A new mode for the diagnosis of angioimmunoblastic T-cell lymphoma.

In order to explore a new mode for the diagnosis of angioimmunoblastic T-cell lymphoma (AITL), 31 cases of AITL and 28 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) were used as the study subjects. Identifying T follicular helper (TFH) cells with CD4, CD10, Bcl-6, and PD-1, identifying proliferative B cells with CD20 and EZH2, identifying proliferative follicular dendritic cells (FDCs) with CD21 and CD23, and analyzing the value of TFH/B/FDC proliferation and immunolocalization in the diagnosis of AITL. (1) Outside the inherent lymphoid follicles, simultaneous proliferation of TFH/B/FDC (a new diagnostic mode) were observed in AITL [83.87%; 26/31], with their immunolocalizations in the same site [83.87%; 26/31], while this phenomenon was not observed in 28 cases of PTCL-NOS (P<0.05). (2) The sensitivity and specificity of using this new mode to diagnose AITL were both high (83.87%, 100%), which was superior to CD2 (100%, 0%), CD3 (100%, 0%), CD4 (100%, 32.14%), CD5 (100%, 25%), CD10 (61.9%, 100%), Bcl-6 (42.86%, 100%), PD-1 (83.87%, 96.43%), and its Youden Index (0.84) was the highest. The areas under the curve (AUC) of CD10, Bcl-6, PD-1, and new mode to diagnosis AITL were 0.81, 0.71, 0.90, and 0.92, respectively, while the new mode had the highest AUC. The simultaneous proliferation of TFH/B/FDC cells outside the inherent lymphoid follicles can be used to assist in the diagnosis of AITL, and the simultaneous spatiotemporal proliferation of TFH/B/FDC cells is a specific immunomorphology of AITL.

Clinicopathologic profile of intra-abdominal follicular dendritic cell sarcoma: A study of three cases with a literature review.

Follicular dendritic cell sarcoma (FDCS) is a rare tumor, which mainly originates from follicular dendritic cells (FDCs) in the lymph nodes. Sometimes FDCS can arise from outside the lymph nodes. FDCS is an extremely rare malignant tumor in intraperitoneal or retroperitoneal tissue. We gathered the detailed clinical data of three patients diagnosed with FDCS in the abdomen. The clinical observations and histopathologic and immunohistochemical features of FDCS were analyzed. The patients included two men and one woman aged 55 ~ 61 years old. The mesentery of the small intestine and colon was involved in case 1, spleen in case 2, and retroperitoneal tissues in case 3. Two patients presented with abdominal masses, and one presented with no obvious symptoms. Histology showed ovoid to spindle neoplastic cells arranged in fascicles and storiforms with inflammatory infiltrate as well as whorled patterns in some areas. Immunohistochemical staining was positive for CD21, CD23, CD35, and SSTR2. FDCS exhibits no characteristic clinical manifestations. Morphologically, FDCS can have overlapping features with many other entities, leading to misdiagnosis. The use of histopathology supplemented with FDC markers, such as CD21, CD23, and CD35, is useful for diagnosis and differential diagnosis.

EBV-Positive Inflammatory Follicular Dendritic Cell Sarcoma of the Spleen: Report of an Aggressive Form With Molecular Characterization.

EBV-positive inflammatory follicular dendritic cell sarcoma (EBV+ inflammatory FDCS) is a rare neoplasm almost exclusively located in the spleen or liver. It is characterized by a proliferation of EBV-positive spindle-shaped cells bearing follicular dendritic cell markers, associated with an abundant lymphoplasmacytic infiltrate. EBV+ inflammatory FDCS is often asymptomatic or responsible for mild symptoms. It usually displays an indolent course and its prognosis is excellent after tumor removal, although relapsing and metastatic forms exist. Herein, we describe an aggressive form of splenic EBV+ inflammatory FDCS in a 79-year-old woman presenting with abdominal pain, deterioration of general health status, major inflammatory syndrome, and symptomatic hypercalcemia. A splenectomy was performed leading to a rapid improvement in her clinical condition and normalization of laboratory abnormalities. Unfortunately, her symptoms and laboratory abnormalities reappeared 4 months later. Computed tomography showed a mass in the splenectomy site and multiple liver and peritoneal nodules. Further analyses were performed on tumor tissue and showed positive phospho-ERK staining of tumoral cells indicating activation of MAPK pathway. Inactivating mutations were found on CDKN2A and NF1 genes. Subsequently, the patient's condition deteriorated rapidly. Since interleukin-6 levels were dramatically increased, tocilizumab was used but only had a transient effect on the patient's symptoms and inflammatory syndrome. Antitumor agent gemcitabine was initiated but her clinical condition continued to deteriorate and the patient died 2 weeks later. The management of aggressive forms of EBV+ inflammatory FDCS remains challenging. However, since these tumors seem to display genetic alterations, better characterization could lead to molecular targeted therapies.

