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. 2001 May;60(5):473–482. doi: 10.1136/ard.60.5.473

Glandular and extraglandular expression of costimulatory molecules in patients with Sjögren's syndrome

R Matsumura 1, K Umemiya 1, T Goto 1, T Nakazawa 1, M Kagami 1, H Tomioka 1, E Tanabe 1, T Sugiyama 1, M Sueishi 1
PMCID: PMC1753631  PMID: 11302869

Abstract

OBJECTIVES—To investigate the expression and regulation of CD80, CD86, and CD28 costimulatory molecules in sialoadenitis and interstitial nephritis in patients with Sjögren's syndrome (SS).
METHODS—Expression of CD80, CD86, and CD28 molecules was studied by immunohistochemical staining of lip biopsy specimens obtained from patients who had sialoadenitis associated with SS, and renal biopsy specimens obtained from patients who had interstitial nephritis associated with SS. To elucidate the mechanism of de novo expression of CD80 and CD86 antigens, their induction by cytokines in human salivary duct cell line (HSG) and renal cortical epithelial cells (HRCE) by cell enzyme linked immunosorbent assay (ELISA) was quantitatively investigated.
RESULTS—In patients with severe sialoadenitis, CD80 and CD86 were strongly expressed on ductal epithelial cells. In contrast, these antigens were not found in the minor salivary glands of normal subjects or of patients with mild sialoadenitis. Some infiltrating cells expressed CD28. In patients who had interstitial nephritis associated with SS, some tubular epithelial cells expressed CD86 but not the CD80 antigen. Unstimulated HSG cells did not express CD80 or CD86. Interferon γ (IFNγ) consistently up regulated levels of CD80 and CD86. In contrast, tumour necrosis factor α (TNFα), interleukin 1β (IL1β), IL2, and IL4 had no effect on either CD80 or CD86 levels. Unstimulated HRCE did not express CD80 or CD86. IFNγ consistently up regulated CD86 expression. No CD80 expression was found on tubular cells. TNFα, IL1β, IL2, and IL4 had no discernible effects.
CONCLUSIONS—Salivary ductal cells in patients with SS can express CD80 and CD86 costimulatory molecules in response to IFNγ. Tubular epithelial cells in patients who have interstitial nephritis associated with SS express only CD86 molecules. In patients with SS, salivary ductal cells and tubular epithelial cells may activate infiltrating CD28 positive T lymphocytes by presenting antigens to T cells, potentially leading to tissue destruction.



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Figure 1  .

Figure 1  

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Immunohistochemical staining of CD80 and CD86 in the salivary gland. (A) CD80 was not seen in normal controls (×180); (B) CD86 was not seen in normal controls (×180); (C) CD80 on ductal epithelial cells (arrow) and some infiltrating mononuclear cells in severe sialoadenitis (×180); (D) CD86 was expressed on ductal epithelial cells (arrow) and some infiltrating mononuclear cells in severe sialoadenitis (×360); (E) CD28 was seen on many infiltrating mononuclear cells in severe sialoadenitis around the duct expressing CD80; (F) serial section of (E) (×180).

Figure 2  .

Figure 2  

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Ductal CD80 (A) and CD86 (B) expression and salivary gland lymphocytic infiltration. Ductal CD80 and CD86 expression was shown by the grading scale. CD80 and CD86 expression of ductal cells correlated with interstitial infiltration. p<0.01 in Spearman rank correlation.

Figure 3  .

Figure 3  

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Immunostaining of CD80 and CD86 in the kidney. (A) CD80 was not seen on tubular epithelial cells in control tissue (×180); (B) CD86 was not seen on tubular epithelial cells in control tissue (×180); (C) CD86 expression on tubular epithelial cells (basal side, arrows) in interstitial nephritis associated with Sjögren's syndrome (SS) (×360); (D) the several tubular cells showed CD86 antigen in SS kidney (arrow) (×180); (E) CD80 was not seen on tubular epithelial cells in interstitial nephritis associated with SS (×180); (F) CD28 expressed on some infiltrating cells (the same portion of the serial section of (C) and (E) (×180)).

Figure 4  .

Figure 4  

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Immunohistochemical staining of anti-CD80 or CD86 antibody on cultured human salivary gland duct (HSG) cell line (×180). Without cytokine stimulation, CD80 (A) or CD86 (B) expression was not seen on HSG. Many HSG cells stimulated by 100 U/ml of interferon γ for 24 hours showed CD80 (C) or CD86 (D) expression.

Figure 5  .

Figure 5  

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Effect of interferon γ (IFNγ) on human salivary gland duct (HSG) CD80 or CD86 expression as measured by immunoperoxidase cell ELISA. Cells were cultured and stimulated with IFNγ. (A) CD80 expression after 24 hours' exposure to increasing concentrations of IFNγ; (B) CD86 expression after 24 hours' exposure to increasing concentrations of IFNγ; (C) time course of induction of CD80 by IFNγ (100 U/ml); (D) time course of induction of CD86 by IFNγ (100 U/ml); (E, F) effect of blockade of CD80 (E) and CD86 (F) expression by anti-IFNγ. HSG cells were cultured and stimulated with 100 U/ml of IFNγ and with 0.01, 0.1, and 1 µg/ml of monoclonal anti-IFNγ antibody (R&D). Addition of 1 µg/ml of anti-IFNγ inhibited the up regulation of IFNγ. All values are expressed as means (SD) of triplicate wells. *p<0.05, **p<0.01 indicate significant difference from the control (untreated) OD. Absence of an error bar indicates that the error was less than the symbol size.

Figure 6  .

Figure 6  

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Immunohistochemical staining of anti-CD80 or CD86 antibody on cultured renal cortical epithelial cells (HRCE) cells (×180). Without cytokine stimulation, CD80 (A) expression was not seen on HRCE and a few CD86 positive cells were seen (C). CD80 expression was not induced by interferon γ (IFNγ) (B). Many HRCE cells stimulated by 100 U/ml IFNγ for 24 hours showed only CD86 (D) expression.

Figure 7  .

Figure 7  

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Effect of interferon γ (IFNγ) in CD80 or CD86 expression on renal cortical epithelial (HRCE) cells as measured by immunoperoxidase cell ELISA. Cells were cultured and stimulated with IFNγ. (A) CD86 expression after 12 hours' exposure to increasing concentrations of IFNγ; (B) CD80 expression was not induced by 12 hours' exposure to IFNγ; (C) Time course of induction of CD86 by IFNγ (100 U/ml); (D) effect of blockade of CD86 expression by anti-IFNγ (a-IFN). HRCE cells were cultured and stimulated with 100 U/ml of IFNγ and 1 µg/ml polyclonal anti-IFNγ (Genzyme). Addition of 1 µg/ml of anti-IFNγ inhibited the up regulation of IFNγ. All values are expressed as means (SD) of triplicate wells. *p<0.05, **p<0.01 indicate a significant difference from control (untreated) OD. No error bar indicates that the error was less than the symbol size.

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