Thomas L Rothstein

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Thomas L. Rothstein

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Grand Challenges in B cell Biology

www.frontiersin.org February 2011 | Volume 2 | Article 2 | 1
Specialty Grand challenGe article
published: 07 February 2011
doi: 10.3389/fimmu.2011.00002
Grand challenges in B cell biology
Thomas L. Rothstein1,2,3*
1 Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY, USA
2 Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USA
3 Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USA
*Correspondence: tr@nshs.edu
“The progress of Science consists in 
observing interconnections and in 
showing with a patient ingenuity that 
the events of this ever-shifting world are 
but examples of a few general relations, 
called laws. To see what is general in what 
is particular, and what is permanent in 
what is transitory, is the aim of scientific 
thought.”A.N. Whitehead
Science, immunology, and, in particular, 
B cell biology, often progress through 
multiple series of successive accomplish-
ments and retrenchments, mixed with 
new discoveries and sometimes rediscov-
eries. But in Whitehead’s terms, we have 
not yet arrived at a set of immutable laws 
for all of B cell biology. We do, however, 
have coherent paradigms that have proven 
durably explanatory (e.g., clonal selec-
tion, serological tolerance), whereas the 
status of others remains uncertain (e.g., 
idiotypic network). And beyond laws and 
paradigms, we have mechanisms that suc-
cessfully account for some B cell behaviors 
(e.g., generation of diversity versus cen-
tral deletion/receptor editing/peripheral 
anergy). And short of mechanisms, we 
have mysteries (such as how activated B 
cells choose plasmacytic versus memory B 
cell differentiation, or just how peripheral 
checkpoints operate) whose resolution will 
become part of future mechanisms, para-
digms, and laws.
Yet even as laws, paradigms, and mech-
anisms are being constructed, tested, and 
deconstructed, B cell modulating therapies 
(e.g., belimumab, epratuzumab, ocrelizu-
mab, ofatumumab, rituximab, tocilizumab, 
veltuzumab) are being successfully applied 
in clinical situations. Thus, operating prin-
ciples that oppose disease and enhance 
health can be discerned in the absence of 
a complete accounting of B cell biology. 
Conversely, whereas much is known about 
the behavior of individual cells and mol-
ecules, how this all adds up to measured 
anti-pathogen immune responses (mean-
ing responses that arise appropriately, end 
promptly, and do not damage normal tis-
sue) when needed, and how this all adds up 
to tolerance for self and for the symbiotic 
or passenger microorganisms therein, in 
real life situations, remain current topics of 
ongoing investigations. So we have made 
much progress in elucidating mechanisms 
and developing paradigms to describe the 
world of B cell biology, but we are not at the 
immutable law stage yet. We are still iden-
tifying new participants (e.g., Breg cells), 
new characteristics of old players (e.g., T3 
B cells), new interactions (e.g., signaling 
crosstalk), and new concepts (e.g., systems 
biology), even as we use what we know to 
construct practical treatments and strate-
gies to counteract illness for the benefit of 
humankind.
One thing that recent and novel B cell 
therapies have emphasized is the impor-
tance of B cells to various immunologi-
cally mediated diseases, most prominently 
including rheumatoid arthritis. This 
coincides with the results of experiments 
conducted in vitro and in murine models 
suggesting that B cells are integral play-
ers, and may in some cases be directors, 
of immune responses and disease states, 
via intercellular interactions that include 
antigen presentation to T cells; polariza-
tion of T cell differentiation; membrane 
expression of modulatory proteins; and 
secretion of cytokines and chemokines 
that promote immune activation, differ-
entiation, inflammation, and/or suppres-
sion; all of which together point to a role 
beyond the conception of B cells as mere 
production facilities for the generation of 
immunoglobulin.
As those whose object of affection is 
the B cell in all its subdivision and glory 
continue to learn more about the B cell life 
story, there are a number of areas in which 
it appears that further advances will follow 
from continued effort. A non-inclusive list-
ing is provided below, to which I hope that 
readers of this brief essay will add, through 
contributions of their own.
