Aberrant expression of Class II major histocompatibility complex molecules by B cells and hyperexpression of Class I major histocompatibility complex molecules by insulin containing islets in Type 1 (insulin-dependent) diabetes mellitus

Foulis, Alan K.; Farquharson, M. A.; Hardman, Rebecca E.

doi:10.1007/bf00299027

Cited by 232 publications

(165 citation statements)

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“…This latter phenomenon is intimately associated with IFN-α production by beta cells [17] and is unique to type 1 diabetes [31]. Thus, vp1 staining of beta cells does not appear to be directly associated with secretion of IFN-α and it is unclear why IFN-α is produced by beta cells in those islets which hyperexpress class I MHC [26] but have no demonstrable viral capsid protein.…”

Section: Discussionmentioning

confidence: 99%

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

et al. 2009

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Aims/hypothesis Evidence that the beta cells of human patients with type 1 diabetes can be infected with enterovirus is accumulating, but it remains unclear whether such infections occur at high frequency and are important in the disease process. We have now assessed the prevalence of enteroviral capsid protein vp1 (vp1) staining in a large cohort of autopsy pancreases of recent-onset type 1 diabetic patients and a range of controls. Methods Serial sections of paraffin-embedded pancreatic autopsy samples from 72 recent-onset type 1 diabetes patients and up to 161 controls were immunostained for insulin, glucagon, vp1, double-stranded RNA activated protein kinase R (PKR) and MHC class I. Results vp1-immunopositive cells were detected in multiple islets of 44 out of 72 young recent-onset type 1 diabetic patients, compared with a total of only three islets in three out of 50 neonatal and paediatric normal controls. vp1 staining was restricted to insulin-containing beta cells. Among the control pancreases, vp1 immunopositivity was also observed in some islets from ten out of 25 type 2 diabetic patients. A strong correlation was established between islet cell vp1 positivity and PKR production in insulin-containing islets of both type 1 and type 2 diabetic patients, consistent with a persistent viral infection of the islets. Conclusions/interpretation Immunoreactive vp1 is commonly found in the islets of recent-onset type 1 diabetes patients, but only rarely in normal paediatric controls. vp1 immunostaining was also observed in some islets of type 2 diabetes patients, suggesting that the phenomenon is not restricted to type 1 diabetes patients.

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Section: Discussionmentioning

confidence: 99%

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

et al. 2009

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“…The degree of overexpression of MHC class I molecules in cells infected with reovirus (7-to 8-fold) (9) or exposed to gamma interferon (10-fold) (6,12), and in thyroid cells infected with simian virus 40 (4-fold on immunofluorescence scoring) (3), is similar to that in the homozygous transgenic mice (4-fold compared with nontransgenic mice). Although not quantitated, the level of MHC class I overexpression in human autoimmune thyroid disease and IDD (4,17,19) appears to approximate that seen in the RIP-Kb model (1) and in the thyroid transgenic model described in this report. The role of MHC class I expression in autoimmunity may, however, be more complex in light of a recent report that the expression of MHC class I is reduced in splenocytes from NOD mice and peripheral blood lymphocytes from humans with IDD (16), although these findings await confirmation.…”

Section: Methodsmentioning

confidence: 48%

“…The overexpression of major histocompatibility complex (MHC) class I molecules is an early feature of the pathology in autoimmune diseases, e.g., in pancreatic islet p cells in insulin-dependent diabetes (IDD) and thyrocytes in Graves' disease (17,19). This feature can be present in the absence of an inflammatory cell infiltrate, suggesting that it may be independent of and precede the effects of cytokines released from infiltrating mononuclear cells (4,17).…”

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confidence: 99%

“…This feature can be present in the absence of an inflammatory cell infiltrate, suggesting that it may be independent of and precede the effects of cytokines released from infiltrating mononuclear cells (4,17). The finding of immunoreactive alpha interferon in the early lesion of IDD could provide an explanation for the overexpression of MHC class I molecules and might itself reflect the presence of underlying virus infection (18).…”

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confidence: 99%

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Nonimmune thyroid destruction results from transgenic overexpression of an allogeneic major histocompatibility complex class I protein.

Frauman¹,

Chu²,

Harrison³

1993

Mol. Cell. Biol.

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The overexpression of major histocompatibility complex (MHC) class I molecules in endocrine epithelial cells is an early feature of autoimmune thyroid disease and insulin-dependent diabetes mellitus, which may reflect a cellular response, e.g., to viruses or toxins. Evidence from a transgenic model in pancreatic beta cells suggests that MHC class I overexpression could play an independent role in endocrine cell destruction. We demonstrate in this study that the transgenic overexpression of an allogeneic MHC class I protein (H-2Kb) linked to the rat thyroglobulin promoter, in H-2Kk mice homozygous for the transgene, leads to thyrocyte atrophy, hypothyroidism, growth retardation, and death. Thyrocyte atrophy occurred in the absence of lymphocytic infiltration. Tolerance to allogeneic class I was revealed by the reduced ability of primed lymphocytes from transgenic mice to lyse H-2Kb target cells in vitro. This nonimmune form of thyrocyte destruction and hypothyroidism recapitulates the beta-cell destruction and diabetes that results from transgenic overexpression of MHC class I molecules in pancreatic beta cells. Thus, we conclude that overexpression of MHC class I molecules may be a general mechanism that directly impairs endocrine epithelial cell viability.

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“…The aberrant expression of MHC class II molecules by non-immune cells has been described in patients with autoimmune thyroid disease on thyrocytes [21] and in IDDM patients on pancreatic p cells [22][23][24]. Patients with RA often show hyperexpression of MHC class I antigens [24,25].…”

Section: Regulation Of Mhc Antigen Expression By Cytokinesmentioning

confidence: 99%

Cytokines and autoimmunity

Cavallo

Pozzilli

Thorpe

1994

Clinical and Experimental Immunology

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SUMMARYAlthough the immunopathology of most autoimmune diseases has been well defined, responsible for the breakdown of self-tolerance and which lead to the development of syste organ-specific autoaggression are still unclear. Evidence has accumulated which supports a role for a disregulated production of cytokines by leucocytes and possibly other cells in the pathogenesis of some autoimmune diseases. However, due to the complexity and heterogeneity of cytokine effects in the regulation of the immune response, it is difficult to determine whether abnormalities in the patterns of eytokine production are primary or secondary to the pathological process. Confusion is also caused by the fact that the biological activities of cytokines are multiple and often overlapping, and consequently it is difficult to focus on a unique effect of any one cytokine. Characterization of the potential and actual involvement of cytokines is important not only for a better understanding of the pathogenesis of autoimmune conditions, but particularly because of the implications for the development of immunotherapeutic strategies for the prevention and treatment of the diseases.

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Aberrant expression of Class II major histocompatibility complex molecules by B cells and hyperexpression of Class I major histocompatibility complex molecules by insulin containing islets in Type 1 (insulin-dependent) diabetes mellitus

Cited by 232 publications

References 21 publications

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

Nonimmune thyroid destruction results from transgenic overexpression of an allogeneic major histocompatibility complex class I protein.

Cytokines and autoimmunity

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