deficiency

Report
Immunodeficiencies
Anna Šedivá
Institute of Immunology, University Hospital Motol
Evolution of immunity
Billions of years
4.5 3.5 procaryota, bacteria
1.5 eucaryota
0.5 organisms
Evolution of immunity
procaryota
invertebrates
vertebrates
lymphatic organs
HLA
Evolution of immunity
An ancient evolutionary origin of genes associated with human
genetic diseases
Tomislav Domazet-Lo and Diethard Tautz
Max-Planck Institut für Evolutionsbiologie
Accepted for publication September 19, 2008
Several thousand genes in the human genome have been linked to a
heritable genetic disease. The majority of these appear to be nonessential genes (i.e. are not embryonically lethal when inactivated) and
one could therefore speculate that they are late additions in the
evolutionary lineage towards humans. Contrary to this expectation, we
find that they are in fact significantly over-represented among the genes
that have emerged during the early evolution of the metazoa. Using a
phylostratigraphic approach, we have studied the evolutionary
emergence of such genes at 19 phylogenetic levels. The majority of
disease genes was already present in the eukaryotic ancestor and the
second largest number has arisen around the time of evolution of
multicellularity. Conversely, genes specific to the mammalian lineage are
highly underrepresented. Hence, genes involved in genetic diseases are
not simply a random subset of all genes in the genome, but are biased
towards ancient genes.
Immne system and its function
useful x damaging
defense of organisms
immune surveillance
tolerance
repeated infections
immunodeficiencies
pathological reaction to
environmental antigens
pathological reaction to internal
antigens
allergy
defects in immune surveillance
oncological diseases
autoimmunity
Common defense mechanisms
• skin and mucosa
• cilia, mucus
• hydrochloric acid
• urine
• tears
Innate and aquired immunity
•
•
•
•
•
•
innate immunity
humoral
complement
cellular
phagocytes, NK cells
aquired immunity
humoral
antibodies
cellular
T lymphocytes
defense against
bacteria, some viruses
bacteria, fungi
defense against
extracelul. bact.,
neutralization of viruses
intracel. bact., fungi, viruses
Immunodeficiencies
1. primary
innate diseases
genes coding for immune system components
2. secondary
secondary immune disorders based on primary
cause
Primary immunodeficiencies
humoral
( 70%)
cellular and combined
( 20%)
phagocytosis
( 10%)
complement
( 1%)
incidence
1:500-700 (IgAdef.)
1:100 000 (SCID)
Development of immune system
• development of cellular immunity - hematopoiesis
• antibodies
IgM
• FcRn
• cytokines
IgG
IgA
birth
6 months
Vaccination
1796
Edward Jenner (1749-1823) variolla
1885
Louis Pasteur (1822-1895) rabies
Vaccination calendar
DIFERENTIAL DIAGNOSIS OF PRIMARY IMMUNODEFICIENCIES
humoral
cellular and
phagocytosis
complement
combined
frequency
70%
clinical
after 6.months
problems - adulthood.
20%
10%
1%
birth
- 2 years
birth
- 2 years
individual
child, adult.
autoim.
SLE
pyogenic inf.
oedema
clinical
picture
respiratory inf.
pneumonias
otitides
arthritides
respir.inf.
pneumonias
diarhoea
dermatitides
omfalitis
adenitides
pyodermias
otitides
cause
extracel.
microorg.
echoviruses
viruses
fungi
mycobakteria
stafylococci
Neisseria
fungi
enterobacteria
DIFERENTIAL DIAGNOSIS OF PRIMARY IMMUNODEFICIENCIES
humoral
cellular and
combined
phagocytosis complement
vaccination enteroviral
vaccines
live
vaccines
BCG
vaccine
individual
survival
adulthood
early childhood
individual
individual
complications
cardiovascul.
problems
echoviral
infections
m.BrutonXLA
CVID
IgA def.