Understand how things happen 
on a molecUlar scale
Despite the many molecules and biochemi-
cal reactions that have been identified, we 
are not at the end of discovery when it 
comes to the factors, adapters, enhancers, 
and modifiers, and the interactions in which 
they engage, that direct B cell behavior. Like 
peeling an onion, new layers become seri-
ally evident, most recently in genetic regula-
tion produced by miRNA and by epigenetic 
modifications. Among the many molecular 
avenues that are likely to be the focus of 
investigational efforts in coming years will 
be studies designed to develop an under-
standing of how events take place within 
the intracellular milieu of the B cell. Much 
has been learned about immune synapses, 
membrane migration of signaling media-
tors, and protein interaction sequences and 
targets in the submembranous region, but 
beyond that, it is sometimes forgotten that 
the inside of a cell is colloidal and not a 
simple aqueous solution, where viscosity, 
topology, location, migration, concentra-
tion, and temperature may all affect the 
likelihood of specific interactions. How 
molecules negotiate space within the inte-
rior of the B cell, and how those peregri-
nations determine the molecular contacts 
that are made, the activation thresholds 
that are experienced, and the biochemical 
rate constants that occur, is not yet clear. A 
second avenue of investigation is likely to 
concern interactions between and among 
molecular signals, in which the B cell acts in 
a dynamic sense to integrate changes pro-
duced by extracellular events (and intracel-
lular conditions) to construct a meaningful 
response. This includes the realm of molec-
ular imprinting, in which the experience of 
one signal, reaction, or event alters subse-
quent responses to another, constituting a 
form of “little memory” of past events at 
the molecular level, and further includes 
the interplay of transcriptional networks 
that control B cell fate determination and 
interconversion.
Frontiers in Immunology | B Cell Biology  February 2011 | Volume 2 | Article 2 | 2
Rothstein Grand challenges in B cell biology
autoimmune  dyscrasias. Murine models 
applied to the human  condition, along with 
tumor genomics, will assist in identifying 
the molecular and cellular mechanisms 
responsible for malignant transformation 
of B cells, which constitute the cell of origin 
for the majority of lymphocytic leukemias 
and lymphomas in the western world. And 
new antibody-based treatments for both, 
as well as for immunodeficiency states 
produced by genetic lesions and infec-
tious conditions, will add to the current 
therapeutic armamentarium. It is hoped 
that this will include vaccination and/or 
passive treatment strategies to counteract 
HIV, hemorrhagic fever viruses, and other 
emerging infectious diseases.
develop new methodology
A common moot discussion topic is the one 
that questions whether the most important 
element in scientific progress is new technol-
ogy that fuels new ideas and hypotheses, or 
new ideas and hypotheses that fuel new tech-
nology. Certainly it is easy in B cell biology to 
point to the former. Flow cytometry provides 
the means to detect low level surface antigen 
expression; this led directly to the identifica-
tion of B1 cells, and, more recently, to sin-
gle cell assessment of intracellular signaling 
events and immunoglobulin gene expression. 
Two photon excitation microscopy provides 
the means to track lymphocyte movement 
in vivo; this has led, and continues to lead, 
to new insights concerning germinal center 
mechanics. Microinjection and genetic 
recombination have led to innumerable 
advances based on over- and under-expres-
sion of specific genes. It is well to remem-
ber, however, that these are not perfect tools, 
and, moreover, sometimes new technology 
becomes broadly used without a full under-
standing of the inherent limitations. Flow 
cytometry (and sorting) can be confused 
by inadequate doublet discrimination; two 
photon microscopy can penetrate only a 
limited depth of tissue for limited periods 
of time; transgenic and knock-out models 
are hindered by effects on expression of mul-
tiple non-targeted genes. It is not clear from 
whence the next technological advance will 
emerge, but among the many innovations 
that may appear in coming years could well 
be advances in single cell analysis of protein 
composition and post-translational modifi-
cation, as well as algorithms to codify B cell 
behavior and interactions during immune 
focus of investigational efforts on immune 
phenomena in coming years will be stud-
ies designed to elucidate the fine regulation 
of B cell responses and disruptions thereof 
that lead to chronic states of infection and 
autoantibody formation. In this endeavor it 
is likely that additional focus on molecular 
and cellular “brakes” involving B cells (such 
as immunosuppressive PD-1 ligands, ILT 
family members, IL-10, and adenosine), as 
opposed to elements that initiate responses, 
will yield important information.
