NB rashChamlin:ภายใน 4 อาทิตย์ (1 week=3; 2 week=2; 4 week=1); 6 mo=1; 11 mo=1Eberting: HIES score 26-39: 5/43; > 40: 38/43; 8 (19%) ทันที; 23 (53%) 7 days; 32 (74%) first 14 days; 34 (79%) first 30 days; เฉลี่ย 7 daysOlaiwan: 10/14 (71%) ที่มาก่อน 2 m เกิดพร้อมผื่นหรือภายใน 2 wkEczemaEberting: UK criteria AD = คัน + >3 (1) history of involvement of the skin creases such as folds of elbows (antecubital), behind the knees (popliteal), fronts of ankles, or around the neck (including cheeks in children younger than 10 years); (2) a personal history of asthma or hay fever (or history of atopic disease in a first-degree relative in children younger than 4 years); (3) generally dry skin in the past year; (4) flexural dermatitis at the time of examination; and (5) onset before age 2 years (criteria not used in children younger than 4 yearsOlaiwan: 16/21 (77%) patients had no personal history of hay fever or asthma, or a ﬁrst-degree relative with AD
Min trauma fx = > 3 ครั้ง
Bx: Eofolliculitisspongiosis, exocytosis involving infundibular region of hair EPFsame distribution, appearance, and histologic characteristics-ต่าง = ages 5 and 10 months, Cultures of thepustules were sterile, does nottend to improve with antibiotic treatment and will sometimes improve with topical steroid treatmentETN-same: appearance, age of onset, distribution, and histologic characteristics-ต่าง = resolves in 1 to 5 days. Milder recurrences may occur within 5 to 11 days after the original eruption.NCP-คล้ายมาก ต่างที่ distribution ของ NCP limit กว่า
Histoplasmosisof the tongue or intestinal cryptococcal infection
Failure of the primary teethto exfoliate, not of the secondary teeth to develop or to eruptAt times, layers of both primaryand secondary teeth are present simultaneously when the secondary teethemerge although the primaries have not fallen out. A shows the lower canines of Patient 8 (age, 11 years)B shows the upper central incisor of Patient 4 (age, 8 years)and a high palate. Persistent deciduous teeth required extraction in both subjects. Panel C shows a panoramic radiograph of Patient11 (age, 23 years)retention of five primary teeth with unresorbed rootseruption of four upper and lower premolarshas been blocked by retained primary teethretained deciduous right lower canine can be seen behind and lateral to itserupted permanent counterpartIn contrast, timely removal of unshed primary teeth in the upper left quadrant of the patient’smouth (upper right) allowed normal eruption of the premolarsCentral depressions in the tongue (central rhomboid glossitis) may becaused by or become secondarily infected with Candida
Scoliosis+associated leg length discrepancy; in others scoliosis develops or worsens after thoracotomy for lung infectionsVariesin severity, and some individuals have required surgical stabilization orcorrectionHyperextensibilityBoth large and small joints-Authors have seen in several patients in their20s to 40s. -Several patients have required stabilization procedures as early asin their third decade, and many suffer from chronic pain caused by extensivearthritis.FxIncreased bone resorptionHealing seems to be normal after surgery or fractures
4had HIES scores <40; 3 of these patients were <10 yearsFocal hyperintensitiesแปรตามอายุ
WBC -relative neutropenia has been seen
It is importantto keep in mind the natural change in IgE levels over time: they usually areundetectable in cord blood and rise to the adult range slowly over the years.The normal IgE level is less than 130 IU per milliliter, as indicated by the dark shading; the mean (±SD) IgE levelsof patients with the hyper-IgE syndrome in this study are indicated by light shading. To convert values for IgE tomicrograms per liter, multiply by 2.4
SPT positive to variety of food, inhalant, bacterial, and fungal antigensClinically apparent allergies do not seem to be increased in HIESIgG, A, M อาจลด (IACNA 2008), อาจเพิ่ม (Steim)
Highly variable chemotactic abnormalities (not present in most)
Wild-type amino acids at the loci where mutations were found are listed immediately below the STAT3 domains, with all the mutant amino acids identified in our study listed below that.The five hot-spot sites, those with multiple mutations, were found in both the DNA-binding and SRC homology 2 (SH2) domainsarginine (R) , phenylalanine (F), valine (V)The hyper-IgE syndrome scores generally correlated well with the STAT3 genotypesFunctional studies- Phosphorylation and expression of STAT3 was equivalent in the leukocytes from patients and those from controls- Trafficking of STAT3 from the cytoplasm into the nucleus of leukocytes from patients was grossly normal.- Superoxide production by neutrophils from patients was normal- Rates of spontaneous and phagocytosis-induced apoptosis did not differ bet. PMN form HIES patients and control
that lead to production of protein with dominant negative activityMutations in the STAT3 DNA-binding domain causedefective IL-6 and IL-10 signaling due to poor binding oftarget DNA and subsequent activation of relevant promotersequences.Mutations within the SH2 domain interfere with STAT3 phosphorylationMutations in the DNA-binding, SH2, andtransactivation domains deleteriously affect the generation ofTH17 cells.
