Download 37-38_Primary Immunodeficiencies_LA

PRIMARY
IMMUNODEFICIENCIES
ARPAD LANYI PhD
IMMUNODEFICIENCIES
• INHERITED
(PRIMARY)
• Loss of function mutation
of genes of the immune
system
• Enhanced susceptibility
to infections
• Particular types of
pathogens depending on
the gene defect
• Did not show up until
1950 - antibiotics
• ACQUIRED
• Due to infectious
diseases
• AIDS
• Other virus infections
• Malnutrition
• Artificial
immunosuppression
• Drugs
• Radioactive irradiation
PRIMARY IMMUNODEFICIENCIES
MOST ARE RECESSIVE MUTATION OF SINGLE GENES
• Autosomal genes
• Recessive traits
• Disease in homozygous children
• Heterozygous children are carriers
• Dominant traits have been eliminated from the population
• IFNγ receptor – dominant/recessive
THE IMPACT OF RECESSIVE AND DOMINANT
MUTATIONS IN THE IFN-γ RECEPTOR ON
MONOCYTE ACTIVATION
Disseminated mycobacterial infection (BCG)
IL-12 RECEPTOR DEFICIENCY
PRODUCES A SIMILAR SUSCEPTIBILITY TO
INTRACELLULAR BACTERIAL INFECTIONS
PRIMARY IMMUNODEFICIENCIES
MOST ARE RECESSIVE MUTATION OF SINGLE GENES
• Autosomal genes
• Recessive traits
• Disease in homozygous children
• Heterozygous children are carriers
• Dominant traits have been eliminated from the population
• IFNγ receptor – dominant, recessive
• X-linked genes
• Single gene defect causes disease in males
• Single gene defect in females renders the affected woman
carrier
NUMEROUS IMMUNODEFICIENCY LOCI RESIDE ON THE X
CHROMOSOME
CGD: Chronic Granulomatous Disease
WAS: Wiscott-Aldrich Syndrome
SCID: Severe Combined Immunodeficiency
XLA: X-linked Agammaglobulinemia
XLP: X-linked Lymphoproliferative Disease
XLHM: X-linked Hyper-IgM Syndrome
TYPES OF INHERITED IMMUNODEFICIENCIES
INNATE IMMUNITY
• PHAGOCYTIC SYSTEM
• Enhanced susceptibility
to bacterial infections
• LAD1: CD18 (CR3, CR4,
LFA1)
• NADPH oxidase
• G6PD
• Myeloperoxidase
• CHS1/LYST
• COMPLEMENT SYSTEM
• Some infections, primarily
with encapsulated organisms
and Neisseriae
• Immunocomplex deposition
•
•
•
•
•
•
Soluble and membrane factors
C1 – C4
Alternative pathway
C3
Terminal components
Complement inhibitors
TYPES OF INHERITED IMMUNODEFICIENCIES
ADAPTIVE IMMUNITY
• ANTIBODY DEFICIENCY
• T-CELL DEFICIENCY
• Recurrent sinopulmonary and • SCID: opportunistic infections
GI infections beginning after manifest early in infancy
3-4 mo.