infection
tumors
autoimmunity
infections
various
SCID
chronic
hereditary
granulomatosis angioedema,
LAD syndrom deficiencies of
indiv.components
clinical
diseases
Humoral immunodeficiencies
diseases:
T lymphocyte
Bruton agammaglobulinemia
IgA deficiency
IgG subclass deficiency
CVID (common variable immunodeficiency)
hyper IgM syndrom
Wiskott Aldrich syndrom
CD40L
CD40
B lymphocyte
Humoral immunodeficiencies
Bruton agammaglobulinemia
X linked agammaglobulinemia
1952 Dr.Bruton
1993 gene, btk, Xq21.3-22
pre B lymphocyte
B lymphocyte
Humoral immunodeficiencies
Hyper IgM syndrom
X linked
gen, Xq26
CD40L
T lymphocytes
T lymphocyte
CD40L
CD40
autosomal recessive
susp. gen 12p13
AID (activation induced cytidinedeaminase)
somatic hypermutation deficiency
B lymphocyte
Humoral deficiencies
Lack of B lymfocytes, decrease of all Ig:
X-linked agammaglobulinemia, μ-Heavy chain deficiency, Igα deficiency, BLNK
deficiency, thymoma with immunodeficiency
Low B ly, low at least 2 Ig isotypes:
common variable immunodeficiency (CVID), ICOS deficiency, CD19
deficiency, TACI (TNFRSF13B) deficiency, BAFF receptor deficiency
Normal B, low IgG,IgA, normal or high IgM:
CD40L def.,AID deficiency, UNG deficiency, CD40 def.,NEMO
Normal B, low isotpyes or light chains:
heavy chain deletions, kappa chain deficiency, isolated IgG subclass
deficiency, IgA with IgG subsclass deficiency,
selective immunoglobulin A deficiency
Deficit of specific Ab:
transient hypogammaglobulinemia of infancy
ID, B lymphocytes
BCR
HLA I.
TAP1,2
BLNK
BTK
CIITA
HLA II.
SLAM
Cellular and combined immunodeficiencies
diseases:
SCID
di George syndrome
reticular dysgenesis
ADA deficiency
gamma chain of interleukin receptor deficiency
PNP deficiency
deficiency MHC II. třídy
deficiency ZAP-70
Omenn syndrome
Cellular defects
SCID
ID, T lymphocytes
TCR
e
CD3
CD4
g
z
cytokine receptor
ZAP-70
p56lck
CD154
CD40L
SLAM
g
JAK-3
WASP
NFAT
Screening - SCID
Možnost Tx kmenových hematopoetických buněk
Tx do 3,5 měsíce věku 94% úspěšnost, poté klesá na 70%
(R.Buckley)
Česká republika
1:100 000
1-2 případy ročně
Tx pro PID od 1994
SCID 13 dětí
mortalita 80%
Screening
Human B- andT-cell differentiation stages including
V(D)J recombination bars (Dik et al., 2005; van Zelm et
al., 2005) and genetic defects underlying PID that
result in impaired precursor differentiation.
Screening -TRECs
T cell Receptor Excision Circles (TRECs). TRECs are episomal DNA circles produced in thymocytes by excisional rearrangements of T cell receptor (TCR) genes; they
are stable, not duplicated during mitosis, diluted out with each cell division, and therefore higher in thymocytes, recent thymic emigrants (RTEs) and naïve T cells.
Quantitative polymerase chain reaction (PCR) of coding-joint (cj) δRec ψJα TREC, produced at TCRα/δ locus within chromosome 14 (14q11) by > 70% of developing
human α:β T cells, counts in the peripheral blood naïve α:β T lymphocytes recently dismetted by thymus: in newborn, values < 25 TRECs/μL indicate SCID.
Cossu Italian Journal of Pediatrics 2010 36:76 doi:10.1186/1824-7288-36-76
Screening - TRECs a KRECs
Newborn screening
CATCH 22
Several clinical conditions caused by the
mutations located in the same region form the
cluster of diseases called CATCH 22.
cardiac defects, abnormal facies, thymic
hypo/aplasia, cleft palate, hypocalcemia, deletion
22q11
Chromosome 22q11 deletion
syndrome is probably better
employed in the description of this
condition.
The poster for film remake of
famous novel of Joseph Heller
CATCH-22.
Well known symbolic name was
used as a sample for CATCH-22
syndrome.
Cellular and combined deficiencies
T-/B+ SCID
γc deficiency, JAK3 deficiency, interleukin 7 receptor chain α deficiency, CD45
deficiency, CD3δ/CD3ε deficiency.