The Follicular Dendritic Cells and HPV 18 Interrelation in Head and Neck Squamous Cell Carcinomas of the Larynx.

Background and Objectives: Even if they are cells of controversial origin (mesenchymal, perivascular, or fibroblastic), follicular dendritic cells (FDC) are present in all organs. The aim of this study was to establish the FDC expression pattern and its interrelation with HPV 18 expression in laryngeal squamous cell carcinoma (LSCC). Materials and Methods: Fifty-six cases of LSCC were evaluated by simple and double immunostaining. The following score was used: 0 (negative or few positive cells), 1 (10-30% of positive cells), 2 (30-50% of cells), and 3 (over 50% of cells). Results: The expression of CD 21-positive cells with dendritic morphology (CDM) was noticed in the intratumoral area of conventional (well and poorly differentiated types and HPV 18 positive cases with a value of 2 for the score) and papillary types (HPV-18 negative cases with a score of 1). The highest value of 2 for the score of CDM in HPV-18 positive cases was found in the peritumoral area of well- and poorly-differentiated conventional LSCCs. A significant correlation was found between scores of CDM from the intratumoral area and those of the peritumoral area (p = 0.001), between CDM and non-dendritic morphology cells (NDM) of the intratumoral area (p = 0.001), and between HPV-18 status and peritumoral NDM cells (p = 0.044). Conclusions: The FDC and NDM cell score values of intratumoral and peritumoral areas may represent important parameters of LSCCs. This may contribute to a better stratification of laryngeal carcinoma cases and the individualized selection of clinical treatment protocols.

Fine needle aspiration cytology of follicular dendritic cell sarcoma of the stomach masquerading as gastrointestinal stromal tumor: A case report of a unique entity with emphasis on cytomorphology.

Follicular dendritic cell sarcoma (FDCS) is a rare malignant neoplasm, postulated to arise from follicular dendritic cells, with approximately 343 reported cases. Less than 100 cases of FDCS were in the gastrointestinal tract, with only four cases described in the stomach, none of them diagnosed on fine needle aspiration (FNA) cytology. We report here the first case of FDCS of the stomach diagnosed on FNA. Our patient is a 31-year-old male who presented with several years history of intermittent abdominal pain prompting occasional emergency-room visits. Imaging showed a 10.6 cm mass arising from the stomach, concerning for gastrointestinal stromal tumor. FNA cytology was performed using five passes with a 22-gauge needle. The smears were moderately cellular consisting of sheets and large, loosely cohesive clusters of ovoid to spindle cells with indistinct cytoplasmic borders and abundant cytoplasm, peppered with numerous small mature lymphocytes. The nuclei of the tumor cells were oval with finely granular chromatin with frequent nuclear grooves, pseudoinclusions, and easily recognizable mitotic figures. The tumor cells were positive for FDCS markers (CD21, CD23, and CD35).

FDC-SP as a diagnostic and prognostic biomarker and modulates immune infiltrates in renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC), one of the top 10 causes of cancer death, is responsible for more than 90% of all cases of primary renal cancer worldwide. Follicular dendritic cell-secreted protein (FDC-SP) specifically binds to activated B cells and regulates the generation of antibodies. It is also thought to promote cancer cell invasion and migration, which could help with tumor metastases. This study aimed to assess the efficacy of FDC-SP in the diagnosis and prognosis of RCC and to investigate the relationship between immune infiltration in RCC and these outcomes. RESULTS: RCC tissues had significantly higher levels of FDC-SP protein and mRNA than normal tissues. The high level of FDC-SP expression was linked to the T stage, histological grade, pathological stage, N stage, M stage, and OS event. Functional enrichment analysis identified the major pathways that were enriched as immune response regulation, complement, and coagulation. Immunological checkpoints and immune cell infiltration were observed to substantially correlate with the levels of FDC-SP expression. FDC-SP expression levels showed the ability to precisely distinguish high-grade or high-stage renal cancer (area under the curve (AUC) = 0.830, 0.722), and RCC patients with higher FDC-SP expression levels had worse prognoses. The AUC values for one-, two-, and five-year survival rates were all greater than 0.600. Moreover, the FDC-SP expression is an independent predictive biomarker of OS in RCC patients. CONCLUSION: FDC-SP may be a prospective therapeutic target in RCC as well as a possible diagnostic and prognostic biomarker associated with immune infiltration.

