CD10+ Cells and IgM in Pathogen Response in Lumpfish (Cyclopterus lumpus) Eye Tissues.

Lumpfish (Cyclopterus lumpus), a North Atlantic "cleaner" fish, is utilized to biocontrol salmon louse (Lepeophtheirus salmonis) in Atlantic salmon (Salmo salar) farms. Lumpfish require excellent vision to scan for and eat louse on salmon skin. The lumpfish eye immune response to infectious diseases has not been explored. We examined the ocular response to a natural parasite infection in wild lumpfish and to an experimental bacterial infection in cultured lumpfish. Cysts associated with natural myxozoan infection in the ocular scleral cartilage of wild adult lumpfish harbored cells expressing cluster of differentiation 10 (CD10) and immunoglobulin M (IgM). Experimental Vibrio anguillarum infection, which led to exophthalmos and disorganization of the retinal tissues was associated with disruption of normal CD10 expression, CD10+ cellular infiltration and IgM expression. We further describe the lumpfish CD10 orthologue and characterize the lumpfish scleral skeleton in the context of myxozoan scleral cysts. We propose that lumpfish develop an intraocular response to pathogens, exemplified herein by myxozoan and V. anguillarum infection involving novel CD10+ cells and IgM+ cells to contain and mitigate damage to eye structures. This work is the first demonstration of CD10 and IgM expressing cells in a novel ocular immune system component in response to disease in a teleost.

Role of cytokines in the clinical manifestation of exophthalmia in newborn calves with tropical theileriosis.

The present study aimed to evaluate the pathology of the exophthalmia and the host-immune response in naturally Theileria annulata-infected calves. The newborn calves detected positive for theileriosis were grouped into calves with theileriosis and absence of exophthalmia (n = 30), and calves with theileriosis and the presence of exophthalmia (n = 13). Sixteen healthy calves, free from any haemoprotozoal infection, were kept as healthy controls. A significantly (P ≤ .001) higher circulating levels of tumour necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were estimated in diseased calves with and without exophthalmia as compared to healthy controls. Contrarily, significantly (P ≤ .01) lower interferon-γ (IFN-γ) level was estimated in diseased calves. The diseased calves with exophthalmia revealed significantly higher levels of TNF-α (P ≤ .001) and IL-10 (P ≤ .006) as compared to the diseased calves without exophthalmia. The diseased calves were not found to have an elevated intraocular pressure; rather they had significantly (P ≤ .001) lower intraocular pressure compared to the healthy controls. An elevated systemic TNF-α level might be attributed to the exophthalmia in calves with tropical theileriosis. The elevated circulatory IL-10 and reduced IFN-γ levels could be one of the strategies of Theileria annulata to escape the host immunity.

Thyroid autoantibodies in adults with acquired binocular diplopia of unknown origin.

Patients with acquired adult-onset strabismus mainly present with binocular diplopia. Although cranial nerve palsies are reportedly the most common cause of binocular diplopia in adults, thyroid disease can also cause diplopia. In patients with thyroid-associated ophthalmopathy, upper lid retraction and proptosis are the most common initial findings, but diplopia could be the first manifestation. So far, there has been little information on the diagnostic value of thyroid autoantibodies in patients with strabismus. Therefore, we examined adults with acquired binocular diplopia from 2008 to 2016 and evaluated the presence of thyroid autoantibodies and the relationship between thyroid autoantibody status and clinical characteristics in adults with acquired binocular diplopia. Thyroid autoantibody tests were performed for all patients, unless other causes of diplopia were identified. Fifty one (39%) of 132 patients were positive for thyroid autoantibodies. In the thyroid autoantibody-positive (TAb+) group, microsomal autoantibodies, thyroid-stimulating hormone receptor antibodies, thyroglobulin antibodies, and thyroid-stimulating antibodies were observed in 30, 27, 12, and 7 patients, respectively. The vertical deviation and grade of duction limitation were greater in the TAb+ group. The presence of ocular torsion was 15.5% and 39.5% in the TAb- and TAb+ groups, respectively. Thyroid autoantibody evaluation may be helpful in adults with idiopathic acquired binocular diplopia.

