Transcript 17_18 pathology-deficiency_short

The immune system is still the big black box
Environment
Immune system
Tolerance
self
Non-self
Dangerous
Pathogenic
Immune
response
PATHOGENS HAVE SHORT GENERATION TIME
PATOGENS
Virus
Bacteria
3 hrs
Viruses
3 hrs
Diversity
Fast development
parasites
Humans have longer generation time,
Need a sophysticated protection system
Birth
Development,
education
Reproducrion
at 35
IMMUNODEFICIENCIES
AGE AND HEALTH DEPENDENT
IMMUNOSUPPRESSIVE DRUGS
• INHERITED (PRIMARY) • ACQUIRED
– 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
– Due to infectious
diseases
– AIDS
– Other virus infections
– Malnutrition
– Artificial
immunosuppression
• Drugs
• Radioactive irradiation
PRIMARY IMMUNODEFICIENCIES
• MOST ARE RECESSIVE MUTATION OF SINGLE GENES
– Dominant traits have been eliminated from the population
– 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
– Mutation in the IFNγ receptor results in binding without
intracellular signaling - dominant
DISSEMINATED INFECTION BY THE BCG STRAIN OF
Mycobacterium USED FOR VACCINATION
The impact of recessive and dominant
mutations in the IFN-γ receptor on monocyte
activation.
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 IMMUNE DEFICIENCIES
• ANTIBODY DEFICIENCY
• T CELL DEFICIENCY
• - recurrent
sinopulmonary and GI
infections beginning after
3-4 mo.
• - SCID, opportunistic
infections beginning
early in infancy
– T cell development
– B cell development
• (XLA, IgA deficiency)
– B – T cell collaborations
• CD40 ligand, hyper IgM
• IL-7/Jak3
• RAG-1 RAG-2
• Artemis
– Thymus epithelial cells
• DiGeorge syndrome
– Purin catabolism
– DNS repair enzyme
defect
– MHC class II synthesis
blockade
TYPES OF INHERITED IMMUNE DEFICIENCIES 2.
• PHAGOCYTIC SYSTEM
– CD18 (CR3, CR4, LFA1)
– NADPH oxidase (CGD)
– Vesicular fusion
• COMPLEMENT SYSTEM
• some infections,
primarily with
encapsulated organisms
and Neisseriae
– Soluble and membrane
factors
– C3
– C1 – C4
– Complement inhibitors
Immunodeficiencies caused by B-cell defects
Approx. 70% of all IDs
Late Manifestation (7-9 month)
Increased sensitivity to:
Encapsulated bacteria
Streptococcus pneumoniae
Haemophylus influenzae
Infection by Enterovirus, parasites
Encapsulated bacteria resist ingestion by
phagocytes unless they are recognized by
antibodies that fix complement.
SERUM IG LEVELS AS THE DEVELOPMENT OF THE IMMUNE
SYSTEM PROGRESSES
ANTIBODY DEFICIENCY
INABILITY TO CLEAR EXTRACELLULAR BACTERIA
• X-LINKED AGAMMAGLOBULINEMIA XLA
(Bruton’s agammaglobulinemia) 1:200,000
Symptoms
– First few months of life is relatively normal (maternal Ig)
– Tonsils are small, lymph nodes are barely palpable
– 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
• Haemophilusinfluenzae, Streptococcus pneumoniae,
Staphylococcus aureus,
– Oral polio vaccine disseminate and cause poliomyelitis
– T-cell responses to intracellular bacteria is normal
(mycobacteria)
– Lack of mature B cells plasma cells in the periphery
„Who are missing?”
ANTIBODY DEFICIENCY
INABILITY TO CLEAR EXTRACELLULAR BACTERIA
• X-LINKED AGAMMAGLOBULINEMIA XLA
(Bruton’s agammaglobulinemia)
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
– Carrier mother XX HEALTHY non-random inactivation of X in B
cells
– Son XY DISEASE
Son XY HEALTHY
– Increased susceptibility to bacteria and enteroviruses
Treatment
– monthly injections of Gamma glob. (IVIG)
In patients with X-linked agammaglobulinemia (XLA), B
cells do not develop beyond the pre-B cell stage.