Cytomorphology of follicular dendritic cell sarcoma: a report of 7 cases with an emphasis on the diagnostic challenges.

BACKGROUND: Follicular dendritic cell sarcoma is a malignant neoplasm derived from germinal center follicular dendritic cells, which both share a characteristic immunophenotype (namely CD21, CD23, and CD35). Cytomorphologic descriptions are few, consisting of only 26 prior cases from 24 publications. Identification by cytologic means appears challenging as the majority of previous reports disclose an erroneous or indeterminate initial cytologic diagnosis. Herein, we present the largest cytology series to date with the aim of expanding upon this small body of literature and discuss possible factors resulting in misinterpretation. MATERIALS AND METHODS: A retrospective search was conducted from 2 academic medical centers to identify histologically confirmed cases of follicular dendritic cell sarcoma with an associated cytologic component. Clinicopathologic data were tabulated and a comparative analysis of cytomorphologic and immunohistochemical features was performed. RESULTS: Seven separate cases were identified. All cases showed cohesive tumor cells with a characteristic voluminous, ill-defined cytoplasm with interconnecting fibrillary processes and intimately admixed mature lymphocytes. Features were maintained across various cytologic preparations, including conventional smear, liquid-based cytology, and touch imprint. Unusual immunohistochemical profiles were noted in a subset of cases. CONCLUSIONS: Cytomorphology is highly conserved across cases and preparations; however, a propensity for aberrant immunoexpression may contribute to diagnostic errors. Cytomorphologic features, supported by immunohistochemistry, suggest fine-needle aspiration as a reasonable diagnostic modality. Tumors with these features should include CD21, CD23, and/or CD35 in the workup.

Extranodal Mesenteric Follicular Dendritic Cell Sarcoma Expressing Keratin Antigens: What Pitfalls Initiate Diagnostic Clues.

Extranodal follicular dendritic cell sarcomas are infrequent diagnostically challenging tumors. Because of their rarity, heterogeneous histomorphologic features and variable histologic grades a significant number of extranodal lesions are prone to be misdiagnosed. Even though they have a characteristic immunoprofile, expression of a range of nonspecific markers is well documented. Even though they are typically negative for keratins, few authors have reported lesions expressing keratin. Keratin expressing tumors are more likely to be misinterpreted by pathologists further deterring their inclusion in the differential diagnosis. We report an intraabdominal mesenteric follicular dendritic cell sarcoma in a 44-year-old male that immunophenotypically expressed keratin antigens. The lesion showed a high-grade pleomorphic epithelioid appearance and the initial differential diagnosis included lymphoma, sarcomas, melanoma, and carcinomas. Follicular dendritic cell sarcoma was not considered. Expression of epithelial membrane antigen and keratin further deterred the diagnosis which was reached only after extensive use of immunomarkers. The tumor cells expressed CD21, CD23, and D2-40. Morphologically, the tumor showed some thymoma-like features with occasional TDT-expressing background T-lymphocytes. These features were hints to reconsider our differential diagnosis to include follicular dendritic cell tumors. Awareness of this aberrant staining of epithelial immunomarkers and attention to certain clues should encourage pathologists to consider this entity. Speculative assumptions may explain this unusual keratin expression in some lesions. The histomorphologic and immunohistochemical heterogeneity may suggest different variants and grades of follicular dendritic cell sarcomas. The prevalence, importance, and histogenesis of keratin expression in follicular dendritic cell sarcomas warrant further studies.

Angioimmunoblastic T-Cell Lymphoma with Exuberant CD30-Positive Follicular Dendritic Cell Proliferation in a SARS-CoV-2 Patient: The Role of Mutational Analysis to Exclude an Associated Follicular Dendritic Cell Sarcoma.

