1. Hyper-IgE SyndromePiyawadee Lertchanaruengrith, MDCompany LOGO18/11/2011

2. Topic Outlines Introduction Clinical manifestation, Immunological profiles, and Immunophenotypes of Autosomal dominant Hyper-IgE syndrome (STAT3mutation) Autosomal recessive Hyper-IgE syndrome Mutation in TYK2 Mutation in DOCK8 Unknown mutation 3. Introduction 4. Historical Aspects Jobs syndrome: 2 girls with severedermatitis, fair skin, recurrentstaphylococcal infections with coldabscess formation, abnormal ininflammatory response, andhyperextensible joints. (Davis et al., 1966) Buckley syndrome: 2 boys with severedermatitis, recurrent cutaneous,pulmonary and joint abscesses,growth retardation, coarse facies,exaggerated with markedly elevatedserum IgE levels and eosinophilia.(Buckley et al., 1972)So went Satan forth from the presence of the Lord, and smote Job with sore boils from the sole of his foot unto his crown Job 2:7 Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 5. Classification Autosomal dominant Hyper-IgE syndrome (STAT3 mutation) Autosomal recessive Hyper-IgE syndrome Mutation in TYK2 Mutation in DOCK8 Unknown mutation Notarangelo LD, et al. JACI 2009;124:1161-78. 6. Autosomal Dominant Hyper-IgESyndrome (STAT3 Deciency) 7. Clinical CharacteristicsImmunologic Non-immunologic characteristics characteristics Newborn rash Characteristic face Boils Retained primary teeth Eczema Minimal trauma fractures Recurrent pneumonias Scoliosis Pneumatocoeles Hyperextensibility Mucocutaneous candidiasis Focal brain hyperintensities Elevated IgE > 2000 IU/mL Chiari 1 malformations Eosinophilia Craniosynostosis Increased incidence of Arterial aneurysmslymphoma Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 8. Grimbacher Chamlin SL,EbertingWoellner C, Olaiwan A et B, et al., et al.,CLD, et al.,et al., al., 1999 2002 200420102011Patients 30 pts, 3-58 8 pts, 1 wk 43 pts, 3-5064 pts21 pts, 2- 37 years11myears yearsDiagnosis of Clinical DxClinical DxHIES score; STAT 3STAT 3AD-HIESMean 61.2 mutationmutationNewborn rash NA 6 (75%) within 35 (81%)37/57 (64.9%) 14 (67%)4 wk within 35 d within 2 mBoils26 (87%) 3 (37.5%)36 (84%)58/64 (90.6%) 19 (90%)Eczema 30 (100%)5 (62.5%)28 (65%) (AD) 58/64 (90.6%) 20 (95%)R pneumonia26 (87%) NA NA61/64 (95.3%) NAPneumatocele 23 (77%) NA NA47/63 (74.6%) NAMC candidiasis 25 (83%) NA Positive25/58 (43.1%) 12 (59%)Elevated IgE 30 (100%)8 (100%) NA64 (100%) 21 (100%)(IU/ml)(1875-58200) (77-51000) (> 1000)(1000-32000)Eosinophilia 28 (93%) NA NA41/58 (70.7%) NA (712-2034) 9. GrimbacherChamlin SL, EbertingWoellner C, Olaiwan A etB, et al.,et al., CLD, et al.,et al., al.,19992002200420102011Patients30 pts, 3-588 pts, 1 wk 43 pts, 3-50 yr 64 pts21 pts, 2- 37years 11m yrDiagnosis ofClinical Dx Clinical Dx HIES score; STAT 3STAT 3AD-HIES Mean 61.2 mutationmutationCharacteristic25 (83%) NA34 (79%)58/64 (90.6%) 10 (47%) Allface(100% for pts adolescents> 16 yr)Retained18/25 (72%) NANA44/55 (80%) NAprimary teethMinimal trauma16/28 (57%) NANA27/59 (45.8%) NAfracturesScoliosis 19 (63%) NANA13/50 (26%) NA(76% for pts> 16 yr)Hyperextensibil 19/28 (68%) NANA29/55 (52.7%) NAity 10. Newborn rash The first manifestation of STAT3 deficiency begins within the first month of life Papulopustular eruptions at scalp and face neck, axillae, shoulders, arms, chest, diaperareas, and buttocks; Bacterial culture: S aureus DDx: Eosinophilic pustular folliculitis of infancy, erythema toxicum neonatorum, neonatalcephalic pustulosis Chamlin SL, et al. J Pediatr 2002;141:572-5.Eberting CLD, et al. Arch Dermatol. 2004;140:1119-25. Olaiwan A, et al. J Am Acad Dermatol 10.1016/j.jaad.2010.09.714. 