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Interferon gamma-inducible protein 16 in primary Sjögren's syndrome: a novel player in disease pathogenesis?

Alunno A, Caneparo V, Carubbi F, Bistoni O, Caterbi S, Bartoloni E, Giacomelli R, Gariglio M, Landolfo S, Gerli R - Arthritis Res. Ther. (2015)

Bottom Line: Moreover, IFI16 positivity was associated with concurrent positivity for rheumatoid factor.Interestingly, the direct correlation between IFI16 positivity and focus score was independent of disease duration and age at diagnosis. pSS minor salivary glands display marked expression and cytoplasmic mislocalization of IFI16 by acinar and ductal epithelial cells as well as infiltrating lymphocytes and peri/intralesional endothelium compared to minor salivary glands with normal architecture or nonspecific chronic sialadenitis.Within the mononuclear cell infiltrate, IFI16 expression appears to parallel the distribution of T lymphocytes.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy. alessia.alunno@libero.it.

ABSTRACT

Introduction: There is evidence that interferon is involved in the pathogenesis of primary Sjögren's syndrome (pSS). The interferon-inducible IFI16 protein, normally expressed in cell nuclei, may be overexpressed, mislocalized in the cytoplasm and secreted in the extracellular milieu in several autoimmune disorders. This leads to tolerance breaking to this self-protein with consequent development of anti-IFI16 antibodies. The aim of this study was to identify the pathogenic and clinical significance of IFI16 and anti-IFI16 in pSS.

Methods: IFI16 and anti-IFI16 were assessed in the serum of 67 pSS patients and over 100 healthy donors by enzyme-linked immunosorbent assay. IFI16 was also evaluated by immunohistochemistry in minor salivary glands of 15 pSS patients and 10 subjects with sicca symptoms but without any clinical, serological or histological features of pSS.

Results: pSS patients display higher serum levels of both IFI16 and anti-IFI16 compared to healthy donors. IFI16 concentration was directly correlated with disease duration and focus score and inversely correlated with age at diagnosis. Moreover, IFI16 positivity was associated with concurrent positivity for rheumatoid factor. Interestingly, the direct correlation between IFI16 positivity and focus score was independent of disease duration and age at diagnosis. pSS minor salivary glands display marked expression and cytoplasmic mislocalization of IFI16 by acinar and ductal epithelial cells as well as infiltrating lymphocytes and peri/intralesional endothelium compared to minor salivary glands with normal architecture or nonspecific chronic sialadenitis. Within the mononuclear cell infiltrate, IFI16 expression appears to parallel the distribution of T lymphocytes.

Conclusion: Our data suggest that the IFI16 protein may be involved in the pathogenesis of glandular inflammation occurring in pSS.

No MeSH data available.


Related in: MedlinePlus

Expression of IFI16 in MSG and tonsil. Immunohistochemical analysis for IFI16 in MSG with normal architecture (a), NSCS (b), FLS (c) and in tonsil (d). Inserts in a, b and c depict a detail of endothelial cells from the corresponding panel. e, f Double immunofluorescence staining for CD3 (red) and CD20 (green) in FLS (e) and tonsil (f). Insert in e depicts immunofluorescence staining for CD21 (green) and DAPI (blue), representing a GC-like structure in the CD20+ B-cell area of panel e
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Fig2: Expression of IFI16 in MSG and tonsil. Immunohistochemical analysis for IFI16 in MSG with normal architecture (a), NSCS (b), FLS (c) and in tonsil (d). Inserts in a, b and c depict a detail of endothelial cells from the corresponding panel. e, f Double immunofluorescence staining for CD3 (red) and CD20 (green) in FLS (e) and tonsil (f). Insert in e depicts immunofluorescence staining for CD21 (green) and DAPI (blue), representing a GC-like structure in the CD20+ B-cell area of panel e

Mentions: The histological analysis of normal MSGs revealed that IFI16 protein was not constitutively expressed by glandular tissue (Fig. 2a). Conversely, few nuclei of glandular epithelial cells were positive for IFI16 staining in NSCS. A cytoplasmic localization of this protein could be only occasionally detected in glandular epithelial cells (Fig. 2b). In this context, IFI16 was also displayed by the nuclei of inflammatory mononuclear cells (Fig. 2b). The scattered or small aggregates of plasma cells, normally present in MSGs or during NSCS, appeared to have nuclei with a lower IFI16 positivity when compared with other inflammatory cells. In contrast, in pSS biopsies intense IFI16-positive nuclei were found in both ductal and acinar epithelial cells. A stronger cytoplasmic staining with respect to normal and NSCS was detected in ductal epithelial cells, while the detection of IFI16 staining in the cytoplasm of acinar epithelial cells was hampered by abundant secretion products (Fig. 2a–c). IFI16 nuclear and cytoplasmic staining was also observed in the inflammatory cells involved in FLS (Fig. 2c). A more detailed analysis of inflammatory infiltrate, according to the distribution of T and B lymphocytes and the presence of GCs, showed a predominance of IFI16 staining in the T- rather than B-cell area containing GC-like structures (Fig. 2e). This particular IFI16 distribution, paralleling B/T cell segregation, was also detectable in the inflammatory follicles of tonsil specimens (Fig. 2d and f). Concerning the nuclear staining for IFI16 in endothelial cells, our results showed that the constitutional expression of IFI16 was more pronounced in pSS FLS peri- and intralesional endothelium compared to normal and NSCS patterns (Fig. 2a–c, inserts).Fig. 2


Interferon gamma-inducible protein 16 in primary Sjögren's syndrome: a novel player in disease pathogenesis?

