FRACP LECTURE 2010 IMMUNE DEFICIENCY 3 DR MARNIE ROBINSON PAEDIATRIC PAEDIATRIC IMMUNOLOGIST/ALLERGIST
FRACP LECTURE 2010 IMMUNE DEFICIENCY 3
Jan 30, 2023
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Microsoft PowerPoint - FRACP LECTURE 2010.ppt [Compatibility Mode]DR MARNIE ROBINSON
• Neutrophil defectsNeutrophil defects
l i d fi i i• Dysregulatory immune deficiencies
NEUTROPHIL DEFECTSNEUTROPHIL DEFECTS • Neutropaenia
– Kostmann, WHIM
• Chediak – higashi syndrome
l k• Aeitiology unknown
• Present with skin and upper respiratory tract infections (pneumonia/meningitis/sepsis less (p / g / p common)
• Neutrophil count usually <0 5 but mayNeutrophil count usually <0.5 but may increase during infection
• Treatment with G CSF (IVIG)• Treatment with GCSF (IVIG)
• Usually remits spontaneously by <24 months
ALLOIMMUNE NEUTROPAENIAALLOIMMUNE NEUTROPAENIA • Caused by transplacental transfer of maternal against the FcyRIIIb isotypes of NA 1 and NA2against the FcyRIIIb isotypes of NA 1 and NA2 causing immune destruction of neutrophils
d f /• Incidence of 1/500
• Usually presents in first weeks of life
• Present with omphalitis, cellulitis, pneumonia
• Diagnosed by detection of neutrophil specificDiagnosed by detection of neutrophil specific alloantibodies in maternal blood
• Treat with G CSF• Treat with GCSF
• resolves with waning of maternal antibodies
KOSTMANN’S SYNDROMEKOSTMANN S SYNDROME
• Bone marrow granulocyte arrest atBone marrow granulocyte arrest at promyeolocyte or myelocyte stage
• Present early in life (usually <6 months)• Present early in life (usually <6 months)
• Present with omphalitis , respiratory tract i f i ki d li binfections, skin and liver abscesses
• Increased susceptibility to AML
CYCLICAL NEUTROPAENIACYCLICAL NEUTROPAENIA
• Neutropaenia occurs classically at intervals of• Neutropaenia occurs classically at intervals of 21 days
U ll b i i hildh d ( 30% 1 )• Usually begins in childhood (~30% <1year)
• Recurrent episodes of malaise, fever , aphthous stomatitis , cervical lymphadenopathy (episodes 56 days)
• May treat with GCSF
WHIM SYNDROMEWHIM SYNDROME • Warts
• Melokathexis :chronic neutropaenia but hyercellularity on BMA +/ lymphopaeniahyercellularity on BMA +/ lymphopaenia
• Autosomal recessive due to mutation in h ki t CXCR4chemokine receptor CXCR4
• Warts , recurrent sinopulmonary infections
• Treatment : steroids , GCSF
• Autosomal recessive
• Hepatic incapacity to convert G6P to glucose and neutropaeniaand neutropaenia
• Present with hypoglycaemia , seizures , lactic acidosis hyperuriciaemia and hyperlipidaemiaacidosis, hyperuriciaemia and hyperlipidaemia
• neutropaenia : skin infections, l h d th l d l llymphadenopathy, oral and anal ulcers
• Treatment : prevention of hypoglycaemia and GCSF
CHRONIC GRANULOMATOUS DISEASECHRONIC GRANULOMATOUS DISEASE
GENETICS • X linked (70%)
– Tend to have earlier onset and more severe disease – x linked carriers : discoid lupus/mouth
ulcers/Raynauds
• Autosomal recessive – P47 phox mutation (ch7)p ( ) – P67 phox mutation (ch1) – P 22 phox mutation (ch16)
CHRONIC GRANULOMATOUS DISEASECHRONIC GRANULOMATOUS DISEASE
