Transcript Primary Immunodeficiencies

Primary Immunodeficiencies
• Heterogenous group of rare, single-gene diseases
leading to impairment of the immune responses
• Inherited as X-linked or autosomal disorders,
either dominant or recessive
• gene defects lead to missing enzymes,
developmental arrest in immune differentiation,
absent or non-functional proteins, abnormal DNA
repair, altered signal transduction, impairment of
cell-to-cell and intracellular communications
• Incidence, Prevalence
• ranges from 1:300 (sIgA deficiency) to 1:100 000
live births (SCID)
• 80% of affected persons < 20 years of age
• 70% males (5:1 males in children; 1:1 in adults)
• over 120 different entities described; of them,
about 20 account for > 90% of cases
• increasing due to better methodologies and
newborn screening programs (2000s: 1 / 10 000
European Society for Immunodeficiencies EDIS
Registry)
60
Humoral
50
Cellular
40
Combined
30
20
Phagocytic
10
Complement
0
%
others
Suspected when:
• - two or more episodes of consolidative pneumonia in one
year
• two or more serious sinus infections in one year
• recurrent deep skin or organ abscesses
• two or more deep-seated infections such as meningitis,
sepsis, osteomyelitis, cellulitis
• iv antibiotics required to clear up infections
• little effect of antibiotics
• persistent oral or skin thrush after age of 1
• Pneumocystis carinii, Aspergillus infections
• Positive family history
• Organ complications from infections (bronchiectasis,
chronic sinusitis, mastoiditis, CNS involvement)
• Chronic diarrhea, malabsorbtion due to recurrent
giardiasis, rotaviruses, cryptosopidiosis
• Chronic GI inflammatory diseases (IBD, gluten
enteropathy, atrophic gastritis with pernicious anemia,
nodular lymphoid hyperplasia)
• Autoimmune disorders (autoimmune hemolytic anemia,
thrombocytopenia, leukopenia, SLE)
• Other causes carefully evaluated and excluded:
• allergic rhinitis, nasal structural abnormalities
(polyps, deviated septum, chronic hyperplastic
rhinitis_
• adenoidal hypertrophy
• cystic fibrosis, ciliary diskinesia, COPD,
bronchiectasis
• immunosupresive therapy, malnutrition,
infiltrative diseases, malignancies, infectious
diseases, protein losing disorders
•
(Atkinson, 2007)
Human Primary Immunodeficiency Diseases
Alain Fischer, Immunity 27, December 2007
Cellular and Genetic Basis of Primary
Immune Deficiencies
James W. Verbsky, MD, PhDa,
William J. Grossman, MD, PhD
Pediatr Clin N Am 53 (2006) 649–684
General categories of PIDs (Saunders & Mak, 2006)
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SCID - low numbers/absence of T cells and sometimes of B cells; lack of B
cell functions due to T cell function impairment
T-PIDs - normal numbers of T, B, NK cells; T cells are non-functional; B cell
function may be affected
B-PIDs - B cells non-functional or absent; T and NK cells are normal
DNA repair defects - low lymphocyte numbers
Lymphoproliferative disorders - mutations in death receptors or ligands, or
in caspase cascade; uncontrolled proliferation of T and B cells
Phagocyte response deficiencies - defects in extravasation, activation,
function of phagocytes
IL-12 / IFN gamma axis - failure in macrophage (hyper-)activation
Autoinflammatory syndromes - severe local inflammation and prolonged
periodic fevers with no obvious cause; lymphocyte numbers are normal
Neutropenias - reduced level of neutrophils in circulation
Complement deficiencies - lack of complement activation; T and B cells are
normal
Laboratory Diagnosis
- flowcytometry for lymphocyte lineage
enumeration
- biochemical tests for soluble molecule
- cellular (functional) tests
- genetic tests
Treatment of PIDs (immunological)
- Intravenous immunoglobulin replacement therapy, established in the 1980s to threat
hypoglobulinemia. The IV-IG preparation most often used: 10% IgG in a form that resists
aggregation and has low risk of complement activation; 400-600mg/kg/month is usually
sufficient to prevent recurrent infections. Risk of IgE-anti-IgA anaphylaxy (in serum/secreted
IgA-deficient patients). Not indicated if hypogammaglobulinemia is secondary of protein-loss
conditions (congenital lymphangiectasia, enteropathies) or in transient hypoglobulinemia of
infancy / steroid induced hypogammaglobulinemia.
- Enzyme replacement: PEGADA (Polyethylene glycol-treated bovine adenosine deaminase) in
infants with ADA-deficient SCID if bone marrow transplantation has already failed.