When a T-cell defect results in antibody
deficiency
X-LINKED HYPER IgM SYNDROME
DIMINISHED ANTIBODY PRODUCTION AS A RESULT
OF INHERITED DEFECT OF T CELL HELP
• HYPER IgM SYNDROME (XLHIM)
Symptoms
– Susceptibility to pyogenic bacteria/opportunistic infection
• Sensitivity to pyogenic bacteria Haemophilusinfluenzae,
Streptococcus pneumoniae, Staphylococcus aureus
• opportunistic infections
– No specific antibody response to T-dependent antigens
• low IgG, IgA, IgE
– No germinal center formation
– No leukocytosis but neutropenia
– No macrophage activation by T cells CD40 – CD40L
• opportunistic infections
• sores and blisters in the mouth and throat
• injection of GM-CSF (GMCSF is produced by macrophages)
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
• HYPER IgM SYNDROME XLHIM
Genetic defect
Defect of the DC40L membrane receptor gene
– X-linked, disease in males
Treatment
– antibiotics,
– monthly injections of Gamma glob. (IVIG)
– injection of GM-CSF (neutropenia)
•HYPER IgM SYNDROME (Autosomal)
-Intrinsic B cell defect, activation induced deaiminase
(AID) deficiency. Cytidine uridine conversion.
-The enyme is involved in affinity maturation and
Ig. class switch
- Lack of opportunistic infections
SELECTIVE IgA DEFICIENCY
1/800
- Chronic lung disease,
- Tendency to develop respiratory
and gastrointestinal allergies and
autoimmunity
- Over 40% of patients have anti-IgA
antibodies – blood products
containing IgA can cause severe
allergic response. -Some are related
to MHC class III region
T CELL IMMUNODEFICIENCIES
SEVERE COMBINED IMMUNODEFICIENCY
SCID
DEFECT IN T CELL FUNCTIONS
T cells are involved in all aspects of adaptive immunity
• Persistent and recurrent infections with a
broader range of pathogens than patients with B
cell deficiences
• Neither T cell-dependent antibody response nor
cellular immunity are functional
• T-, B+ NK- SCID
• T- B- NK+
X-LINKED SEVERE COMBINED IMMUNODEFICIENCY
SCID (Over 50% of cases)
Symptoms
• Small body weight, failure to thrive
• Persistent and recurrent infections with a broader range
of pathogens than patients with B cell deficiences
• Opportunistic infections (Candida albicans,
Pneumocystis carnii pneumonia)
Candida albicans infection
in children with SCID
Normal
SCID
The Hart shadow is clearly visible
In the absence of the thymus
SEVER COMBINED IMMUNODEFICIENCIES
The SCID phenotype can be caused by various gene defects
•
X-SCID – The common γ-chain of interleukin receptors is mutated IL-7 receptor
– Part of IL2,4,7,9, 15, 21 Receptor
•
•
Autosomal SCID – mutation of Jak3 kinase IL-7 receptor-mediated signaling
Defect in the catabolism of purin bases – autosomal (T- B- NK+)
– Adenosine deaminase (ADA) mutation – mental retardation
– Purin nucleotide phosphorilase (PNP)
• Accumulation of purin metabolites
• Highly toxiC for developing lymphocytes,
•
Mutation of RAG enzymes – autosomal (Omen syndrome T- B- SCID)
– No or little somatic gene rearrangement (RAPIDLY FATAL)
– No circulating peripheral lymphocytes or very narrow repertoire
•
Mutation of a DNA repair enzyme – autosomal
– DNA-dependent protein kinase (DNA-PK) involved in the cleavage of hairpins in
somatic gene rearrangement
•
Bare lymphocyte syndrome – inhibited MHC synthesis
– No CD4+ T cell response
– CIITA co-activátor, RFX promoter binding protein or other transcription factor
mutation
•
DiGeorge szyndrome
– Development of thymic epithelial cells is inhibited – T cell development is inhibited
SÚLYOS KOMBINÁLT IMMUNODEFICIENCIÁK
