Germinal Centre Shutdown

Germinal Centres (GCs) are transient structures in secondary lymphoid organs, where affinity maturation of B cells takes place following an infection. While GCs are responsible for protective antibody responses, dysregulated GC reactions are associated with autoimmune disease and B cell lymphoma. Typically, ‘normal’ GCs persist for a limited period of time and eventually undergo shutdown. In this review, we focus on an important but unanswered question – what causes the natural termination of the GC reaction? In murine experiments, lack of antigen, absence or constitutive T cell help leads to premature termination of the GC reaction. Consequently, our present understanding is limited to the idea that GCs are terminated due to a decrease in antigen access or changes in the nature of T cell help. However, there is no direct evidence on which biological signals are primarily responsible for natural termination of GCs and a mechanistic understanding is clearly lacking. We discuss the present understanding of the GC shutdown, from factors impacting GC dynamics to changes in cellular interactions/dynamics during the GC lifetime. We also address potential missing links and remaining questions in GC biology, to facilitate further studies to promote a better understanding of GC shutdown in infection and immune dysregulation.

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Analysis of BCL-6 mutations in classic Hodgkin disease of the B- and T-cell type

Blood ◽

10.1182/blood.v97.8.2401 ◽

2001 ◽

Vol 97 (8) ◽

pp. 2401-2405 ◽

Cited By ~ 15

Author(s):

Volkhard Seitz ◽

Michael Hummel ◽

Ioannis Anagnostopoulos ◽

Harald Stein

Keyword(s):

T Cell ◽

B Cell ◽

Cell Lines ◽

Somatic Mutations ◽

Cell Lymphoma ◽

Regulatory Region ◽

B Cell Lymphoma ◽

Affinity Maturation ◽

Hodgkin Disease ◽

Non Hodgkin Lymphoma

Abstract BCL-6 is essential for germinal center formation and thus for affinity maturation of immunoglobulin (Ig) genes by somatic mutations. The 5′-noncoding region of the BCL-6gene is even a target for the mutation machinery. Translocations of theBCL-6 gene to heterologous promoters and mutations of its 5′-noncoding regulatory region were reported to be potential mechanisms for deregulating BCL-6 expression and for playing a role in the genesis of non-Hodgkin lymphoma. In line with this hypothesis is the observation that B-cell lymphoma with somatic mutations, such as diffuse large B-cell lymphoma and follicular lymphoma, also carryBCL-6 mutations, some of which are recurrently detectable. Classic Hodgkin disease (cHD) is also derived from B cells with high loads of somatic mutations and thus a further candidate forBCL-6 mutations. To determine the presence and potential role of BCL-6 mutations in cHD, the 5′-noncodingBCL-6 proportion of single Hodgkin and Reed-Sternberg (HRS) cells from 6 cases of cHD and 6 cases of HD-derived cell lines was analyzed. All B-cell–derived HD cases and cell lines harboredBCL-6 mutations. In contrast, both T-cell–derived HD cases and cell lines were devoid of BCL-6 mutations. With only one exception, there were no lymphoma-specific recurrentBCL-6 mutations detected, and BCL-6 protein was absent from the HRS cells of most cases. In conclusion, (1) somaticBCL-6 mutations are restricted to cHD cases of B-cell origin, and (2) the BCL-6 mutations represent mostly irrelevant somatic base substitutions without consequences for BCL-6 protein expression and the pathogenesis of cHD.

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Chimeric Antigen Receptor-Engineered T-Cells - A New Way and Era for Lymphoma Treatment

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892814666191022164641 ◽

2020 ◽

Vol 14 (4) ◽

pp. 312-323

Author(s):

Romeo G. Mihăilă

Keyword(s):

