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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
To appear in:
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.
5 6 7
1. Hematology Department, Hospital San Pedro, Logroño, La Rioja, Spain.
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2. Hematology Department, Clínica Universidad de Navarra, Pamplona, Spain.
9 10 11
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
18 19 20 21 22 23
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Abstract.
25
The ultimate cause of follicular lymphoma (FL) remains unknown. Remarkably, almost
26
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
33
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
35
and mature, resistant to negative selection. Additional genetic damage induced by non-
36
apoptotic tolerance mechanisms, such as receptor editing, may transform a self-reactive
37
B cell with t(14;18) into an FL. The result of tolerogenic mechanisms and genetic
38
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
40
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.
44
45 46 47 48
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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.
54
2. Hematology Department, Clínica Universidad de Navarra, Pamplona Spain.
55 56
Keywords: autoimmunity, clonal selection theory, tolerance mechanisms, follicular
57
lymphoma, receptor editing, somatic hypermutation
58 59
Introduction.
60
Burnet´s clonal selection theory, immunological tolerance and the idea of self and non-
61
self discrimination set the scene for modern cellular immunology. In 1960, Frank M.
62
Burnet, during his Nobel lecture, presented the theoretical implications of
63
immunological tolerance and the self-recognition hypothesis, and hoped that his
64
thoughts would guide scientists towards novel discoveries in immunology. The theory
65
formulated by Burnet provides a framework for interpreting the novel findings in
66
follicular lymphoma (FL) biology and introduces the idea of immunological tolerance
67
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.
3
74 75
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
90
germinal center B cells in which centrocytes fail to undergo apoptosis because they
91
have a chromosomal rearrangement t(14;18), that prevents the normal BCL2 gene from
92
switching off (1,2). It has been postulated that a second genetic “hit”, or even simple
93
exposure to antigen in a cell with a BCL2 translocation, could result in the development
94
of lymphoma because once it begins proliferating in response to antigen, it does not
95
respond to the usual stimuli for apoptosis (2). Remarkably, self-antigen recognition by
96
FL B cell receptors (BCRs) has been described in 26% of cases (3). The molecular
97
anatomy of the t(14;18) genetic alteration suggests that it occurs prior to antigen
98
exposure in an immature B cell that expresses nuclear TdT (nuclear enzyme terminal
4
99
deoxynucleotidyltransferase) in the bone marrow (BM) and results from an error in
100
primary V[variable], D[diversity] and J [joining] gene recombination induced by the
101
RAG (recombinase activating genes) complex (4). FL cells typically express surface
102
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
104
(3) but retain the capacity to differentiate from B cell precursors to mutated FL cells,
105
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
109
persistence of B cell receptor changes that induce genetic instability and molecular
110
aberrations that promote the development of a neoplasm (5-8).
111 112 113
In the present article, we first review tolerance mechanisms for avoiding self-reactivity
114
in FL cells. We then propose a hypothesis in which tolerance mechanisms play a key
115
role in FL development.
116 117
The objective of this review is to present a hypothesis about the generation of FL in the
118
light of the clonal selection approach.
119 120 121 122 123
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124 125 126 127 128
Hypothesis: During B cell development translocation t(14;18) protect self-reactive B
129
cells increasing resistance to elimination. Self-BCR-auto-antigen interaction induce
130
chronic activation of tolerance mechanisms specially receptor editing. Unfortunately
131
some times this mechanism increases genomic instability and promotes additional
132
genetic damage that induces FL progression or transformation to aggressive B cell
133
neoplasm.
134 135
The Burnet´s Rules of Tolerance and Autoimmunity (9).
136 137
The basic hypothesis of the origin of autoimmune disease depends of the emergence of a
138
clone or a small number of clones of lymphocytes capable of damaging interaction with
139
normal cells of organ or tissue involved. Each clone is initiated from a cell which has
140
developen an immune receptor adequately reactive with an accessible self-antigen as a
141
result of V/D/J and K/L gene recombination in bone marrow or during somatic
142
mutations in germinal centers. Crucially, this newly self-reactive cell (“forbidden
143
clone”) is anomalously resistant to inactivation by central and peripheral tolerance
144
check points (9)
145 146
FL B lymphocytes qualify as a malignant forbidden clone.