11. Boils Classic and characteristic finding. Degree of inflammation is variable. Cold abscesses are common. Eczema Papular (prurigo-like) or papulopustular (folliculitis-like) DDx with AD: - Absent/mild lichenification, scales, generalized xerosis - Lack of other signs of atopy Chamlin SL, et al. J Pediatr 2002;141:572-5. Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. Olaiwan A, et al. J Am Acad Dermatol 10.1016/j.jaad.2010.09.714. 12. Recurrent Pneumonias Typically start in childhood. Fewer symptoms than in a normal person. Delay in clinical presentation. Respond promptly to antimicrobial therapy. OrganismsFreeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 13. Pneumotoceles Form during the healingprocess and usually persist. Pathogens: Gram-negative bacterial infection (typically Pseudomonas) Fungal infections (typically Aspergillus Indolent and difficult to clear Consequences: Rupture into large pulmonary vessels with life- threatening hemoptysis Fungal dissemination to the Pneumatoceles brainArrow indicates an aspergilloma Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 14. Other InfectionsMucocutaneous candidiasis Common Often are localized -- oral cavity, vagina, nails Systemic Candida infections are very rareand most likely are nosocomial.Cryptococcus and histoplasma infection Often are localized Disseminated form less frequently occurP jiroveci pneumonia 15. Characteristic Faces Develops throughchildhood & adolescence Facial asymmetry Broad nose Deep-set eyes Prominent forehead Rough appearance withexaggerated pore size offacial skinGrimbacher B. NEJM 1999;340:692-702.Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 16. Dental Abnormalities Retained primary teeth past the age of normal primary dental exfoliation. Other features - Central rhomboid glossitis - High-arched palate with central band-type protrusion - Prominent wrinkles on the oral mucosaGrimbacher B. NEJM 1999;340:692-702.Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 17. Musculoskeletal AbnormalitiesScoliosis Emerges during adolescence Similar pattern to idiopathic scoliosisHyperextensible joints may be related to the earlydevelopment of severe degenerativejoint disease, particularly of the spine Instability, chronic painMinimal trauma fractures Long bones, ribs, and pelvic bonesSevere degenerative spineOsteopenia in 48-y-old with AD-HIESFreeman AF, Holland SM. Pediatr Res 2009;65: 32R37R.Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 18. Cranial Abnormalities 50 pts, 3-52 years (mean 24) HIES score 29-100 (mean 69) 9/50 (18%) Type 15/50 (10%) Lacular infarctions Chiari malformations 2/50 (4%) Arachnoid cyst 1/50 (2%) Bilateral internal carotid bifurcation berryaneurysms with SAH, venous angioma of the frontal lobe,capillary telangiectasia of the pons, 3rd ventricle colloid cystCraniosynostosis35/50 (70%) Focal brain lesionswith high signal intensities(majority=subcortical & white matter) Freeman AF, et al. Pediatrics 2007;119:e1121-5. 19. Vascular Abnormalities 30 pts, 3-58 years 1/30 Occlusion of the central retinal artery (age of 18) 1/30 Berry aneurysm and bilateral aneurysms at the internal carotid bifurcations (age of 32) 1/30 Left cerebral embolus (age of 18) 1/30 Thrombotic stroke of the left PICA (age of 54)Grimbacher B, et al. NEJM 1999;340:692-702. Artery aneurysm is common. - Large aneurysm in the left anterior descending coronary artery MI 18 individuals studied by either cardiac CT or MRI (Freeman AF, Holland SM,Gharib A, unpublished data, 2008) - 14/18 Tortuosity and dilation - 4/18 AneurysmsFreeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28: 27791. 