Follicular lymphoma (FL): Immunological tolerance theory in FL

Accepted Manuscript Follicular lymphoma (FL): immunological tolerance theory in FL. Ricardo García-Muñoz, Carlos Panizo PII: DOI: Reference:

S0198-8859(16)30452-9 http://dx.doi.org/10.1016/j.humimm.2016.09.010 HIM 9836

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Human Immunology

Received Date: Revised Date: Accepted Date:

16 September 2014 27 September 2016 28 September 2016

Please cite this article as: García-Muñoz, R., Panizo, C., Follicular lymphoma (FL): immunological tolerance theory in FL., Human Immunology (2016), doi: http://dx.doi.org/10.1016/j.humimm.2016.09.010

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Follicular lymphoma (FL): immunological tolerance theory in FL.

4 Ricardo García-Muñoz1 and Carlos Panizo2.

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1. Hematology Department, Hospital San Pedro, Logroño, La Rioja, Spain.

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2. Hematology Department, Clínica Universidad de Navarra, Pamplona, Spain.

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Corresponding author: +Ricardo García-Muñoz MD E-mail: [email protected].

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+Hematology Service.

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Hospital San Pedro.

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c/Piqueras 98

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Logroño, La Rioja 26006

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Spain

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Phone no: + 34 941 29 89 12

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Abstract.

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The ultimate cause of follicular lymphoma (FL) remains unknown. Remarkably, almost

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nothing is known about immunological tolerance mechanisms that might contribute to

27

FL development. Immunological tolerance mechanisms, like other stimuli, also induce

28

persistent changes of B cell receptors that induce genetic instability and molecular

29

aberrations promoting the development of a neoplasm.

30 31

Using the same method as Burnet, we provide a new perspective taking advantage of

32

the comparison of a normal linear B cell differentiation process and FL development

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within the framework of clonal selection theory. We propose that FL is a malignancy of

34

cells that acquire both translocation t(14;18) and self-BCR, inducing them to proliferate

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and mature, resistant to negative selection. Additional genetic damage induced by non-

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apoptotic tolerance mechanisms, such as receptor editing, may transform a self-reactive

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B cell with t(14;18) into an FL. The result of tolerogenic mechanisms and genetic

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aberrations is the survival of FL B cell clones with similar markers and homogenous

39

gene expression signatures despite the different stages of maturation at which the

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molecular damage occurs. To antagonize further growth advantage due to self-antigen

41

recognition and chronic activation of tolerance mechanisms in the apoptosis-resistant

42

background of FL B cells, inhibitors of BCR signaling may be promising therapeutic

43

options.

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Follicular lymphoma (FL): immunologic tolerance theory in FL.

50 Ricardo García Muñoz1 and Carlos Panizo2.

51 52 53

1. Hematology Department, Hospital San Pedro, Logroño, La Rioja, Spain.

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2. Hematology Department, Clínica Universidad de Navarra, Pamplona Spain.

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Keywords: autoimmunity, clonal selection theory, tolerance mechanisms, follicular

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lymphoma, receptor editing, somatic hypermutation

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Introduction.

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Burnet´s clonal selection theory, immunological tolerance and the idea of self and non-

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self discrimination set the scene for modern cellular immunology. In 1960, Frank M.

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Burnet, during his Nobel lecture, presented the theoretical implications of

63

immunological tolerance and the self-recognition hypothesis, and hoped that his

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thoughts would guide scientists towards novel discoveries in immunology. The theory

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formulated by Burnet provides a framework for interpreting the novel findings in

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follicular lymphoma (FL) biology and introduces the idea of immunological tolerance

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as a novel mechanism to promote lymphoid malignancies.

68 69

A landmark contribution is the “clonal” point of view. It recognizes that expendable

70

lymphocytes can be regarded as belonging to clones stemming from somatic mutation,

71

or conceivably, other inheritable changes. Each such clone will have some individual

72

characteristic and in a special sense will be subject to an evolutionary process of

73

selective survival within the internal environment of the body.

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In 1960, Burnet and Medawar were co-recipients of the Nobel Prize for the discovery of

76

acquired immunological tolerance.

