Immunology

1. TO B1 OR TO NOT B1
That really is still the question

2. Introduction
• CD5-B cells have attracted considerable interest because of
their association with self-reactivity, autoimmunity, and
leukemia.
• In mice, CD5-B cells are readily generated from fetal and
neonatal precursors, but inefficiently from precursors in
adult.
• One model proposed to explain this difference is that their
production occurs through a distinctive developmental
process, termed B-1, that enriches pre-B cells with novel
germline VDJs and that requires positive selection of newly
formed B cells by self-Ag.
• In contrast, follicular B cells are generated throughout adult
life in a developmental process termed B-2, selecting VDJs
that pair well with surrogate L chain, and whose maturation
appears relatively independent of antigenic selection

3. History of B cells
• Any discussion of B cell subsets, including those B
cells in mammals are composed of several
subsets with different functionalities.
• In mice, three major B subsets have been
identified, namely, follicular B2 cells, B1 cells
(including CD51 B1a and CD52 B1b cells) and
marginal zone (MZ) B cells
• Decades of research have demonstrated that
these subsets can be distinguished from one
another according to phenotype, ontogeny,
anatomical location, and function

4. A unified model for B cell development

5. B2- cells
• B2 cells are continually generated from bone
marrow precursors and circulate throughout
the blood and secondary lymphoid tissues.
• Follicular and marginal zone B cells both arise
from the B2 lineage and can respond to a
broad range of T-dependent (TD) and T-
independent antigens.

6. B2-cells
• B2 cells are responsible for immune responses
against thymus dependent antigens, and with
help from T cells, B2 cells undergo germinal
center reactions and generate high-affinity
antibodies with precise antigen specificity.
• B2 cells can undergo class switching, somatic
hypermutation, and generate memory cells,
thereby potentially providing long-lived
antibody-mediated protection a

7. What is B1- B Cells
• B1 cells are a sub-class of B cell lymphocytes
that are involved in the humoral immune
response.
• They are not part of the adaptive immune
system, as they have no memory, but
otherwise, B1 cells perform many of the same
roles as other B cells: making antibodies
against antigens and acting as antigen
presenting cells.

8. Origin
• B1 cells are first produced in the fetus and most B1
cells undergo self-renewal in the periphery, unlike
conventional B cells (B2 cells) that are produced after
birth and replaced in the bone marrow.
• B1 cells are present in low numbers in the lymph
nodes and spleen and are instead found
predominantly in the peritoneal and pleural
cavities.
• CD5- B1a cells producing broadly reactive natural IgM,
whereas CD5-B1b cells can generate T-independent, long-
lasting memory-type IgM responses to some infectious
pathogens.

9. How it function
• B1 B cells express a separable BCR repertoire.
• Sequence analysis indicates antibodies with restricted
sets of V region genes and an increased usage of λ
light chains.
• B1 B cells sequences also show no evidence for
somatic hypermutation (SHM), and few non-
templated nucleotide (N) sequence insertions, a
pattern typical of neonatal B cells.
• Efficient B1 B cell development appears to be
dependent on positive regulators of BCR signaling and
the loss of negative regulators promotes greater
accumulation of B1 B cells.

10. Functions
• CD5-b cells have been shown to be responsible for producing
Abs to bacterial cell wall components, including T15
antiphosphorylcholine.
• The rapid production of Ab by these cells when stimulated can
thus serve to limit bacterial spread before induction of
adaptive immune responses.
• B1 cells are considered innate immune cells that produce the
majority of “natural” immunoglobulin M (IgM) and IgA, which
is largely encoded by germline immunoglobulin genes.
• Because of its polyreactivity ,this natural IgM acts as a first
line of defense against pathogens such as encapsulated
polysaccharide-expressing bacteria.

11. Functions cont.
• B1 receptors also show polyspecificity, meaning that they
have affinities for many different antigens
• Natural IgM not only acts as a first line of defense against
invading microbes, but also plays active roles in maintaining
immune homeostasis, such as removing apoptotic cells and
decreasing inflammatory responses
• In addition to antibody production, B1 cells also actively take
part in immune regulation by acting as antigen-presenting
cells and secreting cytokinins
• CD5- B1a cells plays a roll in the regulation of neonatal
inflammation and immunity.
• On the one hand, IL-10 produced by CD5-B1a cells can impair
the ability of the neonates to generate sufficient immunity
against invading pathogens; on the other hand, IL-10 could be
beneficial for them to avoid overwhelmingly lethal
inflammation.

12. EVIDENCE FOR B1-CELLS IN HUMAN BEINGS
• Despite there being general consensus regarding the
distinct origins and functions of B1 and B2 cells, B1
cells have suffered an identity crisis.
• Debate has raged as to whether B1 cells represent a
distinct B-cell lineage or correspond to a stage of
activation that all B cells experience.
• In human beings, the identification of B1 cells has
proven to be a contentious issue.
• Part of the reason for this relates to the difficulty in
accessing sites such as the peritoneal cavity, where
B1 cells are enriched in mice.

13. Human B1 cells
• n January 2011, human B1 cells were found to have
marker profile of CD20+CD27+CD43+CD70- and could
either be CD5+ or CD5-, which has been debated
since.
• These cells, comprising +-5% to 10% of B cells in cord
or adult blood, were defined as B1 cells based on
shared key features with murine B1 cells:
• The ability to spontaneously secrete IgM,
• to induce proliferation of allogeneic T cells,
• and to exhibit tonic signaling in the absence of direct
B-cell receptor engagement

14. Conclusion
• This initial study has been vigorously debated
though.
• An alternative explanation for some of these data
was that human CD20+, CD27+ and CD43+ B cells
actually correspond to plasmablasttype cells.
• This possibility has now been addressed.
• By employing a phenotypic, functional, gene-
profiling, and in vitro culture approach, it was
concluded that CD20+, CD27 and CD43+ B cells are
more likely to correspond to activated B2 cells
undergoing the early stages of commitment to the
plasma cell lineage—and thus are termed
preplasmablasts rather than belonging to a distinct
B-cell lineage.

15. Conclusion continue..
• The concept that CD20+, CD27+ CD43+ B cells are
preplasmablasts is also consistent with these cells
exhibiting additional features of plasma cells, such as a
CD38(bright) and CD20(dim) phenotype, and greater
expression of PRDM1 and BCMA1 compared with naive
and memory B-cell subsets.
• Additional evidence that CD20+, CD27+, CD43+ B cells, may
not be B1 cells,is that cells with this phenotype could be
generated in vitro following stimulation of memory cell
precursors,
• and that CD20+ CD27+, CD43+ B cells themselves could
undergo further differentiation in vitro, acquiring a
phenotype consistent with plasma cells.

16. Conclusion
• Do these findings definitively resolve the uncertainty
surrounding the nature of human B1 cells?
• Probably not.
• Despite these uncertainties, the current study by
Coven et al,has provided insight into the origins and
functions of at least a subset of CD20+ ,CD27+, CD43+
B cells.
• Studies such as these will ensure that discussion,
analysis, and debate of human B cells, including
putative B1 cells, will continue in earnest for years to
come.

17. Referrences
1. Frontiers in immunology, review article,
October 2014.
2. Blood, January 2016.
3. Cellular and molecular immunology, review
article, October 2013.
4. Journal of Immunology, 18 January 2016.
5. PNAS, April 2006.