• B-cell development/activation
• T-cell development
• RAG-1, RAG-2
• IL-7/Jak3
• Artemis
• RAG-1 RAG-2
• DNA-PK
• Artemis
• ADA
• DNA-PK
• XLA
• ADA
• IgA deficiency
• BLS
• Hyper IgM syndrome
• B-/T-cell collaborations
• CD40 ligand, XLHIM
IMMUNODEFICIENCIES
AFFECTING
INNATE IMMUNITY
DEFECTS IN PHAGOCYTE
FUNCTION
ENHANCED SUSCEPTIBILITY TO
BACTERIAL INFECTIONS
DEFECTS IN PHAGOCYTE FUNCTION
LEUKOCYTE ADHESION DEFICIENCY (LAD1)
CD18 DEFICIENCY (ITGB2;21q22.3)
 Common β-subunit of CR3, CR4 and LFA-1
 Blocked phagocyte migration from blood to the site of
infection
 Inhibited uptake and degradation of opsonized bacteria
DEFECTS IN PHAGOCYTE FUNCTION
LEUKOCYTE ADHESION DEFICIENCY (LAD1)
CD18 DEFICIENCY (ITGB2;21q22.3)
 Common β-subunit of CR3, CR4 and LFA-1
 Blocked phagocyte migration from blood to the site of
infection
Omphalitis
 Inhibited uptake and degradation of opsonized bacteria
 Persistant infection with extracellular bacteria, pyogenic
infections (No opportunistic infections)
 Defect in wound healing, omphalitis, pneumonia, gingivitis,
peritonitis
 Lethal within the first decade of life without bone marrow
transplantation
Gingivitis
Non-healing wound
DEFECTS IN PHAGOCYTE FUNCTION
CHRONIC GRANULOMATOUS DISEASE – CGD
(1 million in the US)
Mutation of NADPH oxidase – any of the 4 subunits (most common: gp91 – X-linked)
• No superoxid O2- radical  antibacterial activity is compromised
• Chronic intracellular bacterial or fungal infections – granuloma formation
• Aspergillus pneumonia, suppurative arthritis, osteomyelitis, superficial skin
infections (cellulitis, impetigo)
CHRONIC GRANULOMATOUS DISEASE – CGD
DEFECTS IN PHAGOCYTE FUNCTION
CHRONIC GRANULOMATOUS DISEASE – CGD
(1 million in the US)
 Mutation of NADPH oxidase – any of the 4 subunits (most common: gp91 – X-linked)
• No superoxid O2- radical  antibacterial activity is compromised
• Chronic intracellular bacterial or fungal infections – granuloma formation
• Aspergillus pneumonia, suppurative arthritis, osteomyelitis, superficial skin
infections (cellulitis, impetigo)
Healthy
• IFN-gamma improves resistance. Mechanism??
• Diagnosis: NBT + PMA treatment of neutrophils
• Lack of blue colour in CGD
CGD
Carrier
DEFECTS IN PHAGOCYTE FUNCTION
 Glucose-6-phosphate dehydrogenase deficiency (X-linked)
• Less severe phenotype
• Reduced NADPH level
• Predisposes to hemolysis
• Selective advantage - malaria
 Myeloperoxidase deficiency (Chr 17)
• Less severe phenotype
• Myeloperoxidase produces cytotoxic hypochlorous
acid (HOCl) from hydrogen peroxide (H2O2) and
chloride anion (Cl−)
• Respiratory burst with a normal nitro blue
tetrazolium (NBT) test
• Disseminated candidiasis
DEFECTS IN PHAGOCYTE FUNCTION
CHÉDIAK-HIGASHI SYNDROME
Lysosomal trafficking regulator deficency CHS1/LYST (1q42)
Neutrophil
 Abnormal intracellular protein transport
 Failure of phagolysosome formation, phagocytosed
material is not delivered to lysosomes
 Abnormally giant granules in white blood cells
 Severe immunodeficiency, NK cell, CTL defect,
neutropenia
 Persistent and recurrent bacterial infections
Eosinophil
 Infections most commonly involve the skin, the
lungs, and the respiratory tract and are usually due
to Staphylococcus aureus, Streptococcus pyogenes,
and Pneumococcus species.
