Autoimmune antibodies to collagen XIII in myasthenia gravis patients.

INTRODUCTION: Evaluation of the nerve fascicular structure can be useful in diagnosing nerve damage, but it is a very challenging task with 3T MRI because of limited resolution. In this pilot study, we present the feasibility of high-resolution 7T MRI for examining the nerve fascicular structure. METHODS: A 3-dimensional (3D) gradient-spoiled sequence was used for imaging peripheral nerves in extremities. Images acquired with different in-plane resolutions (0.42 × 0.42 mm vs. 0.12 × 0.12 mm), and different main field strengths (7T vs. 3T) were compared. RESULTS: The individual nerve fascicles were identified at 0.12 × 0.12 mm resolution in both field strengths but not at 0.42 × 0.42 mm resolution. The fascicular structure was more sharply depicted in 7T images than in 3T images. DISCUSSION: High-resolution 3D imaging with 7T MRI demonstrated feasibility for imaging nerve fascicular structures. Muscle Nerve 57: 506-510, 2018.

[Pathogenesis of thyroid eye disease - does autoimmunity against the TSH receptor explain all cases?]. / Patogeneza orbitopatii tarczycowej--czy reakcja autoimmunologiczna przeciwko receptorowi TSH tlumaczy wszystko?

Thyroid associated ophthalmopathy, or thyroid eye disease (TED), is a complex inflammatory disorder of the eye that, as its name implies, is usually associated with thyroid disease. Clinical observation supports the existence of three main TED subtypes, namely ocular myopathy, congestive myopathy, and mixed congestive and myopathic ophthalmopathy. Although the precise pathophysiology of TED remains unclear, it is likely to reflect an autoimmune reaction involving sensitised T lymphocytes and autoantibodies directed against a specific orbital or thyroid-and-orbital shared antigen(s). One well-studied candidate in this immune reaction is the thyroid-stimulating hormone receptor (TSHR), which is also expressed in the orbital fibroblast and preadipocyte. Most patients with ophthalmopathy have associated Graves' disease, 10% have Hashimoto's thyroiditis in which the eye changes are often mild and expressed mainly as upper eyelid retraction (UER), and 10% have no apparent associated thyroid disease - so-called "euthyroid Graves' disease". Ophthalmopathy can also occur in some patients with transient thyroiditis, thyroid cancer, and Graves' disease many years after treatment of the hyperthyroidism - situations where TSHR antibodies are not expected to be present, suggesting that the relationship between TSHR antibodies and the eye disorder has not been established for all cases. In our studies of TED we have investigated the nature and significance of antibodies targeting other eye muscle and orbital connective tissue (OCT) antigens, in particular the calcium binding protein calsequestrin (CASQ1) and the orbital fibroblast membrane antigen collagen XIII. Our working hypotheses for the pathogenesis of TED are: i) the initial reaction in the orbit is antibody and T lymphocyte targeting of the TSHR in the OCT compartment, and ii) the associated extra ocular and upper eyelid muscle inflammation reflects either autoimmunity against primary skeletal muscle antigens such as CASQ1 or a secondary, non specific effect of the OCT reactions as proposed by the main proponents of the "TSHR hypothesis". Here, we review the evidence that autoimmunity against the TSHR expressed in the orbit can be implicated in the development of all cases of TED. Although there is a close general correlation between ophthalmopathy and TSHR antibodies there are many exceptions, suggesting that the continued study of the possible role of autoimmunity against calsequestrin and collagen XIII is justified.

A mutant collagen XIII alters intestinal expression of immune response genes and predisposes transgenic mice to develop B-cell lymphomas.

