon T cell activation, T cells produce TNFa, and this T-cell derived TNFa may activate endothelial cells to produce various

Table 2. Suppression of the development of aortitis in mice
Osteoarthritis

Osteoarthritis

Thank you for deciding to learn more about the disorder, Osteoarthritis. Inside these pages, you will learn what it is, who is most at risk for developing it, what causes it, and some treatment plans to help those that do have it feel better. While there is no definitive “cure” for Osteoarthritis, there are ways in which individuals can improve their quality of life and change the discomfort level to one that can be tolerated on a daily basis.

Get My Free Ebook


Post a comment