Upregulated Expression of Activation-Induced Cytidine Deaminase in Ocular Adnexal Marginal Zone Lymphoma with IgG4-Positive Cells.
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ABSTRACT:
SUBMITTER: Nishikori A
PROVIDER: S-EPMC8071226 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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/β-actin, IL-10/β-actin, IL-13/β-actin, transforming growth factor (TGF) β1/β-actin, and FOXP3/β-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.
| S-EPMC4550912 | biostudies-other
Project description:The etiology and pathogenesis of ocular adnexal extranodal marginal zone lymphoma (OAEMZL) are still unknown and the association with Chlamydophila psittaci (C. psittaci) has been shown in only some geographic regions. Herein, we comprehensively examined the frequency of chromosomal translocations as well as CARD11, MYD88 (L265P), and A20 mutations/deletions in 45 C. psittaci negative OAEMZLs. t(14;18)(q32;q21) IGH-MALT1 and t(11;18)(q21;q21) API2-MALT1 were not detected in any of the analyzed tumors while three tumors harbored IGH translocations to an unidentified partner. CARD11 mutations were not found in all analyzed tumors, while the MYD88 L265P mutation was detected in three (6.7%) tumors. A20 mutations and deletions were each detected in seven (15.6%) and six (13.3%) tumors, respectively. Therefore, the observed genetic aberrations could account for the activation of the nuclear factor (NF)-kB signaling pathway in only a minority of the cases. Further studies are needed to identify the molecular mechanisms underlying the pathogenesis of OAEMZL.
| S-EPMC3773926 | biostudies-literature
Project description:The pathogenesis of Chlamydophila (C.) psittaci negative ocular adnexal extranodal marginal zone lymphomas (OAEMZLs) is poorly understood. OAEMZLs are monoclonal tumors expressing a biased repertoire of mutated surface immunoglobulins. Antigenic activation of the B cell receptor (BCR) may play a role in the pathogenesis of these lymphomas. We have analyzed the reactivity of recombinant OAEMZL immunoglobulins. OAEMZL antibodies reacted with self-human antigens, as demonstrated by enzyme-linked immunosorbent assays, HEp-2 immunofluorescence and human protein microarrays. All the analyzed recombinant antibodies (rAbs) exhibited polyreactivity by comprehensive protein array antibody reactivity and some rAbs also demonstrated rheumatoid factor activity. The identity of several reactive antigens was confirmed by microcapillary reverse-phase HPLC nano-electrospray tandem mass spectrometry. The tested rAbs frequently reacted with shared intracellular and extracellular self-antigens (e.g. galectin-3). Furthermore, these self-antigens induced BCR signaling in B cells expressing cognate surface immunoglobulins derived from OAEMZLs. These findings suggest that interactions between self-antigens and cognate OAEMZL tumor-derived BCRs are functional, inducing intracellular signaling. Overall our findings suggest that self-antigen-induced BCR stimulation may be implicated in the pathogenesis of C. psittaci negative OAEMZLs. Antibody Specificity Profiling with four OAEMZL rAbs (Ab4438, Ab4726, Ab5334, and Ab11274) performed on ProtoArray Human Protein Microarrays
2015-01-30 | E-GEOD-65443 | biostudies-arrayexpress
Project description:Ocular adnexal mucosa associated lymphoid tissue lymphomas (OAMALTL) are the most common lymphomas of the eye. The potential roles for specific antigens in these lymphomas are still controversial. Previously we examined IGHV usage and mutations in Chlamydophila (C) psittaci-negative OAMALTL, demonstrating biased use of the IGHV4 family and IGHV4-34 gene and evidence for antigen selection. Herein, we examined the IGKV/IGLV gene usage and mutations in 34 C. psittaci-negative OAMALTL originating from the orbit (15), conjunctivae (14), and lacrimal gland (5). Clonal potentially functional IGKV/IGLV gene sequences were identified in 30 tumors (18 kappa and 12 lambda). An overrepresentation of the IGKV4 family (P < 0.01) was observed. The IGKV3-20*01 allele was used at a greater frequency than in normal peripheral blood B-lymphocytes (P = 0.02) and commonly paired with the IGHV4-34 allele. Twenty-seven of the 30 unique light chain sequences displayed mutations from germline and evidence for antigen selection. Overall our findings demonstrate that in C. psittaci-negative OAMALTL there is a biased usage of IGKV families and genes, which harbor somatic mutations. These findings and the specific paring between the IGKV3-20*01 and IGHV4-34 alleles suggest that specific antigens could play an important role in the pathogenesis of these lymphomas.