- Poor wound healing isnot typically described in HIES- Although, these findings may relateto the characteristic porous facial skin, the oralmucosal abnormalities, and eczema that develop inHIES over time.
hBD2,3Mice: IL-21 downregulates IL-4–dependent IgE production inB cells
Bone = IL-10normally acts to inhibit osteoclast activity, while TNFαincreases osteoclast development and activity.TNFαalso has an inhibitory effect on osteoblasts, which maycompound the osteopenia.
Over the period of the last 8 years, we have collected a cohort of 228patientswith the suspected diagnosis of HIES in a worldwide collaboration; 55of these patients have been published elsewhere เหลือ173 เอามา 10072 patients came from Europe, 20 from theMiddle East, 7 from South America, and 1 from North America.>40 suggesting that these patientsprobably had HIES, 20 patients had scores below 40, suggesting adiagnostic uncertainty or a variant of HIES
31 distinct mutations46 patients carried previously described mutations,18 patients harbored distinct, novel mutations.Prospectively scoredthe 100 patients according to the NIH-HIES leave-1-out error estimates for all feature sets testedThere were 12 sets with a leave-1-out accuracy of 85%Of the 12 sets, 1 had 5 features,and 11sets had more than 5 featuresAControl: 11/12 > 1% of IL-17–producing CD41 T cellsSTAT3 mutation group: 13/17 had <0.5% of IL-17–producing CD4+T cellsSTAT3 WT group: 3/17 had <0.5% of IL-17–producing CD4+T cellsBSTAT3 mutation:signiﬁcantly lower frequencies of IFN-g–producing CD41 T cells than healthy controls ; had but signiﬁcantly higher frequencies than patients without STAT3 mutation (P 5 .007)STAT3 WT group: IFN-g–producing CD41 T cells < controls ;1 had >5% IFN-g–producing CD41 T cells.
None of the scores should be used tokeep physicians from pursuing a molecular diagnosis in aparticular patient. Patients with HIES accrue ﬁndings over time.-Aggressive treatment with antibiotics can forestall infectiouscomplications that would be diagnostic if allowed to occur.-Moreover, the unique feature of HIES that abscesses or otherinfections are ‘‘cold,’’ or not accompanied by a normal intensity ofpain or inﬂammation, has not been captured by any score, butshould increase clinical suspicion. -HIES scoring will not replacegood clinical judgment but may help the diagnostic process.- The aim of the proposed guidelines is to discern patients withHIES carrying mutations in STAT3 to facilitate time-saving andresource-saving diagnosis of patients, thereby leading to an earlyand effective treatment. -This screening tool will need to be evaluated and updated as new knowledge is revealed and new mutations causing HIES are identiﬁed. -We acknowledge that mostclinicians will continue to diagnose HIES with its key clinical features.-When itcomes to the question whether to evaluate STAT3, however, thisscoring should be used.
