Distinct groups of autoantigens as drivers of ocular adnexal MALT lymphoma pathogenesis.

Chronic B-cell receptor signals incited by cognate antigens are believed to play a crucial role in the pathogenesis of mucosa-associated lymphoid tissue lymphomas. We have explored the immunoglobulin variable regions (IGHV) expressed by 124 ocular adnexal MALT lymphomas (OAML) and tested the in vitro reactivity of recombinant IgM derived from 23 OAMLs. Six of 124 OAMLs (5%) were found to express a high-affinity stereotyped rheumatoid factor. OAMLs have a biased IGHV4-34 usage, which confers intrinsic super auto-antigen reactivity with poly-N-acetyllactosamine (NAL) epitopes, present on cell surface glycoproteins of erythrocytes and B cells. Twenty-one OAMLs (17%) expressed IGHV4-34-encoded B-cell receptors. Five of the 23 recombinant OAML IgMs expressed IGHV4-34, four of which bound to the linear NAL i epitope expressed on B cells but not to the branched NAL I epitope on erythrocytes. One non-IGHV4-34-encoded OAML IgM was also reactive with B cells. Interestingly, three of the 23 OAML IgMs (13%) specifically reacted with proteins of U1-/U-snRNP complexes, which have been implicated as cognate-antigens in various autoimmune diseases such as systemic lupus erythematosus and mixed connective tissue disease. The findings indicate that local autoimmune reactions are instrumental in the pathogenesis of a substantial fraction of OAMLs.

Post-transplant Lymphoproliferative Disorder of Naso-orbital Region in Adult Renal Transplant Recipients: A Case Report and Literature Review.

Post-transplant lymphoproliferative disorder (PTLD) is an uncommon but fatal complication following both solid organ and hematologic stem cell transplantations. Epstein-Barr virus (EBV) has been considered a main etiologic agent causing PTLD, especially in the first year after transplantation. Extranodal manifestations are frequently found in PTLD; however, naso-orbital involvement in adults is rare. We report a case of EBV-associated PTLD of the naso-orbital region in a 72-year-old patient that occurred 10 years after kidney transplant. Six additional adults with naso-orbital PTLD were identified after completing this literature review, including 2 cases with eyelid swelling, 3 cases with proptosis, and 1 case with facial numbness. The majority of cases occurred after 1 year of transplantation and were associated with EBV. This report emphasizes recognizing PTLD as differential diagnosis in transplant recipients who present with naso-orbital symptoms.

Immune checkpoint inhibitors: what neuro-ophthalmologists need to know.

PURPOSE OF REVIEW: Immune checkpoint inhibitors are currently an exceedingly powerful tool in the management of hitherto incurable malignancies and their use in clinical practice is expected to increase in the near future. The purpose of this review is to discuss the current medical uses of checkpoint inhibitors with a focus on their neuro-ophthalmic side-effects. RECENT FINDINGS: Immune checkpoint inhibitors have emerged as a promising breakthrough in the treatment of several tumor types. However, these targeted therapies can induce a wide range of immune-related ophthalmic and neuro-ophthalmic toxicities. It is important for neuro-ophthamologists to promptly recognize and manage these adverse events that can potentially threaten vision. SUMMARY: There are currently seven FDA-approved immune checkpoint inhibitors and several ones are under investigation. In general, immunotherapy is considered a well tolerated, safe and efficacious treatment option for many cancer patients. Nevertheless, because of their unique mechanism of action, these molecules can alter the immune response and result in immune-related adverse effects in almost every organ with an estimated incidence of ophthalmic side effects in this patient population of less than 1%.

[Ocular natural killer/T cell lymphoma: a clinicopathologic analysis].

