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Plasma cells
University of Birmingham
MRC Centre for Immune regulation
Ian MacLennan
THE UNIVERSITY
OF BIRMINGHAM
Conventional wisdom on the cellular basis of
T dependent antibody responses
Antigen
+ T help and
innate signals
Proliferation in
follicles forming
germinal centres
Long-lived pc in
marrow & gut +
B memory
B cell
Extrafollicular
proliferation as
plasmablasts
local pc, mainly shortlived, no memory
Extrafollicular responses occur in
the spleen and lymph nodes, but
not the GALT
Follicular
responses
seed
plasma
Follicular responses seed plasma
cells
to
the
bone
marrow
and
cells to the bone marrow and
lamina
propria
of
the
gut
lamina propria of the gut
Chemokine directed homing
plasmacytoid cells
CXCR4 on plasmacytoid cells to CXCL12 (SDF1)
in splenic red pulp and bone marrow
CCR9 on IgA plasmacytoid cells to CCL25 (TECK)
in lamina propria
CXCR3 on plasmacytoid cells guide migration into
inflamed tissue
Phases of T-dependent extra-follicular responses
Antigen encounter
& induction of B cell
growth in the T zone
Exponential plasmablast
growth in extra-follicular foci
Long lived red pulp
plasma cells
Antigen
Langerhans cell
And T zone DC
Plasmablastassociated DC
Plasmablast
B cell
T cell
Plasma cell
B blast
T blast
Apoptotic plasmablast
0
24
48
72
96
120
plasma cell bed
Movement to
Apoptosis
of excess
plasmablasts
Transition of plasmablast
to plasma cell
3
2
1
0
Plasmablast
migration to
red pulp
8
7
6
5
4
Cognate T cell :
B cell interaction
Log2 hapten-specific
B cells
Synchronized splenic extrafollicular antibody response model
144
hours after i.v. soluble hapten-protein in protein primed mouse
Germline switch
transcripts
AID expression
Switch circle Transcripts
Antibody secretion
Requirement for P18 ink4c CD11chighDC,
BAFF
log2 extra-follicular
Ag-specific cells/ mm2
Plasmablast growth and plasma cell survival
12
NP-Ficoll in QM mice
NP-CGG in CGG-primed mice
Primary response NP-CGG
9
6
3
<0
0
5
10
15
days after immunization
20
Immunoglobulin levels are
regulated by the number of sites
that can support plasma cell
survival, rather than the rate of
plasma cell production.
Ig V-genehypermutation and
selection of germinal
centre B cells
pc
FOLLICULAR
MANTLE
T
T
T
cc
T
non selection
– apoptosis
cc T
cc
FDC + cc
cc antigen
LIGHT
ZONE
Cb
Ig-V-regionhypermutation
mB
Cb
Cb
DARK ZONE
selection –
differentiation
There appear to be
additional pathways of
antibody production.
Autoantibodies depleted following
anti-CD20 (Rituximab) therapy
Autoimmune haemolytic anaemia: IgG warm antibodies
(Morselli et al Blood 2002: 99, 3478-3479, Zecca et al
Blood 2003;101, 3857-61),
Systemic Lupus Erythematosus, IgG anti-doublestranded DNA (Leandro et al Arthritis & Rheumatism
2002, 46: 2673-2677),
Sero+ve Rheumatoid arthritis: IgM rheumatoid factor
levels (Edwards et al 2004, New England J Med. 350:
2572-2581),
Factor VIII deficiency: acquired anti-factor VIII
antibodies (Jy et al 2003, Acta Haematologica 109: 206208).
Retuximab causes progressive
fall in autoantibody levels
BUT
Serum IgG and levels of tetanus
toxin antibody are relatively
unaffected!
Conclusions
Plasma cells are not directly sensitive to Rituximab,
but B cells are
Plasma cells producing many autoantibodies are
short lived and are renewed within 8 weeks by
maturation of B cells that are Rituximab sensitive
Conversely, antibodies against exotoxins are
produced by long-lived plasma cells that persist for
months following Rituximab
Synchronized plasmablast growth in response
to the T cell-dependent antigen NP-CGG
antibody-containing
cells/mm2
1000
100
10
1
4
0.1
0
3
2
4
6
8
Days after immunization
10
Sze et al
J. Exp. Med.
2000, 192:
813-822
total NP-specific plasmacytoid cells
NP-specific plasmablasts (in cell cycle)
cells per mm 2
What
is
maintaining
this
Splenic NP-specific response to the
pool of NP-specific
T-independent
antigen - NP-Ficoll
plasmablasts three months
all plasmacytoid cells
after immunization?
plasmablasts
1000
100
10
1
0.1
<0.04
36%
15%
70%
//
10%
//
8.4%
7.9%
//
0 1 3 5
7
10
21
90
days after immunization
Vinuesa et al Eur. J. Immunol. (1999) 29: 1314-1327
Possible ways these NP-specific
plasmablasts persist
Continued recruitment of naïve B cells
recently produced in the marrow.
The text book compatible explanation!
Memory B cell clones.
Are memory B cells produced in TI-2 responses?
A self renewing pool of plasmablasts.
Are these recognized?
To test if there is continued recruitment of
naïve B cells into the NP-Ficoll response
RAG-1-deficient mice, which have no capacity
to produce T and B cells, are reconstituted
with mature T and B cells
Conclusions
Productive B cell memory clones can be established
in responses to the T-independent antigen - NP-Ficoll
Cells from these B memory clones can be recruited
into TD responses
Further transfer experiments indicate that the
persistent clones maintaining responses to NP-Ficoll
are CD5-ve B1 cells.
Ig heavy chain class switching and at low level Ig Vregion mutation occurs in these responses