Before the association with heterozygous STAT3 mutationswas discovered, the diagnosis of AD-HIES depended on clinical findings and was often delayed until complications developed. NIHscoring system based on the presenceand severity of 21 clinical and laboratory findingshas beenwidely used to identify patients with HIES. Possibility that patients with only a few clinical findings of HIES carry STAT3 mutations Toinitiate optimal therapy at an early age before serious complications occur
Combination:Pneumonia, abscess formation, and oralcandidiasis were present in only 3 of 30 patients (10%) withwild-type STAT3, including a patient with a homozygousDOCK8 mutation, compared with 23 of 48 patients (48%) with STAT3Bone, face, joint กลุ่ม STAT3 มากกว่าBased on an NIH score of 40 points or greater49/78patients qualiﬁed as having clinically deﬁned HIES (NIH scorerange, 40-89). Mutation 46, WT 3 3 คนที่ score > 40 แต่ไม่ใช่ STAT31. 52 points homozygous DOCK8 mutation 2. ดช 9 ปี 43 points, severe eczema, pneumonia, and mucocutaneous Candida albicans and recurrent staphylococcal skin infections, หน้าเปลี่ยนน้อยๆ3. ดญ2 ปี 43 points, severe eczema, pneumonia, and mucocutaneous Candida albicans and recurrent staphylococcal skin infections, atraumatic femur fracture2 score ranging from 20 to 39 points carried heterozygous STAT3 mutations 1. ดช3 ปี (34) 2. ชาย 19 ปี (37)
BB = 120 mL bleach in a tub of water, soaked in for 15 minutesthree times weeklySteroid = Systemic immune suppression usually is not necessary,because there typically is an excellent response to antimicrobials Because STAT3-deﬁcient patients often feel well and have minimal fever despite signiﬁcantinfection, it is good to have asuch as new cough, chest discomfort, or fatigue, even in the absence of fever.PneumatocoeleThese large cysts may become secondarily infected and be a source of infection, bleeding, and possibly death.On theother hand, thoracic surgery can be complicated by poor expansion of theremaining lung after surgery, often resulting in thoracoplasty.If pneumatocoeles persist formore than 6 mo, surgical excision should be strongly considered because the cysts may enlarge and compress adjacent normal lung, become infected with other organisms, or predispose to fungusballFormation (Buckley 2001)
Levamisoleunusual antihelminthic drug stimulates T-cell and natural killer–cell function.
4 male and 9 female were offspring of consanguineous matingsOnly one generation of each family AR5 families from Turkey and 1 family from MexicoAt diagnosis, patients were between 6 mo. and 5 yrs. Old8 patients have died at ages ranging from 6 mo. to 12 yrs.
TYK2 is the 1st member of the Jakkinase familyEssential for type I IFN signalingNo mutations IL-12 p40, IL-12Rb1, IFNGR1, IFNGR2, and STAT1CD4+T cells isolated from the patient’s PBMCs failed to produce detectable amounts ofIFNg when stimulated with IL-12 plus IL-18T cells also failed to respond to IFNaSTAT4 was expressed at a normal amount in the patient’s T cellsThe second candidate we investigated was Tyk2TYK2 deficiency highlighted the obligatory roles of human TYK2 in multiple cytokine signals involved in innate and acquired immune responses, including type I IFN, IL-6, IL-10, IL-12, IL-23 signalsSusceptibility to infection with intracellular bacteria, such as mycobacteria and salmonella, could be explained by the defect in IL-12 signaling, as seen in IL-12Rβ1 deficiency
HSV (recurrent or persistent orolabial or anogenital involvement, keratitis, or eczema herpeticum)atopic dermatitis with scattered superimposed molluscumcontagio-sum lesions on the inside of the arm (Panel A), chronic ulcerative anogeni-tal herpes simplex virus infection (Panel B), periungual and acral warts (Panel C), and molluscumcontagiosum on the back (Panel D)
-Dermatitis in patients with DOCK8 deficiency wastypically observed in the classic distribution for atopicdermatitis and was more severe than in Job’s syndrome. (90% vs b65%)-asthma and allergies, particularly anaphylaxis to foods, are uncommon in Job’s syndrome.-skeletal and dental abnormalities commonlyfound in Job’s syndrome, including coarse facial features, retention of primary teeth, joint hyperextensibility, and pathologic fractures, were rarely seen in patients with DOCK8 deficiency
Steroid : worsen viral infections, andwhen discontinued the eczema can ﬂareVirus : extremely difﬁcult tomanage
However, the immunoglobulin infusions do not affectthe viral infections, which is consistent with ﬁndings thatpatients already have protective titers to HSV or VZV
This patient (Subject II-3),1 who is now 50 years of age, has had lifelong eczema, multiple atraumatic fractures, hyperkeratotic fin-gernails owing to candida infection, recurrent Staphylococcus aureus abscesses, and pneumonia with lung abscesses and formation of pneumatoceles. She gave birth to three boys by two fathers. Her first son (Subject III-1) died 3 days after birth from pneumonia and sepsis with Pseudomo-nasaeruginosa and acinetobacter. Her second son (Subject III-3) was hospitalized shortly after birth with S. aureus pneumonia. Later, eczema developed, along with rising IgE levels (104,000 IU per milliliter in his second year of life [normal value, <64]), multiple skin abscesses, candidiasis, pneumonia with formation of pneumatoceles, and spontaneous rib factures; he also retained his primary teeth. At 28 years of age, he underwent lobectomy because of multiple pneumatoceles and persistent S. aureus and aspergillus infections. He died at the age of 29 years from respiratory failure. His 8-month-old son (Subject IV-1) was hospitalized at 3 months of age with failure to thrive, pneumothorax, S. aureus pneumonia with ab-scess formation, empyema, and multiple rib fractures. His current IgE level is 45 IU per milliliter (normal value, <15).