 Accelerated phase (85%): fatal in early childhood,
lymphoproliferation, hepatosplenomegaly
 Defective melanization - Oculocutaneous albinism:
hypopigmentation: skin, hair, eyes, photophobia
COMPLEMENT DEFINIENCIES
IMPAIRED ANTIBODY EFFECTOR FUNCTIONS
ACCUMULATION OF IMMUNE COMPLEXES
COMPLEMENT DEFICIENCIES
CLASSICAL PATHWAY
ALTERNATIVE PATHWAY
EARLY COMPONENTS
INFECTIONS
EARLY COMPONENTS
Factor B:
No case described
Inadequate humoral response
Factor D:
Decreased production of the opsonin C3b
Rare, increased risk of infections
Sinopulmonary infections
Properdin:
Streptococcus pneumoniae
Haemophilus influenzae
Neisseria meningitidis
AUTOIMMUNITY
Accumulation of immune complexes
Tissue demage
Inflammation
SLE, RA
C3
C5
C6
C7
C8
C9
The only X-linked complement protein
Increased susceptibility to bacterial
infections of the Neisseria family
(fulminant meningococcal disease)
TERMINAL COMPONENTS
Invasive meningococcal disease
Disseminated gonococcal infection
C3: CENTRAL POSITION
Defective synthesis, expression or secretion of C3:
AUTOIMMUNE/INFECTIONS OR
BOTH
Autoimmune disorders:
SLE-like, glomerulonephritis
Secondary C3 deficiency:
Impairment in the regulatory proteins
factor I or factor H
C3
C5
C6
C7
C8
C9
Recurrent, severe, invasive infections
Gram+/GramS. pneumoniae, S. pyogenes, S. aureus
N. meningitidis, H. influenzae
Impaired responses to immunization
COMPLEMENT INHIBITOR DEFICIENCIES
DEFICIENCIES OF C3 CONVERTASE INHIBITORS
Factor H:
Factor I:
C3bBb inhibitor
Cleavage of C4b, C3b
Co-factor of factor I
Uncontrolled amplification of C3 cleavage results in acquired C3-deficiency
Higher susceptibility to S. pneumoniae and N. meningitidis infections
Immune complex deposition-mediated diseases (SLE, glomerulonephritis)
aHUS: atypic hemolytic uremic syndrome: systemic thrombotic microangiopathy,
heart attack, renal failure, and death
Mutations in factor H and factor I are associated with aHUS
Mutation of membrane co-factor protein CD46 (MCP) is also associated with aHUS
stroke,
COMPLEMENT INHIBITOR DEFICIENCIES
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
Acquired clonal mutation of pig-a gene (X-chromosome) in myeloid progenitors
No GPI-anchored proteins in the cell membrane of affected cells (rbc, plt, wbc)
A CD55 (DAF) és CD59 (MIRL) complement regulatory proteins are
GPI-anchored proteins
COMPLEMENT INHIBITOR DEFICIENCIES
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
Normal, CD55+CD59+ red blood cells can resist complement-mediated lysis
Doi:10.3324/haematol.2009.017848
COMPLEMENT INHIBITOR DEFICIENCIES
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
Absence of CD55/CD59 leads to MAC-mediated intravascular hemolysis
Doi:10.3324/haematol.2009.017848
COMPLEMENT INHIBITOR DEFICIENCIES
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
INTRAVASCULAR HEMOLYSIS
Release of hemoglobin
Release of erythrocyte arginase
Large amounts of Hb deplete haptoglobin
Conversion of L-arginine, the substrate for NO
synthesis, to ornithine
Free Hb irreversibly binds to nitric oxide (NO)
NO SCAVENGING
PLATELET AGGREGATION
THROMBOSIS
Magnetic resonance angiography in a patient
with PNH and superior sagittal sinus
thrombosis with collateral vessel formation
Case of dermal vein thromboses in a
patient known to have PNH
Anita Hill et al. Blood 2013;121:4985-4996
COLOUR OF URINE SAMPLES TAKEN FROM
PNH PATIENT AT DIFFERENT TIMES
COMPLEMENT INHIBITOR DEFICIENCIES
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
TREATMENT
General:
 Blood transfusion
Bone marrow transplantation
Pharmacological:




Immunosuppression – Prednisolone
Iron supplements
Thromboprophylaxis: Anticoagulants (warfarin)
Eculizumab
ECULIZUMAB:
ANTI-C5 HUMANISED MONOCLONAL ANTIBODY
With C5 blocked, PNH red blood cells are protected from hemolysis, but once opsonized by C3 RBCs become
prey to macrophages.