Objective: To evaluate the clinicopathological features of ocular natural killer(NK)/T cell lymphoma. Methods: Data of 21 patients (22 eyes) with ocular NK/T cell lymphoma treated at Eye & ENT Hospital of Fudan University from January 2006 to March 2018 were retrospectively analyzed for clinical data, morphology, immunophenotype and outcomes. Results: There were 10 males and 11 females with ages from 3 to 77 years (mean, 43 years). There were 20 unilateral cases (10 left eyes and 10 right eyes) and 1 bilateral case. Except for 1 case of corneal perforation resulting from the involvement of the conjunctiva and cornea, the other cases all involved the orbit (including eyelids and conjunctiva) as demonstrated by radiologic studies, with the lacrimal sac involved in 3 cases, and the nasal cavity or maxillary sinus involved in 2 cases. Three patients had been previously diagnosed sinonasal NK/T cell lymphoma with radiotherapy and chemotherapy. Two patients had a history of ovarian NK/T cell lymphoma with chemotherapy. One patient had multiple ulcers of skin and mucosa at presentation. There were 13 primary ocular NK/T cell lymphomas without evidence of nasal or systemic involvement. All patients presented with eyelid swelling and decreased visual acuity. There were proptosis in 18 cases, motility restriction in 13 cases, eyelid ulceration in 3 cases, and fever in 4 cases. They had all been previously diagnosed as orbital pseudotumor or cellulitis and there was no response to steroids and antibiotics. Pathological examination showed atypical lymphoid infiltration with an angioinvasive growth pattern causing coagulative necrosis. Cytologically, the medium-sized neoplastic cells showed irregular folded nuclei. The neoplastic cells were positive for cytoplasmic CD3ε, CD56, and cytotoxic molecules and Epstein-Barr virus-encoded RNA (EBER) in situ hybridization. Seven patients were lost to follow-up. Ten patients died 2.0 to 17.0 months after diagnosis (mean, 6.3 months) despite treatment with chemotherapy and radiotherapy. Conclusions: Ocular NK/T cell lymphoma is a rare form of ocular lymphoma. There are primary NK/T cell lymphoma and secondary ocular NK/T cell lymphoma with nasal or systemic involvement. The rarity of this tumor and inflammatory signs make it challenging to identify these tumors early. The neoplastic cells are positive for cytoplasmic CD3ε, CD56, cytotoxic molecules and EBER in situ hybridization. Despite aggressive therapy, it demonstrates high lethality with poor prognosis. (Chin J Ophthalmol, 2019, 55: 374-380).

Immunopathogenesis of ophthalmological paraneoplastic syndromes: Recent findings.

The aim of this study was to summarize the current knowledge of paraneoplastic syndromes involving eyes. The main interest was the immunopathogenesis of the abovementioned entities. A web search was conducted using Medline, Web of Science and Scopus engines. Key words concerning ocular paraneoplastic syndromes (OPS) such as: "ocular paraneoplastic syndrome", "cancer-associated retinopathy", "cancer-associated cone dysfunction", "melanoma-associated retinopathy", "bilateral diffuse uveal melanocytic proliferation", and "paraneoplastic optic neuritis" were combined with "immunology", "immune response", "antibodies", or "autoantibodies". Numerous papers were found as a result of "ocular paraneoplastic syndrome" search and many of them matched the chosen criteria. We focused on the most recent papers - published in the last 5 years - and eventually, 92 items were found. Only several papers from each detailed category fulfilled both OPS and immunologic criteria. Site-specific paraneoplastic syndromes still remain a difficult clinical challenge. The immunopathogenesis of some of them seems to be more complex than previously thought.

Ocular adnexal marginal zone lymphoma of mucosa-associated lymphoid tissue.

Ocular adnexal lymphomas are a group of heterogeneous neoplasms representing approximately 1-2% of non-Hodgkin lymphomas and 8% of extranodal lymphomas. The incidence of primary ocular adnexal lymphoid tumors has raised over the last decades, and this could be probably attributed to the more sophisticated diagnostic techniques. Due to the wide spectrum of clinical manifestations, ocular tissue biopsy is important in order to set a precise diagnosis based on histological, immunophenotypical and, in some cases, molecular findings. The most common subtype, which may account for up to 80% of primary ocular adnexal lymphomas, is extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue. This lymphoma is usually asymptomatic in the early phase of the disease causing a delay in the final diagnosis and prompt therapy. The pathogenesis of a proportion of these tumors has been linked to chronic inflammatory stimulation from specific infectious factors (e.g., Chlamydia psittaci) or to autoimmunity. The further improvement in diagnostic methods and the further understanding of the pathogenesis of ocular adnexal EMZL may contribute to the establishment of a more successful multidisciplinary therapeutic planning.

