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Role of B cells, immunoglobulins and immunoglobulin receptors

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Role of B cells, immunoglobulins and immunoglobulin receptors in the pathogenesis of systemic lupus erythrematosis February 3, 2004 Medical Immunology 165.719 – PowerPoint PPT presentation

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Title: Role of B cells, immunoglobulins and immunoglobulin receptors


1
Role of B cells, immunoglobulins and
immunoglobulin receptors in the pathogenesis of
systemic lupus erythrematosis February 3, 2004
Medical Immunology 165.719
  • Objectives
  • 1) Outline the clinical characteristics and
    immunological abnormalities in systemic lupus
  • erythematosis
  • 2) Discuss the contribution of B cells and
    antibodies in SLE pathogenesis
  • 3) Discuss current evidence implicating FcgRs in
    SLE pathogenesis
  • 4) Review SLE treatment and discuss new data from
    trials using B cell depletion therapy

2
Systemic lupus erythematosus (SLE)
Major clinical manifestations -gt Red rash or
color change on the face, often in the shape of a
butterfly across the nose and cheeks -gt
Painful or swollen joints -gt Unexplained fever
-gt Chest pain with deep breathing -gt Extreme
fatigue -gt Sensitivity to the sun -gt Depression,
trouble thinking, and/or memory problems
Population affected -gt incidence around 1/2000
in North America -gt 81 female/male -gt higher
incidence and severity in African American and
Hispanic women
3
SLE Major diagnostic laboratory findings -gt
Positive lupus erythematosus cell preparation (a
peculiar polymorphonuclear leukocyte which has
injected nuclear material) -gt Hemolytic anemia,
leukopenia, lymphopenia or thrombocytopenia -gt
Heavy proteinuria or cellular casts in urine
sediment -gt Anti-nuclear and/or anti-DNA
antibodies
Related systemic autoimmune diseases with
overlapping findings -gt Rheumatoid arthritis
(mainly restricted to joints, distinguished by
presence of RFs) -gt Sjogrens symdrome (mainly
restricted to salivary and lacrimal glands) -gt
Schleroderma (mainly restricted to skin)
LE cell 1948
ANA
4
ANA Fluorescence Patterns and Disease Association
Nuclear Fluorescence Pattern Rim
(peripheral) Homogeneous (diffuse) Speckled Nucleo
lar
Disease Association SLE Drug-induced LE,
SLE SLE, Sjogren's, scleroderma Scleroderma
-gt 95 of SLE patients are ANA positive, thus a
negative result virtually excludes SLE -gt but ANA
can also found in other autoimmune diseases and
chronic infections, thus a positive result cannot
be the sole basis for diagnosis
5
Identity of specific molecular targets of ANAs
Anti-double-stranded DNA -gt gives rim staining
pattern in ANA -gt most important for SLE (2/3 of
patients have quite specific for
SLE) Anti-single stranded DNA -gt less
specific Anti-histone antibodies Anti-ribonuclea
r proteins -gt antibodies against protein-RNA
complexes -gt anti-Sm present in 1/3 of SLE
patients, not in other conditions -gt anti-U1-RNP,
anti-SS-A/B
6
Immune complexes in SLE pathogenesis
Mechanism for glomerulonephritis Anti-DNA
antibodies in SLE tend to have high isoelectric
point (net positive charge) which promotes their
binding to DNA Circulating DNA from damaged or
dying cells can bind to the basement
glomerular basement membrane Anti-DNA Abs
binding to DNA on the basement membrane can fix
complement Complement split products (C3a, C5a)
trigger inflammatory response
Lupus glomerulonephritis
Similar mechanisms for skin lesions?
7
Other pathogenic roles of auto-Ab in SLE
Anti-red cell and anti-platelets Abs -gt hemolytic
anemia, thrombocytopenia Anti-cardiolipin
antibodies -gt miscarriages, vascular
thrombosis Anti-T cell antibodies -gt immune
dysfunction?
8
Immunological abnormalities in SLE
B cell / antibody / complement systems -gt
increased numbers of plasma cells in the bone
marrow and peripheral lymphoid tissues -gt limited
repertoire of Ig genes used in autoantibodies -gt
antigen-driven-clonal expansion -gt progressive
accumulation of somatic mutations in Ig genes
used in autoantibodies (affinity maturation?) -gt
marked accumulation of circulating immune
complexes during acute flares -gt decreased
clearance of immune complexes through Fc