Epithelial cells of mucosal surfaces are critical for maintaining immune homeostasis by aiding in the discrimination of pathogenic and commensal microorganisms and modulating the activities of antigen-presenting cells and lymphocytes. Functional breakdowns resulting in chronic infection and inflammation are associated with the development of hematologic and solid neoplasms for which detailed pathogenetic mechanisms are poorly understood. Mice heterozygous for a transgene Col13a1(del) expressing a mutant collagen XIII developed clonal mature B-cell lineage lymphomas originating in mesenteric lymph nodes (MLN). The tumors were associated with T cells and macrophages. The incidence of disease was reduced 2-fold in transgenic mice raised under specific pathogen-free conditions, suggesting a role for infectious agents. The lymphomas did not express the mutant collagen XIII, indicating that its influence on tumorigenesis was B-cell extrinsic and likely to be associated with collagen XIII-positive tissues drained by the MLN. Studies of the small intestines of transgenic mice showed that the subepithelial basement membranes (BM) were highly abnormal and that they exhibited heightened expression of genes involved in immune responses. These results define collagen XIII-dependent maintenance of the intestinal BM as a previously unappreciated component of immune responses and a critical determinant of cancer susceptibility.

Eye signs and serum eye muscle and collagen XIII antibodies in patients with transient and progressive thyroiditis.

BACKGROUND: There have been reports of the development of ophthalmopathy in patients with subacute thyroiditis (SAT) in the absence of Graves' disease and thyroid-stimulating hormone receptor (TSH-r) antibodies. OBJECTIVE: The aim of the study was to determine the prevalences of eye and eyelid signs and positive eye muscle and collagen XIII antibody tests in patients with SAT and silent thyroiditis (ST) and in patients with Hashimoto's thyroiditis (HT) as chronic thyroiditis controls. DESIGN: Ophthalmopathy was classified as Nunery type 1 (orbital inflammation, proptosis, without restrictive myopathy) or Nunery type 2 (with restrictive myopathy). We tested for antibodies against calsequestrin, flavoprotein (Fp), G2s, and collagen XIII in 5 patients with SAT, 6 with ST, and 11 with HT, and in 12 age- and sex-matched healthy subjects, using an optimized and standardized enzyme-linked immunosorbent assay (ELISA). MAIN OUTCOME: At the first visit, eye signs were found in two patients with SAT, one with type 1 ophthalmopathy and one with type 2 ophthalmopathy, and in three patients with ST, two with type 1 ophthalmopathy and one with dominant upper eyelid retraction only. Later in the course of their illness, one other patient with ST developed mild type 1 disease, giving an overall prevalence of any eye signs of 50% in patients with TT. Five patients with HT had mild type 1 ophthalmopathy and dominant upper eyelid retraction. One or more eye muscle antibodies were detected in three patients with SAT, four with ST, and seven with HT, of which calsequestrin and Fp antibodies were the most commonly found. TSH-r antibodies were detected in only one patient with ST, at the time when she developed Graves' hyperthyroidism following an episode of ST. CONCLUSION: The development of mild, but definite, ophthalmopathy or dominant upper eyelid retraction in patients with TT and chronic (Hashimoto's) thyroiditis in the absence of TSH-r antibodies or Graves' hyperthyroidism is an interesting observation that should be further addressed in larger groups of patients, including those with postpartum thyroiditis. These preliminary findings also raise questions about the mechanism for the link between ophthalmopathy and thyroid autoimmunity.

Antibodies against calsequestrin and type XIII collagen are good markers for chronic upper eyelid retraction.