20. Malignancies Increased risk of malignancy Both Hodgkins and non-Hodgkins lymphoma have beendescribed, with the majority of the non-Hodgkins lymphomasbeing of B-cell origin with aggressive histology. Other cancers described in HIES Leukemia Cancers of the vulva, liver, and lung Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 21. Hematologic StudiesWhite blood cell counts in HIES are usually normal,but may not increase appropriately during acute infection.Eosinophilia is present in these patients, but is notcorrelated with the serum IgE level.It usually exceeds that present in atopic patients.Acute phase reactants during infection may not be ashigh as expected. Buckley RH. Clin Rev Allerg Immunol 2001;20:139-54. Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 22. Humoral ImmunityElevated serum IgESerum IgE typically peaksabove 2000 IU/mL and usuallyelevates even at time of birth.In adulthood the IgE level maydiminish over time in someindividuals and can normalize,despite persistence of clinicalabnormalities.20% of patients with HIESGrimbacher B. NEJM 1999;340:692-702.whose levels declinedFreeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 23. Humoral ImmunityRAST testing for specific antigens may yield positive results;however, this is confounded by the overall high IgE level.Serum IgG, IgA, and IgM typically are normal.Specific antibody responses are variable.Buckley RH. Clin Rev Allerg Immunol 2001;20:139-54.Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 24. Cellular ImmunityNormal numbers of CD3+, CD4+, and CD8+ lymphocytesDecreased proportion of CD45RO positive CD3+ T cellsLymphocyte responses to PHA, Con A, and PWMare normal.Lymphocyte responses to C albicans and tetanus toxoidare low.Decreased memory B cellsBuckley RH. Clin Rev Allerg Immunol 2001;20:139-54.Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 25. Phagocyte Normal PMN phagocytosis, metabolism, andkilling. Defect in chemotaxis (some cases). Complement Normal serum hemolytic complement activity. Buckley RH. Clin Rev Allerg Immunol 2001;20:139-54. 26. 40 points: Likely 20-40 points: Uncertain < 20 points: UnlikelyGrimbacher B, et al. Am J Hum Genet 1999;65:73544. 27. Mutations in AD-HIESSTAT3 MUTATION 28. JAK-STAT Pathway Levy DE. NEJM 2007;357:1655-8. 29. Levy DE. NEJM 2007;357:1655-8. 30. HIES can be transmitted as AD trait with variable expressivity. Proximal 4q region contains a disease locus for HIES. Grimbacher B, et al. Am J Hum Genet 1999;65:73544. 50 HIES, 48 unaffected relatives 35 independent and unrelated white, Asian, Hispanic, or blackfamilies HIES scores: 0 -15 as unaffected, 16 - 39 as possibly affected,40 - 59 as probably affected, and > 60 as definitely affected. Assay the levels of cytokines secreted by stimulated leukocytesand the gene expression in resting and stimulated cells. STAT3 sequencing in DNA samples. Holland SM, et al. NEJM 2007; 357:1608-19. 31. Holland SM, et al. NEJM 2007; 357:1608-19. 32. 7 patients had de novo STAT3 mutations. 17 had familial transmission of STAT3 mutations. 26 had sporadic STAT3 mutations. 1 of whom had chimerism for the STAT3 mutation. Mutational hot spots were apparent in DNA binding or SH2domains. All mutations are missense or in-frame deletions, consistent withprotein expression. Not find mutations in the 158 unaffected control subjects. Holland SM, et al. NEJM 2007; 357:1608-19. 33. Holland SM, et al. NEJM 2007; 357:1608-19. 