77 78

Burnet´s reflections about tolerance state that:

79 80 81

a) A stem cell, on differentiation, becomes a lymphocyte carrying a specific pattern of B cell receptor (BCR).

82

b) If an immune pattern (B cell receptor) is generated by a random process, a

83

mechanism must exist by which any “self-reactive” cells that may emerge can

84

be eliminated or functionally inhibited.

85 86

c) More than one mechanism may be needed to establish and maintain this intrinsic immunological tolerance toward self-components.

87 88 89

The ultimate cause of follicular lymphoma (FL) remains unknown. FL is a tumor of

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germinal center B cells in which centrocytes fail to undergo apoptosis because they

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have a chromosomal rearrangement t(14;18), that prevents the normal BCL2 gene from

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switching off (1,2). It has been postulated that a second genetic “hit”, or even simple

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exposure to antigen in a cell with a BCL2 translocation, could result in the development

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of lymphoma because once it begins proliferating in response to antigen, it does not

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respond to the usual stimuli for apoptosis (2). Remarkably, self-antigen recognition by

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FL B cell receptors (BCRs) has been described in 26% of cases (3). The molecular

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anatomy of the t(14;18) genetic alteration suggests that it occurs prior to antigen

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exposure in an immature B cell that expresses nuclear TdT (nuclear enzyme terminal

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deoxynucleotidyltransferase) in the bone marrow (BM) and results from an error in

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primary V[variable], D[diversity] and J [joining] gene recombination induced by the

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RAG (recombinase activating genes) complex (4). FL cells typically express surface

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IgM and IgD, and have somatic hypermutations in the variable region of their

103

immunoglobulin genes (1,2,4). Interestingly, if 26% of FL BCR recognize self-antigens

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(3) but retain the capacity to differentiate from B cell precursors to mutated FL cells,

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this implies that some tolerance mechanisms fail and FL evades immunological

106

tolerance.

107 108

Immunological tolerance mechanisms, in a way similar to other stimuli, also induce the

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persistence of B cell receptor changes that induce genetic instability and molecular

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aberrations that promote the development of a neoplasm (5-8).

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In the present article, we first review tolerance mechanisms for avoiding self-reactivity

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in FL cells. We then propose a hypothesis in which tolerance mechanisms play a key

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role in FL development.

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The objective of this review is to present a hypothesis about the generation of FL in the

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light of the clonal selection approach.

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Hypothesis: During B cell development translocation t(14;18) protect self-reactive B

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cells increasing resistance to elimination. Self-BCR-auto-antigen interaction induce

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chronic activation of tolerance mechanisms specially receptor editing. Unfortunately

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some times this mechanism increases genomic instability and promotes additional

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genetic damage that induces FL progression or transformation to aggressive B cell

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neoplasm.

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The Burnet´s Rules of Tolerance and Autoimmunity (9).

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The basic hypothesis of the origin of autoimmune disease depends of the emergence of a

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clone or a small number of clones of lymphocytes capable of damaging interaction with

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normal cells of organ or tissue involved. Each clone is initiated from a cell which has

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developen an immune receptor adequately reactive with an accessible self-antigen as a

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result of V/D/J and K/L gene recombination in bone marrow or during somatic

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mutations in germinal centers. Crucially, this newly self-reactive cell (“forbidden

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clone”) is anomalously resistant to inactivation by central and peripheral tolerance

144

check points (9)

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FL B lymphocytes qualify as a malignant forbidden clone.

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FL can be conceived as a logical and lineal development of the forbidden clone concept

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formed within the framework of clonal selection theory. In humans, B cells develop

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from progenitors within the BM. The stages of B cell ontogeny from pro-B to pre-B to

151

early B to mature B cell are marked by the expression of the BCR for antigen on the cell

152

surface at the early stage of B cell development. The fact that immature B cells are

153

forced to engage with the environment as a test of self-reactivity (negative selection)

154

may induce some lymphocytes to correct their self reactivity and edit their heavy or

155

light chains (receptor editing). Any normal lymphocyte capable of reacting with them

156

will be eliminated or self-reactivity corrected.