Dacrioadenitis por enfermedad relacionada con IgG4 en una adolescente afrodescendiente de Colombia / Dacryoadenitis associated with IgG4-related disease in an Afro-Colombian adolescent

La enfermedad relacionada con IgG4 (ER-IgG4) es una condición clínica recientemente reconocida, con múltiples aspectos aún no dilucidados. Se caracteriza por el compromiso fibroinflamatorio de múltiples órganos; con hallazgos clínicos, serológicos e histopatológicos que representa un importante reto para el clínico. Clásicamente descrita como una lesión tumoral expansiva con fibrosis estoriforme, infiltración linfoplasmocítica (IgG4 positiva) e IgG4 sérica elevada. Las características clínicas son variables, se describe tanto compromiso pancreático como extrapancreático, es de predominio en varones asiáticos mayores de 50 años, y rara vez es descrita en personas de raza negra. Presentamos el caso de una mujer, adolescente, afro-colombiana, que presenta protrusión ocular unilateral inexplicable, con hallazgos histopatológicos que revelan infiltración de células linfocíticas y plasmáticas en la glándula lacrimal, con positividad para IgG4, descartándose otras condiciones, lo que confirma una dacrioadenitis por enfermedad relacionada con IgG4

IgG4-related disease (IgG4-RD) is a recently recognized clinical condition with multiple aspects not yet elucidated. It is characterized by a fibrous inflammatory process that involves multiple organs and clinical, serological and histopathological findings, which represent a major challenge for the clinician. Classically described as an expansive tumor lesion with storiform fibrosis, lymphoplasmacytic infiltration (IgG4-positive) and elevated serum IgG4. Clinical features are variable, and pancreatic as well as extrapancreatic involvement has been reported, more frequently in Asian men over 50 years and rarely described in black people. We report the case of an Afro-Colombian teenage woman, who had a unilateral ocular protrusion of unknown cause, with histopathologic findings that revealed infiltration of lymphocyte and plasma cells into the lacrimal gland. It was positive for IgG4, ruling out other conditions, and confirming IgG4-related dacryoadenitis

Exophthalmos in a young woman with no graves' disease - a case report of IgG4-related orbitopathy.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-rd) is characterized by lymphoplasmacytic infiltration and tissue fibrosis. Orbital manifestations of IgG4-rd may include unilateral or bilateral proptosis, cicatricial extraocular muscle myopathy, orbital inflammation and pain which may mimic ophthalmic Graves' disease. CASE PRESENTATION: A 25-year-old woman has been referred to the endocrinology clinic, 4 months after delivery, with suspected Graves' orbitopathy. She has had bronchial asthma and recurrent skin rashes of unknown aetiology for the last 10 years and was treated for dacryoadenitis with steroid containing eye drops 5 years ago. During pregnancy she developed eyelid swelling. After delivery, eyelid redness and retrobulbar pain evolved. Proptosis was demonstrated by Hertel's exophthalmometry. Orbital magnetic resonance imaging showed enlarged lateral and superior rectus muscles in both orbits. Thyroid function tests were in the normal range and no thyroid stimulating hormone (TSH) receptor autoantibodies were present. The eye muscle involvement pattern raised suspicion, and the high IgG4 level with positive histology of the lacrimal gland confirmed the diagnosis of immunoglobulin G4-related orbitopathy. Rapid improvement was observed following oral methylprednisolone. CONCLUSIONS: IgG4-related orbitopathy may mimic Graves' orbitopathy. Euthyroid patients with no TSH receptor autoantibodies should be evaluated for immunoglobulin G4-related orbitopathy. Once IgG4-related orbitopathy is proven, other manifestations of IgG4-related disease have to be searched for; lifelong follow-up is warranted.

Xanthogranulomatous variant of immunoglobulin G4 sclerosing disease presenting as ptosis, proptosis and eyelid skin plaques.

A 70-year-old male was referred to the oculoplastic clinic with left-sided ptosis and floppy eyelids. During follow-up, bilateral upper lid xanthelasma developed with worsening ptosis and proptosis, which was worse on the left side. A left orbital biopsy showed xanthogranulomatous inflammation of the orbit. The patient was treated with a variety of immune modulator regimes but due to a variety of side-effects, treatment was discontinued. The left orbit was surgically debulked twice and histology revealed xanthogranulomatous inflammation, with the additional features of sclerosis, lymphoid aggregates and a prominent population of plasma cells. Around 80% of the plasma cells expressed immunoglobulin G4 (IgG4). This case report reveals an association between xanthogranulomatous inflammation of the orbit and a prominent population of IgG4-positive plasma cells. We propose that the overall disease is a novel variant of IgG4 sclerosing disease of the orbit and suggest that cases of histologically proven xanthogranulomatous inflammation should be stained for IgG4 if there is an accompanying plasma cell population.

HLA class II distribution in Congolese with hyperthyroidism: preliminary results.