- Bone Marrow (BMT) / Hematopoietic cell transplantation (HCT) from histocompatible (/half
compatible) donors; prenatal diagnosis allows for in utero transplantation; ~ 60% survival rate
(risk of the GvHD <= controlled by Cyclosporine, Methothrexate, steroids); some may require
long term IV-IG
-Thymus transplantation (DiGiorge), from related siblings (either fetal thymus transplantation,
bone marrow cells including residual adult T cells, or cultured HLA-DR-matched cultured
mature thymic epithelial explants)
- gene therapy - still a main topic in research (positive hints for SCID-X1 retroviral-mediated
gene transfer; ADA mutation; of the 20 patients in a French cohort: 3 developed leukemia
apparently associated with LMO2 - locus integration.)
Disorders of Immune regulation
Genetics of PIDs - X
chromosome
Selective IgA deficiency
- 1:333 blood donors
- reported in both apparently healthy and patients
- infections of the respiratory, gastrointestinal, urogenital tracts
- frequent occurrence of autoimmune diseases and increased incidence of
malignacy
- serum IgA < 10mg/dL (! Cross-reactivity of IgG against cow milk and
ruminant serum proteins => false detection of IgA when using goat, but not
rabbit, antisera)
~ 40% have anti-IgA antibodies (including IgE; risk of severe anaphylactic
reactions; only washed erythrocytes can be administered in case of blood
transfusions)
- cause unknown
- heterogeneic condition; some patients: genetic linkage to MHC III (HLA-DR3,
-B8, -A1 in Northern Europeans); in others, it develops secondary to dilantin,
sulfasalazine, d-penicillamine, gold therapy); in vitro: some patients may show B
lymphocytes able to switch to IgA under anti-CD40 and IL-10
Selective IgG deficiency
- recurrent upper and lower respiratory tract infections (autosomal
recessive; defect unknown but mutations were reported of the Igh
locus: gamma3, gamma2
-associate allergy, autoimmunity, malignancies
- IV-IG
Anti-polysaccharide deficiency (APAD)
- revealed often by vaccination (pneumococci and meningococci)
- IV-IG
Hyper IgE Syndrome
- extremely high levels of IgE; often also IgD
- characteristic facies in children; dermatitis and pyogenic infections (staphylococci
affecting lungs, joints, skin: Job’s syndrome, after the Biblical sufferer). Respiratory
allergies are rare, and the dermatitis is quite distinct from that of the atopic form. Associate
abnormalities in tooh root resorbtion (not loosing the primary teeth). Reduced bone density
(fractures). Very rare autoimmunity and malignancies.
- elevated numbers of eosinophils in blood and sputum; some impairments in secondary
humoral responses, chemotaxis of neutrophils.
- some forms are autosomal dominant
- some associate defects in IgE catabolism
- some have low propensity in IFN gamma production by Th, but not increased IL-4;
possible mutations in the IL-4Ralpha receptor chain (common for IL-4 and IL-13) resulting
in increased signaling
- Antibiotics; surgery; no effect for IFNgamma or BMT/HCT
Hyper-IgE syndrome. Also known as Job syndrome, this immunodeficiency has a distinct facial expression with mild asymmetry,
prominent jaw, and wide nasal ala. Eczematous skin lesions, recurrent staphylococcal skin infections, recurrent episodes of
pneumonias often due to Staphylococcus aureus, pneumatoceles, and mucocutaneous candidiasis are common. Delayed shedding of
primary teeth and skeletal abnormalities including severe scoliosis and recurrent pathologic fractures further characterize these
patients. The morbidity of this disease varies, and some patients survive into adulthood, as did the patient pictured here. Written
permission of the patient was obtained for use of this picture for medical publication through the courtesy of Dr Charlotte
Cunningham-Rundles, Mount Sinai Medical Center, New York, NY, and the Immune Deficiency Foundation, Towson, Md. JACI 120982, 2007
Hyper IgM Syndrome
-5 types; the most common is secondary to CD40L-deficiency affecting Th cells
-HIGM2: autosomally inherited mutations in AID: in contrast with HIGM1, no hypermutation detectable and
different opportunistic infections (as CD40L is normal); abnormal giant CGs with many IgD and IgM
harboring B lymphocytes, enlarged lymphoid organs.