PURPOSE: Chronic upper eyelid retraction is a common manifestation of thyroid-associated ophthalmopathy (TAO) but can occur as a dominant feature of ophthalmopathy in patients with Graves' hyperthyroidism and in association with Hashimoto's thyroiditis in the absence of other eye signs except mild proptosis. METHODS: We measured antibodies against calsequestrin, flavoprotein (Fp), G2s, and collagen XIII in an enzyme-linked immunosorbent assay (ELISA) in 15 patients with chronic upper eyelid retraction. RESULTS: Calsequestrin antibodies were detected in 67% of patients with upper eyelid retraction, Fp antibodies in 47%, G2s antibodies in 20%, and collagen XIII antibodies were detected in 40% of these patients at the first visit. These prevalences were significantly greater than normal for calsequestrin and collagen XIII, but not for Fp and G2s antibodies. On follow-up, calsequestrin antibodies were detected in two more patients, for an overall prevalence of 80%. Levels of the four antibodies remained fairly constant over the study period and generally correlated with the presence and severity of upper eyelid signs. CONCLUSIONS: These findings support the notion that autoimmune attack against calsequestrin and collagen XIII in the levator palpebrae superioris (LPS) muscle may play a role in the pathogenesis of upper eyelid retraction and that lid retraction may be the dominant feature of ophthalmopathy in patients with Hashimoto's thyroiditis and non-autoimmune thyroid disease. Because calsequestrin is an intracellular protein, the corresponding autoantibodies probably do not initiate LPS muscle inflammation but may contribute to its damage. The mix of antibodies against calsequestrin and collagen XIII may shed light on the diverse presentations found in thyroid-associated ophthalmopathy.

Serum antibodies to collagen XIII: a further good marker of active Graves' ophthalmopathy.

OBJECTIVE: In Graves' ophthalmopathy (GO) intercellular adhesion molecule-1 (ICAM-1) is thought to play a key role in lymphocyte infiltration into the orbit, and serum levels of its soluble form are positively correlated to clinical activity score (CAS). Serum antibodies against collagen XIII (CollXIIIAb), a plasma membrane protein expressed at a low level in almost all connective tissue-producing cells, have been detected in GO, but their significance is unclear. The aim of this study was to search for CollXIIIAb in Graves' patients with and without ophthalmopathy and to correlate their levels with CAS and with serum soluble ICAM-1 (sICAM-1) values. PATIENTS: We studied 66 patients with Graves' disease whose sera had been previously tested for sICAM-1 levels, grouped as follows: 28 with moderate and active ophthalmopathy (group 1), 12 of them hyperthyroid (group 1a) and 16 euthyroid (group 1b); 13 with mild and inactive ophthalmopathy and normal thyroid function (group 2); 25 without ophthalmopathy (group 3), 11 of them hyperthyroid (group 3a) and 14 euthyroid (group 3b). Finally, 26 sera of normal controls were studied. MEASUREMENTS: CollXIIIAb were evaluated by an enzyme-linked immunosorbent assay (ELISA) method. RESULTS: In group 1 patients, CollXIIIAb were detected at high levels in 8/12 (66.6%) in group 1a [optical density (OD) ranging from 0.529 to 0.894] and in 10/16 (62.5%) in group 1b (OD 0.560-0.855). In group 2 patients, CollXIIIAb were detected but at low levels (OD 0.205-0.260) in 4/13 patients (30.7%). In group 3 patients, CollXIIIAb were present at low levels in 6/11 (54.5%) of group 3a and in 5/14 (35.7%) of group 3b (OD 0.215-0.290 and 0.144-0.245, respectively). CollXIIIAb were detected in only 4/26 normal controls (15%) but at low levels (OD 0.150-0.185). CollXIIIAb values in both groups 1a and 1b were significantly higher than those of the remaining groups. A positive correlation between CollXIIIAb levels and CAS but not thyroid hormone levels was found in groups 1a, 1b and 2. Moreover, a positive correlation between CollXIIIAb levels and sICAM-1-values was also evidenced in all three groups. CONCLUSIONS: Our results suggest that CollXIIIAb could be considered as a further good marker of active inflammatory processes involving the adipose connective tissue in GO. In particular, the high levels of CollXIIIAb in sera of Graves' patients with active ophthalmopathy could reflect an increased expression of type XIII collagen on the membrane of activated fibroblasts in these patients. Thus, the evaluation of these antibodies could be added to other known markers as a useful and inexpensive tool in monitoring Graves' patients and in modulating the treatment of GO.