• Caused by defects in the NADPH oxidaseCaused by defects in the NADPH oxidase which is responsible for the respiratory burst and generation of phagocyte superoxideand generation of phagocyte superoxide
• Inability to generate superoxide leads to failure to make the downstream reactivefailure to make the downstream reactive oxygen species hydrogen peroxide and hydroxyl radicalhydroxyl radical → defective microbial killing of catalase positive bacteria and fungibacteria and fungi
CHRONIC GRANULOMATOUS DISEASECHRONIC GRANULOMATOUS DISEASE
• PATHOPHYSIOLOGYPATHOPHYSIOLOGY
ORGANISMSORGANISMS • Aspergillus • Candida albicans• Candida albicans • Staph aureus N di• Nocardia
• E.coli • Serratia • Salmonella
CHRONIC GRANULOMATOUS DISEASE
• Skin abscesses/lymphadenitis
– Granulomatous inflammatory bowel disease
• Granulomatous disease of lungs
DIAGNOSISDIAGNOSIS
• Nitroblue tetrazloium test (NBT) N t hil i CGD bl t d d– Neutrophils in CGD are unable to reduce dye
– Should usually turn blue but in CGD does not changechange
• NEUTROPHIL FUNCTION
• GENETIC TESTING
( )(1) AGGRESSIVE TREATMENT OF INFECTIONS
(2) PROPHYLAXIS AGAINST INFECTION
• IFN y
70% reduction in in infections 70% reduction in in infections
(3) BONE MARROW TRANSPLANT
TYPE 1TYPE 1
• AR
i i h d f C 8 2• Mutation in gene that codes for CD18 B2 leukocyte integrin subunit
• B2 subunit is responsible for adhesion of neutrophils to endothelial cell surface , migration from circulation and adhesionto C3b opsonised organisms
LEUKOCYTE ADHESION DEFICIENCY
TYPE 1 • Usually present within first months of life• Usually present within first months of life • Delayed separation of umbilical cord >21 days • Omphalitis• Omphalitis • Persistent leukocytosis • Severe gingivitis/periodontitis• Severe gingivitis/periodontitis • Recurrent infections
skin /airway /bowelPerirectal/labial– skin /airway./bowelPerirectal/labial – No pus /absence of neutrophils – Typical signs of inflammationTypical signs of inflammation absent(swelling/eythema etc
– Delayed healing
LEUKOCYTE ADHESION DEFICIENCY • TYPE 2 • AR• AR • Mutation in GDPfucose transporter gene – ligand for E selectin – unable to make initialligand for E selectin unable to make initial attachment to endothelium
• Characteristic facial features :coarseCharacteristic facial features :coarse • Short stature • Mental retardation• Mental retardation • Increased infections:skin/gum/resp • Poor pus formation • Treatment :oral fucose supplemention
LEUKOCYTE ADHESION DEFCIENCYLEUKOCYTE ADHESION DEFCIENCY
DIAGNOSISDIAGNOSIS • Flow cytometry • Decreased chemotaxis• Decreased chemotaxis • FBE : marked neutrophilia Bi f t hil• Biopsy : few neutrophils
TREATMENT • Aggressive mx of infection/prophylaxis • BMT
NEUTROPHIL SPECIFIC GRANULE DEFICIENCY
• Profound reduction or absence of neutrophil specific granules and their contentsspecific granules and their contents
• Recurrent infections : skin , ears , lungs and l h d GRAM ilymph nodes GRAM + cocci
• Absent or very low specific granule contents on blood smear /EM
CHEDIAK –HIGASHI SYNDROMECHEDIAK HIGASHI SYNDROME
• ARAR
• LYST gene mutation:codes cytoplasmic protein involved in vascular formation function andinvolved in vascular formation, function and transport