OBJECTIVE: Incidence of the hyperthyroidism is continuously increasing, whereas our knowledge concerning the facilitating or etiologic factors of this increase are still partial. To evaluate some of these unknown factors, we started this preliminary study, in order to identify HLA genes in hyperthyroid Congolese, and to determine their susceptibilty in the appearance and development of hyperthyroidism at the Hospital Clinic of Kinshasa. MATERIALS AND METHODS: Nine Congolese women with hyperthyroidism, and thirteen healthy controls (3 women and 10 men) were examined and compared for HLA-DR and HLA-DQ genes analyses, from August 2000 to August 2002. DRB1 and DQB1 alleles were identified, using the Polymerase Chain Reaction (PCR) and immobilized sequence-specific oligonucleotide (SSO HLA-DRB1 and DQB1 test) probes assays. RESULTS: In the group with hyperthyroidism, three alleles (HLA-DR1, HLA-DR2, HLA-DR3) and an allele group (HLA-DR11,13,14) were found for DRB1 locus, while only one allele (HLA-DQB1*0602) was identified for DQB1 locus; allele group HLA-DR11,13,14 was the most frequent (allele frequency=0.50), followed by HLA-DR3 allele (allele frequency=0.222); 6 haplotypes were observed, with predominance of haplotype DR3/DR11,13,14 (genotype frequency=0.333), followed by haplotype DR11,13,14/DR11,13,14-DQB1*0602 (genotype frequency=0.222). In the group of healthy controls, three alleles (HLA-DR2, HLA-DR3, HLA-DR4) and an allele group (HLA-DR11,13,14) were identified for DRB1; HLA-DR2 allele was predominant (allele frequency=0.615), followed by allele group HLA-DR11,13,14 (allele frequency=0.231); a statistic significant difference was observed between the frequencies of DR2 allele and allele group DR11,13,14 in the healthy controls compared to those of hyperthyroid patients (p=0.02); 6 haplotypes were also detected in this group, the most frequent haplotype being HLA-DR2/DR2-DQB1*0602 (genotype frequency=0.540 versus 0.333 in the hyperthyroid group) (p=0.048). HLA-DQB1*0602 was dominant in the healthy controls group (allele frequency=0.890), versus HLA-DQB1*0302 (allele frequency=0.110). CONCLUSIONS: HLA-DR2, HLA-DQB1*0602 and DR2/DR2-DQB1*0.602 would play a protective role against the hyperthyroidism, while DR3 allele, allele group DR11,13,14 and haplotype HLA-DR3/DR11,13,14 would predispose to this disease or to Graves' exophtalmopathy. A large and profound study is needed to confirm our preliminary results.

Magnetic resonance imaging determination of extraocular eye muscle volume in patients with thyroid-associated ophthalmopathy and proptosis.

PURPOSE: Recent studies concerning the association between extraocular muscle (EOM) enlargement in thyroid-associated ophthalmopathy (TAO) and immunological and clinical activity have not been conclusive, probably due to a lack of uniform imaging methods (ultrasonography, computer tomography [CT] or magnetic resonance imaging [MRI]) and difficulties in the determination of EOM volume. The aim of the present study was to examine the significance of EOM enlargement as established by MRI-based volume determination, with reference to proptosis and the presence of autoantibodies, clinical activity and the duration of active disease. METHODS: We determined EOM volume using MRI in 15 patients concomitantly with the determination of TSH, thyroid hormones, thyrotropin receptor antibodies (TRab) thyroid peroxidase antibodies (TPOab) and clinical activity score (CAS) at entry. We also established the duration until cessation of clinically active TAO. RESULTS: All 15 patients had bilateral EOM enlargement, but swelling of orbital fatty tissue was absent. Significant correlations between thickness of musculi rectales and proptosis, values of TRab, CAS, and duration of activity were observed. CONCLUSION: Our results support the hypothesis of a role of thyrotropin receptor antibodies in the pathogenesis of TAO and suggest that only EOM enlargement is responsible for proptosis in TAO.

Two cases of refractory endocrine ophthalmopathy successfully treated with extracorporeal immunoadsorption.

Endocrine ophthalmopathy (EO) is a severe disease entity that is characterized by retrobulbar swelling due to accumulation of glycosaminoglycans on an autoimmune basis. This disorder can lead to the loss of vision and often is resistant to conventional therapy. There is a relation to Graves' hyperthyroidism, but probably no close association. Two patients with severe EO that was resistant to usual therapeutic approaches including steroids and radiological and surgical measures underwent a 20 session course of intensive immunoadsorption therapy (Plasmaselect/Therasorb Anti-IgG) with a mean 2- to 3-fold plasma volume treated. After the first sessions, both patients voiced an impressive relief of their major symptoms, which was confirmed by ophthalmological investigation. Throughout the time of therapy until present, these patients have remained at their respective levels of improvement. We consider immunoadsorption an effective therapeutic opportunity in severe EO resistant to conventional treatment.

