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The immune system is still the big black box. Environment. Immune system. Tolerance. self. Non-self Dangerous Pathogenic. Immune response. V i rus. 3 hrs. Diversity Fast development. 3 hr s. PATHOGENS HAVE SHORT GENERATION TIME. PATOGENS. Bact eria. Vi ruses. parasites. - PowerPoint PPT Presentation
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Environment
self
Non-self
Dangerous
Pathogenic
Immune system
Tolerance
Immune response
The immune system is still the big black box
BactBacteriaeria
ViVirusesruses
parasitesparasites
VViirusrus
3 3 hrshrs
3 3 hrhrss
DiversityFast development
PATOGENS
PATHOGENS HAVE SHORT GENERATION TIME
Humans have longer generation time, Need a sophysticated protection system
Development, education
Birth
Reproducrionat 35
IMMUNODEFICIENCIESAGE AND HEALTH DEPENDENTIMMUNOSUPPRESSIVE DRUGS
• 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– 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
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
• - recurrent sinopulmonary and GI infections beginning after 3-4 mo.
– B cell development• (XLA, IgA deficiency)
– B – T cell collaborations • CD40 ligand, hyper IgM
• T CELL DEFICIENCY
• - SCID, opportunistic infections beginning early in infancy
– T cell development• IL-7/Jak3• RAG-1 RAG-2• Artemis
– Thymus epithelial cells• DiGeorge syndrome
– Purin catabolism– DNS repair enzyme
defect– MHC class II synthesis
blockade
• 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
TYPES OF INHERITED IMMUNE DEFICIENCIES 2.
Immunodeficiencies caused by B-cell defects
Approx. 70% of all IDs
Late Manifestation (7-9 month)
Increased sensitivity to:Encapsulated bacteriaStreptococcus pneumoniaeHaemophylus influenzae
Infection by Enterovirus, parasites
Encapsulated bacteria resist ingestion by phagocytes unless they are recognized by
antibodies that fix complement.
• 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
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)
ANTIBODY DEFICIENCY INABILITY TO CLEAR EXTRACELLULAR BACTERIA
In patients with X-linked agammaglobulinemia (XLA), B cells do not develop beyond the pre-B cell stage.
• 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)
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)
DIMINISHED ANTIBODY PRODUCTION AS A RESULT OF INHERITED DEFECT OF T CELL HELP
•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
• 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+
DEFECT IN T CELL FUNCTIONST cells are involved in all aspects of adaptive immunity
SEVERE COMBINED IMMUNODEFICIENCYSCID
• 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)
X-LINKED SEVERE COMBINED IMMUNODEFICIENCYSCID (Over 50% of cases)
Symptoms
Candida albicans infection in children with SCID
The Hart shadow is clearly visibleIn the absence of the thymus
Normal SCID
• 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
SEVER COMBINED IMMUNODEFICIENCIESThe SCID phenotype can be caused by various gene defects
• X-SCID – Az interleukin receptorok közös γ-láncának hibája közös gamma lánc55% totál, része az IL2,4,7,9, 15, 21 receptoroknakT- B+, NK-, a periférián a limfociták gykorlatilag csak B sejtek
• Jak3 kináz mutációja IL-7 receptor jelátvitel
SÚLYOS KOMBINÁLT IMMUNODEFICIENCIÁKA SCID fenotípust eltérő gén hibák okozhatják
• 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
SEVER COMBINED IMMUNODEFICIENCIESThe SCID phenotype can be caused by various gene defects
ADA conc. A tímuszban kb 10-szeres
Treatment:Bone marrow transplantation, preferably from a Bone marrow transplantation, preferably from a histocompatible siblinghistocompatible siblingGene therapyGene 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
Loop of interveningDNA is excised
V1 DJ
V2
V3
V4
V8
V7
V6
V5
V9
Somatic recombination produces T-cell receptor excision circle TREC
A TREC can be detected by QPCR
Early detection with practically no false positive results
• 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 megakaryocytesTreatmentBone 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 WASDefective T/B communication
Expressed in white blood cells and megakaryocytes
Capping of TCR is defective in WASP negative T cells
T cells from wt-mice
T cells from WASP-/- mice
resting anti CD3 treated
• 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 gumsLethal within the first decade of life without bone marrow
transplant
DEFECTS IN PHAGOCYTE FUNCTIONENHANCED SUSCEPTIBILITY TO BACTERIAL INFECTIONS
Omphalitis in
LAD I patient
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 formationAspergilus pneumoniaIFN-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
DEFECTS IN PHAGOCYTE FUNCTIONENHANCED SUSCEPTIBILITY TO BACTERIAL INFECTIONS
CGD patient with
skin infections
due to Serratia
marcescens
MUTATION OR FUNCTIONAL INACTIVATION OF SOLUBLE COMPLEMENT PROTEINS RESULTS IN IMMUNODEFICIENCY
B-factor
D-faktor
Pyogenic infections immune complex disease
Alternative
Properdin
C5
C6
C7
C8
C9
C3I-factorH-faktor
Classical Lectin
Neisseria-infection immune complex disease
C1Inh
HANE*
Neisseria-infection severe pyogenic infections
Pyogenic infections immune complex disease
C1MBL
MASP
C2C4
*HANE - hereditary angioneurotic edema
Stabilizes alternative C3convertase
Intra va sc ula rhem olysis
(c o m p le m e nt re c e p to r 1)C R1SLE* -
a ssoc ia tion
Pyo g enicinfec tio ns
(De c a y Ac c e le ra ting Fa c to r) (Ho m o lo g o us Re stric tio n Fa c to r) (M e m b ra ne inhib ito r o f Re a c tive Lysis)
DAFHRFM IRL
*SLE- syste m ic lup us e rythe m a to sus
(c o m p le m e nt re c e p to r 3,4)LFA
MUTATION OF MEMBRANE BOUND COMPLEMENT PROTEINS RESULTS IN IMMUNODEFICIENCY
MIRL = CD59
DAF accelerates the decay of classical and alternative C3 convertase
• 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
DEFECTS IN COMPLEMENT COMPONENTS IMPAIR ANTIBODY RESPONSES
ACCUMULATION OF IMMUNE COMPLEXES