D f i i b l hil ’• Defect in microtubules – neutrophils can’t orientate correctly during chemotaxis
• Oversized lysozymes , storage granules
• Partial oculocutaneous albinsmPartial oculocutaneous albinsm • Neuropathy :sensory or motor • Mild mental retardation• Mild mental retardation • Nystagmus Bl di• Bleeding
• Infection – mucous membranes, skin peridontal/respiratory
• Accelerated phase
DIAGNOSISDIAGNOSIS
• Blood film : large inclusions in all nucleated blood cellsblood cells
• TREATMENT
THE INTERFERONY/IL12 PATHWAY DEFECTS
Characterised by susceptibility to ;Characterised by susceptibility to ;
• BCG / other poor pathogenic mycobacteria
i i d• Disemminated TB
• Systemic and/or persistent non typhi salmonella
• Severe herpes virus (CMV/HSV/VZV)p ( / / )
INF γ Monocyte d i d IL 12γ
INFγR1
STAT Killing of i ll lintracellular organisms
Defects of IFNg/IL12 AxisDefects of IFN g/IL 12 Axis
• Usually ARUsually AR
• Complete (IFNgR1s; IL12 p40; IL12RB1)
• Normal cellular and humoral IFNormal cellular and humoral IF
Defects of IFNg/IL12 AxisDefects of IFN g/IL 12 Axis
• Screening Ix – serum IFNg↑↑↑Screening Ix serum IFNg↑↑↑
GMANAGEMENT
• Some pt benefit from s/c IFNg (partial IFNgR; IL12p40; IL12BR1
• ?BMT (esp complete)( p p )
INTERFERON –Y RECEPTOR DEFICIENCIES
• Tend to develop severe mycobacterial disease• Tend to develop severe mycobacterial disease in early infancy or childhood
M b t i l t liti– Mycobacterial osteomyelitis
• May get disseminated infection from BCG vaccine
INTERFERONY DEFECTSINTERFERON Y DEFECTS
• DiagnosisDiagnosis – Measurement of STAT 1 after stimulation with
IFN y stimulation requires Functional IFN yIFNy stimulation – requires Functional IFNy receptor
Invitro TNF alpha production by PBMC in Invitro TNF alpha production by PBMC in response to LPS – impaired
geneticsgenetics
– Mycobacterial prophylaxis
• Present with disseminated nontuberculousPresent with disseminated nontuberculous mycobacterial and salmonella infections or progressive BCG infection following BCGprogressive BCG infection following BCG vaccination
• Defect in IL 12 signalling leads to poor• Defect in IL12 signalling leads to poor production of IFNY by T and NK cells
T IFN d i b i l• Treatment : IFN – y and antimycobacterials
STAT 1 DEFICIENCYSTAT 1 DEFICIENCY
• STAT1 is a critical molecule in the transduction or signal from both the IFNy.R and IFN a/BR
• Autosomal and recessive formsAutosomal and recessive forms – AD : IFNy mediated function impaired
– AR: : IFNy mediated function and IFN a/BAR: : IFN y mediated function and IFN a/B mediated function impaired
• Disseminated mycobacterim avium infectionDisseminated mycobacterim avium infection
• AD form associated with susceptibility to severe fatal mycobacterial infectionsevere fatal mycobacterial infection
IRAK 4 DEFICIENCYIRAK 4 DEFICIENCY
• Autosomal recessive ~ 25 described cases
• IRAK 4 (interleukin 1 receptor associated kinase 4 ) deficiency results in impairment in Toll receptor and Il1 receptor
di t d i llimediated signalling
• Recurrent invasive pyogenic infections with poor inflammatory responsesy p
• Infections classically involve S.pneumoniae and Staph aureus.