Case 2 serumIgE once again became elevated, and infections recurred despite engraftmentof the donor cellsHLA-identical siblingMyeloablativeconditioning with 16 mg/kg busulfan, 40 mg/kg VP-16, and 200 mg/kg cyclophosphamideDonor bone marrow nucleated cellswere infused. Prophylaxis for GVHD:cyclosporine (until day 180) and methotrexate, 15 mg/m2on day 1 and 10 mg/m2on days 3 and 6 aftertransplantation. Myeloid engraftment for patients 1 and 2 occurred on days 111 and114, respectively.Platelet engraftment occurred on days 120 and 127, respectively. In the earlyposttransplantation period, both patients had severe hemorrhagicenteritis caused by adenoviral infection.In addition, patient 1 had severe hemorrhagic cystitison day 124 that resolved completely after 5 weeks. Neitherpatient had acute or chronic GVHD. Complete donor-derived hematopoietic chimerism has consistently been detected after day160 after transplantation by studying short tandem repeats. Fulldonor chimerism was also detected on puriﬁed CD31 cells atboth patients’ most recent follow-up visit. IgE levels were normal(<250 IU/mL) 2 months after transplantation
function as a GEF for the Rho-GTPases Cdc42and Rac1 active, GTP-bound form on receptor engagement (eg, receptor tyrosinekinases, antigen receptors, and adhesion receptors). An unknown protein possibly stabilizes theinteraction of DOCK8 with Cdc42 and Rac1.GTPase activation induces dynamic ﬁlamentousactinrearrangements and lamellipodia formation, possibly via WASP cell growth, migration, andadhesion. Given the clinical phenotype of the AR-HIES patients with DOCK8 deﬁciency, we propose animportant role of DOCK8 in T-cell actin dynamics, which might be important for the formation of the im-munologic synapse, leading to T-cell activation, proliferation, and differentiation.
Hyper-IgE SyndromePiyawadee Lertchanaruengrith, MD Company LOGO 18/11/2011
Topic Outlines Introduction Clinical manifestation, Immunological profiles, and Immunophenotypes of Autosomal dominant Hyper-IgE syndrome (STAT3 mutation) Autosomal recessive Hyper-IgE syndrome Mutation in TYK2 Mutation in DOCK8 Unknown mutation
Historical Aspects Job’s syndrome: 2 girls with severe dermatitis, fair skin, recurrent staphylococcal infections with cold abscess formation, abnormal in inflammatory response, and hyperextensible joints. (Davis et al., 1966) Buckley syndrome: 2 boys with severe dermatitis, recurrent cutaneous, pulmonary and joint abscesses, growth retardation, coarse facies, exaggerated with markedly elevated serum 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.
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.