Alunno A, Caneparo V, Carubbi F, Bistoni O, Caterbi S, Bartoloni E, Giacomelli R, Gariglio M, Landolfo S, Gerli R - Arthritis Res. Ther. (2015)

Expression of IFI16 in MSG and tonsil. Immunohistochemical analysis for IFI16 in MSG with normal architecture (a), NSCS (b), FLS (c) and in tonsil (d). Inserts in a, b and c depict a detail of endothelial cells from the corresponding panel. e, f Double immunofluorescence staining for CD3 (red) and CD20 (green) in FLS (e) and tonsil (f). Insert in e depicts immunofluorescence staining for CD21 (green) and DAPI (blue), representing a GC-like structure in the CD20+ B-cell area of panel e
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4536589&req=5

Fig2: Expression of IFI16 in MSG and tonsil. Immunohistochemical analysis for IFI16 in MSG with normal architecture (a), NSCS (b), FLS (c) and in tonsil (d). Inserts in a, b and c depict a detail of endothelial cells from the corresponding panel. e, f Double immunofluorescence staining for CD3 (red) and CD20 (green) in FLS (e) and tonsil (f). Insert in e depicts immunofluorescence staining for CD21 (green) and DAPI (blue), representing a GC-like structure in the CD20+ B-cell area of panel e
Mentions: The histological analysis of normal MSGs revealed that IFI16 protein was not constitutively expressed by glandular tissue (Fig. 2a). Conversely, few nuclei of glandular epithelial cells were positive for IFI16 staining in NSCS. A cytoplasmic localization of this protein could be only occasionally detected in glandular epithelial cells (Fig. 2b). In this context, IFI16 was also displayed by the nuclei of inflammatory mononuclear cells (Fig. 2b). The scattered or small aggregates of plasma cells, normally present in MSGs or during NSCS, appeared to have nuclei with a lower IFI16 positivity when compared with other inflammatory cells. In contrast, in pSS biopsies intense IFI16-positive nuclei were found in both ductal and acinar epithelial cells. A stronger cytoplasmic staining with respect to normal and NSCS was detected in ductal epithelial cells, while the detection of IFI16 staining in the cytoplasm of acinar epithelial cells was hampered by abundant secretion products (Fig. 2a–c). IFI16 nuclear and cytoplasmic staining was also observed in the inflammatory cells involved in FLS (Fig. 2c). A more detailed analysis of inflammatory infiltrate, according to the distribution of T and B lymphocytes and the presence of GCs, showed a predominance of IFI16 staining in the T- rather than B-cell area containing GC-like structures (Fig. 2e). This particular IFI16 distribution, paralleling B/T cell segregation, was also detectable in the inflammatory follicles of tonsil specimens (Fig. 2d and f). Concerning the nuclear staining for IFI16 in endothelial cells, our results showed that the constitutional expression of IFI16 was more pronounced in pSS FLS peri- and intralesional endothelium compared to normal and NSCS patterns (Fig. 2a–c, inserts).Fig. 2

Bottom Line: Moreover, IFI16 positivity was associated with concurrent positivity for rheumatoid factor.Interestingly, the direct correlation between IFI16 positivity and focus score was independent of disease duration and age at diagnosis. pSS minor salivary glands display marked expression and cytoplasmic mislocalization of IFI16 by acinar and ductal epithelial cells as well as infiltrating lymphocytes and peri/intralesional endothelium compared to minor salivary glands with normal architecture or nonspecific chronic sialadenitis.Within the mononuclear cell infiltrate, IFI16 expression appears to parallel the distribution of T lymphocytes.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy. alessia.alunno@libero.it.

ABSTRACT

Introduction: There is evidence that interferon is involved in the pathogenesis of primary Sjögren's syndrome (pSS). The interferon-inducible IFI16 protein, normally expressed in cell nuclei, may be overexpressed, mislocalized in the cytoplasm and secreted in the extracellular milieu in several autoimmune disorders. This leads to tolerance breaking to this self-protein with consequent development of anti-IFI16 antibodies. The aim of this study was to identify the pathogenic and clinical significance of IFI16 and anti-IFI16 in pSS.

Methods: IFI16 and anti-IFI16 were assessed in the serum of 67 pSS patients and over 100 healthy donors by enzyme-linked immunosorbent assay. IFI16 was also evaluated by immunohistochemistry in minor salivary glands of 15 pSS patients and 10 subjects with sicca symptoms but without any clinical, serological or histological features of pSS.

Results: pSS patients display higher serum levels of both IFI16 and anti-IFI16 compared to healthy donors. IFI16 concentration was directly correlated with disease duration and focus score and inversely correlated with age at diagnosis. Moreover, IFI16 positivity was associated with concurrent positivity for rheumatoid factor. Interestingly, the direct correlation between IFI16 positivity and focus score was independent of disease duration and age at diagnosis. pSS minor salivary glands display marked expression and cytoplasmic mislocalization of IFI16 by acinar and ductal epithelial cells as well as infiltrating lymphocytes and peri/intralesional endothelium compared to minor salivary glands with normal architecture or nonspecific chronic sialadenitis. Within the mononuclear cell infiltrate, IFI16 expression appears to parallel the distribution of T lymphocytes.

Conclusion: Our data suggest that the IFI16 protein may be involved in the pathogenesis of glandular inflammation occurring in pSS.

No MeSH data available.


Related in: MedlinePlus