PRIMARYIMMUNODEFICIENCIES
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
• Recessive traits• Autosomal genes
• Disease in homozygous children • Heterozygous children are carriers
• X-linked genes• Single gene defect causes disease in males• Single gene defect in females renders the affected
woman carrier
PRIMARY IMMUNODEFICIENCIESMOST ARE RECESSIVE MUTATION OF SINGLE GENES
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
• Recessive traits• Autosomal genes
• Disease in homozygous children • Heterozygous children are carriers
• X-linked genes• Single gene defect causes disease in males• Single gene defect in females renders the affected
woman carrier
• Dominant traits have been eliminated from the population
Disseminated infection by the BCG strain of Mycobacterium used for vaccination
PRIMARY IMMUNODEFICIENCIESMOST ARE RECESSIVE MUTATION OF SINGLE GENES
Mutation in the IFNγ receptor results in binding without intracellular signaling -
dominant
THE IMPACT OF RECESSIVE AND DOMINANT
MUTATIONS IN THE IFN-γ RECEPTOR ONMONOCYTE ACTIVATION
• PHAGOCYTIC SYSTEM• Enhanced susceptibility
to bacterial infections
• LAD1: CD18 (CR3, CR4, LFA1)
• CGD• NADPH oxidase
• G6PD
• Myeloperoxidase
• Vesicular fusion
• 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
INNATE IMMUNITY
• ANTIBODY DEFICIENCY• Recurrent
sinopulmonary and GI infections beginning after 3-4 mo.• B cell development
• RAG-1, RAG-2
• Artemis
• DNA-PK
• ADA
• XLA
• IgA deficiency
• Hyper IgM
• B – T cell collaborations • CD40 ligand, XLHIM
• T CELL DEFICIENCY• SCID, opportunistic
infections manifest early in infancy • T cell development
• IL-7/Jak3
• RAG-1 RAG-2
• Artemis
• DNA-PK
• ADA
• BLS
ADAPTIVE IMMUNITY
TYPES OF INHERITED IMMUNODEFICIENCIES
IMMUNODEFICIENCIES
AFFECTING INNATE IMMUNITY
DEFECTS IN PHAGOCYTE FUNCTION
ENHANCED SUSCEPTIBILITY TOBACTERIAL INFECTIONS
LEUKOCYTE ADHESION DEFICIENCY (LAD1)CD18 DEFICIENCY (ITGB2;21q22.3)
Common β-subunit of CR3, CR4 and LFA-1.
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 infection site. 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.
DEFECTS IN PHAGOCYTE FUNCTION
Omphalitis in
LAD I patient
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).
DEFECTS IN PHAGOCYTE FUNCTION
CHRONIC GRANULOMATOUS DISEASE – CGD
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).
• IFN-gamma improves resistance. Mechanism??
• Diagnosis: NBT + PMA treatment of neutrophils. Lack of blue colour in CGD.
Healthy
CGD
Carrier
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).
• IFN-gamma improves resistance. Mechanism??
• Diagnosis: NBT + PMA treatment of neutrophils. Lack of blue colour in CGD.
Defect of glucose-6-phosphate dehydrogenase
• Less severe phenotype
• X-linked
• Reduced NADPH level
• Predisposes to hemolysis
• 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
• Affected gene: chs1 (1q42-43)
• Defect in vesicle fusion mechanism. Failure of phagolysosome formation, phagocytosed material is not
delivered to lysosomes. Persistent and recurrent bacterial infections. Infections most commonly involve the skin, the lungs, and the
respiratory tract and are usually due to Staphylococcus aureus, Streptococcus pyogenes, and Pneumococcus species.
