Dysregulated TRAF3 and BCL2 Expression Promotes Multiple Classes of Mature Non-hodgkin B Cell Lymphoma in Mice

Autor: Gema Perez-Chacon, Magdalena Adrados, Maria T. Vallejo-Cremades, Sophie Lefebvre, John C. Reed, Juan M. Zapata
Přispěvatelé: Instituto de Salud Carlos III, European Commission, CSIC - Unidad de Recursos de Información Científica para la Investigación (URICI), Consejo Superior de Investigaciones Científicas (España), National Institutes of Health (US)
Rok vydání: 2018
Předmět:
lcsh:Immunologic diseases. Allergy
0301 basic medicine
BCL2
Lymphoma
B-Cell
Immunology
Somatic hypermutation
Mice
Transgenic
Mice
SCID
pathogen recognition receptors (PRRs)
Immunoglobulin D
03 medical and health sciences
Mice
0302 clinical medicine
B cell homeostasis
Mice
Inbred NOD
medicine
Immunology and Allergy
Alarmins
Animals
Humans
B-cell lymphoma
B cell
Original Research
B cell lymphomas
B-Lymphocytes
Mice
Inbred BALB C
biology
TNF Receptor-Associated Factor 3
Pathogen-Associated Molecular Pattern Molecules
Gene rearrangement
Plasma cell neoplasm
medicine.disease
Molecular biology
Complementarity Determining Regions
V(D)J Recombination
3. Good health
Up-Regulation
B cell lymphoma
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Proto-Oncogene Proteins c-bcl-2
TRAF3
plasma cell neoplasms
biology.protein
lcsh:RC581-607
DLBCL—diffuse large B cell lymphoma
Diffuse large B-cell lymphoma
030215 immunology
Zdroj: Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid
Consejería de Sanidad de la Comunidad de Madrid
Frontiers in Immunology
Digital.CSIC. Repositorio Institucional del CSIC
instname
Frontiers in Immunology, Vol 9 (2019)
Popis: TNF-Receptor Associated Factor (TRAF)-3 is a master regulator of B cell homeostasis and function. TRAF3 has been shown to bind and regulate various proteins involved in the control of innate and adaptive immune responses. Previous studies showed that TRAF3 overexpression renders B cells hyper-reactive to antigens and Toll-like receptor (TLR) agonists, while TRAF3 deficiency has been implicated in the development of a variety of B cell neoplasms. In this report, we show that transgenic mice overexpressing TRAF3 and BCL2 in B cells develop with high incidence severe lymphadenopathy, splenomegaly and lymphoid infiltrations into tissues and organs, which is the result of the growth of monoclonal and oligoclonal B cell neoplasms, as demonstrated by analysis of VHDJH gene rearrangement. FACS and immunohistochemical analyses show that different types of mature B cell neoplasms arise in TRAF3/BCL2 double-transgenic (tg) mice, all of which are characterized by the loss of surface IgM and IgD expression. However, two types of lymphomas are predominant: (1) mature B cell neoplasms consistent with diffuse large B cell lymphoma and (2) plasma cell neoplasms. The Ig isotypes expressed by the expanded B-cell clones included IgA, IgG, and IgM, with most having undergone somatic hypermutation. In contrast, mouse littermates representing all the other genotypes (TRAF3-/BCL2-; TRAF3+/BCL2-, and TRAF3-/BCL2+) did not develop significant lymphadenopathy or clonal B cell expansions within the observation period of 20 months. Interestingly, a large representation of the HCDR3 sequences expressed in the TRAF3-tg and TRAF3/BCL2-double-tg B cells are highly similar to those recognizing pathogen-associated molecular patterns and damage-associated molecular patterns, strongly suggesting a role for TRAF3 in promoting B cell differentiation in response to these antigens. Finally, allotransplantation of either splenocytes or cell-containing ascites from lymphoma-bearing TRAF3/BCL2 mice into SCID/NOD immunodeficient mice showed efficient transfer of the parental expanded B-cell clones. Altogether, these results indicate that TRAF3, perhaps by promoting exacerbated B cell responses to certain antigens, and BCL2, presumably by supporting survival of these clones, cooperate to induce mature B cell neoplasms in transgenic mice.
Funding was from Instituto de Salud Carlos III (ISCIII) PI080170, PI12/01135, and PI16/00895 to JZ and from the National Institutes of Health (AI070859 to JZ and CA163743 to JR).
The cost of this publication was paid in part by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI) and by funds from the European Fund for Economic and Regional Development (FEDER).
Databáze: OpenAIRE
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