T Cells ◽

T Cell ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Car T Cells ◽

Future Developments ◽

Car T Cell ◽

Large B Cell Lymphoma ◽

Car T

Background: Patients with refractory or relapsed diffuse large B-cell lymphoma have a poor prognosis with the current standard of care. Objective: Chimeric Antigen Receptor T-cells (CAR T-cells) are functionally reprogrammed lymphocytes, which are able to recognize and kill tumor cells. The aim of this study is to make progress in this area. Method: A mini-review was achieved using the articles published in Web of Science and PubMed in the last year and the new patents were made in this field. Results: The responses to CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel are promising; the objective response rate can reach up to 83%, and the complete response rate ranges between 40 and 58%. About half of the patients may have serious side effects, such as cytokine release syndrome and neurotoxicity. Current and future developments include the improvement of CAR T-cell expansion and polyfunctionality, the combined use of CAR T-cells with a fusion protein between interferon and an anti-CD20 monoclonal antibody, with checkpoint inhibitors or small molecule sensitizers that have apoptotic-regulatory effects. Furthermore, the use of IL-12-expressing CAR T-cells, an improved technology for the production of CAR T-cells based on targeted nucleases, the widespread use of allogeneic CAR T-cells or universal CAR T-cells obtained from genetically engineered healthy donor T-cells are future developments actively considered. Conclusion: CAR T-cell therapy significantly improved the outcome of patients with relapsed or refractory diffuse large B-cell lymphoma. The advances in CAR T-cells production technology will improve the results and enable the expansion of this new immunotherapy.

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Epidemiology of Non-Hodgkin’s Lymphoma

Medical Sciences ◽

10.3390/medsci9010005 ◽

2021 ◽

Vol 9 (1) ◽

pp. 5

Author(s):

Krishna C. Thandra ◽

Adam Barsouk ◽

Kalyan Saginala ◽

Sandeep Anand Padala ◽

Alexander Barsouk ◽

...

Keyword(s):

T Cell ◽

Radiation Treatment ◽

Cell Lymphoma ◽

Breast Implants ◽

Occupational Exposures ◽

B Cell Lymphoma ◽

Large Cell ◽

T Cell Lymphoma ◽

Human Herpes Virus 8 ◽

Human T Cell

Non-Hodgins’s lymphoma (NHL) is the most common hematological malignancy worldwide, accounting for nearly 3% of cancer diagnoses and deaths. NHL is the seventh most prevalent cancer and has the sixth highest mortality among cancers in the US. NHL accounts for 4% of US cancer diagnoses, and incidence has increased 168% since 1975 (while survival has improved 158%). NHL is more common among men, those >65 years old, and those with autoimmune disease or a family history of hematological malignancies. NHL is a heterogenous disease, with each subtype associated with different risk factors. Marginal zone lymphoma (MZL) is strongly associated with Sjogren’s syndrome (SS) and Hashimoto’s thyroiditis, while peripheral T-cell lymphoma (PTCL) is most associated with celiac disease. Occupational exposures among farm workers or painters increases the risk of most of the common subtypes. Prior radiation treatment, obesity, and smoking are most highly associated with diffuse large B-cell lymphoma (DLBCL), while breast implants have been rarely associated with anaplastic large cell lymphoma (ALCL). Infection with Epstein–Barr Virus (EBV) is strongly associated with endemic Burkitts lymphoma. HIV and human herpes virus 8 (HHV-8), is predisposed to several subtypes of DLBCL, and human T-cell lymphoma virus (HTLV-1) is a causative agent of T-cell lymphomas. Obesity and vitamin D deficiency worsen NHL survival. Atopic diseases and alcohol consumption seem to be protective against NHL.

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T cell/histiocyte rich B-cell lymphoma: A difficult diagnosis to make

Current Problems in Cancer: Case Reports ◽

10.1016/j.cpccr.2020.100041 ◽

2020 ◽

Vol 2 ◽

pp. 100041

Author(s):

Olutayo A. Sogunro ◽

Rachael Steinhauer ◽

Eugene Lewis

Keyword(s):

T Cell ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Difficult Diagnosis

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Tumor staging in a Beagle dog with concomitant large B-cell lymphoma and T-cell acute lymphoblastic leukemia

Journal of Veterinary Diagnostic Investigation ◽

10.1177/10406387211011024 ◽

2021 ◽

pp. 104063872110110

Author(s):

Alessandro Ferrari ◽

Marzia Cozzi ◽

Luca Aresu ◽

Valeria Martini

Keyword(s):