Serum levels of soluble Fas in patients with Graves' ophthalmopathy.

AIM: To assess levels of soluble Fas (sFas) in the sera of patients with Graves' ophthalmopathy. METHODS: The subjects in this study were 43 patients with Graves' ophthalmopathy and 11 normal subjects. Serum levels of sFas were determined by sandwich enzyme linked immunosorbent assay. In addition, serum levels of thyroid stimulating antibody (TSAB) were also measured in all the patients. RESULTS: The mean serum level of sFas was 1.35 (SD 2.03) ng/ml in patients with Graves' ophthalmopathy, and 0.93 (0.32) ng/ml in normal subjects. Serum levels of sFas in the subgroup of 24 patients with diplopia (1.98 (2.56) ng/ml) were significantly higher than those in the subgroup of 19 patients without diplopia (0.56 (0.24) ng/ml) and normal subjects (p <0.001). Serum levels of sFas in the subgroup of 27 patients with extraocular muscle hypertrophy (1.81 (2. 46) ng/ml) were significantly higher than those in the subgroup of 16 patients without extraocular muscle hypertrophy (0.58 (0.26) ng/ml) among the patients with Graves' ophthalmopathy and normal subjects (p <0.001). Serum levels of sFas were not significantly different between the subgroup of 24 patients with proptosis (1.15 (0.98) ng/ml) and the subgroup of 19 patients without proptosis (1. 61 (2.88)). In contrast, the serum levels of TSAB in the subgroup of patients with proptosis (723% (1161%)) were significantly higher than those in the subgroup of patients without proptosis (194% (122%)) (p <0.05). CONCLUSIONS: Elevated sFas levels were associated with extraocular muscle disorders but not with proptosis. On the other hand, elevated TSAB levels were associated with proptosis but not with extraocular muscle disorders, suggesting different immunological mechanisms for the extraocular muscle disorders and proptosis in Graves' ophthalmopathy. Determination of the serum levels of sFas and TSAB could provide useful markers for evaluation of the immunological processes involved in the development of Graves' ophthalmopathy.

Factors at onset predictive of lasting remission in pediatric patients with Graves' disease followed for at least three years.

Seventeen pediatric patients (mean age at diagnosis 10 yr and 9 mo +/- 2 yr and 9 mo) with Graves' disease treated with 0.3-0.7 mg/kg/day methimazole and followed for at least three years, during which drug suspension was attempted on attainment of good clinical and metabolic compensation, were retrospectively studied to look for factors predictive of lasting remission present at onset. Lasting remission was defined as a clinical and laboratory picture of euthyroidism lasting at least one year in the absence of treatment at the end of the follow-up. A distinction was drawn between patients who reached remission after one or two courses (groups 1 and 2) and those who never attained a lasting remission (group 3). TRAb (TBIAb) levels at onset were the only factor significantly correlated with the response to treatment. Age at diagnosis, goiter size and fT3 and fT4 concentrations were not significantly correlated with the clinical picture. The series was too small to allow any assessment of the real importance of these factors, though a generally better response was displayed by children over 11 years old, without appreciable or with very small goiter and moderately increased thyroid hormone levels at onset (fT3 < 25 pg/ml in 10/10 in groups 1 and 2 and 2/7 in group 3 patients; fT4 < 40 pg/ml in 7/10 in groups 1 and 2 and 3/7 in group 3 patients). It was also found that better results were obtained when the initial drug course was protracted for at least two years.

[Orbital myopathy in metastatic malignant paraganglioma: a paraneoplastic syndrome?]. / Orbitale Myopathie bei metastasiertem malignem Paragangliom: Eine Paraneoplasie?