T-/B- SCID
RAG 1/2 deficiency, Omenn syndrome
adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP)
deficiency
DNA ligase type IV deficiency, Artemis deficiency
CD40 ligand deficiency, CD40 deficiency
MHC class II deficiency
CD3γ deficiency, CD8 deficiency, ZAP-70 deficiency
TAP-1/2 deficiency
Reticular dysgenesis
Deficiency of phagocytosis
diseases:
chronic granulomatosis
LAD syndrom 1, 2
deficiency of myeloperoxidase
deficiency of G6PD
Chédiak-Higashi syndrome
neutropenia
LAD syndrom
adhesion molecules
LAD syndrome I.
CD 18
Phagocytic immunodeficiencies
Chronic granulomatosis
inability of phagocyts to generete reactive oxygen radicals
gene defect of one or more components of NADPH oxidase
X - linked
defect in genefor gp91-phox membrane bound part of the molecule of cytochrom b558
autosomal recesive
defect in genes of membrane or
cytoplasmatic subunits
p47-phox, p67-phox, p22-phox
NADPH oxidase
membrane and
cytoplasmatic
subunits
phagocyte
Phagocytic deficiencies
Neutropenias
Severe congenital neutropenia: ELA2 deficiency (with myelodysplasia), G-CSFR
deficiency Kostmann syndrome, Cyclic neutropenia, X-linked
neutropenia/myelodysplasia, Shwachman-Diamond syndrome
LAD
Leukocyte adhesion deficiency types 1, 2 and 3
Functional defects
Chronic granulomatous disease: X-linked, AR
Neutrophil glucose-6-phosphate dehydrogenase deficiency
Specific granule deficiency
Susceptibility to mycobacteria
IL-12 and IL-23 β1 chain deficiency,IL-12p40 deficiency
Interferon γ receptor deficiency, STAT1 deficiency
Complement deficiencies
diseases:
deficiencies of early components of complement cascade
deficiencies of late components of complement cascade
angioneurotic oedema
deficiencies in alternative complement pathway
Innate immune deficiencies
TLR membrane
TLR intracelular
Intracelular sensors
-NLRs, Nod1, Nod2, Ipaf and NALPs
-RIG-I a Mda-5
Innate immunity
herpetic encefalitis – TLR3, UNC-93B
pneumococcal infections – IRAK4
Anhydrotic epidermal dysplasia, viral infections - NEMO
interferon production defects
Mycobacterial susceptibility
IL 12 (IL 23) – IFN g
Susceptibility to Mycobacteria
Recessive, loss of function
Recessive, non functional molecule
Recessive, partial deficiency
Dominant, partial deficiency
Combined immunodeficiencies
Hyper IgE syndrom
Eczema, cold abscesses, Staf. Infections, skin and
lungs, candidiasis, face features, dental problems,
joints and skeletal problems
High IgE, eosinofilia
HIES scoring system (NIH) (1999)
19
(>40 suspected HIES, <20 unlikely dg)
HIES – scoring system, 2010
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•
•
•
•
recurrent pneumonia
eczema
recurrent skin abscesses
characteristic face
failure to shed deciduous
teeth
lung cyst formation
eosinophilia
newborn rash
other unusual infections
•
•
•
•
•
•
•
•
•
increased interalar distance
cathedral palate
hyperextensibility
pathologic bone fractures
recurrent upper respiratory
infections
candidiasis
scoliosis
midline anomaly
IgE, Th17
0-8
HIES >30 STAT3 mutace
5 typických znaků
Woellner et al: Mutations in STAT3 and diagnostic guidlines for HIES, J Allergy Clin Immunol, february 2010
HIES – AD
2007 – mutace v „signal transducer and activator of transcription 3 (STAT 3)
Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, Metin A, Karasuyama
Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature, Aug 2007
Holland SM, Deleo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML, Anderson VL, Darnell DN, Welch
PA, Kuhns DB, Frucht DM, Malech HL, Gallin JI, Kobayashi SD, Whitney AR, Voyich JM, Musser JM, Woellner C, Schäffer AA, Puck JM,
Grimbacher B. STAT3 Mutations in the Hyper-IgE Syndrome. NEJM Sep 2007
HIES
HIES
Prenatal diagnostics
history, affected sibling
ID with known gene, possible molecular diagnostics
XLA
some forms of SCID
WAS
AT
chronic granulomatosis
All known genes
Prenatal diagnostics