• Infections tend to decrease with advancing age (if survive)
• Normal immune function
ALPS SYNDROMEALPS SYNDROME • Disorder of lymphocyte apoptosis (fas pathway)
PRESENTATION
• Autoimmune hepatitisp
TREATMENT • Lymphoproliferation :steroids/chemotherapy • ?BMT
O• ENTEROPATHY
• X LINKED
• Mutation in FOX P3 geneMutation in FOX P3 gene – Expressed in lymphoid tissue (thymus , spleen , lymph nodes) and CD4+CD25+ regulatory T cellslymph nodes) and CD4+CD25+ regulatory T cells
IPEX SYNDROME
• Present usually in first year of life with severe diarrhoea and FTT from enteropathydiarrhoea and FTT from enteropathy
• Dermatitis
– Thyroid disease : hypo or hyperthyroidism
• Other autoimmune diseases – Cytopaenias
• Diagnosis – Intermittent eosinophilia
– Markedly elevated IgE
– T AND B cell numbers normal , normal neutrophil function and complement
– Increased Th2 cytokines (IL4,5,10,130
– Decreased Th1 cytokines : IFN Y
IPEX SYNDROMEIPEX SYNDROME
• Neutrophil defectsNeutrophil defects
l i d fi i i• Dysregulatory immune deficiencies
NEUTROPHIL DEFECTSNEUTROPHIL DEFECTS • Neutropaenia
– Kostmann, WHIM
• Chediak – higashi syndrome
l k• Aeitiology unknown
• Present with skin and upper respiratory tract infections (pneumonia/meningitis/sepsis less (p / g / p common)
• Neutrophil count usually <0 5 but mayNeutrophil count usually <0.5 but may increase during infection
• Treatment with G CSF (IVIG)• Treatment with GCSF (IVIG)
• Usually remits spontaneously by <24 months
ALLOIMMUNE NEUTROPAENIAALLOIMMUNE NEUTROPAENIA • Caused by transplacental transfer of maternal against the FcyRIIIb isotypes of NA 1 and NA2against the FcyRIIIb isotypes of NA 1 and NA2 causing immune destruction of neutrophils
d f /• Incidence of 1/500
• Usually presents in first weeks of life
• Present with omphalitis, cellulitis, pneumonia
• Diagnosed by detection of neutrophil specificDiagnosed by detection of neutrophil specific alloantibodies in maternal blood
• Treat with G CSF• Treat with GCSF
• resolves with waning of maternal antibodies
KOSTMANN’S SYNDROMEKOSTMANN S SYNDROME
• Bone marrow granulocyte arrest atBone marrow granulocyte arrest at promyeolocyte or myelocyte stage
• Present early in life (usually <6 months)• Present early in life (usually <6 months)
• Present with omphalitis , respiratory tract i f i ki d li binfections, skin and liver abscesses
• Increased susceptibility to AML
CYCLICAL NEUTROPAENIACYCLICAL NEUTROPAENIA
• Neutropaenia occurs classically at intervals of• Neutropaenia occurs classically at intervals of 21 days
U ll b i i hildh d ( 30% 1 )• Usually begins in childhood (~30% <1year)
• Recurrent episodes of malaise, fever , aphthous stomatitis , cervical lymphadenopathy (episodes 56 days)
• May treat with GCSF
WHIM SYNDROMEWHIM SYNDROME • Warts
• Melokathexis :chronic neutropaenia but hyercellularity on BMA +/ lymphopaeniahyercellularity on BMA +/ lymphopaenia
• Autosomal recessive due to mutation in h ki t CXCR4chemokine receptor CXCR4
• Warts , recurrent sinopulmonary infections
• Treatment : steroids , GCSF
• Autosomal recessive
• Hepatic incapacity to convert G6P to glucose and neutropaeniaand neutropaenia
• Present with hypoglycaemia , seizures , lactic acidosis hyperuriciaemia and hyperlipidaemiaacidosis, hyperuriciaemia and hyperlipidaemia
• neutropaenia : skin infections, l h d th l d l llymphadenopathy, oral and anal ulcers
• Treatment : prevention of hypoglycaemia and GCSF
CHRONIC GRANULOMATOUS DISEASECHRONIC GRANULOMATOUS DISEASE
GENETICS • X linked (70%)
– Tend to have earlier onset and more severe disease – x linked carriers : discoid lupus/mouth
ulcers/Raynauds
• Autosomal recessive – P47 phox mutation (ch7)p ( ) – P67 phox mutation (ch1) – P 22 phox mutation (ch16)