Bone Marrow ◽

Lymph Node ◽

T Cell ◽

B Cell ◽

Cell Lymphoma ◽

Tumor Staging ◽

Lymphoblastic Leukemia ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Cell Acute Lymphoblastic Leukemia

An 8-y-old spayed female Beagle dog was presented with peripheral lymphadenomegaly. Lymph node cytology and flow cytometry led to the diagnosis of large B-cell lymphoma (LBCL). We detected minimal percentages of LBCL cells in peripheral blood and bone marrow samples. However, a monomorphic population of neoplastic cells different from those found in the lymph node was found in the bone marrow. T-cell acute lymphoblastic leukemia was suspected based on flow cytometric immunophenotyping. PCR for antigen receptor rearrangement (PARR) revealed clonal rearrangement of both B-cell and T-cell receptors, and the presence of both neoplastic clones in the lymph node, peripheral blood, and bone marrow. The dog was treated with multi-agent chemotherapy but died 46 d following diagnosis. Tumor staging and patient classification are needed to accurately establish a prognosis and select the most appropriate therapeutic protocol.

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A WIDE T‐CELL EXHAUSTION PATTERN IS FREQUENTIN THE TUMOR MICROENVIRONMENT OF RELAPSED/REFRACTORY B‐CELL LYMPHOMA PATIENTS AND COULD BE CIRCUMVENTED BY PDL1 BLOCKADE

Hematological Oncology ◽

10.1002/hon.10_2881 ◽

2021 ◽

Vol 39 (S2) ◽

Author(s):

C Laurent ◽

C Syrykh ◽

C Herbaux ◽

E Gat ◽

P Gravelle ◽

...

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

T Cell Exhaustion ◽

Cell Exhaustion

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Use of immune repertoire sequencing to resolve discordant microscopic and immunochemical findings in a case of T cell-rich large B cell lymphoma in a young dog

BMC Veterinary Research ◽

10.1186/s12917-021-02783-3 ◽

2021 ◽

Vol 17 (1) ◽

Author(s):

Gary Kwok Cheong Lee ◽

Dorothee Bienzle ◽

Stefan Matthias Keller ◽

Mei-Hua Hwang ◽

Nikos Darzentas ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Immune Repertoire ◽

Large B Cell Lymphoma ◽

Repertoire Sequencing ◽

Reactive Lymphocytes ◽

Large B Cell

Abstract Background Lymphocytic neoplasms with frequent reactive lymphocytes are uncommonly reported in dogs, and can pose a diagnostic challenge. Different diagnostic modalities such as cytology, flow cytometry, histopathology, immunohistochemistry, and clonality testing, are sometimes required for a diagnosis. This report illustrates the value of using a multi-modal diagnostic approach to decipher a complex lymphocytic tumor, and introduces immune repertoire sequencing as a diagnostic adjunct. Case presentation A 10-month-old Great Dane was referred for marked ascites. Cytologic analysis of abdominal fluid and hepatic aspirates revealed a mixed lymphocyte population including numerous large lymphocytes, yielding a diagnosis of lymphoma. Flow cytometrically, abdominal fluid lymphocytes were highly positive for CD4, CD5, CD18, CD45, and MHC II, consistent with T cell lymphoma. Due to a rapidly deteriorating clinical condition, the dog was euthanized. Post mortem histologic evaluation showed effacement of the liver by aggregates of B cells surrounded by T cells, suggestive of hepatic T cell-rich large B cell lymphoma. Immune repertoire sequencing confirmed the presence of clonal B cells in the liver but not the abdominal fluid, whereas reactive T cells with shared, polyclonal immune repertoires were found in both locations. Conclusions T cell-rich large B cell lymphoma is a rare neoplasm in dogs that may be challenging to diagnose and classify due to mixed lymphocyte populations. In this case, the results of histopathology, immunohistochemistry and immune repertoire sequencing were most consistent with a hepatic B cell neoplasm and reactive T cells exfoliating into the abdominal fluid. Immune repertoire sequencing was helpful in delineating neoplastic from reactive lymphocytes and characterizing repertoire overlap in both compartments. The potential pitfalls of equating atypical cytomorphology and monotypic marker expression in neoplasia are highlighted.

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