translate to/investigate the 
hUman condition
The overall goal of immune system study 
is, of course, to improve the human con-
dition. We wish to apply all that we know 
to prevent, reverse or ameliorate clinical 
disease. In that sense it is well to remem-
ber that Mus musculus and Homo sapiens 
diverged evolutionarily tens of millions 
years ago, time enough for many immune 
system differences to emerge and mani-
fest themselves. As an example, Btk muta-
tion produces widely divergent levels of B 
cell impairment in mouse (wherein B cell 
numbers are reduced by about half) and 
human (wherein agammaglobulinemia 
results from a virtually complete loss of 
B cells). Other examples abound: CD27 
marks memory B cells in human, but not 
in mouse; CD5 marks B1 cells in mouse, but 
is a poor indicator of B1 cells in the human 
system; LPS stimulates mouse B cells but 
not human B cells; and so on. There will 
always be cogent reasons to probe and per-
turb the rodent immune system because 
factors that might otherwise confuse 
experimental results can be controlled (by 
inbreeding and standardized environmen-
tal conditions) and because experiments 
involving genetic manipulation and adop-
tive transfer are technically and ethically 
feasible. Animal studies provide insights 
that are typically not available in the 
human condition except through genetic 
“accidents of nature,” but they cannot com-
pletely replace the direct study of human B 
cell biology. It is likely that the testing and 
application of murine-derived paradigms 
on human B cells will be an important focus 
of future investigational efforts. Within this 
context, further studies will examine the 
newly appreciated role of B cell dysfunction 
within the multifactorial pathogenesis of 
complex diseases such as lupus and other 
elUcidate cellUlar interactions
Although much is known regarding key 
intercellular interactions involving B cells, 
new information continually impacts this 
arena, such as identification and characteri-
zation of follicular T helper cells, and evi-
dence that B cells influence T cells. Among 
the many cellular avenues that are likely to 
be the focus of investigational efforts in 
coming years will be studies designed to 
elucidate a fuller understanding of how B 
cell development, differentiation, and activ-
ity is influenced and supported by stromal 
cell niches, new flavors of T cells, and ambi-
ent cytokines. A particular conundrum lies 
in the interactions and influences gathered 
by germinal center B cells as they move 
within the germinal center from dark to 
light zone (to the extent such zones can be 
defined) and interact with dendritic cells 
and T cells. Aside from evaluating how B 
cells are impacted by cellular interactions, 
additional study is likely to revolve around 
how B cells influence other cells, in particu-
lar the role that B cells play in presenting 
antigen to, and in stimulating the activa-
tion and differentiation of, T cells, as well 
as the role B cells play in downmodulat-
ing immune cell activity. It would not be 
farfetched to speculate that results of this 
work will lead to a more balanced view of 
B cells and T cells as equal partners in an 
intercommunicating and interinfluencing 
pathogen responsive system.