Clinical and pathological classification of canine intraocular lymphoma.

The objectives of this retrospective study of 100 dogs with intraocular lymphoma were to describe the histomorphologic and immunohistochemical features of canine intraocular lymphoma, determine the proportion of cases with presumed solitary ocular lymphoma (PSOL) compared to multicentric disease, and assess the clinical outcomes of these patients. Selected cases from Penn Vet Diagnostic Laboratory and Comparative Ocular Pathology Lab of Wisconsin (2004-2015) were evaluated and subtyped using the WHO classification system. Peripheral T-cell lymphoma and diffuse large B-cell lymphoma were the two most common subtypes. Questionnaires were distributed to the referring veterinarians and veterinary ophthalmologists inquiring about clinical signs at time of enucleation, staging, patient outcome, treatment, and disease progression. Cases were categorized as PSOL if only ocular involvement was noted at the time of diagnosis based on the clinical staging criteria. The majority of cases (61%) did not have systemic involvement at the time of diagnosis, and these cases did not progress postoperatively. Median survival time (MST) was significantly higher for the presumed solitary intraocular cases: 769 vs. 103 days, hazard ratio of 0.23 (95% CI: 0.077-0.68). The subtype of lymphoma did not affect survival time. The results of this study suggest two significant points of clinical interest: the majority of dogs (61%) presented without signs of systemic involvement of lymphoma at the time of enucleation, and dogs with only ocular involvement showed no disease progression postenucleation.

Comprehensive analysis of vitreous specimens for uveitis classification: a prospective multicentre observational study.

PURPOSE: To determine the clinical relevance of vitreous biomarkers in patients with uveitis. DESIGN: Multicentre, prospective, observational study. SETTING: Uveitis outpatient clinics of two academic medical centres in Japan. PATIENT POPULATION: This study included 234 eyes of 191 patients with various uveitis aetiologies: definitive sarcoidosis (61 eyes of 46 patients), suspected sarcoidosis (60 eyes of 45 patients), intraocular tumour (34 eyes of 27 patients), viral infection (20 eyes of 18 patients), non-sarcoidosis (16 eyes of 16 patients) and unknown aetiology (43 eyes of 39 patients). OBSERVATION PROCEDURE: Vitreous samples (taken by pars planta vitrectomy) were analysed with flow cytometry, cytology and multiplex PCR analysis. MAIN OUTCOME MEASURES: The primary outcome measures were the diagnostic values of various biomarkers (T cells, B cells and pathogen DNA) in vitreous samples. The secondary outcome was visual acuity after vitrectomy. RESULTS: Sarcoidosis showed higher CD4/CD8 or CD4+ measurements than other aetiologies (p<0.01). In samples with viral infection, pathogen DNA was detected, and CD8+ counts were higher than the other aetiologies (p<0.01). Eyes with tumour had higher CD19+ (p<0.05). Non-sarcoidosis had lower CD4/CD8 than sarcoidosis, higher CD8+ than sarcoidosis and lower CD19+ than tumour (p<0.01). Unknown uveitis had lower CD4/CD8 than sarcoidosis (p<0.01), and higher CD4/CD8 than non-sarcoidosis, viral infection or tumour (p<0.001). Visual acuity improved after vitrectomy (p<0.001). CONCLUSIONS: Uveitis aetiologies had distinct vitreous biomarker profiles, especially of infiltrating lymphocytes. Analyses of CD4/CD8 ratio, T-lymphocyte and B-lymphocyte subset, and pathogen DNA in vitreous samples have good safety profiles and high diagnostic value for uveitis classification. TRIAL REGISTRATION NUMBER: UMIN000004980; Pre-results.