Follicular dendritic cell (FDC) proliferation in angioimmunoblastic T-cell lymphoma (AITL) is still not well defined, challenging the accurate differential diagnosis between the AITL with expanded follicular dendritic cell meshwork and the combined AITL and follicular dendritic cell sarcoma (FDCS). Herein, we reported the case of a 58-year-old male with coexisting SARS-CoV-2 infection and AITL with an exuberant CD30-positive FDC proliferation, in which genetic analysis identified mutations of genes commonly involved in AITL but not in FDC sarcoma (i.e., RHOA, TET2, DNMT3A, and IDH2), thus supporting the reactive nature of the CD30-positive FDC expansion.

Follicular dendritic cells.

Follicular dendritic cells (FDCs) are unique accessory immune cells that contribute to the regulation of humoral immunity. They are multitasker cells essential for the organization and maintenance of the lymphoid architecture, induction of germinal center reaction, production of B memory cells, and protection from autoimmune disorders. They perform their activities through both antigen-driven and chemical signaling to B cells. FDCs play a crucial role in the physiological regulation of the immune response. Dis-regulation of this immune response results when FDCs retain antigens for years. This provides a constant antigenic stimulation for B cells resulting in the development of immune disorders. Antigen trapped on FDCs is resistant to therapeutic intervention causing chronicity and recurrences. Beyond their physiological immunoregulatory functions, FDCs are involved in the pathogenesis of several immune-related disorders including HIV/AIDS, prion diseases, chronic inflammatory, and autoimmune disorders. FDCs have also been recently implicated in rare neoplasms of lymphoid and hematopoietic tissues. Understanding FDC biology is essential for better control of humoral immunity and opens the gate for therapeutic management of FDC-mediated immune disorders. Thus, the biology of FDCs has become a hot research area in the last couple of decades. In this review, we aim to provide a comprehensive overview of FDCs and their role in physiological and pathological conditions.

Histiocytic and follicular dendritic cell sarcoma: Diagnostically challenging rare entities.

BACKGROUND: Follicular dendritic cell sarcomas (FDCSs) and histiocytic sarcomas (HSs) are exceedingly rare tumors. Most of the data on those entities are based on case reports or small case series. The natural history and response to different treatment modalities have not been well established. AIMS: To analyze the clinicopathologic features, immunophenotypic profile, treatment responses and to add to the existing data on FDCS and HS. STUDY DESIGN: Retrospective descriptive study. MATERIALS AND METHOD: The study was conducted at the department of Oncopathology at a tertiary care cancer hospital in India, retrospectively within the time period of four years (2016-2019). Total eight (8) cases were diagnosed: four cases of FDCS and four cases of HS involving nodal and extra-nodal sites. Clinical, histopathological, immunohistochemistry (IHC) and therapeutic data of the eight cases were retrieved and analyzed. STATISTICS: Descriptive statistics. RESULT: Among the four patients of FDCS, two had nodal and two had extra-nodal disease. Mean tumor size was 6 cm. Tumor cells expressed CD23, CD21, CD45, CD68 and S100. One patient received adjuvant chemotherapy (Gemcitabine and Docetaxel). Median survival was 36 months. None of them developed distant metastasis. Two of the patients having HS, developed bone metastasis. Median survival was 8.5 months. CD68 was consistently expressed in all cases of HS. Other applied IHC markers were negative in all the eight cases. CONCLUSION: FDCS and HS are under-recognized and easily prone to a wrong diagnosis. Therefore, considering these rare entities in differential diagnoses and inclusion of proper IHC biomarkers are necessary to avoid potential misdiagnosis.

Divergent immunohistochemical expression of CD21 and CD23 by follicular dendritic cells with increasing grade of follicular lymphoma.