relate molecUlar events and 
cellUlar interactions to 
immUnological phenomena
The impetus to study molecular events and 
cellular interactions is to understand and 
explicate the big immunological features 
that we are familiar with on a macroscopic 
level: construction and maintenance of a 
serological immune system that counter-
acts the assault of invasive organisms (and, 
perhaps, self-components, such as oxidized 
LDL) that would do us harm, and that can 
(hopefully) be manipulated by vaccination 
or other means to enhance defenses against 
pathogens, cellular debris, and possibly neo-
plastic aberrations, while maintaining self-
tolerance in the midst of diversity to avoid 
autoreactivity and destruction of autolo-
gous tissue. In this sense it is not always 
clear how the individual molecular and cel-
lular parts make the in vivo whole. Among 
the many avenues that are likely to be the 
www.frontiersin.org February 2011 | Volume 2 | Article 2 | 3
Rothstein Grand challenges in B cell biology
challenge for the future is simply this: to 
 elucidate and understand the laws, para-
digms, and mechanisms that direct and 
guide B cell development and function, and 
to improve the human condition, by using 
what we have learned about B cell biology to 
prevent and treat disease. In these endeav-
ors it is well to remember that our most 
important resource lies in the aggregated 
intellectual talent, unbridled enthusiasm, 
and deep-seated motivation of those who 
find B cells the most intriguing players on 
the field of immunology and cell biology.
acknowledgments
I thank members of my laboratory, past 
and present, who have made many impor-
tant contributions to the ideas expressed in 
this piece. I thank the National Institutes 
of Health for funding these efforts over 
many years time. I thank Drs. Barbara Kee, 
Tim Manser, and Kendall Smith for critical 
review of the manuscript.
Received: 21 January 2011; accepted: 24 January 2011; 
published online: 07 February 2011.
Citation: Rothstein TL (2011) Grand challenges in B cell biol-
ogy. Front. Immun. 2:2. doi: 10.3389/fimmu.2011.00002
This article was submitted to Frontiers in B Cell Biology, a 
specialty of Frontiers in Immunology.
Copyright © 2011 Rothstein. This is an open-access arti-
cle subject to an exclusive license agreement between the 
authors and Frontiers Media SA, which permits unrestricted 
use, distribution, and reproduction in any medium, pro-
vided the original authors and source are credited.
 knowledge, new  discovery tools, ferment 
among conceptual paradigms, development 
of antibody reagents, and movement from 
bench to bedside and back again. Not to 
be overly Panglossian, but in terms of the 
basic science and clinical translation of B 
cell biology, this would seem to be the best 
of all possible worlds. Now is the time to put 
the “pedal to the metal,” to re-invigorate and 
re-commit our efforts, and by doing so to 
capitalize on all that has gone before, and to 
effectuate the promise that the present holds 
for the future. For this to occur, we must 
move beyond the current penurious and 
debilitating level of support provided by 
government, institutional, and foundation 
sources. The rosy future for which current 
discoveries have already produced a frame-
work cannot come to pass without cost, but 
the costs incurred will more than pay for 
themselves in a reduction in human suf-
fering, and an improvement in the human 
condition, not to mention a decline in 
clinical expenditures (and, for those with 
an entrepreneurial spirit, an increase in tan-
gible profits to be obtained from commer-
cialization of novel reagents and therapies). 
Any and all of these outcomes will inure to 
the benefit of society at large. Thus, there 
is every reason, both moral and financial, 
for a marked increase in governmental sup-
port for NIH and in funding for biomedi-
cal research from all available sources. The 
activity  resulting in promulgation of testable 
predictions. Most importantly, it is critical to 
imagine new ways of probing B cell biology 
that can provide new kinds of information, 
and then make those new ways a reality.
Find new molecUles, cells, and 
interactions. relate to 
immUnological phenomena. 
translate to hUman condition. 
iterate
Perhaps it is most important to recognize 
that we are nowhere near the end of dis-
covery about B cell biology or immune 
system function. We may have passed the 
beginning of the beginning, but, to quote 
Winston Churchill in a very different con-
text, “This is not the end. It is not even the 
beginning of the end. But it is, perhaps, the 
end of the beginning.” Someday, we can 
imagine, immunodeficiencies will be com-
pletely corrected, autoimmune disease will 
be a thing of the past, cyclic viral pandemics 
will be thwarted, fatal viral diseases will be 
counteracted, chronic mycobacterial and 
worm diseases will be successfully treated, 
if not prevented, and transplants will be 
fully accepted, all through manipulation 
of the immune system based on investi-
gations that are taking place right at this 
moment, and will, with societal support, 
continue into the future. We are entering 
a golden age in terms of accumulated raw 


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