Severe immunodeficiency, NK cell, CTL defect, neutropenia Oculocutaneous albinism: hypopigmentation: skin, hair, eyes,
photophobia. Accelerated phase: lymphoma-like syndrome, early childhood, life
threatening
DEFECTS IN PHAGOCYTE FUNCTION
COMPLEMENT DEFINIENCIES
IMPAIRED ANTIBODY EFFECTOR FUNCTIONSACCUMULATION OF IMMUNE COMPLEXES
C5C6C7C8C9
C3
C1C4C2
EARLY COMPONENTSAUTOIMMUNITY
Accumulation of immune complexes
Tissue demage
Inflammation
SLE, RA
INFECTIONS Inadequate humoral response
Decreased production of the opsonin C3b
Sinopulmonary infections
Streptococcus pneumoniae
Haemophilus influenzae
Neisseria meningitidis
C2 deficiency is the most common
(1 in 10,000)
COMPLEMENT DEFICIENCIESCLASSICAL PATHWAY ALTERNATIVE PATHWAY
C3b B
D P
EARLY COMPONENTSFactor B:
No case described
Factor D:
Rare, increased risk of infections
Properdin:
The only X-linked complement protein
Increased susceptibility to bacterial
infections of the Neisseria family
(fulminant meningococcal disease)
TERMINAL COMPONENTSInvasive meningococcal disease
Disseminated gonococcal infection
COMPLEMENT DEFICIENCIES
C5C6C7C8C9
C3
C1C4C2
C3b B
D P
C3: CENTRAL POSITIONDefective synthesis, expression or secretion of C3:
AUTOIMMUNE/INFECTIONS OR BOTHAutoimmune disorders: SLE-like, glomerulonephritis
Recurrent, severe, invasive infections
Gram+/Gram-
S. pneumoniae, S. pyogenes, S. aureus
N. meningitidis, H. influenzae
Impaired responses to immunization
Secondary C3 deficiency: Impairment in the regulatory proteins factor I or factor
H
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, stroke, heart attack, renal failure, and death.
Mutations in factor H and factor I are associated with HUS.
Mutation of membrane co-factor protein CD46 (MCP) is also associated with HUS.
Factor I:
Cleavage of C4b, C3b
Factor H:
C3bBb inhibitor
Co-factor of factor I
COMPLEMENT INHIBITOR DEFICIENCIESDEFICIENCIES OF C3 CONVERTASE INHIBITORS
Acquired clonal mutation of pig-a gene (X-chromosome) in myeloid progenitors
No GPI-enchored proteins in the cell membrane of affected cells (rbc, plt, wbc)
A CD55 (DAF) és CD59 (MIRL) complement regulatory proteins are GPI-enchored proteins
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
COMPLEMENT INHIBITOR DEFICIENCIES
Normal, CD55+CD59+ red blood cells can resist complement-mediated lysis
Doi:10.3324/haematol.2009.017848
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
COMPLEMENT INHIBITOR DEFICIENCIES
Doi:10.3324/haematol.2009.017848
Absence of CD55/CD59 leads to MAC-mediated intravascular hemolysis
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
COMPLEMENT INHIBITOR DEFICIENCIES
INTRAVASCULAR HEMOLYSIS
Release of hemoglobin
Large amounts of Hb deplete haptoglobin
Free Hb irreversibly binds to nitric oxide (NO)
Release of erythrocyte arginase
Conversion of L-arginine, the substrate for NO synthesis, to ornithine
NO SCAVENGING
THROMBOSIS
PLATELET AGGREGATION
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
COMPLEMENT INHIBITOR DEFICIENCIES
Anita Hill et al. Blood 2013;121:4985-4996
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.
COLOUR OF URINE SAMPLES TAKEN FROM PNH PATIENT AT DIFFERENT
TIMES
TREATMENTGeneral: Blood transfusion
Bone marrow transplantation
Pharmacological: Immunosuppression – Prednisolone Iron supplements Thromboprophylaxis: Anticoagulants (warfarin) Eculizumab
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)
COMPLEMENT INHIBITOR DEFICIENCIES
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)
Inhibition by C1INH in many steps
Uncontrolled production of vasoactive peptides
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
Child with symptoms of HANE
Treatment:
Anabolic steroid (Winstrol)
iv. C1INH, FFP (fresh frozen plasma)
Kallikrein inhibitor
Bradykinin receptor antagonists
C1inh deficiency predisposes to autoimmune diseases (SLE) due to its consumptive effect on complement factors 3, 4.
Enhanced permeability of postcapillar venules
IMMUNODEFICIENCIES
AFFECTINGADAPTIVE IMMUNITY
B-CELLIMMUNODEFICIENCIES
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
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
X-LINKED AGAMMAGLOBULINEMIA, XLA(Bruton’s agammablobulinemia), 1:200,000
DIAGNOSIS OF THE LACK OF B-CELLS BY FLOW CYTOMETRY
Normal XLA
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 disseminate and cause 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
Treatment:
• Monthly injections of Gamma globulin (IVIG OR SC).
