FRACP LECTURE 2010 IMMUNE DEFICIENCY 3

DR MARNIE ROBINSON PAEDIATRIC IMMUNOLOGIST/ALLERGIST IMMUNOLOGY LECTURE 3

• defects • INTERFERON –Y /IL‐12 pathway defect • Dysregulatory immune dfiideficienc ies NEUTROPHIL DEFECTS • Neutropaenia – Allo immune /au to immune – Kostmann, WHIM – cyclllical • Chronic granulomatous disease • Leukocyte adhesion deficiency • Neutrophil specific granule deficiency • Chediak –higashi syndrome AUTOIMMUNE NEUTROPAENIA • Antibodies against different neutrophil antigen • Aeitiology unknown • Slightly more common in females • Present with skin and upper respiratory tract (pneumonia /menin gitis /se psis less common) • Neutrophil count usually <0.5 but may increase during infection • Treatment with G‐CSF (IVIG) • Usually remits spontaneously by <24 months ALLOIMMUNE NEUTROPAENIA • Caused by transplacental transfer of maternal against the FcyRIIIb isotypes of NA 1 and NA2 causing immune destruction of • Incidence of 1/500 • Usually presents in first weeks of life • Present with omphalitis, cellulitis, pneumonia • Diagnosed by detection of neutrophil specific alloantibodies in maternal • Treat with G‐CSF • resolves with waning of maternal antibodies KOSTMANN’S SYNDROME

• arrest at promyeolocyte or stage • Present early in life (usually <6 months) • Present with omphalitis , respiratory tract ifinfect ions, skin and liver abscesses • Increased susceptibility to AML • Treatment is with G‐CSF CYCLICAL NEUTROPAENIA

• Defect in elastase 2 • Sporadic 2/3, familial 1/3(AD) • Neutropaenia occurs classically at intervals of 21 days • UllUsually bibegins in childhoo d (~ 30% <1)1year) • Recurrent episodes of malaise, fever , aphthous stomatitis , cervical lymphadenopathy (episodes 5‐6 days) • May treat with G‐CSF WHIM SYNDROME • Warts • Hypogammaglobulinaemia • Infections • Melokathexis :chronic neutropaenia but hyercellularity on BMA +/‐ lymphopaenia • Autosomal recessive due to mutation in chkihemokine receptor CXCR4 • Warts , recurrent sinopulmonary infections • Treatment : steroids , G‐CSF GLYCOGEN STORAGE TYPE 1B • Autosomal recessive • Hepatic incapacity to convert G‐6P to glucose and neutropaenia • Present with hypoglycaemia , seizures , lactic acidosis, hyperuriciaemia and hyperlipidaemia • neutropaenia : skin infections, lhdthlymphadenopathy, oral and anal ulcers • Treatment : prevention of hypoglycaemia and G‐CSF CHRONIC 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) – P67 phox mutation (ch1) – P 22 phox mutation (ch16) CHRONIC GRANULOMATOUS DISEASE

• Caused by defects in the NADPH oxidase which is responsible for the and generation of phagocyte superoxide • Inability to generate superoxide leads to failure to make the downstream reactive oxygen species hydrogen peroxide and hydroxyl radical → defective microbial killing of catalase positive and fungi CHRONIC GRANULOMATOUS DISEASE

• PATHOPHYSIOLOGY CHRONIC GRANULOMATOUS DISEASE

ORGANISMS • Aspergillus • Candida albicans • Staph aureus • NdiNocardia • E.coli • Serratia • Salmonella CHRONIC GRANULOMATOUS DISEASE

PRESENTATION (1) Early onset severe bacterial and fungal infections • Skin abscesses/lymphadenitis • Lung/splenic/liver abscesses • Recurrent pneumonia • Osteomyelitis • Peritonitis • Gingivitis/mouth ulcers CHRONIC GRANULOMATOUS DISEASE

PRESENTATION (2) Granulomatous disease • Skin granulomas • Granulomas of GIT – Gastric outlet obstruction – Granulomatous inflammatory bowel disease • Genitourinary granulomatous disease – Urinary retention. dysuria • Granulomatous disease of lungs CHRONIC GRANULOMATOUS DISEASE

DIAGNOSIS • Nitroblue tetrazloium test (NBT) – NtNeutrophil s in CGD are unable to reduce dye – Should usually turn blue but in CGD does not change • NEUTROPHIL FUNCTION • GENETIC TESTING CHRONIC GRANULOMATOUS DISEASE TREATMENT ()(1) AGGRESSIVE TREATMENT OF INFECTIONS (2) PROPHYLAXIS AGAINST • Bacterial prophylaxis – Bactrim/ itrakonazole • IFN y ‐ 70% reduction in in infections (3) BONE MARROW TRANSPLANT (4) GENETIC COUNSELLING LEUKOCYTE ADHESION DEFICIENCY

TYPE 1 • AR • Mutation in gene that codes for C8CD18 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 • Delayed separation of umbilical cord >21 days • Omphalitis • Persistent • Severe gingivitis/periodontitis • Recurrent infections – skin /airway./ bowelPerirectal/labial – No /absence of neutrophils – Typical signs of absent(swelling/eythema etc – Delayed healing LEUKOCYTE ADHESION DEFICIENCY • TYPE 2 • AR • Mutation in GDP‐fucose transporter gene – ligand for E selectin – unable to make initial attachment to endothelium • Characteristic facial features :coarse • Short stature • Mental retardation • Increased infections:skin/gum/resp • Poor pus formation • Treatment :oral fucose supplemention LEUKOCYTE ADHESION DEFCIENCY