34. STAT3 Mutations STAT3 is located on human chromosome 17q21. Ubiquitously expressed and not limited to immune cells. Predominantly missense and in-frame deletions. Normal STAT3 expression and trafficking to nucleus isobserved, but effector functions of are abnormal. Mutations are located predominantly in the SH2,transactivation, and DNA binding regions. No clear correlations between phenotype and the affected region of STAT3. Heimall J, Freeman AF, Holland SM. Clin Rev Allerg Immunol 2010;38:32-8. 35. Cytokines and JAK-STAT signaling STAT3 is activated by IL-6 family,Disease of IL-10 family, IFN, G-CSF, and leptin both too little & too muchinflammationIL-6, TGF-, MCP-1Regulation of Key Cytokines: IL-6, IL-10, IL-17, IL-21, and IL-22IL-12, IFN-, TNF- Heimall J, Freeman AF, Holland SM. Clin Rev Allerg Immunol 2010;38:32-8. 36. STAT3 function Up-regulation Down-regulation Myeloid adhesion Expression of T-bet, Expression ofGATA3, IL12Rb2, andsecondary granuleIFN-,proteins in neutrophils Formation of IL-23 receptor osteoclasts Th17 cells Antiinflammatoryeffects of interleukin-10Holland SM, et al. NEJM 2007; 357:1608-19. 37. Immunophenotype & STAT3 mutationManifestationsPossible mechanismsBoils Ligand binding of the receptor for IL-22 expressed predominantly on epithelial cells (skin and lung) invokes STAT3-mediated expression of -defensins Cold abscess: lack of inflammatory responses governed by IL-6Skin Mouse keratinocytes lacking STAT3 were associated with normal initial hair growth but aberrant hair follicles in subsequent growth cycles, leading to epidermal hyperplasia and keratosis. Mice demonstrated poor wound healing after biopsy.MC candidiasis Impaired IL-17 expression & Th17 differentiationHeimall J, Freeman AF, Holland SM. Clinic Rev Allerg Immunol 2010;38:328. 38. Th17 differentiationTh17 cells Defense against fungi andextracellular bacteria Role in neutrophil recruitment& activation Antimicrobial peptideexpression Heimall J, Freeman AF, Holland SM. Clinic Rev Allerg Immunol 2010;38:328. 39. IL-17 Regulates Immune Responses Afzali et al., 2007 Clin. Exp. Immunol. 40. Hanna S, Etzoni A. JACI 2011;127:1433-7. 41. Impaired Th17 differentiationin AD-HIES Impaired expression of RORt mRNA. Purified nave T cells were unable to differentiate toTH17 cells in the presence of a cocktail of cytokines(IL-1b, IL-6, and IL-23). Diminished circulating TH17 cells. Cells from patients did not secrete either IL-17 or IL-22. Increased risk of fungal infection. Ochs HD, Oukka M, Torgerson TR. JACI 2009;123:977-83. 42. Immunophenotype & STAT3 mutation Manifestations Possible mechanismsRecurrent pneumonia Multiple mechanismsPneumatocoeles Pulmonary epithelium-STAT3 deficiency shows excessive inflammation and airspace enlargement with poor repression of inflammatory responseElevated IgE Human: IL-21 induces IgE secretion and synergizes with IL-4 to promote IgE synthesis by B cells Reduced production of IL-10 by CD4+ T cells may contribute to sustained IL-4 signaling in HIES B cells.Eosinophilia Reduced production of IL-10 by CD4+ T cells may contribute to sustained IL-4 signaling in HIES B cells.Ozcan E, Notarangelo LD.Geha RS. JACI 2008;122:1054-62.Heimall J, Freeman AF, Holland SM. Clin Rev Allerg Immunol 2010;38:32-8. 43. Immunophenotype & STAT3 mutationManifestationsPossible mechanismsBone Myeloid-specific STAT3-deficient mice have increased osteoclast numbers and activity. Increase formation of osteoclasts & higher bone resorption activity of osteoclasts in HIES patients Decreased IL-10 activity and increased TNF- levelBrain Astrocyte-specific STAT3 deficiency in mice led to increased inflammation and demyelination after neurologic injury ? Disruption of IL-6 signaling in astrocyte differentiationHeart Cardiac myocyte-specific STAT3 deficiency in mice is associated with decreased endothelial but increased fibroblast proliferation. After stimulation with LPS, increased TNF levels with subsequent cardiac inflammation. Heimall J, Freeman AF, Holland SM. Clinic Rev Allerg Immunol 2010;38:328. 