Proteasome subunits, low‐molecular‐mass polypeptides 2 and 7 are hyperexpressed by target cells in autoimmune thyroid disease but not in insulin‐dependent diabetes mellitus: implications for autoimmunity

Abstract

Autoimmune thyroid diseases (AITD) and insulin-dependent diabetes mellitus (IDDM) are two autoimmune syndromes of unknown etiology with common immune features. One is that the target cells, thyrocytes and pancreatic islet beta cells respectively, hyperexpress several proteins encoded in the HLA region: HLA class I, HLA class II and transporter associated with antigen processing (TAP-1): the clinical course and many aspects of the immunopathology are, however, quite different. Low-molecular-mass polypeptides 2 and 7 (LMP2 and LMP7) are proteasome subunits that increase the efficiency of endogenous antigen processing and are encoded in close vicinity to the TAP genes. We investigated whether LMP2 and LMP7 are hyperexpressed in thyrocytes and islet cells in AITD and IDDM. Thyroid tissue from Graves' disease patients (GD, n = 8) and Hashimoto thyroiditis (HT, n = 1) and pancreatic tissue from IDDM patients (n = 4) as well as control tissues were examined by the two-color indirect immunofluorescence technique. The results demonstrate that, in normal glands, thyrocytes and pancreatic islet cells express comparable moderate to low levels of LMP2 and LMP7. In AITD and IDDM, expression of LMP2/7 in the endocrine cells was disparate: while in AITD glands there was hyperexpression of LMP2 and 7 parallel to that of HLA class I and TAP-1, in the islet cells of recent onset diabetic pancreases (n = 2) the level of LMP2 and 7 expression was totally normal, including islets that were infiltrated by lymphocytes and hyperexpressed HLA class I and TAP-1. These observations suggest different mechanisms of endogenous peptides generation at the target cells in AITD from IDDM. Since this is a key step for the maintenance of peripheral tolerance, it may help to understand some of the different clinical features of the two autoimmune diseases.

NOD Mice Are Defective in Proteasome Production and Activation of NF-κB

“…One of the early pathogenic lesions of autoimmune diabetes in both humans and rodent models is hyperexpression of correctly assembled MHC class I molecules on the surface of ␤ cells, a step requiring intact proteasome function (23,33,42,57,73,85,89). Early up-regulation of LMP2 or the TAP1 protein, a transporter protein delivering proteasome-cleaved fragments to MHC class I molecules, is similarly observed in target tissues affected by autoimmune thyroid disease or diabetes (86). Furthermore, immortalized NOD mouse islet cell lines overexpress NF-B (73), the processing of which we have now shown to be dependent on LMP2 and which is required for resistance to apoptosis.…”

Immunoproteasome Overexpression Underlies the Pathogenesis of Thyroid Oncocytes and Primary Hypothyroidism: Studies in Humans and Mice

“…It is likely that the tissue levels of LMP2 change throughout the course of the autoimmune process in a tissue-specific manner. For example, Vives-Pi and colleagues, studying eight patients with Graves disease patients and four with type 1 diabetes, reported that thyroid glands expressed high but variable levels of LMP2 and LMP7, whereas pancreases had levels similar to those found in healthy controls [21]. LMP2 increase did not always correspond to a similar LMP7 increase, in keeping with the notion that these two subunits are not always assembled together [22] in the immunoproteasome, contrary to the pairing of LMP2 and LMP10 [23].…”

Analysis of the cumulative changes in Graves’ disease thyroid glands points to IFN signature, plasmacytoid DCs and alternatively activated macrophages as chronicity determining factors

“…For example, the immune response in GD declines after thyroidectomy [5], and GD thyroid tissue engrafted into immunodeficient mice produces anti-thyroid antibodies [6]. The thyroid tissue itself undergoes many changes in GD, such as thyroid follicular cells (TFCs) express HLA class I and class II [7,8], TAPs and LMPs [9], HLA-DMA [10], ICAM-1 and NCAM [11e14], CD40 [15], Fas and Fas-L molecules [16] and also produce CXCL12 [17] and IL-16 [18]. In addition, GD entails the frequent extensive infiltration of the thyroid gland by lymphocytes, macrophages and dendritic cells making up germinal centers containing Thyroid Peroxidase (TPO) and Thyroglobulin (TG) specific B-lymphocytes [19].…”