| S-EPMC3644856 | biostudies-literature
Project description:The pathogenesis of Chlamydophila (C.) psittaci negative ocular adnexal extranodal marginal zone lymphomas (OAEMZLs) is poorly understood. OAEMZLs are monoclonal tumors expressing a biased repertoire of mutated surface immunoglobulins. Antigenic activation of the B cell receptor (BCR) may play a role in the pathogenesis of these lymphomas. We have analyzed the reactivity of recombinant OAEMZL immunoglobulins. OAEMZL antibodies reacted with self-human antigens, as demonstrated by enzyme-linked immunosorbent assays, HEp-2 immunofluorescence and human protein microarrays. All the analyzed recombinant antibodies (rAbs) exhibited polyreactivity by comprehensive protein array antibody reactivity and some rAbs also demonstrated rheumatoid factor activity. The identity of several reactive antigens was confirmed by microcapillary reverse-phase HPLC nano-electrospray tandem mass spectrometry. The tested rAbs frequently reacted with shared intracellular and extracellular self-antigens (e.g. galectin-3). Furthermore, these self-antigens induced BCR signaling in B cells expressing cognate surface immunoglobulins derived from OAEMZLs. These findings suggest that interactions between self-antigens and cognate OAEMZL tumor-derived BCRs are functional, inducing intracellular signaling. Overall our findings suggest that self-antigen-induced BCR stimulation may be implicated in the pathogenesis of C. psittaci negative OAEMZLs.
2015-01-30 | GSE65443 | GEO
Project description:Background and Objectives: Extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT) type is the most common subtype of the ocular adnexal lymphoma. Despite its excellent prognosis, some patients experience partial remission or progressive disease. We aimed to evaluate clinicopathologic differences in the treatment responder group by comparing complete remission (CR) and non-complete remission (non-CR). Materials and Methods: This study retrospectively reviewed 48 patients who were diagnosed with ocular adnexal MALT lymphoma at Ulsan University Hospital between March 2002 and August 2018. Patients who were followed up for less than 6 months were excluded. Histologic and clinical features were analyzed. The patients were divided into two groups: CR and non-CR. Results: Among the 48 patients, 33 achieved CR and 15 achieved non-CR during the median follow-up period of 40.00 months (range, 7-109 months). In univariable analysis, more patients tend to undergo treatment in the CR group, and post-radiotherapy (post-RT) SUVmax, PET and serum lactate dehydrogenase (LDH) levels were higher in the non-CR group (p = 0.043, p = 0.016, and p = 0.042, respectively). In a multivariable analysis, only application of treatment, including radiotherapy or chemotherapy with immunotherapy, was related to CR (odd ratio 7.301, 95% confidence interval 1.273-41.862, p = 0.026). In subgroup analysis according to the site of involvement, none of the variables were significant except for the post-RT SUVmax of PET and level of serum LDH in the non-conjunctiva group (p = 0.026, and p = 0.037, respectively). Seven (14.6%) patients had a recurrence, and those with a recurring site other than the primary site had a higher Ki-67 labeling index, although it was not statistically significant (9.56% vs. 18.00%, p = 0.095). Conclusions: Although belonging to the early stages, the non-CR rate was high in patients with high serum LDH levels, and recurred patients had higher Ki-67. Thus, considering active treatment is recommended in this group of patients.
| S-EPMC9229471 | biostudies-literature
Project description:The pathogenesis of ocular adnexal marginal zone lymphomas of mucosa-associated lymphatic tissue-type (OAML) is still poorly understood. We analyzed 63 cases of such lymphomas for non-synonymous mutations in 24 candidate genes by amplicon sequencing. We validated frequent mutations in the NF-κB regulators MYD88, TNFAIP3 and TNIP1 in OAML, but also identified recurrent mutations in several additional components of the NF-κB pathway, including BCL10 and NFKBIA. Overall, 60% of cases had mutations in at least one component of NF-κB signaling, pointing to a central role of its genetic deregulation in OAML pathogenesis. Mutations in NOTCH1 and NOTCH2 were each found in 8% of cases, indicating a pathogenetic function of these factors in OAML. KMT2D was identified as the first epigenetic regulator with mutations in OAML, being mutated in 22% of cases. Mutations in MYD88 were associated with an inferior disease-free survival. Overall, we identified here highly recurrent genetic lesions in components of the NF-κB pathway, of NOTCH1 and NOTCH2 as well as KMT2D in OAML and thereby provide major novel insights into the pathogenesis of this B cell malignancy.
