Tolerance and Autoimmunity

Kamradt, Thomas; Mitchison, N. A.

doi:10.1056/nejm200103013440907

Cited by 393 publications

(219 citation statements)

References 149 publications

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“…Infectious agents have been linked to the etiology of immune disorders, including diabetes (Dahlquist 1998;EURODIAB 2000;Kamradt and Mitchison 2001;Notkins and Lernmark 2001), RA (Albert and Inman 1999;Ebringer and Wilson 2000;, and asthma (Blasi et al 2001). A lack of infections in early life may also adversely affect immune development-the so-called hygiene hypothesis (Bach 2002).…”

Section: Resultsmentioning

confidence: 99%

Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence.

Staples

Ponsonby

Lim

et al. 2003

Environ Health Perspect

157

104

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The apparent immune-suppressive effect of ultraviolet radiation (UVR) has suggested that this environmental exposure may influence the development of immune-related disorders. Self-reported prevalence rates of type 1 diabetes mellitus, rheumatoid arthritis (RA), eczema/dermatitis, and asthma, from the 1995 Australian National Health Survey, were therefore examined by latitude and ambient level of UVR. A positive association of type 1 diabetes mellitus prevalence was found with both increasing southern latitude of residence (r = 0.77; p = 0.026) and decreasing regional annual ambient UVR (r = -0.80; p = 0.018); a 3-fold increase in prevalence from the northernmost region to the southernmost region was evident. In contrast, asthma correlated negatively with latitude (r = -0.72; p = 0.046), although the change in asthma prevalence from the north to the south of Australia was only 0.7-fold. For both RA and eczema/dermatitis, there were no statistically significant associations between latitude/UVR and disease prevalence. These ecologic data provide some support for a previously proposed beneficial effect of UVR on T-helper 1-mediated autoimmune disorders such as type 1 diabetes. The inverse association of type 1 diabetes prevalence with UVR is consistent with that previously reported for another autoimmune disease, multiple sclerosis, in Australia, and also with type 1 diabetes latitudinal gradients in the Northern Hemisphere. The finding also accords with photoimmunologic evidence of UVR-induced immunosuppression and may suggest a beneficial effect of UVR in reducing the incidence of such autoimmune conditions. In light of this study, analytic epidemiologic studies investigating risk of immune disorders in relation to personal UVR exposure in humans are required.

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Section: Resultsmentioning

confidence: 99%

Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence.

Staples

Ponsonby

Lim

et al. 2003

Environ Health Perspect

157

104

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show abstract

“…A utoimmune disease is a pathological condition in which the immune system turns on itself and causes serious damage to the organism's tissues by as yet unknown mechanisms (1). A unifying concept for the mechanisms underlying the development of autoimmune disease has been one of the major challenges of immunological studies.…”

Section: Nf-b-inducing Kinase Establishes Self-tolerance In a Thymicmentioning

confidence: 99%

NF-κB-Inducing Kinase Establishes Self-Tolerance in a Thymic Stroma-Dependent Manner

Kajiura¹,

Sun²,

Nomura

et al. 2004

The Journal of Immunology

197

225

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Physical contact between thymocytes and the thymic stroma is essential for T cell maturation and shapes the T cell repertoire in the periphery. Stromal elements that control these processes still remain elusive. We used a mouse strain with mutant NF-κB-inducing kinase (NIK) to examine the mechanisms underlying the breakdown of self-tolerance. This NIK-mutant strain manifests autoimmunity and disorganized thymic structure with abnormal expression of Rel proteins in the stroma. Production of immunoregulatory T cells that control autoreactive T cells was impaired in NIK-mutant mice. The autoimmune disease seen in NIK-mutant mice was reproduced in athymic nude mice by grafting embryonic thymus from NIK-mutant mice, and this was rescued by supply of exogenous immunoregulatory T cells. Impaired production of immunoregulatory T cells by thymic stroma without normal NIK was associated with altered expression of peripheral tissue-restricted Ags, suggesting an essential role of NIK in the thymic microenvironment in the establishment of central tolerance.

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“…1 In addition to central tolerance, various peripheral mechanisms, including T-cell anergy or peripheral T-cell deletion, cooperate to prevent unwanted T-cell immune responses directed against self-antigens. 1 Recently, active suppression by CD4 þ CD25 þ regulatory T cells (Treg) has been extensively explored as a mechanism involved in limiting autoimmunity 2,3 as well as a way to induce transplantation tolerance. 4 Thus, CD4 þ CD25 þ Treg cells have been shown to prevent acute graft-versus-host disease (GvHD), 5,6 a frequent complication of allogeneic hematopoietic cell (HC) transplantation.…”

Section: Introductionmentioning

confidence: 99%

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

et al. 2005

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Apoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-bdependent donor CD4 þ CD25 þ T-cell expansion. Such cells have a regulatory phenotype (CD62L high and intracellular CTLA-4 þ ), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover.

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Tolerance and Autoimmunity

Cited by 393 publications

References 149 publications

Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence.

Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence.

NF-κB-Inducing Kinase Establishes Self-Tolerance in a Thymic Stroma-Dependent Manner

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

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