157 158

Immunoglobulin rearrangement is hierarchical. In pro-B cells, DH-JH joining precedes

159

VH-DJH rearrangement; followed by VL-JL joining in the late-stage pre-B cells.

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Clones with an immune receptor sufficiently reactive with an available self-antigen can

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be the result from a V/D/J gene recombination in bone marrow or during somatic

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mutations in germinal centers. If a newly self-reactive cell (“forbidden clone”) is

163

anomalously resistant to inactivation by central and peripheral tolerance checkpoints, it

164

can produce an autoimmune disease or a lymphoid malignancy.

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FL B cells qualify as a malignant forbidden clone because they carry translocation

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t(14;18), which induces increased resistance to apoptosis, and also express self-reactive

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BCRs, which induce chronic activation of tolerance mechanisms. Figure 1.

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If we assume that the acquisition of (self-reactive) BCR is simultaneous with the

171

acquisition of genetic or molecular disturbances such as t(14;18) in FL B cells, several

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important questions need to be answered.

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a) Why can these B cells not be eliminated or inhibited by tolerance mechanisms?

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b) Why can these B cells not produce their BCR as an autoantibody and induce an

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autoimmune disease?

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c) What is the driving force to induce genetic and molecular abnormalities in these self-

178

reactive B cells?

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The essence of the FL forbidden clone concept.

181 182

On differentiation, a FL stem cell becomes a B cell carrying a specific BCR (some

183

times self-reactive BCR) that acquire the translocation t(14;18)(q32;q21) involving the

184

anti-apoptotic gene BCL2; the gene rearrangements usually involve the non-functional

185

IG gene at the 5´ end of J heavy chain (JH) gene segments, pointing to mistakes

186

occurring at the DH to JH stage in bone marrow (BM) lymphoid progenitors or in B cell

187

precursors (pro-B and pre-B cells) (10-15). This precursor B cell with t(14;18)(q32;q21)

188

is then left with the capacity to differentiate. Importantly, BCR of some FL cells can

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potentially recognize self-antigens during their differentiation within the BM or later in

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peripheral lymphoid organs such as lymph nodes (LN). Figure 2. For this reason, B

191

cells that acquire the translocation t(14;18)(q32;q21) during VDJ recombination in pro-

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B, pre-B or immature B cell stages in BM must be forced to engage with environmental

193

factors as a test of self-reactivity. In human B cells, 55 to 75% of BCRs expressed by

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early immature B cell display self-reactivity; however, the central tolerance checkpoint

195

removes the vast majority of developing self-reactive B cells (16-17). Significantly, 25-

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30% of patients with FL express IgM or IgG with autoantibody activity (3,18,19).

197

Approximately 20% of cases of FL and mantle cell lymphoma were found to have non-

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stereotyped BCRs that bind to a common self-antigen in the N-terminal region of the

199

cytoskeletal component vimentin (19). Importantly, stromal cells (20) and mesenchymal

200

stromal cells of both BM and LN actively display vimentin on their surface (20-23).

201

Notably, vimentin also is present on the surface of cells undergoing apoptosis (24). FL

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B cells may be selected by “self-antigens” such as vimentin on the surface of apoptotic

203

cells or stromal cells in both BM and germinal centers (apoptotic blebs) within LN..

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Surprisingly, almost all FL BCRs (much like other lymphomas) exhibit a strikingly high

205

incidence of N-glycosylation in the antigen-binding sites introduced by somatic

206

mutation (SHM) (25-27). Binding studies indicate that the oligomannose glycans

207

occupying the V regions are accessible to mannose-binding lectin (MBL) (27).

208

Remarkably, the binding of mannose-binding lectins to FL BCRs triggers B-cell

209

receptor-mediated signaling events (27). FL BCRs can bind to specific lectins on

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dendritic cells or macrophages. We consider that FL BCRs recognize vimentin and

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MBL on the surface of both stromal cells and apoptotic cells (19,21,22), because

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vimentin functions as an engulfment receptor on neighboring phagocytes, which

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recognize O-linked N-acetylglucosamine modified proteins from apoptotic cells as “eat

214

me” ligands (28). Due to the clearance of apoptotic cells that occurs in the BM and in

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the germinal centers of LN, it is possible that FL BCRs recognize self-antigens

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expressed in apoptotic blebs. SHM then introduces N-glycosylation in BCRs as a

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mechanism of affinity maturation of the antibody repertoire in response to repeated

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exposure to self-antigens (such as vimentin). Translocation t(14;18)(q32;q21) protects

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self-reactive (vimentin)/MBL) FL cells from elimination during tolerance mechanisms.