DIAGNOSIS • Flow cytometry • Decreased • FBE : marked neutrophilia • Biopsy : few neuthiltrophils TREATMENT • Aggressive mx of infection/prophylaxis • BMT NEUTROPHIL SPECIFIC GRANULE DEFICIENCY • Autosomal recessive • Profound reduction or absence of neutrophil specific granules and their contents • Recurrent infections : skin , ears , lungs and lhlymph nodes‐ GRAM + cocci • Absent or very low specific granule contents on blood smear /EM CHEDIAK –HIGASHI SYNDROME

• AR • LYST gene mutation:codes cytoplasmic protein involved in vascular formation, function and transport • DfDefect in miblicrotubules – neutrophils can’t orientate correctly during chemotaxis • Oversized lysozymes , storage granules CHEDIAK –HIGASHI SYNDROME

• Partial oculocutaneous albinsm • Neuropathy :sensory or motor • Mild mental retardation • Nystagmus • Blee ding • Infection – mucous membranes, skin ‐ peridontal/respiratory • Accelerated phase CHEDIAK –HIGASHI SYNDROME

DIAGNOSIS • : large inclusions in all nucleated blood cells

• TREATMENT • BMT curative but does not alter neurological outcome THE INTERFERON‐Y/IL‐12 PATHWAY DEFECTS Characterised by susceptibility to ; • BCG / other poor pathogenic mycobacteria • Diidisemminated TB • Systemic and/or persistent non typhi salmonella • Severe herpes virus (//)(CMV/HSV/VZV) The Interferon‐γ‐ IL‐12 Pathway

Monocyte INF‐ γ didderived IL‐12 INF‐γR1 INF‐ γR2 T‐cell

JAK STAT Killing of illlintracellular organisms Defects of IFN‐g/IL‐12 Axis

• Usually AR • Occas AD (partial IFNgRa; partial STAT1) • Partilial (IFNgRs; SS)TAT1) • Complete (IFNgR1s; IL‐12 p40; IL‐12RB1)

• Normal cellular and humoral IF Defects of IFN‐g/IL‐12 Axis

• Screening Ix – serum IFNg↑↑↑

MANAGEMENT • Some pt benefit from s/c IFN‐g (partial IFNgR; IL‐12p40; IL‐12BR1 • ?BMT ((pesp compp)lete) INTERFERON –Y RECEPTOR DEFICIENCIES • Autosomal recessive and dominant forms (dominant tends to present later) • Tend to develop severe mycobacterial disease in early infancy or childhood – MbtilMycobacterial osteomye litis • May get disseminated infection from BCG vaccine INTERFERON‐Y DEFECTS

• Diagnosis – Measurement of STAT 1 after stimulation with IFN‐y stimulation – requires Functional IFN‐y receptor ‐ Invitro TNF‐ alpha production by PBMC in response to LPS –impaired ‐ genetics • Treatment : – IFN –Y – Mycobacterial prophylaxis IL‐12 RECEPTOR DEFICIENCY

• Present with disseminated nontuberculous mycobacterial and salmonella infections or progressive BCG infection following BCG vaccination • Defect in IL‐12 signalling leads to poor production of IFN‐Y by T and NK cells • Treatment : IFN – y and antiibilmycobacterials STAT 1 DEFICIENCY • STAT1 is a critical molecule in the transduction or signal from both the IFN‐y.R and IFN a/BR • Autosomal and recessive forms – AD : IFN‐y mediated function impaired – AR: : IFN‐y mediated function and IFN a/B mediated function impaired • Disseminated mycobacterim avium infection • AD form associated with susceptibility to severe fatal mycobacterial infection IRAK 4 DEFICIENCY

• Autosomal recessive ~ 25 described cases • IRAK 4 (interleukin 1 receptor associated kinase 4 ) deficiency results in impairment in Toll receptor and Il‐1 receptor media te d signa lling • Recurrent invasive pyogenic infections with poor inflammatory responses • Infections classically involve S.pneumoniae and Staph aureus. • Infections tend to decrease with advancing age (if survive) • Normal immune function • Treatment : IVIG and antibiotic prophylaxis

ALPS SYNDROME • Disorder of lymphocyte apoptosis (fas pathway) PRESENTATION • Lymphoproliferation • Splenomegaly • Massive lymphadenopathy • Autoimmune disease • Blood cells • Autoimmune hepatitis • malignancy ALPS SYNDROME

DIAGNOSIS • ↑ Double negative T cells (CD4‐/CD8‐) • APOPTOSIS studies • autoantibodies

TREATMENT • Lymphoproliferation :steroids/chemotherapy • ?BMT IPEX SYNDROME

• IMMUNE DYSREGULATION • POLYENDOCRINOPATHY • ENTEROPATHY • X LINKED

• Mutation in FOX P3 gene – Expressed in lymphoid tissue (thymus , spleen , lymph nodes) and CD4+CD25+ regulatory T cells IPEX SYNDROME • Present usually in first year of life with severe diarrhoea and FTT from enteropathy • Dermatitis • Endocrinopathy – Early onset type 1 diabetes – Thyroid disease : hypo or hyperthyroidism • Other autoimmune diseases – Cytopaenias – Tubular nephropathy – alopecia IPEX SYNDROME • ~50% have serious infections : sepsis , meningitis , pneumonia , osteomyelitis • Most common pathogens Staphylococcus , CMV and candddida • Diagnosis – Intermittent – Markedly elevated IgE – T AND B cell numbers normal , normal neutrophil function and complement – Increased Th2 cytokines (IL‐4,5,10,130 – Decreased Th1 cytokines : IFN ‐Y IPEX SYNDROME

• Immunsuppression

• Stem cell transplant curative