BACKGROUND: Ultrastructural and immunohistochemical differences have been described in FDCs of primary and secondary follicles, illustrating the highly compartmentalized structure of lymph follicles. Differences in FDC immunophenotype in different grades of FL may reflect some parallelism between reactive and neoplastic conditions in terms of FDC-B cell interaction and may be used as a valuable additional tool for grading FL. METHODS: A total of 60 paraffin blocks from patients with follicular lymphoma, 30 cases each of grade 1 and 3, were retrieved from our archive. Immunohistochemical analysis was carried out for CD21, CD23, cyclin A, and Ki-67. RESULTS: Our study demonstrates that during evaluation, six patterns of FDC distribution were distinguished. The intensity of stain for CD21 was not statistically significant in grade 1 and grade 3 FL (p = 0.340). In contrast, grade 3 FLs exhibited a significant decrease of CD23 expression by the FDCs (p < 0.001). By CD21 stain, there was no significant difference in the distribution of pattern 1 in grades 1 and 3 (p = 0.098). In contrast, in grade 3, this pattern was significantly less observed by CD23 stain (p = 0.016). The same was observed for pattern 2 for CD21 (p = 0.940) and CD23 (p = 0.010) and pattern 4 for CD21 (p = 0.305) and CD23 (p = 0.005), respectively. Distribution of pattern 5 was significantly different between grades 1 and 3 both for CD21 (p = 0.005) and CD23 (p < 0.001). Distribution of patterns 2 and 6 was not significantly different between grades 1 and 3 for CD21 and CD23. The values of cyclin A and Mib-1 were also significantly different between grades 1 and 3 (p < 0.001). CONCLUSIONS: The observed patterns of FDCs lead us to believe that similar to reactive lymph node follicles, neoplastic follicles in FL, at least in early stages, have an organized structure. Hypothetically, with CD21, CD23, and cyclin A immunohistochemistry, the sequence of events in FL progression may be traced.

Differential expression of estrogen receptor-α on follicular dendritic cells from patients with grade 1-2 and grade 3 follicular lymphoma.

Hormone therapy has been used for patients with estrogen receptor alpha (ERα)-positive breast cancers. Recently, some studies reported the expression of ERα on neoplastic cells from B-cell lymphomas. However, there has been only one report of ERα expression on the follicular dendritic cells (FDCs) that structurally and functionally support the microenvironment of follicular lymphomas (FLs). The objective of this study was to investigate the frequency of ERα expression on FDCs in nonneoplastic reactive lymphoid tissues and to compare the frequency of ERα expression on FDCs in the axillary lymph nodes between patients with and without antiestrogen therapy and among patients with grades 1-3 of FL. Reverse transcription-polymerase chain reaction was performed to detect ERα mRNA in FL. In nonneoplastic germinal centers (GCs) from patients with tonsillitis or reactive lymphadenitis, ERα was expressed in the light zone. ERα-positive cells strongly correlated with the width of GCs (rs  = 0.81, P < 0.01) and the CD21-positive (rs  = 0.69, P < 0.01) and CD23-positive (rs  = 0.83, P < 0.01) FDC meshwork. The axillary lymph nodes had fewer ERα-positive cells, smaller GCs, and a looser CD21- and CD23-positive FDC meshwork with hormone therapy than without hormone therapy (P < 0.01). Neoplastic follicles of G1-2 FL had more ERα-positive cells and a larger CD23+ FDC meshwork than those of G3 FL (P < 0.01). ERα mRNA was detected in both G1-2 FL and G3 FL by reverse transcription-polymerase chain reaction. In conclusion, these results suggested that antiestrogen hormone therapy may decrease the number of ERα-positive FDCs and that the responses mediated by the estrogen-ERα interaction on FDCs may differ between G1-2 FL and G3 FL.

Use of Smooth Muscle Myosin Heavy Chain as an Effective Marker of Follicular Dendritic Cells.

Smooth muscle myosin heavy chain (SMMHC) is a major structural component of the contractile apparatus in smooth muscle cells. Even though it is considered a relatively specific marker for terminal smooth muscle cell differentiation, expression in other cell types such as follicular dendritic cells (FDCs) has rarely been reported. To determine whether SMMHC represents an effective FDC marker in lymphoid tissues, we compared the immunohistochemical results for SMMHC with those of the traditional FDC markers podoplanin (D2-40) and CD21. Paraffin sections of 44 lymphoid tissues were analyzed, including 31 cases of follicular hyperplasia, 6 cases of follicular lymphoma, 2 cases of peripheral T-cell lymphoma, 3 cases of diffuse large B-cell lymphoma arising in follicular lymphoma, 1 case of nodular sclerosis classical Hodgkin lymphoma, and 1 case of small lymphocytic lymphoma. There was no statistically significant difference between the number of SMMHC-positive and D2-40-positive or CD21 lymph nodes (P>0.05). The extent and intensity of SMMHC-positive FDCs were similar to those of D2-40-positive FDCs (P=0.127 and 0.733, respectively), but significantly lower compared with those of CD21 cells (P=0.009 and 0.00002, respectively). However, in contrast to CD21 which was also positive in some germinal center B cells, SMMHC expression was restricted to FDCs. Our results indicate that SMMHC is an excellent marker for FDCs and can be particularly helpful in demonstrating the underlying architecture in lymphoid processes.