Chronic treatment increases the risk of infections with Neisseria meningitidis.
It does not appear to change the risk of myelodysplastic syndrome, acute myelogenous leukemia, or aplastic
anemia.
Doi:10.3324/haematol.2009.017848
HEREDITARY ANGIONEUROTIC EDEMA (HANE)
C1 inhibitor deficiency; Autosomal dominant (1 in 30000)
Uncontrolled production of vasoactive peptides
Enhanced permeability of postcapillar venules
Non-inflammatory swellings of skin and mucosal membranes due
to leakage of fluid from blood vessels into connective tissue
Subcutaneous tissues: face, hands, arms, legs, genitals
Abdominal organs: stomach, intestines, bladder, and urethra;
vomiting, diarrhea, serious abdominal spasms
Larynx swelling – suffocation, may cause death
C1inh deficiency predisposes to autoimmune
diseases (SLE) due to its consumptive effect
on complement factors 3, 4.
Treatment:
Anabolic steroid (Winstrol)
iv. C1INH, FFP (fresh frozen plasma)
Kallikrein inhibitor
Bradykinin receptor antagonists
Inhibition by C1INH in many steps
Child with symptoms
of HANE
IMMUNODEFICIENCIES
AFFECTING
ADAPTIVE IMMUNITY
B-CELL
IMMUNODEFICIENCIES
SYMPTOMS OF B-CELL DEFICIENCIES MANIFEST REALTIVELY
LATE DUE TO THE PRESENCE OF MATERNAL ANTIBODIES
Approx. 70% of all IDs.
Increased sensitivity to: Encapsulated bacteria, Streptococcus pneumoniae, Haemophylus influenzae,
Enteroviruses, parasites
ANTIBODY DEFICIENCY
INABILITY TO CLEAR EXTRACELLULAR BACTERIA
X-LINKED AGAMMAGLOBULINEMIA, XLA
(Bruton’s agammablobulinemia), 1:200,000
Genetic defect:
• Mutation in the Bruton’s tyrosine kinase,
essential for B-cell activation and development
• NO B-CELLS IN THE PERIPHERY – block at
pre B-cell stage
• Male XY HEALTHY – XY DISEASE
• Carrier female XX HEALTHY – non-random
inactivation of X in B-cells
DIAGNOSIS OF THE LACK OF B-CELLS
BY FLOW CYTOMETRY
Normal
XLA
ANTIBODY DEFICIENCY
INABILITY TO CLEAR EXTRACELLULAR BACTERIA
X-LINKED AGAMMAGLOBULINEMIA, XLA
(Bruton’s agammablobulinemia), 1:200,000
Symptoms:
• First few months of life is relatively normal (maternal Ig)
• Tonsils are small, lymph nodes are barely palpable
• Increased susceptibility to bacteria and enteroviruses (likely due to IgA
defficiency)
• Encapsulated bacteria resisting ingestion by phagocytes unless they are
coated with antibody and complement
• Recurrent infection of sinuses and of the middle ear, pneumonia
• Pyogenic bacteria – permanent tissue demage caused by enzyme release
from bacteria and phagocytes – bronchiectasis, chronic lung disease
• Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus
aureus
• Oral polio vaccine disseminates and causes poliomyelitis
• T-cell responses to intracellular bacteria is normal (mycobacteria)
ANTIBODY DEFICIENCY
INABILITY TO CLEAR EXTRACELLULAR BACTERIA
X-LINKED AGAMMAGLOBULINEMIA, XLA
(Bruton’s agammablobulinemia), 1:200,000
Source: wiki
Treatment:
• Monthly injections of Gamma globulin (IVIG or SC)
ANTIBODY DEFICIENCY
INABILITY TO CLEAR EXTRACELLULAR BACTERIA
NON BRUTON’S AGAMMAGLOBULINEMIA
AUTOSOMAL




µ heavy chain (IGHM)
λ5 (IGLL1)
lgα (CD79A)
lgß (CD79B)
DIMINISHED ANTIBODY PRODUCTION AS A
RESULT OF INHERITED DEFECT OF T-CELL HELP
X-LINKED HYPER IgM SYNDROME (XLHIM)
Genetic defect:
• Defect of the CD40L gene (Xq26)
Symptoms:
• No specific antibody response to T-dependent antigens