receptors and complement receptors (cause or
effect of increased IC?) -gt decreased circulating
C3/C4, increased split products such as C3a, C3d
T cell system -gt in some cases, anti-T cell
antibodies -gt T cell lymphopenia -gt generalized
depression in cell mediated immunity -gt apparent
oligoclonal expansion of pathogenic T cells
9
Genetic factors in SLE
-gt different disease frequencies in different
ethnic groups -gt sibling recurrence-risk ratio
15-20 (thus, if your sibling has SLE your risk
is 1 rather than 0.05) -gt high clinical
disease concordance among twins 2-5 for
dizygotic twins, 24-58 for monozygotic
twins -gt complement deficient patients (rare)
very frequently develop SLE (40-75) -gt evidence
for linkage to specific gene loci
Environmental factors?
10
Animal models for studying SLE genetics and
pathogenesis
(NZBxNZW)F1 -gt Spontaneously develop a systemic
autoimmune disease similar to lupus -gt
autoantibodies, immune complex disease, premature
death -gt Parental NZB mice have milder for of
disease -gt Useful model for dissecting the
complex genetics of the disease -gt multigenic,
with different genes controlling different
immunological abnormalities/production of specifc
autoantibodies MRL lpr/lpr and MRLgld -gt develop
SLE-like syndrome associated with massive
lymphoproliferation/splenomegaly -gt gene defect
identified as mutation in the death receptor Fas
(lpr) or mutation in Fas ligand (gld)
11
BREAK
12
Activating and inhibitory Fcg receptors
13
FcgRIIB inhibitory signaling
14
Evidence implicating Fcg receptors in lupus
-gt Genetic deficiency of activation receptors
attenuates disease in lupus-prone mouse
strains -gt Reduced expression of inhibitory
receptors in autoimmune-prone mouse strains due
to promotor polymorphisms -gt Genetic deficiency
of inhibitory receptor leads to spontaneous
development of lupus in some non-lupus prone
mouse strains -gt Human linkage studies
15
Interaction between FcgRII and other genetic
factors
Bolland et al, J. Exp. Med 195 1167
16
Science 307 593January 28, 2005
17
Effect of FcgRIIB retroviral-mediated bone marrow
transduction on spontaneous autoimmunity in
lupus-prone mice
18
Retroviral transduction of FcgRIIB inhibits
kidney pathology
19
Retroviral transduction only increased FcgRII
expression by 2-fold in about half of B cells!
Small changes tip the balance
Marked reduction in HAS-negative population less
B cell activation
20
FcgRII reguates the accumulation of autoreactive
plasma cells through a cell-autonomous feedback
loop?
Fukuyama et al, Nature Immunol. 699 Dec.12,
2004
21
Treatment of SLE
Current standard treatments immunosuppression -
gt anti-inflammatories corticosteroids,
NSAIDs -gt immunosuppressives cyclophosphamide, pr
ednisone, methotrexate, hydroxychloroquine, Azathi
oprine -gt I.e. severe patients ore on some very
nasty drugs
22
Efficacy of B cell depletion
11/17 patients showed effective depletion (some
other studies have seen higher)
Looney et al, Arthritis Rheum. 50 2580
23
Improved Systemic Lupus Activity Measure (SLAM)
scores, but no reduction in titre of anti-dsDNA
-gt Clinical response was especially notable for
rashes, mucositis, alopecia, and arthritis -gt
The average daily dose of prednisone was 13 mg at
the start of the study and 10 mg at the
completion of the study -gt Overall, rituximab
was well tolerated. Only 1 mild infusion reaction
was noted (bronchospasm)
24
Development of human anti-chimeric antibody
(HACA) in some patients is associated with poor B
cell depletion
25
Summary of B cell depletion therapy for SLE
-gt Rituximab holds significant promise for
treatment of severe refractory SLE -gt Clinical
response is linked with B cell depletion
however, total Ig levels and anti-dsDNA levels
are not markedly affected (why?? Selective
targeting of sub-populations?, modulation Of
costimulatory molecule expression?) -gt therapy
seems safe and well-tolerated -gt more extensive
controlled trials are warranted -gt Despite lack
of marketing authorization, rituximab is already
being used to treat various refractory
autoimmune diseases in daily rheumatological
practice -gt as for all monoclonal Ab therapies,
efficacy might be improved with fully human Abs
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