| S-EPMC5308752 | biostudies-literature
Project description:AIMS:To determine the long-term outcomes of ocular adnexal lesions in immunoglobulin G4-related ophthalmic disease (IgG4-ROD). METHODS:This retrospective, non-randomised exploratory study included 82 patients with ocular adnexal lesions. We evaluated the long-term outcomes in 71 patients during the median follow-up period of 30 months, who underwent either watchful waiting (n=20; range 12-90 months) or systemic corticosteroid treatment, delivered according to consensus guidelines (n=51; range 9- 115 months). We also analysed factors that might contribute to recalcitrance to treatment. RESULTS:Of 82 patients, 40 (49%) were male, and the median patient age was 60 years old. Twenty-one (26%) patients with extraocular muscle (EOM) and/or trigeminal nerve branch (CN V) enlargements had a significantly high frequency of multiple ocular adnexal lesions (p<0.0001, Fisher's exact test). In addition, two patients developed EOM and/or CN V enlargements de novo over time. Twenty patients with solitary lacrimal gland enlargements preferred watchful waiting, due to mild symptoms. Of these, 18 (90%) lesions remained dormant throughout a median follow-up of 27 months. Among 51 patients treated with corticosteroids, 31 (61%) experienced relapses after treatment and required systemic low-dose maintenance treatment. A multivariate analysis indicated that EOM and/or CN V enlargements comprised a risk factor for relapse (HR 2.7; 95% CI 1.1 to 6.7). CONCLUSIONS:This exploratory study showed that different types of ocular adnexal lesions in IgG4-ROD displayed distinct proliferative activities. Our results suggested that EOM and/or CN V enlargements might be secondary lesions that confer refractoriness to systemic corticosteroid treatment recommended by consensus guidelines.
| S-EPMC7041505 | biostudies-literature
Project description:PurposeTo characterize demographic, clinical, and histopathologic features of ocular adnexal lymphoma (OAL) at a single institution.MethodsRetrospective review of all patients with pathologic diagnosis of OAL between 2015 and 2020.ResultsThere were 133 patients with OAL, with a median age of 65 years (range 23-97) and a slight female predominance (male: female = 1:1.46), (n = 79, 59%). The majority of tumors were non-Hodgkin B-cell lymphomas (n = 131, 99%), most frequently Extranodal Marginal Zone B-Cell Lymphoma (EMZL, n = 93, 70%), followed by follicular lymphoma (n = 21, 16%), chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 7, 5%), diffuse large B-cell lymphoma (n = 5, 4%), and mantle cell lymphoma (n = 5, 4%). The most frequently involved sites included the orbit (n = 85, 64%) and conjunctiva (n = 43, 32%). Information was available on oncologic staging in 78 (59%), treatment in 82 (62%), and follow-up in 75 (56%) patients. By the Ann-Arbor classification system, patients were classified as IE (54/78, 69%), IIE (9/78, 12%), IIIE (6/78, 8%), and IVE (9/78, 12%). The most common treatments included external beam radiotherapy (standard and ultra-low-dose) (48/82, 59%), biologics (22/82, 27%), and surgical excision with cryotherapy (14/82, 17%) (some patients had >1 therapy). Median follow-up time was 24 months (range 0-221 months). Recurrence was observed in 13% (10/75) with a median time to recurrence of 60 months (95% confidence interval 47-73 months). Excision with cryotherapy as a sole treatment modality was associated with earlier recurrence (P = 0.003).ConclusionIn this largest single-center study of OAL, we found that most OAL were Ann-Arbor Stage IE EMZL, occurring in older patients with a female predominance. Early recurrence was noted in tumors treated with excision and cryotherapy alone.
| S-EPMC9116088 | biostudies-literature
Project description:In 2016 there were an estimated 7,460 newly diagnosed patients with marginal zone lymphoma (MZL) in the US, which comprised 7% of all mature non-Hodgkin lymphomas (NHL). Based on data from the US SEER-18 program from 2001-2017, the age-standardized incidence rate for MZL was 19.6 per 1,000,000 person-years; 9% of MZL cases were splenic MZL (SMZL), 30% nodal MZL (NMZL), and 61% extranodal MZL (EMZL) of mucusa-associated lymphoid tissue (MALT). Incidence rates were slightly higher in men for SMZL and NMZL, but similar for EMZL, and increased steeply with age for all MZL subtypes. The incidence (age-standardized per 1,000,000) of MZL was highest among non-Hispanic whites (20.7), followed by Hispanics of all races (17.6), non-Hispanic blacks (15.4), and Asian/Pacific islanders (15.0). The incidence of MZL increased +1.0% per year in the US from 2001-2017, with increases reported in other countries during this timeframe. The 5-year relative survival rate for MZL in the US was 89.8% and was similar across racial/ethnic groups and by sex; survival rates have been increasing in the US and other countries. Established risk factors for MZL (or MZL subtypes) include family history of NHL, genetic loci in the HLA region, Helicobacter pylori infection (gastric MALT lymphoma), and several autoimmune diseases (Sjögren syndrome, systemic lupus erythematosus and Hashimoto thyroiditis), with strong (but not definitive) evidence for Chlamydia psittaci (ocular adnexal MALT lymphoma), Borrelia burgdorferi (cutaneous MZL), hepatitis C virus, human immunodeficiency virus, and solid organ transplantation. Promising risk factors that require additional study include other infections, other autoimmune conditions, trichloroethylene exposure, certain occupations, hair dye, cigarette smoking, sun exposure (protective), and alcohol use (protective). MZL is a model of an antigen-driven malignancy, where epidemiologic risk factors, tissue-specific factors, and host immune response (including the impact of chronic inflammation and immunosuppression) drive lymphomagenesis with implications for prevention.
| S-EPMC8020862 | biostudies-literature