FRACP LECTURE 2010 IMMUNE DEFICIENCY 3

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1 FRACP LECTURE 2010 IMMUNE DEFICIENCY 3 DR MARNIE ROBINSON PAEDIATRIC IMMUNOLOGIST/ALLERGIST

2 IMMUNOLOGY LECTURE 3 Neutrophil defects INTERFERON Y /IL 12 pathway defect Dysregulatory immune dfii deficienciesi

3 Neutropaenia NEUTROPHIL DEFECTS Alloimmune/autoimmune i Kostmann, WHIM cyclical l Chronic granulomatous disease Leukocyte adhesion deficiency Neutrophil specific granule deficiency Chediak higashi syndrome

4 AUTOIMMUNE NEUTROPAENIA Antibodies against different neutrophil antigen Aeitiology unknown Slightly more common in females Present with skin and upper respiratory tract infections (pneumonia/meningitis/sepsis / p less common) Neutrophil count usually <0.5 but may increase during infection Treatment with G CSF (IVIG) Usually remits spontaneously by <24 months

5 ALLOIMMUNE NEUTROPAENIA Caused by transplacental transfer of maternal against the FcyRIIIb isotypes of NA 1 and NA2 causing immune destruction of neutrophils 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 blood Treat with G CSF resolves with waning of maternal antibodies

6 KOSTMANN S S SYNDROME Bone marrow granulocyte arrest at promyeolocyte or myelocyte stage Present early in life (usually <6 months) Present with omphalitis, respiratory tract infections, i skin and liver abscesses Increased susceptibility to AML Treatment is with G CSF

7 CYCLICAL NEUTROPAENIA Defect in elastase 2 Sporadic 2/3, familial 1/3(AD) Neutropaenia occurs classically at intervals of 21 days Usually begins in childhood d (~30% <1year) Recurrent episodes of malaise, fever, aphthous stomatitis, cervical lymphadenopathy (episodes 5 6 days) May treat with G CSF

8 Warts WHIM SYNDROME Hypogammaglobulinaemia Infections Melokathexis :chronic neutropaenia but hyercellularity on BMA +/ lymphopaenia Autosomal recessive due to mutation in chemokine receptor CXCR4 Warts, recurrent sinopulmonary infections Treatment : steroids, G CSF

9 GLYCOGEN STORAGE TYPE 1B Autosomal recessive Hepatic incapacity to convert G 6P to glucose and neutropaenia Present with hypoglycaemia, seizures, lactic acidosis, hyperuriciaemiaand and hyperlipidaemia neutropaenia : skin infections, lymphadenopathy, oral and anal ulcers Treatment : prevention of hypoglycaemia and G CSF

10 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)

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

12 CHRONIC GRANULOMATOUS DISEASE PATHOPHYSIOLOGY

13 CHRONIC GRANULOMATOUS DISEASE ORGANISMS Aspergillus Candida albicans Staph aureus Nocardia E.coli Serratia Salmonella

14 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

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

16 CHRONIC GRANULOMATOUS DISEASE DIAGNOSIS Nitroblue tetrazloium test (NBT) Neutrophils in CGD are unable to reduce dye Should usually turn blue but in CGD does not change NEUTROPHIL FUNCTION GENETIC TESTING

17 CHRONIC GRANULOMATOUS DISEASE TREATMENT (1) AGGRESSIVE TREATMENT OF INFECTIONS (2) PROPHYLAXIS AGAINST INFECTION Bacterial prophylaxis Bactrim/ itrakonazole IFN y 70% reduction in in infections (3) BONE MARROW TRANSPLANT (4) GENETIC COUNSELLING

18 LEUKOCYTE ADHESION DEFICIENCY TYPE 1 AR 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

19 LEUKOCYTE ADHESION DEFICIENCY TYPE 1 Usually present within first months of life Delayed separation of umbilical cord >21 days Omphalitis Persistent leukocytosis Severe gingivitis/periodontitis Recurrent infections skin /airway./bowelperirectal/labial /bowelperirectal/labial No pus /absence of neutrophils Typical signs of inflammation absent(swelling/eythema etc Delayed healing

20 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

21 LEUKOCYTE ADHESION DEFCIENCY DIAGNOSIS Flow cytometry Decreased chemotaxis FBE : marked neutrophilia Biopsy : few neutrophils TREATMENT Aggressive mx of infection/prophylaxis BMT

22 NEUTROPHIL SPECIFIC GRANULE Autosomal recessive DEFICIENCY Profound reduction or absence of neutrophil specific granules and their contents Recurrent infections : skin, ears, lungs and lymph nodes GRAM + cocci Absent or very low specific granule contents on blood smear /EM

23 CHEDIAK HIGASHI SYNDROME AR LYST gene mutation:codes cytoplasmic protein involved in vascular formation, function and transport Df Defect in microtubules neutrophils can t orientate correctly during chemotaxis Oversized lysozymes, storage granules

24 CHEDIAK HIGASHI SYNDROME Partial oculocutaneous albinsm Neuropathy :sensory or motor Mild mental retardation Nystagmus Bleeding Infection mucous membranes, skin peridontal/respiratory Accelerated phase

25 CHEDIAK HIGASHI SYNDROME DIAGNOSIS Blood film : large inclusions in all nucleated blood cells TREATMENT BMT curative but does not alter neurological g outcome

26 THE INTERFERON Y/IL 12 PATHWAY DEFECTS Characterised by susceptibility to ; BCG / other poor pathogenic mycobacteria Disemminated i TB Systemic and/or persistent non typhi salmonella Severe herpes virus (CMV/HSV/VZV) /

27 The Interferon γ IL 12 Pathway INF γ INF γr1 INF γr2 T cell Monocyte derived dil 12 JAK STAT Killing of intracellular l organisms

28 Defects of IFN g/il 12 Axis Usually AR Occas AD (partial IFNgRa; partial STAT1) Partial il( (IFNgRs; STAT1) Complete (IFNgR1s; IL 12 p40; IL 12RB1) Normal cellular and humoral IF

29 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 (esp complete)

30 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 Mycobacterial osteomyelitis May get disseminated infection from BCG vaccine

31 Diagnosis INTERFERON Y DEFECTS 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

32 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 antimycobacterials i

33 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 Disseminatedmycobacterimavium mycobacterim avium infection AD form associated with susceptibility to severe fatal mycobacterial infection

34 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 mediated d signalling 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

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

37 ALPS SYNDROME DIAGNOSIS Double negative T cells (CD4 /CD8 ) APOPTOSIS studies autoantibodies TREATMENT Lymphoproliferation :steroids/chemotherapy?bmt

38 IPEX SYNDROME IMMUNE DYSREGULATION POLYENDOCRINOPATHY ENTEROPATHYO X LINKED Mutation in FOX P3 gene Expressed in lymphoid tissue (thymus, spleen, lymph nodes) and CD4+CD25+ regulatory T cells

39 IPEX SYNDROME Present usually in first year of life with severe diarrhoea and FTTfromenteropathy Dermatitis Endocrinopathy Early onset type 1 diabetes Thyroid disease : hypo or hyperthyroidism Other autoimmune diseases Cytopaenias Tubular nephropathy alopecia

40 IPEX SYNDROME ~50% have serious infections : sepsis, meningitis, pneumonia, osteomyelitis Most common pathogens Staphylococcus, CMV and candida dd Diagnosis Intermittent eosinophilia 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

41 IPEX SYNDROME Immunsuppression Stem cell transplant curative