44. Objectives: To determine correlation between genotype & phenotype of HIES patients To establish diagnostic criteria to distinguish between STAT3 mutated &STAT3 wild-type patientsPatients: 100 unrelated patients (61 male; age 1-58 years) Strong clinical suspicion of HIES 80/100 HIES scores > 40 IgE >1000 IU/mL,Methods: Clinical data collection TH17 cell numbers determination STAT3 sequencing Woellner C, et al. JACI 2010;125:424-32. 45. ResultsSTAT3 sequencing: 64/100 STAT3 mutation 36/100 No mutation in coding regions or their anking intronic sequences Woellner C, et al. JACI 2010;125:424-32. 46. Diagnostic guidelines for STAT3-mutant HIESPossible: IgE > 1000 IU/mL + a weighted score of clinicalfeatures >30 based on recurrent pneumonia, newbornrash, pathologic bone fractures, characteristic face, andhigh palateProbable: These characteristics + lack of TH17 cells or afamily history for definitive HIES.Definitive: These characteristics plus a dominant-negativeheterozygous mutation in STAT3. Woellner C, et al. JACI 2010;125:424-32. 47. Objectives: To differentiate atopic dermatitis patients from patients with STAT3mutationPatients: 78 patients (50 male; age 8 months-57 years; median 20 years) Possible HIES: increased serum IgE levels, eczema, staphylococcalinfections, no other well-defined PIDD, HIES scores > 20 points (except for3 patients with HIES score 14 points)Methods: Clinical phenotypes (HIES score > 40 points) TH17 cell numbers determination STAT3 sequencingSchimke LF, et al. JACI 2010;126:611-7. 48. ResultsSchimke LF, et al. JACI 2010;126:611-7. 49. Clinical key findings combinedwith TH17 cell countspredict patients with HIES with STAT3 mutations 50. Treatment of AD-HIES Effective skin care Pneumonia Bleach baths Lower threshold for investigating slightchanges in Swimming in chlorinated poolssigns and symptoms. Topical steroids help in difficult cases Bronchoscopy is helpful to recover the pathogenand to assist with clearance of mucus and pus. Prophylactic drugs Antimicrobial prophylaxis to prevent S aureus infection Pneumatoceles of trimethoprim twice daily) may be(e.g., 2.5 mg/kg broadened if gram-negative lung infections occur.Resection of the large pneumatocoeles that Antifungal prophylaxis to prevent pulmonarysometimes form following pneumonia is complex.aspergillosis remains attractive but unproven, but it ishighly effective in treating and preventingmucocutaneous candidiasis. Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 51. Treatment of AD-HIES Levamisole Inferior to placebo IVIG Decrease number of infections for some patients Omalizumab Bone marrow transplantation Bisphosphonates Improved BMD without adverse events, ? fewer fractures Coronary artery aneurysms or other blood vessel abnormalities undefinedFreeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91. 52. Objectives: To identify the cause of death in patients with HIES To describe pathologic findings in fatal HIESMethods: Reviewed the medical records and autopsy slides of 6 patients with HIES Freeman AF, et al. JACI 2007;119:1234-40. 53. Other causes of death In patients with HIES and lymphoma, 7 of 11 withreported outcome died, with at least 5 secondary tothe lymphoma. Leonard GD, et al. Leuk Lymphoma2004;45:2521-5. 