147
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FL can be conceived as a logical and lineal development of the forbidden clone concept
149
formed within the framework of clonal selection theory. In humans, B cells develop
150
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.
160
Clones with an immune receptor sufficiently reactive with an available self-antigen can
161
be the result from a V/D/J gene recombination in bone marrow or during somatic
162
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.
165 166
FL B cells qualify as a malignant forbidden clone because they carry translocation
167
t(14;18), which induces increased resistance to apoptosis, and also express self-reactive
168
BCRs, which induce chronic activation of tolerance mechanisms. Figure 1.
169 170
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
172
important questions need to be answered.
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173 174
a) Why can these B cells not be eliminated or inhibited by tolerance mechanisms?
175
b) Why can these B cells not produce their BCR as an autoantibody and induce an
176
autoimmune disease?
177
c) What is the driving force to induce genetic and molecular abnormalities in these self-
178
reactive B cells?
179 180
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
189
potentially recognize self-antigens during their differentiation within the BM or later in
190
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-
192
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
194
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-
196
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-
8
198
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
202
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..
204
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
210
dendritic cells or macrophages. We consider that FL BCRs recognize vimentin and
211
MBL on the surface of both stromal cells and apoptotic cells (19,21,22), because
212
vimentin functions as an engulfment receptor on neighboring phagocytes, which
213
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
215
the germinal centers of LN, it is possible that FL BCRs recognize self-antigens
216
expressed in apoptotic blebs. SHM then introduces N-glycosylation in BCRs as a
217
mechanism of affinity maturation of the antibody repertoire in response to repeated
218
exposure to self-antigens (such as vimentin). Translocation t(14;18)(q32;q21) protects
219
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
221
editing/revision into dangerous mechanisms that may promote progressive disease
222
(3,29,30). Figure -3. Other mechanisms such as germinal center exclusion (31-34) could
9
223
be ineffective because FL cells can migrate from LN to BM and vice versa (35). At both
224
sites, FL cells may receive BCR stimulation by stromal cells and self-antigens
225
(vimentin, MBL and apoptotic blebs). Figure 2. Abnormal tolerance checkpoints in
226
germinal centers may also play an important role and some FL B cells express IgG
227
BCRs with self-reactivity (20.4%) (19) Selection against self-reactivity during IgM
228
memory B cell development also may be compromised because self-reactive IgM+
229
memory B cells constitute 2.1% in healthy donors (34,36) compared with 3.4% in IgM
230
FL patients (19). Interestingly, the kappa light chain was more frequently expressed in
231
the IgM FL, whereas the lambda light chain was more commonly expressed in the IgG+
232
FL (19). This finding suggests that receptor editing occurs in IgG+ FL. Nevertheless,
233
under normal conditions, self-reactive normal IgG+ memory B cells may be anergic
234
(36). However, FL BCR signaling is increased and not anergic (37).
235 236
Burnet´s Rules of Tolerance and Autoimmunity in FL.
237 238
Taking advantage of the comparison with a normal linear B lymphocyte differentiation
239
we can observe that at all stages of B cell development, there is evidence that FL may
240
be induced or promoted by a persistent tolerance mechanism.
241
242
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
250
lymphocytes with t(14;18) may be primed to proliferate by surface immune receptors
251
(41) causing them to potentially recognize self-antigens (3,19). This stimulus may in the
252
future lead to an FL (42). Figure 4. In mice, the expression of a BCL2 transgene in the
253
B lymphoid compartment profoundly perturbed homeostasis and, depending on the
254
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
257
lymphocytes retain the BCR signaling capacity acquired during the pre-B cell
258
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
260
apoptotic cell surfaces (29,38).
261
Moreover, FL B lymphocytes are in constant receptor editing to avoid self-reactivity,
262
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
266
autoimmune disease?
267 268
Peripheral tolerance.
269 270
An important peripheral checkpoint is the entry into the T lymphocyte-dependent, long-
271
term memory compartment. Lymphocytes that express antibodies encoded by the VH4-
272
34 gene are self-reactive B cells (31,32). B cells that express self-reactive BCRs
11
273
encoded by IGHV4-34 are excluded from T lymphocyte-dependent IgG memory and
274
plasma cell populations suggesting that these self-reactive lymphocytes fail to cross a
275
developmental checkpoint following activation in normal individuals (31,32). This
276
implies that negative selection of autoreactive cells occurs at the transition from naive to
277
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
279
acquire somatic mutations (SHM) in GC-like memory B cells.