history, affected sibling
ID with known phenotype,
possible functional diagnosis from fetal blood
XLA
SCID
syndrome diGeorge
LAD
chronic granulomatosis
Investigation of primary immunodeficiencies
• history
• clinical examination
• laboratory investigation
–
–
–
–
–
–
–
–
blood count
immunoglobulins
specific antibodies
lymphocytes
complement
phagocytic cells
genetics
other
Therapy of primary immunodeficiencies
substitution with immunoglobulins
intravenous immunoglobulins
indication
Bruton agammaglobulinemia
CVID
hyperIgM syndrome
Wiskott-Aldrich syndrome
phagocytic deficiencies
others
subcutaneous immunoglobulins
Therapy of primary immunodeficiencies
antibiotic and antimycotic
therapy
chronic granulomatosis
LAD
bone marrow transplantation
SCID
LAD
Wiskott-Aldrich syndrome
Interferon g
chronic granulomatosis
G-CSF a GM-CSF
neutropenia
gene therapy
ADA deficiency
X -linked SCID
(LAD, chronic granulomatosis.)
other forms of therapy
Gene therapy
deficit ADA
X - SCID
(LAD, CGD..)
Gene therapy
a | In patients with severe combined immune deficiency (SCID),
blocked lymphocyte production leads to immune deficiency. Blood
cells are produced by the proliferation and differentiation of
pluripotent haematopoietic stem cells (HSCs) through stages of
lineage-restricted progenitors, the common lymphoid progenitor
(CLP) and the common myeloid progenitor (CMP).These yield
mature blood cells, including B cells (B), T cells (T), natural-killer
cells (NK), granulocytes (Gran), monocytes (Mono), platelets (Plat)
and erythrocytes (RBCs). Inherited mutations of genes that are
needed for the production, survival or function of lymphocytes can
cause severe combined immune deficiency (SCID), with absent or
non-functional B, T and NK cells. b | The block to immune-cell
production that occurs in patients with SCID leads to expansion of
the progenitor-cell pool (CLPs). The number of CD34+
haematopoietic stem and progenitor cells obtained from the bone
marrow of the youngest infant with X-linked SCID was relatively
high for their size. This finding indicates that the pool of progenitor
cells could be expanded in patients with X-linked SCID because of
the absence of the c-chain, which is required for cytokine
signalling and differentiation of CLP. c | Gene correction of
haematopoietic and progenitor cells leads to immune
reconstitution. In gene therapy for X-linked SCID, a retroviral
vector was used to transfer the normal human c cDNA into HSCs
that were isolated from the patient's bone marrow. Expression of c
restores the cytokine response and allows differentiation of CLP to
B, T and NK cells, yielding immune reconstitution. The success in
immune reconstitution in these patients might be due to the large
pool of progenitor cells that were available for transduction, and to
the high level of engraftment of the genetically altered cells, due to
the absence of endogenous mature lymphocytes.
Secondary imunodeficiencies
HIV
reverse transcription
HIV
RNA
transcription DNA
CD4
proteases
Secondary immunodeficiencies
central lymphatic organs
bone marrow, thymus, spleen
number and function of peripheral leucocytes
secondary antibody deficiencies
metabolic diseases, malnutrition,
hypovitaminosis
therapy, surgery, intensive care
infection
tumors
Primary immunodeficiencies
Oxford University Press 1999
90 diseases
2011 WHO/IUIS classification there are 181 PIDs
Oxford University Press 2006
140 diseases
Autoinflammatory disorders
imunotherapy
Research
T and B cells in diGeorge syndrom
Switched memory B cells
45
40
35
30
25
20
15
10
5
0
35
Samples
30
Controls
Sample
averages
Control 5./95.
percentile
% of CD19+ cells
% of CD19+ cells
Transitional B cells
20
Controls
15
10
Sample
averages
5
0
Age groups (3 months - 20 years)
Samples
25
Age groups (3 months - 20 years)
Control 5./95.
percentile

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