• low IgG, IgA, IgE
• No macrophage/B-cell/DC activation by T-cells – CD40 – CD40L
DIMINISHED ANTIBODY PRODUCTION AS A
RESULT OF INHERITED DEFECT OF T-CELL HELP
X-LINKED HYPER IgM SYNDROME (XLHIM)
Genetic defect:
• Defect of the CD40L gene (Xq26)
Symptoms:
• No specific antibody response to T-dependent antigens
• low IgG, IgA, IgE
• No macrophage/B-cell/DC activation by T-cells – CD40 – CD40L
• No germinal center formation
LACK OF GERMINAL CENTERS
IN LYMPH NODES OF X-LINKED
HYPER-IGM SYNDROME PATIENTS
DIMINISHED ANTIBODY PRODUCTION AS A
RESULT OF INHERITED DEFECT OF T-CELL HELP
X-LINKED HYPER IgM SYNDROME (XLHIM)
Genetic defect:
• Defect of the CD40L gene (Xq26)
Symptoms:
• No specific antibody response to T-dependent antigens
• low IgG, IgA, IgE
• No macrophage/B-cell/DC activation by T-cells – CD40 – CD40L
• No germinal center formation
• No leukocytosis but neutropenia
• Susceptibility to pyogenic bacteria/opportunistic infection
• Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus
• Pneumocystis carnii infection, not seen in XLA
Treatment:
• Antibiotics
• IVIG
• Injection of GM-CSF (neutropenia)
AUTOSOMAL HYPER IgM SYNDROME
•
Intrinsic B-cell defect, activation induced deaminase (AID) deficiency
AID: Cytidine uridine conversion
•
Three major abnormalities:
•
absence of immunoglobulin class switch recombination
•
lack of immunoglobulin somatic hypermutations
•
lymphoid hyperplasia caused by the presence of giant germinal centers
•
Recurrent bacterial sino-respiratory and gastro-intestinal tract infections
•
Lack of opportunistic infections (in contrast to XLHIM)
doi:10.1038/nri1489
SELECTIVE IgA DEFICIENCY
IgA: protection against infections of the mucous membranes
 Occurance: 1:160-1:800 (Europe, less in Asia)
 May be asymptomatic, but often associated with
chronic or recurrent disease of the respiratory system
 Giardia infection with chronic diarrhea is frequent
 Higher frequency of allergies
 Tenfold risk of coeliac disease
 Autoimmune disease, autoimmune cytopenia
 40% of patients develop
(transfusion, anaphylaxis)
Chest radiograph of a 50-year-old man with
immunoglobulin A deficiency and severe
bilateral pneumonia
anti-IgA
antibodies
COMMON VARIABLE IMMUNODEFICIENCY,CVID
A GENETICALLY AND CLINICALLY HETEROGENEOUS GROUP OF DISEASES
CHARECTERIZED BY LOW ANTIBODY LEVELS AND RECURRENT INFECTIONS
Symptoms:
1:25000
•Low IgG and IgA/IgM levels
•Frequent respiratory infections
•Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus
•Pure response to vaccination
•Autoimmune manifestations: cytopenia, RA, psoriasis
•Lymphocytic infiltration: lymphadenopathy, splenomegaly, hepatomegaly
•Granulomas in lung and in the GI system
•GI problems: lactose intolerance, lymphoid hyperplasia/diffuse lymphoid
infiltration, loss of villi and infection, especially with Giardia lamblia, diarrhea
•Hematological malignancies, Non-Hodgkin's lymphoma
COMMON VARIABLE IMMUNODEFICIENCY,CVID
Therapy: IVIG
Only 10 % has a family history
Only 10% with a known genetic defect
Transmembrane activator and CAML (calcium
modulator and cyclophilin ligand) interactor
(TACI)
SIGNALING PATHWAYS
EMANATING FROM
TRANSMEMBRANE ACTIVATOR
AND CAML INTERACTOR (TACI)
X
transmembrane activator and calcium modulator
and cyclophylin ligand interactor (TACI).