280 281
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
286
exclusion may be altered in FL because in healthy individuals only a very small
287
population of “FL-like B cells” remains unmutated (49). Interestingly, the class switch
288
recombination (CSR) status of FL B cells indicates a selective pressure in favor of sIgM
289
expression in a B cell population that is at the same time permanently driven to switch
290
(49,50), because in >80% of cases CSR occur in both alleles.
291 292 293
Tolerance mechanisms involved in development of memory B cells.
294 295
The t(14;18)(q32;q21) is generated during early B cell development in the BM, making
296
possible the maturation and expansion of affected cells in GC (51,52), even though they
297
recognize self-antigens such as vimentin.
12
298
Usually, B cells expressing self-reactive and broadly bacterially reactive antibodies are
299
removed from the repertoire in the transition from naive to IgM+ memory B cells (34).
300
However, rare IgM+ memory B cells that produce antibodies with low levels of self-
301
reactivity acquire this reactivity by somatic hypermutation (34). In a similar way, auto-
302
reactivity in human IgG+ memory B cells is mostly created by somatic hypermutation
303
(36). The fact that FL B cells undergo isotype switching and the acquisition of somatic
304
mutations suggests that GC check points may be disrupted in FL patients (51,52,53).
305
What is the driving force to induce genetic and molecular abnormalities in these
306
self-reactive B cells?
307 308
The tolerance mechanism may promote oncogenic transformation. (29,30,54)
309 310
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
313
pre-malignant B cells with t(14;18) persist.
314 315
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
318
contact..
319 320
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
13
322
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
326
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
14
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
15
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
S0198-8859(16)30452-9 http://dx.doi.org/10.1016/j.humimm.2016.09.010 HIM 9836
To appear in:
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.
5 6 7
1. Hematology Department, Hospital San Pedro, Logroño, La Rioja, Spain.
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2. Hematology Department, Clínica Universidad de Navarra, Pamplona, Spain.
9 10 11
Corresponding author: +Ricardo García-Muñoz MD E-mail: [email protected].
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+Hematology Service.
13
Hospital San Pedro.
14
c/Piqueras 98
15
Logroño, La Rioja 26006
16
Spain
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Phone no: + 34 941 29 89 12
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1
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Abstract.
25
The ultimate cause of follicular lymphoma (FL) remains unknown. Remarkably, almost
26
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
33
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
35
and mature, resistant to negative selection. Additional genetic damage induced by non-
36
apoptotic tolerance mechanisms, such as receptor editing, may transform a self-reactive
37
B cell with t(14;18) into an FL. The result of tolerogenic mechanisms and genetic
38
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
40
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.
44
45 46 47 48
2
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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.
54
2. Hematology Department, Clínica Universidad de Navarra, Pamplona Spain.
55 56
Keywords: autoimmunity, clonal selection theory, tolerance mechanisms, follicular
57
lymphoma, receptor editing, somatic hypermutation
58 59
Introduction.
60
Burnet´s clonal selection theory, immunological tolerance and the idea of self and non-
61
self discrimination set the scene for modern cellular immunology. In 1960, Frank M.
62
Burnet, during his Nobel lecture, presented the theoretical implications of
63
immunological tolerance and the self-recognition hypothesis, and hoped that his
64
thoughts would guide scientists towards novel discoveries in immunology. The theory
65
formulated by Burnet provides a framework for interpreting the novel findings in
66
follicular lymphoma (FL) biology and introduces the idea of immunological tolerance
67
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.