Safe Administration of An Anti-PD-1 Antibody to Kidney-transplant Patients: 2 Clinical Cases and Review of the Literature.

Antiprogrammed cell-death protein 1 (PD-1) antibodies have revolutionized therapy of metastatic melanoma and other tumors, but some subgroups of patients such as immunosuppressed patients after solid-organ transplantation, have regularly been excluded from clinical studies. We report 2 cases of kidney-transplant patients who received an anti-PD-1 antibody to treat metastatic melanoma. Treatment was tolerated well with no relevant adverse events and stable kidney functions, but the melanoma progressed in both patients. Factors potentially affecting risk of allograft rejection and response to treatment, for example, immunosuppressive regimen and therapeutic sequence, are discussed on the basis of current literature. Further studies are necessary to determine the risk of allograft rejection and the therapeutic benefit of anti-PD-1 antibodies for organ-transplanted patients, in particular as these checkpoint inhibitors have become therapeutic standard in a variety of tumors other than melanoma.

The Effect of Ophthalmic Artery Chemosurgery on Immune Function in Retinoblastoma Patients: A Single Institution Retrospective Analysis.

BACKGROUND: Ophthalmic artery chemosurgery (OAC) is associated with grade 3 and 4 neutropenia, however the effect on T-cell number and function is unknown. The purpose of this retrospective review was to confirm that patients treated with OAC do not develop immunosuppression warranting Pneumocystis pneumonia prophylaxis. PROCEDURE: IRB approval was obtained for a single center retrospective review of immune function tests in retinoblastoma patients who received OAC. RESULTS: Twenty-three patients received ≥3 cycles of OAC and had immune function testing (absolute CD4 count) performed at a median of 34 days postcompletion of therapy (range, 15 to 63 d). Only 1 patient had a low absolute CD4 count of 189 cells/µL (normal, 359 to 1570 cells/µL) 2 and a half months after IV carboplatin and 28 days after their third dose of OAC. This patient was found to have coexisting hypogammaglobulinemia. Repeat immune function testing normalized through continued OAC treatment. CONCLUSIONS: Clinically significant immune suppression appears rare following OAC alone, but patients previously treated with IV chemotherapy may be immunosuppressed and may benefit from pneumocystis pneumonia prophylaxis until the CD4 count recovers.

Significant association between TNFAIP3 inactivation and biased immunoglobulin heavy chain variable region 4-34 usage in mucosa-associated lymphoid tissue lymphoma.

Both antigenic drive and genetic change play critical roles in the development of mucosa-associated lymphoid tissue (MALT) lymphoma, but neither alone is sufficient for malignant transformation, and lymphoma development critically depends on their cooperation. However, which of these different events concur and how they cooperate in MALT lymphomagenesis is totally unknown. To explore this, we investigated somatic mutations of 17 genes and immunoglobulin heavy chain variable region (IGHV) usage in 179 MALT lymphomas from various sites. We showed that: (1) there was a significant association between the biased usage of IGHV4-34 (binds to the carbohydrate I/i antigens) and inactivating mutation of TNFAIP3 [encoding a global negative regulator of the canonical nuclear factor-κB (NF-κB) pathway] in ocular adnexal MALT lymphoma; (2) IGHV1-69 was significantly overrepresented (54%) in MALT lymphoma of the salivary gland, but was not associated with mutation in any of the 17 genes investigated; and (3) MALT lymphoma lacked mutations that are frequently seen in other B-cell lymphomas characterized by constitutive NF-κB activities, including mutations in CD79B, CARD11, MYD88, TNFRSF11A, and TRAF3. Our findings show, for the first time, a significant association between biased usage of autoreactive IGHV and somatic mutation of NF-κB regulators in MALT lymphoma, arguing for their cooperation in sustaining chronic B-cell receptor signalling and driving oncogenesis in lymphoma development. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[Novel Adjuvant Therapy for Ocular Melanoma]. / Neue adjuvante Therapien beim okulären Melanom.