A SCID fenotípust eltérő gén hibák okozhatják
•
X-SCID – Az interleukin receptorok közös γ-láncának
•
hibája közös gamma lánc
55% totál, része az IL2,4,7,9, 15, 21 receptoroknak
T- B+, NK-, a periférián a limfociták gykorlatilag csak B
sejtek
Jak3 kináz mutációja IL-7 receptor jelátvitel
SEVER COMBINED IMMUNODEFICIENCIES
The SCID phenotype can be caused by various gene defects
• Defect in the catabolism
of purin bases –
autosomal (T- B- NK+)
– Adenosine deaminase
(ADA) mutation – mental
retardation
– Purin nucleotide
phosphorilase (PNP)
• Accumulation of purin
metabolites
• Highly toxic for
developing T
lymphocytes, less toxic
for developing B
lymphocytes
ADA conc. A tímuszban kb 10-szeres
Treatment:
Bone marrow transplantation, preferably from a
histocompatible sibling
Gene therapy
Diagnosis?
• Most often SCID patients are in critical condition when they come to the clinic.
•Their life can not always be saved. Need to be „healed” before bone marrow
Transplantation.
Is it possible to identify SCIDs before they get sick?
21, 2010, the Advisory Committee on Heritable Disorders in Newborns and Children voted
unanimously to add screening for Severe Combined Immune Deficiency or SCID – commonly known
as bubble boy disease – to the core panel for universal screening of all newborns in the United States.
On May 21, 2010 Kathleen Sebelius, Secretary of Health and Services announced the addition of
Severe Combined Immunodeficiency (SCID) to the core panel of 29 genetic disorders as part of her
recommendation to adopt the national Recommended Uniform Screening Panel. SCID is the first
nominated condition to be added to the core panel of disorders.
States and US Territories screening all newborns for SCID are: WI, MA, NY, CA, CT, MI, CO, MS, DE,
FL, TX, MN, IA, PA, UT and OH.
T-cell receptor excision circle assay has revolutionized early identification of infants with SCID or
severe T-cell lymphopenia. TREC fragments are identified by QPCR
Somatic recombination produces T-cell receptor excision circle TREC
V4
A TREC can be
detected by QPCR
V5
V3
V2
Early detection with
practically no false
positive results
V6
Loop of
intervening
DNA is
excised
V7
V8
V9
V1
DJ
Immunodeficiency caused by defects in B and T cell development
• Wiskott-Aldrich syndrome WAS – X-linked
A disease of defective reorganization of the actin cytoskeleton
Symptoms
– Thrombocytopenia, small platelet size (decreased production of
platelets in B. Marrow, increased destruction in spleen)
– Eczema
– No antibodies to carbohydrate antigens (role for T cells?)
– pyogenic and opportunistic infections
severe infection with varichella (chicken pox) and herpes simplex
(impaired CD8+ T-cell response)
– Rearrangement of cytoskeleton upon T cell activation in the
polarized contact with B cells, macrophages and target cells
– Low IgM high IgA, IgE serum levels
– Pyogenic bacterial, and opportunistic infections
– B cell lymphomas
Genetic defect
– Mutation in the WAS protein (WASP) expressed in white blood cells
and megakaryocytes
Treatment
Bone marrow transplantation
• Wiskott-Aldrich syndrome WAS – X-linked
Thrombocytopenia 40000 /μL + smaller thrombocytes
Loss of microvilli on T cells in Wiskott–Aldrich syndrome.
Scanning electron micrographs of normal lymphocytes
(panel a) and lymphocytes from a patient with Wiskott–
Aldrich syndrome (panel b). Note that the normal
lymphocyte surface is covered with abundant microvilli,
which are sparse or absent from the patient's
lymphocytes. Photographs courtesy of Dianne Kenney.