3
74 75
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
90
germinal center B cells in which centrocytes fail to undergo apoptosis because they
91
have a chromosomal rearrangement t(14;18), that prevents the normal BCL2 gene from
92
switching off (1,2). It has been postulated that a second genetic “hit”, or even simple
93
exposure to antigen in a cell with a BCL2 translocation, could result in the development
94
of lymphoma because once it begins proliferating in response to antigen, it does not
95
respond to the usual stimuli for apoptosis (2). Remarkably, self-antigen recognition by
96
FL B cell receptors (BCRs) has been described in 26% of cases (3). The molecular
97
anatomy of the t(14;18) genetic alteration suggests that it occurs prior to antigen
98
exposure in an immature B cell that expresses nuclear TdT (nuclear enzyme terminal
4
99
deoxynucleotidyltransferase) in the bone marrow (BM) and results from an error in
100
primary V[variable], D[diversity] and J [joining] gene recombination induced by the
101
RAG (recombinase activating genes) complex (4). FL cells typically express surface
102
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
104
(3) but retain the capacity to differentiate from B cell precursors to mutated FL cells,
105
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
109
persistence of B cell receptor changes that induce genetic instability and molecular
110
aberrations that promote the development of a neoplasm (5-8).
111 112 113
In the present article, we first review tolerance mechanisms for avoiding self-reactivity
114
in FL cells. We then propose a hypothesis in which tolerance mechanisms play a key
115
role in FL development.
116 117
The objective of this review is to present a hypothesis about the generation of FL in the
118
light of the clonal selection approach.
119 120 121 122 123
5
124 125 126 127 128
Hypothesis: During B cell development translocation t(14;18) protect self-reactive B
129
cells increasing resistance to elimination. Self-BCR-auto-antigen interaction induce
130
chronic activation of tolerance mechanisms specially receptor editing. Unfortunately
131
some times this mechanism increases genomic instability and promotes additional
132
genetic damage that induces FL progression or transformation to aggressive B cell
133
neoplasm.
134 135
The Burnet´s Rules of Tolerance and Autoimmunity (9).
136 137
The basic hypothesis of the origin of autoimmune disease depends of the emergence of a
138
clone or a small number of clones of lymphocytes capable of damaging interaction with
139
normal cells of organ or tissue involved. Each clone is initiated from a cell which has
140
developen an immune receptor adequately reactive with an accessible self-antigen as a
141
result of V/D/J and K/L gene recombination in bone marrow or during somatic
142
mutations in germinal centers. Crucially, this newly self-reactive cell (“forbidden
143
clone”) is anomalously resistant to inactivation by central and peripheral tolerance
144
check points (9)
145 146
FL B lymphocytes qualify as a malignant forbidden clone.
147
6
148
FL can be conceived as a logical and lineal development of the forbidden clone concept
149
formed within the framework of clonal selection theory. In humans, B cells develop
150
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.
160
Clones with an immune receptor sufficiently reactive with an available self-antigen can
161
be the result from a V/D/J gene recombination in bone marrow or during somatic
162
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.
165 166
FL B cells qualify as a malignant forbidden clone because they carry translocation
167
t(14;18), which induces increased resistance to apoptosis, and also express self-reactive
168
BCRs, which induce chronic activation of tolerance mechanisms. Figure 1.
169 170
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
172
important questions need to be answered.
7
173 174
a) Why can these B cells not be eliminated or inhibited by tolerance mechanisms?
175
b) Why can these B cells not produce their BCR as an autoantibody and induce an
176
autoimmune disease?
177
c) What is the driving force to induce genetic and molecular abnormalities in these self-
178
reactive B cells?
179 180
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
189
potentially recognize self-antigens during their differentiation within the BM or later in
190
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-
192
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
194
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-
196
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-
8
198
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
202
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..
204
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
210
dendritic cells or macrophages. We consider that FL BCRs recognize vimentin and
211
MBL on the surface of both stromal cells and apoptotic cells (19,21,22), because
212
vimentin functions as an engulfment receptor on neighboring phagocytes, which
213
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
215
the germinal centers of LN, it is possible that FL BCRs recognize self-antigens
216
expressed in apoptotic blebs. SHM then introduces N-glycosylation in BCRs as a
217
mechanism of affinity maturation of the antibody repertoire in response to repeated
218
exposure to self-antigens (such as vimentin). Translocation t(14;18)(q32;q21) protects
219
self-reactive (vimentin)/MBL) FL cells from elimination during tolerance mechanisms.