SSTR2a Is a Useful Diagnostic Marker for Follicular Dendritic Cells and Their Related Tumors.

SSTR2a, a member of the somatostatin receptor family, has been used as a diagnostic marker of meningioma. However, the expression of SSTR2a in follicular dendritic cells (FDCs) and their related tumors has been poorly characterized. This study aimed to assess the potential diagnostic utility of measuring SSTR2a immunohistochemically in FDCs and their related tumors. We evaluated whole-tissue sections from 182 cases including 83 lymphoid reactive follicular hyperplasias, 17 follicular lymphomas, 18 follicular dendritic cell sarcomas (FDCSs), 6 inflammatory pseudotumor-like FDCSs, and 58 other histologic mimics. Immunohistochemistry for SSTR2a and other FDC markers (CD21, CD23, CD35, clusterin, and podoplanin) were performed in all 182 cases. Diffuse membrane immunoreactivity for SSTR2a in FDCs was observed in 100% of follicular lymphoma and FDCS cases and in 96.4% of the reactive follicular hyperplasias cases. Notably, the positive rate of SSTR2a in FDCSs was higher than that of CD21 (88.9%), CD23 (77.8%), CD35 (94.4%), clusterin (55.6%), and podoplanin (94.4%). All inflammatory pseudotumor-like FDCSs were negative for SSTR2a. The histologic mimics were negative for SSTR2a, except for 1 leiomyosarcoma case that showed focal (~10%) positive expression for SSTR2a. Overall, our findings indicate that SSTR2a is a highly sensitive and diagnostically useful marker for FDCs and FDCSs. Furthermore, immunohistochemistry for SSTR2a may be helpful to distinguish FDCSs from inflammatory pseudotumor-like FDCSs and other histologic mimics. Moreover, our findings suggest that SSTR2a may be a potential therapeutic target for treatment of FDCSs.

Follicular Dendritic Cell Sarcoma With Indolent T-Lymphoblastic Proliferation Is Associated With Paraneoplastic Autoimmune Multiorgan Syndrome.

Nonclonal expansions of immature T cells outside of the thymus, termed indolent T-lymphoblastic proliferation (iT-LBP), have been identified in rare lymphoproliferative disorders. We report that iT-LBP is a frequent finding in cases of follicular dendritic cell sarcoma (FDCS), and shows an association with paraneoplastic autoimmune multiorgan syndrome (PAMS). We studied 31 cases of FDCS by paraffin immunohistochemistry using antibodies to CD21, CD23, CD35, clusterin, CXCL13, podoplanin, CD3, CD4, CD8, CD20, CD1a, and TdT. Chart review was performed to characterize the clinical behavior including evidence of autoimmune disease. FDCS occurred in a wide variety of nodal and extranodal sites. Fourteen of 31 (45%) cases contained immature TdT-positive T cells; in 5 cases these cells were numerous and present throughout the tumor. Four of these 5 patients with numerous immature T cells developed autoimmune disease, clinically categorized as PAMS and/or myasthenia gravis. PAMS persisted after tumor resection, causing severe morbidity and mortality. These findings suggest that the neoplastic follicular dendritic cells can recruit or foster the proliferation of immature T cells and that these cells may play a role in mediating PAMS. Recognition of iT-LBP in FDCS is important to avoid misdiagnosis as thymoma or T-lymphoblastic lymphoma, and may predict serious autoimmune complications in some patients.

Tertiary Lymphoid Structures: Autoimmunity Goes Local.

Tertiary lymphoid structures (TLS) are frequently observed in target organs of autoimmune diseases. TLS present features of secondary lymphoid organs such as segregated T and B cell zones, presence of follicular dendritic cell networks, high endothelial venules and specialized lymphoid fibroblasts and display the mechanisms to support local adaptive immune responses toward locally displayed antigens. TLS detection in the tissue is often associated with poor prognosis of disease, auto-antibody production and malignancy development. This review focuses on the contribution of TLS toward the persistence of the inflammatory drive, the survival of autoreactive lymphocyte clones and post-translational modifications, responsible for the pathogenicity of locally formed autoantibodies, during autoimmune disease development.