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Figure 3. Additionally, the presence of t(14;18)(q32;q21) converts the receptor

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editing/revision into dangerous mechanisms that may promote progressive disease

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(3,29,30). Figure -3. Other mechanisms such as germinal center exclusion (31-34) could

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be ineffective because FL cells can migrate from LN to BM and vice versa (35). At both

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sites, FL cells may receive BCR stimulation by stromal cells and self-antigens

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(vimentin, MBL and apoptotic blebs). Figure 2. Abnormal tolerance checkpoints in

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germinal centers may also play an important role and some FL B cells express IgG

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BCRs with self-reactivity (20.4%) (19) Selection against self-reactivity during IgM

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memory B cell development also may be compromised because self-reactive IgM+

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memory B cells constitute 2.1% in healthy donors (34,36) compared with 3.4% in IgM

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FL patients (19). Interestingly, the kappa light chain was more frequently expressed in

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the IgM FL, whereas the lambda light chain was more commonly expressed in the IgG+

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FL (19). This finding suggests that receptor editing occurs in IgG+ FL. Nevertheless,

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under normal conditions, self-reactive normal IgG+ memory B cells may be anergic

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(36). However, FL BCR signaling is increased and not anergic (37).

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Burnet´s Rules of Tolerance and Autoimmunity in FL.

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Taking advantage of the comparison with a normal linear B lymphocyte differentiation

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we can observe that at all stages of B cell development, there is evidence that FL may

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be induced or promoted by a persistent tolerance mechanism.

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Why can these B cells not be eliminated or inhibited by tolerance mechanisms?

243 244

FL

hematopoietic

stem

cells

(38)

aberrantly

245

t(14;18)(q32;q21) in pro-B and pre-B lymphocytes (39) that tend to be intrinsically

246

resistant to apoptosis (40). In pro-B lymphocytes, DH-JH joining precedes VH-DJH

247

rearrangement, followed by VL-JL joining in late-stage pre-B lymphocytes. During

10

generate

the

translocation

248

these rearrangements, some B cells may express self-reactive BCRs that recognize self-

249

antigens (3), such as vimentin (19) or apoptotic cells. In healthy subjects, B

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lymphocytes with t(14;18) may be primed to proliferate by surface immune receptors

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(41) causing them to potentially recognize self-antigens (3,19). This stimulus may in the

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future lead to an FL (42). Figure 4. In mice, the expression of a BCL2 transgene in the

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B lymphoid compartment profoundly perturbed homeostasis and, depending on the

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genetic background, predisposed them to a severe autoimmune disease resembling

255

human systemic lupus erythematosus (43). Notably, some normal individuals have two

256

to five unrelated t(14;18)-carrying B cell clones (44). This suggests that FL B

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lymphocytes retain the BCR signaling capacity acquired during the pre-B cell

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development even though they recognize self-antigens. This is also supported by the

259

fact that 30% of FL cases recognize vimentin, a ligand expressed in stromal cells and

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apoptotic cell surfaces (29,38).

261

Moreover, FL B lymphocytes are in constant receptor editing to avoid self-reactivity,

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and present changes from initial kappa light chain rearrangements to lambda chain

263

suggesting that receptor editing may play a role in progression to high-grade B cell

264

lymphoma (29,30,40).

265

Why can these B cells not produce their BCR as an autoantibody and induce an

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autoimmune disease?

267 268

Peripheral tolerance.