220
Figure 3. Additionally, the presence of t(14;18)(q32;q21) converts the receptor
221
editing/revision into dangerous mechanisms that may promote progressive disease
222
(3,29,30). Figure -3. Other mechanisms such as germinal center exclusion (31-34) could
9
223
be ineffective because FL cells can migrate from LN to BM and vice versa (35). At both
224
sites, FL cells may receive BCR stimulation by stromal cells and self-antigens
225
(vimentin, MBL and apoptotic blebs). Figure 2. Abnormal tolerance checkpoints in
226
germinal centers may also play an important role and some FL B cells express IgG
227
BCRs with self-reactivity (20.4%) (19) Selection against self-reactivity during IgM
228
memory B cell development also may be compromised because self-reactive IgM+
229
memory B cells constitute 2.1% in healthy donors (34,36) compared with 3.4% in IgM
230
FL patients (19). Interestingly, the kappa light chain was more frequently expressed in
231
the IgM FL, whereas the lambda light chain was more commonly expressed in the IgG+
232
FL (19). This finding suggests that receptor editing occurs in IgG+ FL. Nevertheless,
233
under normal conditions, self-reactive normal IgG+ memory B cells may be anergic
234
(36). However, FL BCR signaling is increased and not anergic (37).
235 236
Burnet´s Rules of Tolerance and Autoimmunity in FL.
237 238
Taking advantage of the comparison with a normal linear B lymphocyte differentiation
239
we can observe that at all stages of B cell development, there is evidence that FL may
240
be induced or promoted by a persistent tolerance mechanism.
241
242
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
250
lymphocytes with t(14;18) may be primed to proliferate by surface immune receptors
251
(41) causing them to potentially recognize self-antigens (3,19). This stimulus may in the
252
future lead to an FL (42). Figure 4. In mice, the expression of a BCL2 transgene in the
253
B lymphoid compartment profoundly perturbed homeostasis and, depending on the
254
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
257
lymphocytes retain the BCR signaling capacity acquired during the pre-B cell
258
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
260
apoptotic cell surfaces (29,38).
261
Moreover, FL B lymphocytes are in constant receptor editing to avoid self-reactivity,
262
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
266
autoimmune disease?
267 268
Peripheral tolerance.
269 270
An important peripheral checkpoint is the entry into the T lymphocyte-dependent, long-
271
term memory compartment. Lymphocytes that express antibodies encoded by the VH4-
272
34 gene are self-reactive B cells (31,32). B cells that express self-reactive BCRs
11
273
encoded by IGHV4-34 are excluded from T lymphocyte-dependent IgG memory and
274
plasma cell populations suggesting that these self-reactive lymphocytes fail to cross a
275
developmental checkpoint following activation in normal individuals (31,32). This
276
implies that negative selection of autoreactive cells occurs at the transition from naive to
277
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
279
acquire somatic mutations (SHM) in GC-like memory B cells.
280 281
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
286
exclusion may be altered in FL because in healthy individuals only a very small
287
population of “FL-like B cells” remains unmutated (49). Interestingly, the class switch
288
recombination (CSR) status of FL B cells indicates a selective pressure in favor of sIgM
289
expression in a B cell population that is at the same time permanently driven to switch
290
(49,50), because in >80% of cases CSR occur in both alleles.
291 292 293
Tolerance mechanisms involved in development of memory B cells.
294 295
The t(14;18)(q32;q21) is generated during early B cell development in the BM, making
296
possible the maturation and expansion of affected cells in GC (51,52), even though they
297
recognize self-antigens such as vimentin.
12
298
Usually, B cells expressing self-reactive and broadly bacterially reactive antibodies are
299
removed from the repertoire in the transition from naive to IgM+ memory B cells (34).
300
However, rare IgM+ memory B cells that produce antibodies with low levels of self-
301
reactivity acquire this reactivity by somatic hypermutation (34). In a similar way, auto-
302
reactivity in human IgG+ memory B cells is mostly created by somatic hypermutation
303
(36). The fact that FL B cells undergo isotype switching and the acquisition of somatic
304
mutations suggests that GC check points may be disrupted in FL patients (51,52,53).
305
What is the driving force to induce genetic and molecular abnormalities in these
306
self-reactive B cells?
307 308
The tolerance mechanism may promote oncogenic transformation. (29,30,54)
309 310
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
313
pre-malignant B cells with t(14;18) persist.
314 315
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
318
contact..
319 320
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
13
322
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
326
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
14
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
15
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
such as SHM and Ig class switch, also contribute to genetic instability and
461
transformation.
462 463
References.
464 465 466
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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