Grimbacher Chamlin SL, Eberting Woellner C, Olaiwan A et B, et al., et al., CLD, et al., et al., al., 1999 2002 2004 2010 2011Patients 30 pts, 3-58 8 pts, 1 wk – 43 pts, 3-50 64 pts 21 pts, 2- 37 years 11m years yearsDiagnosis of Clinical Dx Clinical Dx HIES score; STAT 3 STAT 3AD-HIES Mean 61.2 mutation mutationNewborn rash NA 6 (75%) within 35 (81%) 37/57 (64.9%) 14 (67%) 4 wk within 35 d within 2 mBoils 26 (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 pneumonia 26 (87%) NA NA 61/64 (95.3%) NAPneumatocele 23 (77%) NA NA 47/63 (74.6%) NAMC candidiasis 25 (83%) NA Positive 25/58 (43.1%) 12 (59%)Elevated IgE 30 (100%) 8 (100%) NA 64 (100%) 21 (100%)(IU/ml) (1875-58200) (77-51000) (> 1000) (1000-32000)Eosinophilia 28 (93%) NA NA 41/58 (70.7%) NA (712-2034)
Grimbacher Chamlin SL, Eberting Woellner C, Olaiwan A et B, et al., et al., CLD, et al., et al., al., 1999 2002 2004 2010 2011Patients 30 pts, 3-58 8 pts, 1 wk – 43 pts, 3-50 yr 64 pts 21 pts, 2- 37 years 11m yrDiagnosis of Clinical Dx Clinical Dx HIES score; STAT 3 STAT 3AD-HIES Mean 61.2 mutation mutationCharacteristic 25 (83%) NA 34 (79%) 58/64 (90.6%) 10 (47%) Allface (100% for pts adolescents > 16 yr)Retained 18/25 (72%) NA NA 44/55 (80%) NAprimary teethMinimal trauma 16/28 (57%) NA NA 27/59 (45.8%) NAfracturesScoliosis 19 (63%) NA NA 13/50 (26%) NA (76% for pts > 16 yr)Hyperextensibil 19/28 (68%) NA NA 29/55 (52.7%) NAity
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.
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.
Recurrent Pneumonias Typically start in childhood. Fewer symptoms than in a normal person. Delay in clinical presentation. Respond promptly to antimicrobial therapy. Organisms Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91.
Pneumotoceles Form during the healing process 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 brain•Arrow indicates an aspergilloma Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91.
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
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.
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 mucosa Grimbacher B. NEJM 1999;340:692-702. Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91.
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 bones Severe degenerative spineOsteopenia in 48-y-old with AD-HIES Freeman AF, Holland SM. Pediatr Res 2009;65: 32R–37R. Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91.
Cranial Abnormalities• 50 pts, 3-52 years (mean 24)• HIES score 29-100 (mean 69) 9/50 (18%) Type 1 5/50 (10%) Lacular infarctions Chiari malformations • 2/50 (4%) Arachnoid cyst • 1/50 (2%) Bilateral internal carotid bifurcation berry aneurysms with SAH, venous angioma of the frontal lobe, capillary telangiectasia of the pons, 3rd ventricle colloid cyst Craniosynostosis 35/50 (70%) Focal brain lesions with high signal intensities(majority=subcortical & white matter) Freeman AF, et al. Pediatrics 2007;119:e1121-5.
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 Aneurysms Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28: 277–91.
Malignancies• Increased risk of malignancy• Both Hodgkin’s and non-Hodgkin’s lymphoma have beendescribed, with the majority of the non-Hodgkin’s 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.
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.
Humoral Immunity Elevated serum IgE Serum 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.
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.
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 cells Buckley RH. Clin Rev Allerg Immunol 2001;20:139-54. Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91.
Phagocyte Normal PMN phagocytosis, metabolism, and killing. Defect in chemotaxis (some cases). Complement Normal serum hemolytic complement activity. Buckley RH. Clin Rev Allerg Immunol 2001;20:139-54.
• 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;65:735–44.• 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.
Holland SM, et al. NEJM 2007; 357:1608-19.
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 SH2 domains. All mutations are missense or in-frame deletions, consistent with protein expression. Not find mutations in the 158 unaffected control subjects. Holland SM, et al. NEJM 2007; 357:1608-19.
Holland SM, et al. NEJM 2007; 357:1608-19.
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 is observed, 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.
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 muchinflammation IL-6, TGF-β, MCP-1 Regulation of Key Cytokines: IL-6, IL-10, IL-17, IL-21, and IL-22 IL-12, IFN-γ, TNF-α Heimall J, Freeman AF, Holland SM. Clin Rev Allerg Immunol 2010;38:32-8.
STAT3 function Up-regulation Down-regulation Myeloid adhesion Expression of T-bet, Expression of GATA3, IL12Rb2, and secondary granule IFN-γ, proteins in neutrophils Formation of IL-23 receptor osteoclasts Th17 cells Antiinflammatory effects of interleukin- 10 Holland SM, et al. NEJM 2007; 357:1608-19.