54. Autosomal RecessiveHyper-IgE Syndrome 55. Methods 13 patients from 6 consanguineous families and 68 of their relatives. Unusual, severe, recurrent infections and eczematoid rashes Elevated serum IgE levels (1992-45100 IU/ml) and eosinophilia(2610-17874/ul) All patients > 1yr old fulfilled the clinical triad of HIES : recurrent skinabscesses, recurrent pneumonia, and elevated IgE levels HIES scores with AR-HIES > 1 yr old ranged from 36 to 53 All 68 relatives had < 20 points, unlikely to be affected by HIES Renner ED, et al. J Pediatr 2004;144:93-9. 56. ResultsInfections features Skin abscesses in AR-HIESwere amost frequently caused by S. Severe eczematoid rashes were universal finding. In 3 patients, aureus. occurred within the 1st 6 wk of life, the others developed eczema Other bacterial infections yr. severe eczema by age 3 included fatal sepsis caused by S. aureus, Escherichia coli, Enterococcus faecalis caused by Staphylococcus > 4 URTI/yr, respiratory infections were Chronic Haemophilus influenzae, Proteus mirabilis, Pseudomonas aureus, candidiasis of mucosal sites (10/13) aeruginosa, and Cryptococcus neoformans 4 patients had chronic molluscum contagiosum infection Pleural effusion or empyema often accompanied pneumonia. In AD- 7 patients had recurrent herpes simplex infections HIES, pneumonias tend to form lung abscess and pneumatoceles, 1 patient had recurrent varicella-zoster infection these did not occur in the 13 patients with AR-HIES.Renner ED, et al. J Pediatr 2004;144:93-9. 57. ResultsImmunologic featuresDental and Skeletal Abnormalities High levels of IgE and eosinophilia primary teeth was notFailure or delay of shedding of the were persistent in all patientswith AR-HIES in the AR-HIESdocumented AR-HIES patients had significantly higher development, 2 required5 subjects with AR-HIES had normal dental eosinophil counts whenprimary tooth extractions because of severe caries, and 6 patientscampared with the large cohort of sporadic HIES and AD-HIES casespublished by Grimbacher et al. (P 20. 17/21 (81%) patients had candidiasis.Engelhardt KR, et al. JACI 2009;124:1289-302. 68. 21/21 (100%) had severe AD. 10/21 (48%) had multiple food allergies. 7/21 (33%) had asthma. 6/21 (29%) had environmental allergies. 4/21 (19%) had meningitis. 2/21 (10%) had JC virus-associated progressive multifocalleukoencephalopathy. 2/21 (10%) had CNS vasculitis. 1/21 (5%) had brain infarction. 1/21 (5%) had Burkitt lymphoma. 1/21 (5%) had AIHA.Engelhardt KR, et al. JACI 2009;124:1289-302. 69. Elevated serum IgE2830-90,910 IU/mL (median 20,225). Eosinophilia290-37,880 cells/mL (median 5675). 38% Decreased total T-cell numbers. 54% Decreased CD4+ T cells. 25% Decreased CD8+ T cells T-cell proliferative defect affected both CD4+ and CD8+ subsets. 54% Increased B cells, 46% normal range. 92% Normal NK cells. 85% Normal IgG serum levels. 62% Normal IgA serum levels. 77% Decreased IgM serum levels. Engelhardt KR, et al. JACI 2009;124:1289-302. 70. Su HC. Curr Opin Allergy Clin Immunol 2010:51520. 71. Dedicator of cytokinesis 8 (DOCK8) DOCK8 gene is chromosome 9p24.3. Members of the DOCK protein family. Cells of immune system, especially bylymphocytes; placenta, kidney, lung, pancreas. Plays a critical role in cytoskeletal organization. DOCK8 deficiency Impaired T-cell activation and effector responses. Impaired TH17 differentiation caused by a failure inthe maintenance of memory TH17 cells. Engelhardt KR, et al. JACI 2009;124:1289-302.Su HC. Curr Opin Allergy Clin Immunol 2010:51520. 72. Rezaei N, et al. J Allergy Clin Immunol 2011;127:1329-41. 73. Chu EY, Freeman AF, Jing H, et al. Arch Dermatol 2011; doi:10.1001 /archdermatol.2011.262 74. Treatment of AR-HIES Less explored than therapy for STAT3 deficiency Decrease S aureus colonization: bleach baths,topical antiseptics, or antimicrobials. Eczema: corticosteroids Viral infections of the skin HSV: Valacyclovir, acyclovir Warts and molluscum contagiosum: topicalimiquimod, cidofovir, and interferon-Su HC. Curr Opin Allergy Clin Immunol 2010:51520. 