DOI:10.1111/j.1749-6632.2011.06266.x
T-CELL
IMMUNODEFICIENCIES
SEVERE COMBINED IMMUNODEFICIENCY,SCID
DEFECT IN T-CELL FUNCTIONS
T-cells are involved in all aspects of adaptive immunity
• Neither T-cell-dependent antibody response nor cellular immunity
are functional
• Persistent and recurrent infections with a broader range of
pathogens than patients with B-cell deficiences
SEVERE COMBINED IMMUNODEFICIENCIES
The SCID phenotype can be caused by various gene defects
X-LINKED SEVERE COMBINED
IMMUNODEFICIENCY
• The common γ-chain of interleukin receptors is mutated, IL-7 receptor
• Part of IL-2, 4 ,7, 9, 15, 21 receptor
• T-, B+, NK- (non functional B-cells)
• Over 50% of SCID cases
• Small body weight, failure to thrive, diarrhea, sepsis, otitis media
• Opportunistic infections (Candidiasis, Pneumocystis carnii pneumonia)
David Vetter, 12 years in a bubble
AUTOSOMAL SCID
•
Mutation of Jak3 kinase – IL-7 receptor-mediated signaling – T-B+NK- (IL-15-NK, non-functional B-cells)
(less than 10%)
•
IL-7Rα deficiency – T-B+NK+ 11% of SCID cases.
•
Defect in the catabolism of purin bases
– Adenosine deaminase (ADA) mutation – T- B- NK dATP accumulation - inhibition of ribonucleotide reductase
 15% of SCID cases
 Underdeveloped thymus
 Neurological problems: hearing and visual impairment,
mental retardation, low muscle tone and movement disorders
AUTOSOMAL SCID
• Mutation of RAG enzymes – T-B-NK+
• Mutation of DNA-PK/Artemis – T- B-NK+
• Omenn syndrome – T+B-/low, hypomorphic mutation of RAG1/2 (or Artemis)
– T-cell counts are normal to elevated
– Restricted TCR repertoire
– Activated Th2 phenotype
– Eosinophilia, elevated IgE level
– Recurrent infections,
mainly opportunistic
– Autoimmunity: T-cell infiltration:
GI tract, skin, hepatosplenomegaly,
lymphadenopathy
– Exfoliative dermatitis (erythroderma)
– Failure to thrive, RAPIDLY FATAL
AUTOSOMAL SCID
• Bare lymphocyte syndrome
– BLS I
 TAP1/2 deficiency – low abundance of MHC I
 Selective loss of CD8+ T-cells
– BLS II
 Lack of MHC II – CD4+ T-cells fail to develop
 Compromises all aspects of adaptive immunity
DOI: 10.1152/nips.01462.2003
TREATMENT
• Gene therapy
• Bone marrow transplantation (BMT), preferably from a histocompatible
sibling
• Often SCID babies need to be stabilized first before BM-transplant as
they have severe infections when brought to the clinic
• Survival of HEALTHY SCID babies after BMT is over 95%!
• Testing before diseases develops??? EARLY DIAGNOSIS CAN SAVE
MANY LIVES !!!!
EARLY DIAGNOSIS OF SCID PATIENTS
TREC-ASSAY
At TCR recombination T-cell
receptor excision circle (TREC)
is produced as a result of
excision of the δ segments
from the TCRA locus.
TRECs can be detected with QPCR.
Early diagnosis practically no
false positives.