BACKGROUND: Several disease entities of the orbit are known which display an autoimmunological pathogenesis. Among these disease entities the thyroid-related immune orbitopathy and the idiopathic orbital inflammatory syndrome (orbital pseudotumor). The pathogenesis of these diseases is not well understood; however, an autoimmune inflammatory reaction histologically characterized by a chronic inflammatory cell infiltrate has been suggested. One care of orbital pseudotumor presumably of paraneoplastic origin occurring in a patient with a non-Hodgkin's lymphoma has been reported. We report a patient with a metastatic paraganglioma and a proptosis secondary to enlargement of all extraocular muscles. CASE REPORT: A 52-year-old woman presented with a recent decline in visual clarity of her left eye and diplopia. Two years ago, the diagnosis of a hormonally inactive paraganglioma has been made. Ophthalmologic examination displayed a lagophthalmos caused by a right-sided facial paralysis secondary to a cerebral metastasis and a bilateral enlargement of all extraocular muscles. Curative therapy for the paraganglioma was not available. Palliative therapy as well as a high-dose corticosteroid therapy for the orbitopathy was refused by the patient. The patient died 18 months later. DISCUSSION: Our patient developed orbital changes similar to thyroid-related immune orbitopathy; however, there was no dysfunction of the thyroid. We believe that the orbital changes were a paraneoplastic immune reaction caused by the metastatic paraganglioma. We recommend that in patients who do not conform to the prototypical profile of well-known orbital disease entities should undergo further testing to exclude a remote neoplasm.

Glycosaminoglycans in thyroid-associated ophthalmopathy.

Glycosaminoglycan (GAG) accumulation in the retrobulbar space of patients with thyroid-associated ophthalmopathy (TAO) has been documented in a number of immunohistochemical studies. In order to gain further insight into possible immunopathogenic mechanisms, the influence of humoral immunity on retrobulbar fibroblasts (RF) as GAG producing cells as well as on GAGs themselves was investigated. The effect of lymphocytes on hyaluronic acid (HA) synthesis of RF as well as in turn the influence of RF on lymphocytes were evaluated. In search of methods which would facilitate management of patients with TAO and allow assessment of disease activity, GAGs were determined in both urine and plasma. Immunoglobulin G (IgG) of patients with TAO were found to markedly stimulate the 3H-GAG secretion of RF. Patients with TAO exhibited significantly greater antibody values directed against HA than controls. Preliminary results concerning the influence of lymphocytes on RF indicate a tendency for patients' lymphocytes to increase the synthesis of HA. Furthermore, these lymphocytes in turn were stimulated more by irradiated autologous RF than by irradiated heterologous RF. Urine and plasma GAG determination proved to be suitable for the routine assessment of disease activity and outcome of therapy. In conclusion, GAGs seem to play an important role in the pathogenesis of the disease and their measurement may provide aid to the endocrinological evaluation of patients with TAO.

Nature and significance of orbital autoantigens and their corresponding autoantibodies in thyroid-associated ophthalmopathy.

There is now considerable evidence that the pathogenesis of thyroid-associated ophthalmopathy is closely linked to the presence of a shared autoantigen(s) in the thyroid and the eye muscle, against which cytotoxic mechanisms are directed. Although the orbital connective tissue is certainly involved in the orbital inflammatory process, a 64 kDa membrane protein expressed by both the eye muscle and the thyroid and recognized consistently by antibodies in the sera of TAO patients, seems to be the most likely target candidate. While its presence in non ocular skeletal muscle is not as well established, more recent data tend to suggest the existence of a 64 kDa molecule in the three tissues. The availability of a cDNA encoding a 572 amino acid protein corresponding to a MW of 63-64 kDa, which may be the same molecule, will allow us to determine more clearly the structural characteristics of the different molecules proposed as targets. The role of the corresponding autoantibodies in the pathogenesis of the eye disease is far less well defined. Whether they play a role in the induction of the ophthalmopathy or only represent helpful markers remains to be clarified.

Relationship of eye muscle antibodies with HLA phenotypes and thyroid-stimulating immunoglobulins in endocrine orbitopathy.

The relationship between endocrine orbitopathy and Graves' hyperthyroidism is still not clarified. The purpose of this study was to elucidate the incidence of eye muscle antibodies and the relationship with HLA phenotypes and thyroid antibodies in 65 patients with endocrine orbitopathy classes 1-5. Both bovine and abdominal muscles were used as antigens in ELISA systems in which IgG and IgM antibodies were assayed. Before starting the immunosuppressant therapy, 46/65 patients (71%) showed a positive result for eye muscle antibodies. Those patients with an active disease had such antibodies more frequently. Where the ophthalmopathy was of recent onset IgM antibodies were found, whereas patients with chronic disease were mostly IgG-Ab positive. No association was found either with HLA phenotypes (B8, DR3) or with antibodies directed against thyroglobulin, thyroid microsomes, and the TSH receptor measured as thyroid-stimulating immunoglobulins. Furthermore, there was no correlation between ophthalmopathy class and optic muscle antibody-binding activity. There was no relation between the degree of exophthalmos and eye muscle, thyroid-stimulating, antithyroglobulin, or antithyroid microsomal antibodies. These results suggest that, although very closely related, endocrine orbitopathy and Graves' hyperthyroidism are separate, organ-specific autoimmune diseases.