269 270

An important peripheral checkpoint is the entry into the T lymphocyte-dependent, long-

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term memory compartment. Lymphocytes that express antibodies encoded by the VH4-

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34 gene are self-reactive B cells (31,32). B cells that express self-reactive BCRs

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encoded by IGHV4-34 are excluded from T lymphocyte-dependent IgG memory and

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plasma cell populations suggesting that these self-reactive lymphocytes fail to cross a

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developmental checkpoint following activation in normal individuals (31,32). This

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implies that negative selection of autoreactive cells occurs at the transition from naive to

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germinal center cells. Interestingly, some FL use this self-reactive VH4-34 gene (45),

278

suggesting that peripheral tolerance mechanisms are also altered because FL B cells

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acquire somatic mutations (SHM) in GC-like memory B cells.

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Germinal centers.

282 283

Within germinal centers, naïve t(14;18)-carrying B cell clones and FL B cells undergo

284

activation, proliferation, somatic hypermutation (46,47), isotype switching (46,47) and

285

subsequent positive and negative selection by antigen (48). Importantly, germinal center

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exclusion may be altered in FL because in healthy individuals only a very small

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population of “FL-like B cells” remains unmutated (49). Interestingly, the class switch

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recombination (CSR) status of FL B cells indicates a selective pressure in favor of sIgM

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expression in a B cell population that is at the same time permanently driven to switch

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(49,50), because in >80% of cases CSR occur in both alleles.

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Tolerance mechanisms involved in development of memory B cells.

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The t(14;18)(q32;q21) is generated during early B cell development in the BM, making

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possible the maturation and expansion of affected cells in GC (51,52), even though they

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recognize self-antigens such as vimentin.

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Usually, B cells expressing self-reactive and broadly bacterially reactive antibodies are

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removed from the repertoire in the transition from naive to IgM+ memory B cells (34).

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However, rare IgM+ memory B cells that produce antibodies with low levels of self-

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reactivity acquire this reactivity by somatic hypermutation (34). In a similar way, auto-

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reactivity in human IgG+ memory B cells is mostly created by somatic hypermutation

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(36). The fact that FL B cells undergo isotype switching and the acquisition of somatic

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mutations suggests that GC check points may be disrupted in FL patients (51,52,53).

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What is the driving force to induce genetic and molecular abnormalities in these

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self-reactive B cells?

307 308

The tolerance mechanism may promote oncogenic transformation. (29,30,54)

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Mistakes in VDJ joining may generate t(14;18) in B cells (55) of healthy individuals

311

(56). Taken together with the generation of several self-reactive BCRs during this VDJ

312

rearrangement (16-17), this provides indirect support for assuming that self-reactive

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pre-malignant B cells with t(14;18) persist.

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If this is so, it can be hypothesized that some B lymphocytes are insusceptible to

316

elimination or inhibition by the “censorship” mechanisms or that a SHM develops,

317

inducing in these B lymphocytes an undue resistance to elimination by antigenic

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contact..

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Chromosomal abnormalities and other genetic alterations in MLL2, EPHA7,

321

TNFRSF14 and EZH2 beyond t(14;18) are common in FL patients (57-65). Most FL

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are characterized by recurrent secondary genetic alterations including genomic gains,

323

losses and mutations with the successive clone survival advantage (57).

324 325

We suggest that genetic programs are progressively disrupted during B cell

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development and tolerance checkpoints.

327 328

We speculate that t(14;18) self-reactive B cells repeatedly exposed to tolerance

329

checkpoints evolve as clones and acquire genetic and chromosomal damage. These

330

changes support their survival despite various attempts by the immune system to

331

eliminate these cells. Several lines of evidence suggest that normal cells that become FL

332

lymphocytes progress through several stages before becoming overtly malignant.

333 334

The tolerogenic microenvironment induced by FL B cells

335 336

The FL B cells themselves can induce profound immunosuppression by direct contact

337

with T cells as an active immunosuppressive mechanism. Direct contact with FL

338

lymphocytes can induce a synaptic inhibition in previously healthy T lymphocytes (66)

339

and also promote the induction of regulatory T cells (67). Once that regulatory T cells

340

are generated by the FL microenvironment, they may also inhibit CD8 and CD4 T cells

341

(68,69,70). Notably, the BCR of non-malignant B cells resembles that observed in

342

mature B cells from peripheral blood of healthy subjects (71).