Wiskott-Aldrich syndrome WAS
Defective T/B communication
Expressed in white blood cells
and megakaryocytes
Capping of TCR is defective in WASP negative T cells
resting
anti CD3 treated
T cells from wt-mice
T cells from WASP-/- mice
DEFECTS IN PHAGOCYTE FUNCTION
ENHANCED SUSCEPTIBILITY TO BACTERIAL INFECTIONS
• DEFICIENCY OF CD18/LEUKOCYTE ADHESION (LAD)
– 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
• Defect in wound healing, severe inflammation of the gums
Lethal within the first decade of life without bone marrow
transplant
Omphalitis in
LAD I patient
DEFECTS IN PHAGOCYTE FUNCTION
ENHANCED SUSCEPTIBILITY TO BACTERIAL INFECTIONS
CHRONIC GRANULOMATOUS DISEASE – CGD (1 million in the US)
Mutation of NADPH oxidase – any of the 4 subunits (gp91 X-linked)
No superoxid O2- radical  antibacterial activity is compromised
Chronic intracellularbacterial or fungal infections – granuloma
formation
Aspergilus pneumonia
IFN-gamma improves resistance. Mechanism??
Defect of glucose-6-phosphate dehydrogenase and myeloperoxidase
 less severe phenotype
Diagnosis: NBT + PMA treatment of neutrophils. Lack
of blue colour in CGD
CGD patient with
skin infections
due to Serratia
marcescens
CHRONIC GRANULOMATOUS DISEASE – CGD
Phox complex
NBT staining of neutrophils
Healthy
CGD
Carrier
MUTATION OR FUNCTIONAL INACTIVATION OF SOLUBLE
COMPLEMENT PROTEINS RESULTS IN IMMUNODEFICIENCY
Classical
Lectin
MBL
C1Inh
C1
MASP
C4
C2
Alternative
B-factor
D-faktor
Properdin
HANE*
C3
Pyogenic infections
immune complex
disease
I-factor
H-faktor
C5
C6
C7
C8
Neisseria-infection
severe pyogenic
infections
C9
*HANE - hereditary angioneurotic edema
Neisseria-infection
immune complex
disease
Pyogenic infections
immune complex
disease
Stabilizes
alternative C3
convertase
MUTATION OF MEMBRANE BOUND COMPLEMENT
PROTEINS RESULTS IN IMMUNODEFICIENCY
DAF (Decay Accelerating Factor)
HRF (Homologous Restriction Factor)
MIRL (Membrane inhibitor of Reactive Lysis)
CR1 (complement receptor 1)
LFA(complement receptor 3,4)
Intravascular
hemolysis
SLE* association
Pyogenic
infections
*SLE- systemic lupus erythematosus
MIRL = CD59
DAF accelerates the decay of classical and alternative C3 convertase
DEFECTS IN COMPLEMENT COMPONENTS IMPAIR
ANTIBODY RESPONSES
ACCUMULATION OF IMMUNE COMPLEXES
• DEFICIENCY OF C3 OR ITS ACTIVATION
– Susceptibility to pyogenic bacteria – inefficient opsonization
• DEFICIENCY OF C5-C9
– Neisseria – NO complement mediated lysis
• DEFICIENCY OF EARLY C1-C4
– No C3b and C4b fragments  No CR1-mediated erythrocyte transport of
immune complexes
– Accumulation of immune complexes in blood, lymph, extracellular fluid 
deposition in tissues  tissue demage  macrophage activation 
inflammation
• DEFICIENCY IN COMPLEMENT INHIBITORY FACTORS
– I factor – uncontrolled C3  C3b  C3 depletion  inefficient opsonization
– Decay Accelerating Factor DAF or CD59 MAC inhibitor – autoimmune-like
condition  lysis of autologous erythrocytes  paroxysmal nocturnal
hemoglobulinuria
– C1 inhibitor – uncontrolled activation of the classical pathway  vasoactive C2
 accumulation of fluid in tissues – epiglottal swelling may lead to death by
suffocation