WISKOTT-ALDRICH SYNDROME (WAS)
A disease of defective re-organization of the actin cytoskeleton
Genetic defect:
– Mutation in the WAS protein (WASP) expressed in white blood cells and megakaryocytes, X-linked
Symtomps:
– Thrombocytopenia, small platelet size (decreased production of platelets in bone
increased destruction in spleen)
marrow,
WAS VERSUS NORMAL PLATELETS
WISKOTT-ALDRICH SYNDROME (WAS)
A disease of defective reorganization of the actin cytoskeleton
Genetic defect:
– Mutation in the WAS protein (WASP) expressed in white blood cells and megakaryocytes, X-linked
Symtomps:
– Thrombocytopenia, small platelet size (decreased production of platelets in bone
increased destruction in spleen)
marrow,
– Rearrangement of cytoskeleton upon T-cell activation in the polarized contact with B-cells,
macrophages and target cells is defective.
CAPPING OF TCR IS DEFECTIVE IN WASP NEGATIVE T-CELLS
WT,ctrl.
WT,α-CD3
WASP-/ctrl.
WASP-/-, α-CD3
WISKOTT-ALDRICH SYNDROME (WAS)
A disease of defective reorganization of the actin cytoskeleton
Genetic defect:
– Mutation in the WAS protein (WASP) expressed in white blood cells and megakaryocytes, X-linked
Symtomps:
– Thrombocytopenia, small platelet size (decreased production of platelets in bone
increased destruction in spleen)
marrow,
– Rearrangement of cytoskeleton upon T-cell activation in the polarized contact with B-cells,
macrophages and target cells is defective.
– Normal lymphocyte surface is covered with abundant microvilli, which are sparse or absent from
the patient's lymphocytes.
– The marginal zone which contains B lymphocytes and specialized macrophages is severely
reduced in size.
SEVERE REDUCTION OF THE MARGINAL ZONE IN
THE SPLEEN FROM WISKOTT–ALDRICH SYNDROME
PATIENTS
The
germinal
centers
(GC)
are
surrounded by the mantle (M) and by the
marginal zone (MZ), which contains B
lymphocytes
and
specialized
macrophages.
In patients with WAS, the MZ is
severely reduced in size.
WISKOTT-ALDRICH SYNDROME (WAS)
A disease of defective reorganization of the actin cytoskeleton
Genetic defect:
– Mutation in the WAS protein (WASP) expressed in white blood cells and megakaryocytes, X-linked
Symtomps:
– Thrombocytopenia, small platelet size (decreased production of platelets in bone
increased destruction in spleen)
marrow,
– Rearrangement of cytoskeleton upon T-cell activation in the polarized contact with B-cells,
macrophages and target cells is defective.
– Normal lymphocyte surface is covered with abundant microvilli, which are sparse or absent from
the patient's lymphocytes.
– The marginal zone which contains B lymphocytes and specialized macrophages is severely
reduced in size.
– Low IgM high IgA, IgE serum levels
– Eczema.
– B-cell lymphomas
– Pyogenic and opportunistic bacterial infections
– Severe infection with varichella (chicken pox) and herpes simplex (impaired CD8+ T-cell response)
Treatment:
Bone marrow transplantation
CONGENITAL GENE DEFECTS DISRUPT LYMPHOCYTE
DEVELOPMENT AT VARIOUS STAGES
Non-Bruton’s/ Bruton’s
agammaglobulinemia (µ, λ5, lgα, lgß, btk)
proB
CLP
preB
I
preB
II
Autosomal hyper IgM syndrome (AID)
Selective IgA deficiency
Imm.
B
ADA
RAG, DNA-PK, Artemis
deficiency deficiencies, SCID
SCID
proT
preT
Cγ-chain, IL-7Rα, Jak3
deficiencies, SCID
DP
Mat.
B
CVID?
SP
Imm.
T
BLS
(TAP, RFX,CIITA)
Mat.
T
Beff
XLHIM
CD40L
Teff
WAS
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