Immunophenotype & STAT3 mutationManifestations Possible mechanismsBoils • Ligand binding of the receptor for IL-22 expressed predominantly on epithelial cells (skin and lung) invokes STAT3-mediated expression of β-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 differentiation Heimall J, Freeman AF, Holland SM. Clinic Rev Allerg Immunol 2010;38:32–8.
Th17 differentiationTh17 cells Defense against fungi and extracellular bacteria Role in neutrophil recruitment & activation Antimicrobial peptide expression Heimall J, Freeman AF, Holland SM. Clinic Rev Allerg Immunol 2010;38:32–8.
Impaired Th17 differentiation in AD-HIES• Impaired expression of RORγt mRNA.• Purified naïve 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.
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.
Immunophenotype & STAT3 mutationManifestations Possible 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-α 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 TNFα levels with subsequent cardiac inflammation. Heimall J, Freeman AF, Holland SM. Clinic Rev Allerg Immunol 2010;38:32–8.
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.
ResultsSTAT3 sequencing:• 64/100 STAT3 mutation• 36/100 No mutation in coding regions or their ﬂanking intronic sequences Woellner C, et al. JACI 2010;125:424-32.
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.
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 sequencing Schimke LF, et al. JACI 2010;126:611-7.
Results Schimke LF, et al. JACI 2010;126:611-7.
Clinical key findings combined with TH17 cell countspredict patients with HIES with STAT3 mutations
Treatment of AD-HIES Effective skin care Pneumonia Bleach baths Lower threshold for investigating slight changes in Swimming in chlorinated pools signs and symptoms. Topical steroids help in difficult cases Bronchoscopy is helpful to recover the pathogen and 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 pulmonary sometimes form following pneumonia is complex. aspergillosis remains attractive but unproven, but it is highly effective in treating and preventing mucocutaneous candidiasis. Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91.
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 undefined Freeman AF, Holland SM. Immunol Allergy Clin N Am 2008;28:277-91.
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.
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.
Autosomal RecessiveHyper-IgE Syndrome
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 skin abscesses, 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.
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.
ResultsImmunologic featuresDental and Skeletal Abnormalities High levels of IgE and eosinophilia primary teeth was not Failure or delay of shedding of the were persistent in all patients with AR-HIES in the AR-HIES documented AR-HIES patients had significantly higher development, 2 required 5 subjects with AR-HIES had normal dental eosinophil counts when primary tooth extractions because of severe caries, and 6 patients’ campared with the large cohort of sporadic HIES and AD-HIES cases published by Grimbacher et al. (P<0.005 , two-sided t test) dental status could not be assessed Lymphocytic proliferation assays, T-cellof AR-HIES patients, 1 patient There were no fractures in the cohort counts, NK-cell, B-cell counts, and NBT were not significantly impaired. secondary to spasticity of developed scoliosis, which may have been all extremities, 1 patient had mild hyperextensibility. Autoimmune phenomena, including hemolytic anemia, may occur. AR-HIES had no facial phenotype. Renner ED, et al. J Pediatr 2004;144:93-9.
ResultsConclusionCentral Nervous System Disease and Neurologic Symptoms AR-HIES had a distinctive immunologic and infectious 7/13 AR-HIES patients had neurologic symptoms ranging from hemiplegia phenotypeof the facial nerve skeletal or dental abnormalities to paralysis and lacked the seen in with this complication. 4/7 died AD-HIES. AR-HIESwere performed in 2/4 patients (Ruptured cerebral aneurysm, Autopsies is distinguished by a striking vasculitis of the CNS, severe necrotizing encephalitis of the gray matter) increased susceptibility to intractable viral infection and The 3rd patient was radiologically well studied and had 2 cerebral strokes. autoimmune complications more frequent than in sporadic The 4th case, fatality was associated with sepsis, leukocytoclastic vasculitis HIES or AD-HIES. and retinal hemorrhages. Patients who have AR-HIES have more symptomatic neurologic disease than those who have STAT3 deficiency. Renner ED, et al. J Pediatr 2004;144:93-9.
• 22-year-old Japanese male was diagnosed as HIES (HIES score 48 points).• The patient’s parents are consanguineous.• Recurrent otitis media, sinusitis, pneumonias, skin abscesses, oral candidiasis, Molluscum contagiosum, and Herpes simplex infection.• BCG infection at 22 months• Nontyphi salmonella gastroenteritis at 15 years of age• The numbers of T, B and NK cells were normal , neutrophils showed normal functions. Minegishi Y, et al. Immunity 2006;25:745-55.