343 344

Bone marrow central tolerance in B cell precursors with t(14;18) (q32;q21) induce

345

a self-antigen driven clonal tumor selection.

346

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347

The inappropriate expression of BCL2 alone seems to be insufficient for malignant

348

transformation of B cells and multistep process is required for FL development. We

349

speculate that the interaction of a pre-B cell with t(14;18) induce a cell trapped in a

350

narrow intermediate stage of maturation (to avoid self-reactivity) that maintains the

351

capacity of undergo SHM. Interestingly, B lymphopoiesis is driven by the sequential

352

rearrangement and expression of immunoglobulin heavy (Igµ) and then light

353

(Igκ followed by Igλ) chains. Each recombination constitutes a discrete transition win

354

with rearrangements capable of supporting expression of a surface receptor are selected

355

for further development. The fact that bone marrow could be the origin of FL cells and

356

induce clonal selection obligatory imply that several FL recognize bone marrow-self-

357

antigens. The fact that bone marrow central tolerance decreases the frequency of self

358

reactive B cells from 75% in BM to 20% in the circulating compartment imply that B

359

cells that recognize self-antigens were edited or deleted. However, if a B cell precursor

360

with t(14:18) (q32;q21) is forced to engage with a bone marrow self-antigen to induce

361

tolerance the result is a self-antigen driven tumor clonal selection . This is a new

362

concept in which an immune protective mechanism to avoid autoimmunity derive in a

363

lymphoid neoplasm.

364 365

Therapeutic approaches at the immunological level.

366 367

a) Immunomodulatory drugs: FL B cells may induce a tolerogenic microenvironment,

368

which may be a direct consequence of leukemic cell action (70,72). This finding

369

supports the use of immunomodulatory drugs (IMids) such as lenalidomide to

370

antagonize this defect (73-75).

371

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372 373

b) BCR inhibitors: The fact that BCRs of FL cells have SHM and abnormal

374

glycosylation in variable regions of immunoglobulins supports the use of both novel

375

and classic treatments that can inhibit or diminish BCR signaling/recognition. BCR

376

inhibitors such as Ibrutinib, a Bruton´s tyrosine kinase (BTK) inhibitor, have

377

demonstrated significant activity against FL (76-79). FL is considered to be a tumor

378

with t(14;18) in neoplastic B cells, variably stimulated following exposure to antigen in

379

lymphoid tissue. Recent evidence supports that C-type lectins, DC-SIGN and mannose

380

receptor, bound to FL surface BCR generates an intracellular Ca2+ flux (80,81), similar

381

to chronic lymphocytic leukemia (CLL) B cells that have a BCR recognizing itself (self-

382

autoantibody-self BCR recognition) (82,83,84). This self-autoantibody-self BCR

383

interaction promotes survival and increases the activation of immunological tolerance

384

mechanisms such as receptor editing. These mechanisms, in turn, increase the genomic

385

instability and promote additional genetic damage (84,85). Importantly, in parallel to

386

CLL development, in FL the lectin binding generates signals via sIg, supporting an

387

antigen-independent signal in vivo (80,81). Equivalent to CLL, this lectin-induced

388

antigen-independent signal supports the immunological tolerance theory, which states

389

that it is irrelevant if the whole BCR recognizes a self-antigen or foreign antigen, as the

390

chronic activation of autonomous BCR signaling is viewed by the immune system as

391

dangerous (84,85). This is in concordance with our hypothesis considering that FL B

392

lymphocytes are persistently under check by the tolerance mechanism because they are

393

chronically exposed to self-antigens or autonomous BCR signaling. In this context, the

394

inhibition of BCR signaling is very important because it can control FL BCR signaling

395

capacity and self-antigen BCR activation. The consequence of this BCR inhibition may

16

396

be the inhibition of tolerance mechanisms such as receptor editing and a reduced risk of

397

acquiring new molecular aberrations and clonal evolution.

398 399

c) Idiotypic vaccines: The fact that idiotypic vaccines may induce specific humoral and

400

cellular immune responses against tumor idiotypes provides formal proof that humans

401

could be immunized against an antigen derived from their own tumor. However,

402

because crosstalk between follicular T cells and tumor cells in human FL promotes

403

immune evasion in the tumor microenvironment (86), it is important to design

404

treatments to eradicate the disease (87-90).