CHRONIC GRANULOMATOUS DISEASECHRONIC GRANULOMATOUS DISEASE
• Caused by defects in the NADPH oxidaseCaused by defects in the NADPH oxidase which is responsible for the respiratory burst and generation of phagocyte superoxideand generation of phagocyte superoxide
• Inability to generate superoxide leads to failure to make the downstream reactivefailure to make the downstream reactive oxygen species hydrogen peroxide and hydroxyl radicalhydroxyl radical → defective microbial killing of catalase positive bacteria and fungibacteria and fungi
CHRONIC GRANULOMATOUS DISEASECHRONIC GRANULOMATOUS DISEASE
• PATHOPHYSIOLOGYPATHOPHYSIOLOGY
ORGANISMSORGANISMS • Aspergillus • Candida albicans• Candida albicans • Staph aureus N di• Nocardia
• E.coli • Serratia • Salmonella
CHRONIC GRANULOMATOUS DISEASE
• Skin abscesses/lymphadenitis
– Granulomatous inflammatory bowel disease
• Granulomatous disease of lungs
DIAGNOSISDIAGNOSIS
• Nitroblue tetrazloium test (NBT) N t hil i CGD bl t d d– Neutrophils in CGD are unable to reduce dye
– Should usually turn blue but in CGD does not changechange
• NEUTROPHIL FUNCTION
• GENETIC TESTING
( )(1) AGGRESSIVE TREATMENT OF INFECTIONS
(2) PROPHYLAXIS AGAINST INFECTION
• IFN y
70% reduction in in infections 70% reduction in in infections
(3) BONE MARROW TRANSPLANT
TYPE 1TYPE 1
• AR
i i h d f C 8 2• Mutation in gene that codes for CD18 B2 leukocyte integrin subunit
• B2 subunit is responsible for adhesion of neutrophils to endothelial cell surface , migration from circulation and adhesionto C3b opsonised organisms
LEUKOCYTE ADHESION DEFICIENCY
TYPE 1 • Usually present within first months of life• Usually present within first months of life • Delayed separation of umbilical cord >21 days • Omphalitis• Omphalitis • Persistent leukocytosis • Severe gingivitis/periodontitis• Severe gingivitis/periodontitis • Recurrent infections
skin /airway /bowelPerirectal/labial– skin /airway./bowelPerirectal/labial – No pus /absence of neutrophils – Typical signs of inflammationTypical signs of inflammation absent(swelling/eythema etc
– Delayed healing
LEUKOCYTE ADHESION DEFICIENCY • TYPE 2 • AR• AR • Mutation in GDPfucose transporter gene – ligand for E selectin – unable to make initialligand for E selectin unable to make initial attachment to endothelium
• Characteristic facial features :coarseCharacteristic facial features :coarse • Short stature • Mental retardation• Mental retardation • Increased infections:skin/gum/resp • Poor pus formation • Treatment :oral fucose supplemention
LEUKOCYTE ADHESION DEFCIENCYLEUKOCYTE ADHESION DEFCIENCY
DIAGNOSISDIAGNOSIS • Flow cytometry • Decreased chemotaxis• Decreased chemotaxis • FBE : marked neutrophilia Bi f t hil• Biopsy : few neutrophils
TREATMENT • Aggressive mx of infection/prophylaxis • BMT
NEUTROPHIL SPECIFIC GRANULE DEFICIENCY
• Profound reduction or absence of neutrophil specific granules and their contentsspecific granules and their contents
• Recurrent infections : skin , ears , lungs and l h d GRAM ilymph nodes GRAM + cocci
• Absent or very low specific granule contents on blood smear /EM
CHEDIAK –HIGASHI SYNDROMECHEDIAK HIGASHI SYNDROME
• ARAR
• LYST gene mutation:codes cytoplasmic protein involved in vascular formation function andinvolved in vascular formation, function and transport
D f i i b l hil ’• Defect in microtubules – neutrophils can’t orientate correctly during chemotaxis
• Oversized lysozymes , storage granules
• Partial oculocutaneous albinsmPartial oculocutaneous albinsm • Neuropathy :sensory or motor • Mild mental retardation• Mild mental retardation • Nystagmus Bl di• Bleeding
• Infection – mucous membranes, skin peridontal/respiratory
• Accelerated phase
DIAGNOSISDIAGNOSIS