Sequence analysis on the families with HIES one patient from 15 autosomal-recessive genomic DNA ofeach of these consanguineous marriages including for human (7/15 from five families by using the primers 3 unrelatedTYK2 Noout of the initially 6 published families exons and the patients mutation in the coding regions of (Renner etadjacent intronic sequences of TYK2. al.2004)) 5 families were homozygous at marker D19S586 within 1 Mb of the TYK2 geneHuman TYK2 deficiency is a distinct disease entity that is 4/5 families had at least 1 that is a childgenetically and clinically entityunaffectedgenetically and clinically 3/4 genotype data were consistent withdifferent from the patients with AR-HIES. genetic linkage to the TYK2 locus on chromosome 19 Woellner C, et al. Immunity 2007;26:535-6.
Levy DE. NEJM 2007;357:1655-8.
Defects of both IL-12 and type1IFN signaling,leading to impaired Th1 differentiation and IFN-γ production Watford WT, O’Shea JJ. Immunity 2006;25:695-7.
Immunophenotype & TYK2 mutation Manifestations Possible mechanismsViral infection • Defect in IFN signalingInfection • Defect in IL-12 signalingwith intracellular bacteriaHigh amount of serum IgE • Severe signaling defect in the IL-10 pathway and the AD-like skin accelerated Th2 differentiationinflammation Minegishi Y, et al. Immunity 2006;25:745-55.
11/11 (100%) had atopic dermatitis. 11 patients from 8 families (3 families were 9/11 (82%) had severe and extensive food or environmental allergies, including anaphylaxis.6-21 years. consanguineous), age 6/11 (55%) had asthma or reactive airway disease. 2/11 (18%) had eosinophilic esophagitis. Homozygous or birth. 2/11 (18%) had rash at compound heterozygous deletions and point mutations in gene encoding 11/11 (100%) had recurrent respiratory8 protein (DOCK8). the dedicator of cytokinesis tract infections. 9/11 (82%) had had recurrent pneumonias or bronchitis. 7/11 (64%) had recurrent sinusitis. 2/11 (18%) had mastoiditis. 2/11 (18%) had bronchiectasis Pulmonary pathogens: S pneumoniae, H influenzae, P jiroveci, adenovirus, RSV. Zhang Q, et al. NEJM 2009;361:2046-55.
11/11 (100%) had extensive, frequently co-existing, cutaneous viral infections. 7/11 (64%) had superficial HSV infection. 7/11 (64%) had persistent flat and verrucous warts. 5/11 (45%) had extensive M contagiosum infections. 2/11 (18%) had recurrent herpes zoster. 1/11 (9%) had severe primary VZV infection. 8/11 (73%) had S aureus skin infections/abscesses. 2/11 (18%) had S aureus osteomyelitis. 5/11 (45%) had mucosal or nail candidiasis. Zhang Q, et al. NEJM 2009;361:2046-55.
• 1/11 (9%) had cryptococcal and H influenzae Elevated serum IgE 5630 to 43,600 IU/mL. meningitis.• Eosinophilia 2.021±1.292×103 cells/cubic millimeter. Other infections included several occurrences of• 82% Low absolute lymphocyte counts. salmonella enteritis, giardiasis, and pericarditis.• 91% Decreased total T-cell numbers.• 100% Decreased CD4+ T cells. 1/11 (9%) had neurologic, vasculitic, and autoimmune• 91% Decreased CD8+ T cells. findings.• Selective defect in CD8+ T-cell activation. Vulvar, facial, and anal squamous-cell dysplasia and• 45% Decreased B cells. carcinomas had occurred.• 60% Decreased NK cells. metastatic squamous-cell 2/11(18%) died from carcinoma.• 45% Normal IgG serum levels; 55% Increased IgG serum levels. 1/11 (9%) had resected microcystic adenoma and died• Varied IgA serum levels. from cutaneous T-cell lymphoma–leukemia.• 100% Decreased IgM serum levels. Zhang Q, et al. NEJM 2009;361:2046-55.