75. Treatment of AR-HIES IVIG: decrease the frequency of sinopulmonary infections. Bone marrow transplantation: controversy a 8-year-old child with DOCK8 deciency, congenital splenia. 2 DOCK8 deficiency patients have undergone myeloablative & reduced Allogeneic HCT after myeloablative conditioningintensity conditioning Full donor chimerism early after transplant.followed by allogeneic HCT. Day 4 years follow-up: complete & stable engraftment, near normalized +58 post-HCT: High fever and septic shock.lymphocyte functions and completely resolved M contagiosum and She died 6 hours later ofrecurrent HSV infections. overwhelming K pneumoniae bacteremia.Gatz SA, et al. Bone Marrow Transplant 2010 McDonald DR, et al. JACI 2010;1304-5.Su HC. Curr Opin Allergy Clin Immunol 2010:51520. 76. STAT3 Mutation in the OriginalPatient with Jobs Syndrome This patient is now 50years of age Lifelong eczema Multiple atraumatic First patient who was described as Jobs Syndromefractures Hyperkeratoticfingernails (candida What is the mutation?infection) Recurrent S aureusabscesses Recurrent S aureuspneumonia with lungSTAT3 gene: heterozygous point mutation abscesses andin exon 12 (1144CT; protein, R382W)pneumatoceles Renner ED, et al. NEJM 2007;357:1667-8. 77. Take-home messages Notarangelo LD, et al. JACI 2009;124:1161-78. 78. Company LOGO 79. 26-year-oldskin withwith severeLichenified woman extensive unremitting eczematous erythema and eczematous dermatitis poorly controlled by plaques hypersensitive to light tacrolimus and systemic dry scaly touch, excoriations, and steroidsDermatitis since birth, multiple plaques along the flexor surfaces cutaneous complications of upper and lower extremities, chest, and back.Omalizumab 450 mg SC q 2 weeksViral meningitis, recurrent infectious bronchitis,Hypertelorism, widened nasal pneumonias, and cystitisroot and alae, scoliosis, and teeth Retained several of primary joint hyperextensibility.Controlled asthma and allergicEosinophil 9.2% rhinitisIgE 1083 IU/mL AIHA, HCV infection, alopecia universalis, autoimmune hypothyroidismHIES score 41 points Marked improvement after 1 month of Rx.Bard S, et al. Arch Dermatol 2008;144:1662-3. Complete remission after 3 months of Rx. 80. 32 year-old Thai woman with pruritic skin lesions onNail clippings: Candida spp face, upper back and extremities for 2 yearsEosinophils 12% (AEC 1,476 cells/l) History of recurrent multiple abscesses on scalp, IgE 17,300 IU/mlalopecia universalis HIES score 30 points No history of atopic diseases, lung diseases, or dentalor skeletal abnormalities Treatment Omalizumab 300 mg SC erythematous not Multiple discretesteroid and topicalweeks Potent topical and confluentq 2 tacrolimuspapules improvedand plaques on the trunk, back, and all extremities Marked corticosteroids improved, of could not Systemicimprovement after 1 monthbut Rx Onychodystrophy be stopped Normal dentition systemic no scoliosisDiscontinues and face, corticosteroidsChularojanamontri L, et al. APJAI 2009;27:233-6. 81. Bone Marrow Transplantation An adult who died of transplantation-related complications 6 months after transplantation but with decreased serum IgE levels and fewer HIES- related symptoms. (Nester TA et al., 1998) A 7-year-old girl experienced a relapse of HIES 4 years after transplantation, despite full donor chimerism in all leukocyte lineages. (Gennery AR et al., 2000) Goussetis E, et al. JACI 2010;126:392-3. 82. Rosenzweig SD, Holland SM. Immunological Reviews 2005;203:38-47.