Background Malignant melanoma is the most common cancer of the eye in adults that originates either in the intra-ocular uveal tract or extra-ocular conjunctiva. Although the primary tumor can be treated successfully, no effective therapy for both metastatic conjunctival and uveal melanoma currently exits. Tumor-associated lymphangiogenesis and immune cell infiltration play a pivotal role in the development and therapeutic targeting of metastases. Project description Here, we provide an overview of current translational research on lymphangiogenesis and its therapeutic inhibition as well as modulation of immune cell infiltration by passive and active immunotherapy in melanoma of the eye. Specifically, our previous and ongoing work on lymphangiogenesis and immune cells in ocular melanoma within the clinical research unit FOR 2240 "(Lymph)Angiogenesis and Cellular Immunity in Inflammatory Diseases of the Eye" is summarized. Conclusions Translational research on the modulation of tumor-associated lymphangiogenesis and immune cell infiltration could provide novel targets for adjuvant therapy in melanoma of the eye.

Lymphoepithelial Carcinoma of the Nasolacrimal Duct: Clinical, Radiologic, and Immunopathologic Features.

Undifferentiated lymphoepithelial carcinoma (exhibiting both begin lymphoid and malignant epithelial components) most commonly arises in the head and neck, especially in the nasopharynx. It may also be encountered in various ocular adnexal sites, including the nasolacrimal duct. A 63-year-old woman developed a swelling in the region of the right lacrimal sac accompanied by epiphora. CT scanning revealed an enlargement of the nasolacrimal duct from the lacrimal sac to the inferior nasal meatus. A biopsy during dacryocystorhinostomy for symptomatic epiphora revealed hypercellular sheets of small lymphocytes which were interpreted as evidence for a chronic dacryocystitis. Two years later the subtotally excised lesion had substantially grown in size. Repeat CT scans demonstrated an inferonasal anterior orbital mass with further enlargement of the nasolacrimal duct with a solid mass in its lumen, and bone erosion. The biopsy combined a rich background of lymphocytes within which were clusters of undifferentiated carcinoma cells that were cytokeratin and p63 positive. Critical review of the earlier biopsy led to the detection of the same cells, but in smaller numbers, that had been overlooked. An awareness of the possibility of lymphoepithelial carcinoma of the lacrimal sac/duct should improve diagnostic accuracy with the aid of immunohistochemistry. Radiation therapy is often successful in managing this highly sensitive malignant tumor.

Natural Killer T Cells Contribute to Neutrophil Recruitment and Ocular Tissue Damage in a Model of Intraocular Tumor Rejection.

PURPOSE: Immune privilege of the eye protects the nonregenerative ocular tissues from innate and adaptive immune-mediated inflammation. In the case of intraocular tumors, immune privilege can be arrested to allow for immune-mediated rejection. Activation of innate immune cells can contribute to necrosis of the intraocular tumor and bystander ocular tissue. Identifying the cellular components of the innate immune system that contribute to ocular destruction, but are not needed for tumor rejection, provides insights into the immunopathological sequelae in intraocular tumor rejection. METHODS: Wild-type (WT), Jα18 knockout (KO) mice lacking type I natural killer T (NKT) cells, and CD1d KO mice lacking all NKT cells, were used to identify the role of type II NKT cells in intraocular tumor rejection immunopathology. RESULTS: CD1d KO mice had significantly lowered rates of necrotic eye destruction during tumor rejection compared to WT or Jα18 KO mice. Transcriptome and protein analyses revealed that CD1d KO mice had significantly lower expression of CXCL3 compared to WT or Jα18 KO mice, and this was associated with decreased neutrophil recruitment. The presence of type II NKT cells in WT or Jα18 KO mice led to increased CXCL3, which attracted neutrophils to the intraocular tumor and culminated in destruction of the eye. CONCLUSIONS: We found that type II NKT cells are critical in initiating a damaging inflammatory antitumor response involving the recruitment of neutrophils that compromises the integrity of the eye. Loss of type II NKT cells or depleting neutrophils allows for a productive intraocular tumor response that converts the rejection phenotype to preserve the eye.