20 families with 27 patients with AR-HIES. 21 patients had biallelic deletions or intragenic small mutations involving DOCK8. IgE, eczema, Criteria for AR-HIES: elevated hypereosinophilia, and significant infections 18/21 19/21 (90%) patients had recurrent URI, and (86%) had recurrent pneumonia. (particularly with molluscum contagiosum and herpes family viruses). 4/21 (19%) patients developed bronchiectasis. There (81%)13 families with positive history of 17/21 were patients had skin abscesses. consanguineous marriage from Turkey, 2 from Iran, 17/21 (81%) patients had severe susceptibility to and 1 each from Lebanon, Oman, Mexico, Italy, and recurrent viral infections (HSV, molluscum Ireland. contagiosum. All affected individuals had an NIH HIES score > 20. 17/21 (81%) patients had candidiasis. Engelhardt KR, et al. JACI 2009;124:1289-302.
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 multifocal leukoencephalopathy. 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.
• Elevated serum IgE 2830-90,910 IU/mL (median 20,225).• Eosinophilia 290-37,880 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.
Su HC. Curr Opin Allergy Clin Immunol 2010:515–20.
Dedicator of cytokinesis 8 (DOCK8) DOCK8 gene is chromosome 9p24.3. Members of the DOCK protein family. Cells of immune system, especially by lymphocytes; 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 in the maintenance of memory TH17 cells. Engelhardt KR, et al. JACI 2009;124:1289-302. Su HC. Curr Opin Allergy Clin Immunol 2010:515–20.
Rezaei N, et al. J Allergy Clin Immunol 2011;127:1329-41.
Chu EY, Freeman AF, Jing H, et al. Arch Dermatol 2011; doi:10.1001 /archdermatol.2011.262
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: topical imiquimod, cidofovir, and interferon-α Su HC. Curr Opin Allergy Clin Immunol 2010:515–20.
Treatment of AR-HIES IVIG: decrease the frequency of sinopulmonary infections. Bone marrow transplantation: controversy• a 8-year-old child with DOCK8 deﬁciency, congenital splenia. • 2 DOCK8 deficiency patients have undergone myeloablative & reduced• Allogeneic HCT after myeloablative conditioning intensity 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 of recurrent 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 2010:515–20.
STAT3 Mutation in the Original Patient with Job’s Syndrome This patient is now 50 years of age Lifelong eczema Multiple atraumatic First patient who was described as Job’s Syndrome fractures Hyperkeratotic fingernails (candida What is the mutation? infection) Recurrent S aureus abscesses Recurrent S aureus pneumonia with lungSTAT3 gene: heterozygous point mutation abscesses and in exon 12 (1144C→T; protein, R382W) pneumatoceles Renner ED, et al. NEJM 2007;357:1667-8.
Take-home messages Notarangelo LD, et al. JACI 2009;124:1161-78.
26-year-oldskin withwith severe Lichenified woman extensive unremitting eczematous erythema and eczematous dermatitis poorly controlled by plaques hypersensitive to light tacrolimus and systemic dry scaly touch, excoriations, and steroids Dermatitis since birth, multiple plaques along the flexor surfaces cutaneous complications of upper and lower extremities, chest, and back.Omalizumab 450 mg SC q 2 weeks Viral meningitis, recurrent infectious bronchitis, Hypertelorism, widened nasal pneumonias, and cystitis root and alae, scoliosis, and teeth Retained several of primary joint hyperextensibility. Controlled asthma and allergic Eosinophil 9.2% rhinitis IgE 1083 IU/mL AIHA, HCV infection, alopecia universalis, autoimmune hypothyroidism HIES 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.
32 year-old Thai woman with pruritic skin lesions on Nail clippings: Candida spp face, upper back and extremities for 2 years Eosinophils 12% (AEC 1,476 cells/µl) History of recurrent multiple abscesses on scalp, IgE 17,300 IU/ml alopecia universalis HIES score 30 points No history of atopic diseases, lung diseases, or dental or skeletal abnormalities Treatment • Omalizumab 300 mg SC erythematous not Multiple discretesteroid and topicalweeks Potent topical and confluentq 2 tacrolimuspapules improved and 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 scoliosis Discontinues and face, corticosteroids Chularojanamontri L, et al. APJAI 2009;27:233-6.
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.
Rosenzweig SD, Holland SM. Immunological Reviews 2005;203:38-47.