• Blood film : large inclusions in all nucleated blood cellsblood cells
• TREATMENT
THE INTERFERONY/IL12 PATHWAY DEFECTS
Characterised by susceptibility to ;Characterised by susceptibility to ;
• BCG / other poor pathogenic mycobacteria
i i d• Disemminated TB
• Systemic and/or persistent non typhi salmonella
• Severe herpes virus (CMV/HSV/VZV)p ( / / )
INF γ Monocyte d i d IL 12γ
INFγR1
STAT Killing of i ll lintracellular organisms
Defects of IFNg/IL12 AxisDefects of IFN g/IL 12 Axis
• Usually ARUsually AR
• Complete (IFNgR1s; IL12 p40; IL12RB1)
• Normal cellular and humoral IFNormal cellular and humoral IF
Defects of IFNg/IL12 AxisDefects of IFN g/IL 12 Axis
• Screening Ix – serum IFNg↑↑↑Screening Ix serum IFNg↑↑↑
GMANAGEMENT
• Some pt benefit from s/c IFNg (partial IFNgR; IL12p40; IL12BR1
• ?BMT (esp complete)( p p )
INTERFERON –Y RECEPTOR DEFICIENCIES
• Tend to develop severe mycobacterial disease• Tend to develop severe mycobacterial disease in early infancy or childhood
M b t i l t liti– Mycobacterial osteomyelitis
• May get disseminated infection from BCG vaccine
INTERFERONY DEFECTSINTERFERON Y DEFECTS
• DiagnosisDiagnosis – Measurement of STAT 1 after stimulation with
IFN y stimulation requires Functional IFN yIFNy stimulation – requires Functional IFNy receptor
Invitro TNF alpha production by PBMC in Invitro TNF alpha production by PBMC in response to LPS – impaired
geneticsgenetics
– Mycobacterial prophylaxis
• Present with disseminated nontuberculousPresent with disseminated nontuberculous mycobacterial and salmonella infections or progressive BCG infection following BCGprogressive BCG infection following BCG vaccination
• Defect in IL 12 signalling leads to poor• Defect in IL12 signalling leads to poor production of IFNY by T and NK cells
T IFN d i b i l• Treatment : IFN – y and antimycobacterials
STAT 1 DEFICIENCYSTAT 1 DEFICIENCY
• STAT1 is a critical molecule in the transduction or signal from both the IFNy.R and IFN a/BR
• Autosomal and recessive formsAutosomal and recessive forms – AD : IFNy mediated function impaired
– AR: : IFNy mediated function and IFN a/BAR: : IFN y mediated function and IFN a/B mediated function impaired
• Disseminated mycobacterim avium infectionDisseminated mycobacterim avium infection
• AD form associated with susceptibility to severe fatal mycobacterial infectionsevere fatal mycobacterial infection
IRAK 4 DEFICIENCYIRAK 4 DEFICIENCY
• Autosomal recessive ~ 25 described cases
• IRAK 4 (interleukin 1 receptor associated kinase 4 ) deficiency results in impairment in Toll receptor and Il1 receptor
di t d i llimediated signalling
• Recurrent invasive pyogenic infections with poor inflammatory responsesy p
• Infections classically involve S.pneumoniae and Staph aureus.
• Infections tend to decrease with advancing age (if survive)
• Normal immune function
ALPS SYNDROMEALPS SYNDROME • Disorder of lymphocyte apoptosis (fas pathway)
PRESENTATION
• Autoimmune hepatitisp
TREATMENT • Lymphoproliferation :steroids/chemotherapy • ?BMT
O• ENTEROPATHY
• X LINKED
• Mutation in FOX P3 geneMutation in FOX P3 gene – Expressed in lymphoid tissue (thymus , spleen , lymph nodes) and CD4+CD25+ regulatory T cellslymph nodes) and CD4+CD25+ regulatory T cells
IPEX SYNDROME
• Present usually in first year of life with severe diarrhoea and FTT from enteropathydiarrhoea and FTT from enteropathy
• Dermatitis
– Thyroid disease : hypo or hyperthyroidism
• Other autoimmune diseases – Cytopaenias
• Diagnosis – Intermittent eosinophilia
– Markedly elevated IgE
– T AND B cell numbers normal , normal neutrophil function and complement
– Increased Th2 cytokines (IL4,5,10,130
– Decreased Th1 cytokines : IFN Y
IPEX SYNDROMEIPEX SYNDROME
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