Rare Presentations of Epstein-Barr Virus--Associated Smooth Muscle Tumor in Children.

Epstein-Barr virus (EBV) has oncogenic potential and has been implicated in the etiology of a wide range of malignancies. Certain EBV-driven neoplasms, such as smooth muscle tumors (SMTs), manifest typically in immunocompromised patients. In children, these neoplasms have been encountered in the setting of primary immune disorders, specifically severe combined and common variable immunodeficiency syndromes. Human immunodeficiency virus infection and posttransplant immunosuppression, in particular liver and kidney transplantation, likewise increase the risk in the pediatric population. The location of these neoplasms appears related to the type of immunodeficiency: in acquired immunodeficiency syndrome they are frequently located intracranially or intraspinally, whereas after transplant they usually involve the liver or lung. We report 2 distinct cases of EBV-related SMT, unique through their coassociated immunosuppressive state or location: the 1st occurred in a patient with immunodeficiency secondary to NEMO gene mutation following hematopoietic stem cell transplantation; the 2nd developed in the orbit after heart transplant.

Role of interferon-γ and cytotoxic T lymphocytes in intraocular tumor rejection.

The eye is normally an immunosuppressive environment. This condition is better known as immune privilege and protects the eye from immune-mediated inflammation of tissues that cannot regenerate. However, immune privilege creates a dilemma for the eye when intraocular neoplasms arise. In some cases, immune privilege is suspended, resulting in the immune rejection of intraocular tumors. This study employed a mouse model in which interferon-γ-dependent intraocular tumor rejection occurs. We tested the hypothesis that this rejection requires interferon-γ for the generation and functional capacity of cytotoxic T lymphocyte-mediated rejection of intraocular tumors. Tumors grew progressively in the eyes of interferon-γ knockout mice, even though the mice generated tumor-specific cytotoxic T lymphocyte responses in the periphery. However, interferon-γ knockout mice rejected tumors that were introduced into extraocular sites. Subcutaneous tumor immunization before intraocular challenge led to tumor rejection and preservation of the eye in wild-type mice. By contrast, tumors grew progressively in the eyes of interferon-γ knockout mice despite their ability to generate peripheral tumor-specific cytotoxic T lymphocytes as well as the capacity of CD8(+) T cells to enter the eye as shown by the presence of CD8 and perforin message and CD3(+)CD8(+) leukocytes within the tumor-bearing eye. We found that cytotoxic T lymphocytes generated in wild-type mice and adoptively transferred into interferon-γ knockout mice mediated the rejection of intraocular tumors in interferon-γ knockout hosts. The results indicate that interferon-γ is critical for the initial priming and differentiation of cytotoxic T lymphocytes residing in the periphery to produce the most effect antitumor function within the eye.

A subset of ocular adnexal marginal zone lymphomas may arise in association with IgG4-related disease.

We previously suggested a relationship between ocular immunoglobulin (Ig)G4-related disease (IgG4-RD) and marginal zone lymphomas (MZLs). However, the cytokine background associated with these disorders and whether it differs between ocular adnexal MZLs with (IgG4-associated MZL) and without (IgG4-negative MZL) numerous IgG4(+) plasma cells are unknown. In this study, we identified the mRNA expression pattern of Th2 and regulatory T-cell (Treg) cytokines in IgG4-RD and in IgG4-associated MZL and IgG4-negative MZL using real-time polymerase chain reaction analysis. Ocular IgG4-RD and IgG4-associated MZL exhibited significantly higher expression ratios of interleukin (IL)-4/ß-actin, IL-10/ß-actin, IL-13/ß-actin, transforming growth factor (TGF) ß1/ß-actin, and FOXP3/ß-actin than did IgG4-negative MZL (p < 0.05). This finding further supports our prior observations that a significant subset of ocular MZLs arises in the setting of IgG4-RD. Furthermore, the presence of a different inflammatory background in IgG4-negative MZLs suggests that IgG4-associated MZLs may have a different pathogenesis.