-HIGM3: autosomal recessive mutations CD40; very similar to X-linked HIGM1, with deficits of cell
mediated immunity
-HIGM4 - similar to, and milder than HIGM2, but impaired humoral immune responses (opportunistic
bacterial and mycobacterial infections). Hypermutation is not affected. CD40, CD40L, AID, UNG, NEMO are
normal, but defects downstream of CD40 signaling and DNA-repair prevent class switch
- HIGM5 - very similar to HIGM2, with susceptibility to bacterial (not opportunistic) infections. The defect
lies in uracil DNA glycosilase UNG, that acts downstream of AID, removing the uracil residues deaminated
by AID, removal that initiate the double-stranded breaks required for class switch.
- HIGM-NEMO (HIGM associated with X-linked hypohydrotic ectodermal dysplasia) is a mild form of
HIGM; sparse hair and abnormal or missing teeth, lack swat glands. Impaired responses to polysaccharides,
but also of cell-mediated immunity. Frequent opportunistic bacterial and mycobacterial infections. NEMO =
NF-kappaB essential modulator, part of the IKK (IbB kinase) complex that phosphorylates IkB - the inhobitor
of the NF-kB. That stands that NF-kB is involved in the CD40-indiced class switch, but details are still
missing
CONGENITAL Agammaglobulinemia (Brunton XLA)
- rare (1:200 000); affects boys; lack of mature B cells and
all isotypes; unusually suceptible to pyogenic bacterial
infections. Over 300 distinct mutations invove the Btk,
those continous signaling is required for differentiation
from the preB stage. Myeloid cells appears normal, T cells
are not affected. Within families, there were described
different phenotypes. Mouse models reveals a less
devastating picture than in humans.
Non Brunton-Agammaglobulinemia (NBA)
- accounts for ~10% of the patients with XLA-phonotype
-mutations in the miu heavy chain gene, lambda5, Igalpha,
BLNK = > blocks in proB or preB cell transition (earlier
than in Btk mutations).
- involved genes are autosomal, so both boys and girls are
affected
CVID, Common Variable Immunodeficiencies / acquired
hypogammaglobulinemia (~1:30 000)
-heterogenous group of disease, general impairment in humoral immune responses
- profound decrease in IgG, IgA, and ~50% also lack IgM. There are circulating,
mature, B cells, but no memory B cells.
- recurrent bacterial infections starting in childhood similar with XLA, but
ENLARGED lymphoid tissues (particularly Peyer’s patches). 1/4 die of chronic
pulmonary disease or B cell lymphomas; amyloidosis, non-caseating granulomasta
of the lung, splle, skin, liver and autoimmunity are common.
- IV-IG improves the clinical conditions; in some of them also IL-2
-reported defects: PKC activation pathway, DNA repair, protein tyrosine
phosphorylation paths, upregulated Fas. Other appears to be seccondary to T cell
defects
- mutations in MHC III (linked to TNF and LT).
~30%: low counts for Th cells; ~40%: decreased CD40L expression on Th)
- defects of the ICOS gene (inducible costimulator that contributed to T activation,
GC formation, class switch): normal counts for T cells, but deficits of naïve and
memory B cells
Lymphoprolipherative syndromes
XLP (X-linked lymphoprolipherative disorder)
-young boys: inappropriate response to the common EBV infection (leading to fulminant
liver necrosis)
-uncontrolled proliferation of B cells, lymphadenopathy, hepatosplenomegaly, aplastic
anemia, fever, associated with high serum levels for IFN gamma (Th1). Survivors may
develop a selective Ig deficiency or Burkitt’s lymphoma; death occurs before age 50 years
due to hepatic necrosis or bone marrow failure).
- only EBV triggers the disease
- the defect is in the SAP gene (SLAM-associated protein= SH2D1A = DSHP). SAP
associated with SLAM (measles virus receptor) - molecule that is a minor costimulator for
B, T cells, and is also expressed on DCs. SAP appears to downmodulate the IFNgamma
production by T cells. If SAP is defective, Th are constimulated by a CD28-independent
way. NK cells also use SAP; they fail to lyse EBV-infected B lymphocytes.
Lymphoprolipherative syndromes
ALPS (Autoimmune lymphoprolipherative syndromes)
- hyperproliferation of B cells (CD5+), Tc, and DN thymocytes, but not other
subsets/types.
-enlargement of lymphoid organs (lymphadenopathy and hepatosplenomegaly)
diagnosed usualy until age of 5.