405 406

Therefore, the future of immunotherapy with vaccines seems to be in combining

407

vaccines with immunomodulators or BCR inhibitors, which maintain and enhance the

408

generated immune response, while reducing immunoregulatory mechanisms and the

409

characteristic immunosuppressive environment in patients with FL.

410 411

412

Conclusion.

413 414

We suggest that FL may be promoted by a coordinated normal immunologic tolerance

415

mechanism to destroy t(14;18) self-reactive B cells. Additional genetic damage induced

416

by tolerance mechanisms may immortalize and transform a t(14;18) self-reactive B cell

417

into a lymphomatous one. The result of tolerogenic mechanisms and genetic aberrations

418

is the survival of FL B cell clones with similar markers and homogenous gene

419

expression signatures, despite the different stages of maturation at which the molecular

420

damage occurs. It is possible that BCR signaling inhibitors may correct the

17

421

immunological disturbances blocking the stimuli that induce chronic activation of

422

tolerance mechanisms in FL B-lymphocytes. Combinations of vaccines with IMids or

423

BCR inhibitors may overcome the immunosuppressive microenvironment induced by

424

FL B cells and generate a sustained immunosurveillance to eradicate minimal residual

425

disease in some FL patients.

426 427 428 429 430

The authors declare no conflict of interest.

431 432 433 434 435 436 437 438

Corresponding author: +Ricardo García-Muñoz MD E-mail: [email protected]. +Hematology Service. Hospital San Pedro. c/Piqueras 98 Logroño, La Rioja 26006 Spain Phone n: + 34 941 29 89 12

439 440

Figure 1. FL is a malignancy of cells that acquire both t(14;18) and self-BCR, inducing

441

them to proliferate and mature.

442 443

Figure 2. The BCR of some t(14;18)-carrying cells can potentially recognize self-

444

antigens during their differentiation within the BM or later in peripheral lymphoid

445

organs, such as lymph nodes. Germinal center exclusion may be critical in the

446

protection against the transformation of self-reactive t(14;18) B cells into follicular

447

lymphoma B cells.

448 449 450

Figure 3. LF t(14;18)(q32;q21) protect self-reactive (vimentin/MBL) FL cells from

451

elimination

452

t(14;18)(q32;q21) converts the receptor editing/revision into dangerous mechanisms

453

that may promote progressive disease because they induce genetic instability. This

454

process has been reported in patients with FL during idiotypic vaccine treatment.

during

tolerance

mechanisms.

18

Additionally,

the

presence

of

455 456

Figure 4. B lymphocytes with t(14;18) in healthy subjects may be primed to proliferate

457

by surface immune receptors, causing them to potentially recognize self-antigens (3,34).

458

This stimulus may in the future lead to an FL by chronic activation of the BCR and

459

immunologic tolerance through receptor editing/revision. Diversification mechanisms,

460

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27

pro-B cell

BONE MARROW pre-B cell

V/D/J rearrangement

K/l rearrangement

BCL-2

Immature B cell BCL-2

T(14;18)(q32;q21) BCL-2

V/D/J recombination generates t(14;18)(q32;q21) and self-reactive B cell receptor

stem cell

pro-B cell

BONE MARROW pre-B cell

V/D/J rearrangement

K/l rearrangement

t(14;18)

t(14;18)

immature-B cell

t(14;18)

BLOOD T(14;18)

t(14;18)

t(14;18)

t(14;18) follicular B cell

memory Secondary lymphoid organs B cell /follicular lymphoma

t(14;18)

Mechanism for receptor editing in follicular lymphoma

self-reactive B cells

kappa + self-reactive B cells t(14;18)

t(14;18)

genetic instability

t(14;18)

t(14;18)

lambda + self-reactive B cells

self-reactive t(14;18) B cells acquire BCL-2/IGL kappa or BCL2/IGL lambda junctions by receptor secondary acute lymphoblastic leukemia or FL progression. editing mechanism

T(14;18)

self-reactive B cell with t(14;18) with immunologic tolerance and apoptotic resistance