ANTIBODY DEFICIENCY INABILITY TO CLEAR EXTRACELLULAR BACTERIA
X-LINKED AGAMMAGLOBULINEMIA, XLA(Bruton’s agammablobulinemia), 1:200,000
µ heavy chain (IGHM)
λ5 (IGLL1) lgα (CD79A) lgß (CD79B)
ANTIBODY DEFICIENCY INABILITY TO CLEAR EXTRACELLULAR BACTERIA
NON BRUTON’S AGAMMAGLOBULINEMIAAUTOSOMAL
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.
DIMINISHED ANTIBODY PRODUCTION AS A RESULT OF INHERITED DEFECT OF T-CELL HELP
LACK OF GERMINAL CENTERS IN LYMPH NODES OF X-LINKED
HYPER-IGM SYNDROME PATIENTS
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)
DIMINISHED ANTIBODY PRODUCTION AS A RESULT OF INHERITED DEFECT OF T-CELL HELP
AUTOSOMAL HYPER IgM SYNDROME• Intrinsic B-cell defect, activation induced deaiminase (AID) deficiency.
Cytidine uridine conversion.• The enyme is involved in affinity maturation and Ig. class switch.• Limphoid hyperplasia.• Lack of opportunistic infections.
doi:10.1038/nri1489
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 anti-IgA antibodies.
SELECTIVE IgA DEFICIENCYIgA: protection against infections of the mucous
membranes
Chest radiograph of a 50-year-old man with immunoglobulin A deficiency and
severe bilateral pneumonia
COMMON VARIABLE IMMUNODEFICIENCY,CVID
Symptoms:•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
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)
A GENETICALLY AND CLINICALLY HETEROGENEOUS GROUP OF DISEASES
CHARECTERIZED BY LOW ANTIBODY LEVELS AND RECURRENT INFECTIONS 1:25000
SIGNALING PATHWAYS EMANATING FROM TRANSMEMBRANE
ACTIVATOR AND CAML INTERACTOR (TACI)
DOI:10.1111/j.1749-6632.2011.06266.x
T-CELLIMMUNODEFICIENCIES
• 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.
DEFECT IN T-CELL FUNCTIONST-cells are involved in all aspects of adaptive
immunity
SEVERE COMBINED IMMUNODEFICIENCY,SCID
• 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).
X-LINKED SEVERE COMBINED IMMUNODEFICIENCY
SEVER COMBINED IMMUNODEFICIENCIES
The SCID phenotype can be caused by various gene defects
David Vetter, 12 years in a bubble
• 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
AUTOSOMAL SCID
• 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 !!!!
TREATMENT
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 Q-PCR.
Early diagnosis practically no false positives.
WISKOTT-ALDRICH SYNDROME (WAS)A disease of defective reorganization of the actin
cytoskeletonGenetic 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 marrow,
increased destruction in spleen).
WAS VERSUS NORMAL PLATELETS
WISKOTT-ALDRICH SYNDROME (WAS)A disease of defective reorganization of the actin
cytoskeletonGenetic 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 marrow,
increased destruction in spleen).– Rearrangement of cytoskeleton upon T-cell activation in the polarized contact with B-cells,
macrophages and target cells is defective.
WT,ctrl.
WASP-/-, α-CD3WASP-/-ctrl.
WT,α-CD3
CAPPING OF TCR IS DEFECTIVE IN WASP NEGATIVE T-CELLS
WISKOTT-ALDRICH SYNDROME (WAS)A disease of defective reorganization of the actin
cytoskeletonGenetic 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 marrow,
increased destruction in spleen).– 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 PATIENTSThe 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 marrow,
increased destruction in spleen).– 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.– No antibodies to carbohydrate antigens (role for T-cells?).– 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
Cγ-chain, IL-7Rα, Jak3 deficiencies, SCID
CLP
Non-Bruton’s/ Bruton’s agammaglobulinemia (µ, λ5, lgα, lgß, btk)
Autosomal hyper IgM syndrome (AID)Selective IgA deficiency
proB
preBI
preBII
Imm. B
TeffMat.T
SPImm
.TDP
preT
proT
Mat.B
Beff
XLHIMCD40L
ADA deficiency
SCID
RAG, DNA-PK, Artemis deficiencies, SCID
WASCVID?
BLS(TAP, RFX,CIITA)
THE END