-increased levels of IgG, IgA
-autoimmunity: anemia, thrombocytopenia; breat, colon, lung cancers and lymphomas
-defects in the Fas-mediated pathway
-ALPS Ia: mutations in CD95; ALPS Ib: defects in CD95L; ALPS II: mutations in
caspase 10; unknown for ALPS III
-although the transmission is autosomal, the effect is genre-independent, as CD95
must function as a trimer (similar to the TRAPS)
DiGeorge syndrome
-complex disorder affecting thymus genesis (~1:4
000 live births)
-abnormal facies (long narrow face, small mouth,
prominent nose, hooded or full upper eyelids, low-set
cupped ears), small hands, abundant hair on the head,
cardiac and renal malformations, cleft palate, neural
tube defects, parahypothyroidism, recurrent
infections.
-translocations or large (2Mbp) deletions 22q1,
(sometimes associated with maternal alcoholism,
diabetes, chemicals), and possible TBX1 mutation, a
transcription factor involved also in aortal
development, GSCL (goosecoid-like) - involved in
neurogenesis, and HIRA, a corepressor involved in
embryonic histone transcription in heart, cranium,
pharyngeal arches.
-T cells, if present, display abnormal tendency to
spontaneous apoptosis. NK and B counts appear
normal
-murine equivalent: nude defect.
DiGeorge syndrome. The characteristic facies of infants
with DiGeorge syndrome include widened epicanthal folds,
flattened nasal bridge, short philtrum, recessed chin, rounded
small mouth, and low set, posteriorly rotated ears with simplified
helices.
WAS Wiscott-Aldrich Syndrome
-X-linked recessive heterogenous disorder, WAS protein gene.
WASP is expressed by all hematopoietic cells; is involved in
HSC survival.
~1/3 patients (classic WAS) CID, eczema, thrombocytopenia;
increased susceptibility to viral, pyogenic, opportunistic
infecitons, autoimmunity, allergy, lymphomas)
~1/5 patients: only some of the above (Thrombocytopenia,
XLT)
WASP is critical for both lymphocyte and platelet survival.
DTH responses are affected; normal IgG but reduced IgM and
elevated IgA and E levels.
- unclear mechanism; WASP binds to SH3-containing signaling
molecules, Src kinases, Grb2 adaptor protein, PLC gamma,
Btk, nut also with the cytoskeleton (acting as direct effector of
the GTPase Cdc42, a regulator of the cytoskeleton
organization). All these are important in T cell activation.
IV-IG, splenectomy, BMT/HCT
Wiskott-Aldrich syndrome (WAS). Recurrent
bacterial,
fungal, and, in this case, viral (Herpes
simplex) infections
plague patients with WAS. Equally a problem
is that of
bleeding into eczematous skin lesions,
mucosal surfaces,
and other tissues because of concomitant
thrombocytopenia
and small platelet size. The long-term
prognosis is complicated
by an increased risk of malignancies and
autoimmune
disorders. Patient died at age of 14.
Defects in DNA repair
-non-homologous end joining repair of DSB, homologous recombination repair, nucleotide excision
repair (NHEJ, NER, NER)
AT, Ataxia-Telangiectasia
-autosomal recessive, progressive cerebellar ataxia, oculocutaneous telangiectasia, variable CID
recurrent severe lung infections, sins infections, hypo IgA, IgE, IgG2, IgG4; hypersensitive to ionizing
radiation, increased risk of cancer (lymphomas, acute leukemias), autoimmunity.
Due to neurological defects, patients confined to weelchair before age 20, and die before 30. No
effective treatment.
Defects: in ATM gene (ataxia telangiectasia mutated), that encodes a PI3K family protein that
phosphorylated p53, thus preventing it’s interaction with Mdm2 and subsequent ubiquitin-directed
degradation.
Ataxia telangiectasia (AT). This patient demonstrates
facial cellulitis and periorbital telangiectasias. The AT mutated
gene produces pleiotropic changes in cellular response to
radiation, cell cycle control, and intracellular transport of
proteins that manifest themselves in choreoathetosis, cerebellar
ataxia, susceptibility to malignancies, and humoral and
cellular (T-cell) deficiency. Patients with AT frequently have
greatly elevated serum levels of a-fetoprotein due to defective
liver metabolism. Patient died at less than 10 years of age.
Nijmengen Breakage Syndrome (NHEJ
defects)
Bloom syndrome
Xeroderma pigmentosum
T cell defects
-CD8 lymphocytopenia, or Zap70 deficiency
-p56lck defects
-HLA I defects
-HLA II defects
SCID. This patient typifies the wasted infant with SCID
with failure to thrive and repeated infections. This patient has
no human leukocyte antigen/mixed leukocyte culture matched
siblings and at the time (circa 1970s) was not a candidate for a
mismatched bone marrow transplant. This child succumbed to
his infections.