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  • 1. - -
  • 2. OUTLINES • Types of hyper-IgM syndrome • Molecular basis & Pathogenesis • Clinical manifestations & Diagnosis • Treatment • Conclusion
  • 3. NOTARANGELO et al. J ALLERGY CLIN IMMUNOL 2009 ; (6) : 1161-78
  • 4. NOTARANGELO et al. J ALLERGY CLIN IMMUNOL 2009 ; (6) : 1161-78
  • 5. CSR & SHM
  • 6. OUTLINES • Types of hyper-IgM syndrome • Molecular basis & Pathogenesis • Clinical manifestations & Diagnosis • Treatment • Conclusion
  • 7. Types of Hyper-IgM syndrome 1. HIGM1 (CD40L Def) 2. HIGM2 (AICDA Def) 3. HIGM3 (CD40 Def) 4. HIGM4 (molecular defect unknown) 5. HIGM5 (UNG Def) 6. XHM-ED (NEMO Def) Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Clinical Immunology,Principles and Practice 3th ed.2008:520-521
  • 8. OUTLINES • Types of hyper-IgM syndrome • Molecular basis & Pathogenesis • Clinical manifestations & Diagnosis • Treatment • Conclusion
  • 9. Molecular basis & Pathogenesis  Abnormal gene in Xq26  gene product : CD154(CD40L)  found only on activated T cells  Result in  B cells fail to undergo CSR,  no upregulation CD80, CD86  fail to become IgD-CD27+ memory B cells Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Clinical Immunology,Principles and Practice 3th ed.2008:520-521
  • 10. CD40L (TNFSF5, CD154) CD40 (TNFRSF5) -261 amino acids -277 amino acid -encoded by gene Xq26-27 -encoded by AR (20q12-13.2) -type II transmembrane protein -type I transmembrane protein -expressed at cell surface of T cells -expressed on surface of B cells, (only activated T cell, primarily CD4+ dendritic cells and macrophage phenotype) -also on endothelial and neural cells NOTARANGELO et al. J ALLERGY CLIN IMMUNOL 2006 ; (4) : 855-64
  • 11. NOTARANGELO et al. J ALLERGY CLIN IMMUNOL 2006 ; (4) : 855-64
  • 12.  Cross-linking of CD40L-CD40 • promote B cell proliferation • rescues B cells from apoptosis • induces homotypic cell adhesion • triggers CSR & SHM • generate of long-lived plasma cells • required for germinal center formation • on surface of monocyte-dendritic cells  induces IL-12 secretion  promotes terminal differentiation of monocyte-drived DC NOTARANGELO et al. J ALLERGY CLIN IMMUNOL 2006 ; (4) : 855-64
  • 13. Ig heavy chain isotype (class) switching
  • 14. Clinical manifestations & Diagnosis  Increased susceptibility of OI : PCP, persistent cryptosporidium infection, sclerosing cholangiolitis, and chronic progressive liver dz.  Progressive neurodegeneration  Susceptibility to tumor of liver, biliary tract Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Clinical Immunology,Principles and Practice 3th ed.2008:520-521 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 15. Clinical manifestations & Diagnosis (cont.)  intermittent or chronic neutropenia (50%) may cause recurrent oral ulcers, proctitis  most data related to autoimmune manifestration  in cohort of 56 pts. Reported by Levy et al 1997 -6% in inflammatory bowel disease -11% seronegative arthritis -44.6% chronic neutropenia of unknown origin -1.7% Coombs positive hemolytic anemia Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Adriana A. Jesus et al. J Clin Immunol 2008; 28(suppl 1): s62-s66 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 16. Clinical manifestations & Diagnosis (cont.)  In 2003 Winkelstein et al. found that -in 79 pts. With XHIM (HIGM 1) -60% presented neutropenia -15% anemia -4% thrombocytopenia Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Adriana A. Jesus et al. J Clin Immunol 2008; 28(suppl 1): s62-s66 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 17. Clinical manifestations & Diagnosis (cont.)  Dx : -number of B cells normal, marked decreased serum IgG & IgA levels and normal to increased IgM levels -flow cytometric assay for screening test -followed by sequence analysis of CD40L -LN histologic features : abortive germinal center formation & severe depletion with phenotypic abnormality of follicular DC Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Clinical Immunology,Principles and Practice 3th ed.2008:520-521 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 18. Molecular basis & Pathogenesis  mutation in gene on chromosome 12p13, usually AR, also found inheritance of autosomal dominant  encode an activation-induced cytidine deaminase (AICDA) : RNA- & DNA- editing enzyme specifically expressed in germinal center B cells (only in activated B cells) Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Clinical Immunology,Principles and Practice 3th ed.2008:520-521 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64
  • 19. Mechanism of Ig heavy chain isotype switching
  • 20.  result in • impaired terminal differentiation of B cells • failure of CSR & SHM Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Clinical Immunology,Principles and Practice 3th ed.2008:520-521 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64
  • 21. Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64
  • 22. Clinical manifestations & Diagnosis  present during early childhood, late diagnoses also detect  enlarged tonsils and lymph nodes  recurrent bacterial sinorespiratory & GI tract infection (including giardiasis  malabsorption)  do not develop OI  both defect in CSR and SHM Middleton’s Allergy 7th ed. 2009 (2): 806-807, 817-818 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 23.  Clinical manifestations & Diagnosis (cont.)  autoimmunity (hemolytic anemia, thrombocytopenia) about 20-25%  central nervous system infection, arthritis 12-27% • Dx : -clinical manifestration -number of circulating B cells normal, memory (CD27+) B cell also normal Middleton’s Allergy 7th ed. 2009 (2): 806-807, 817-818 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 24.  Clinical manifestations & Diagnosis (cont.) • Dx : -profound deficiency of serum IgG & IgA, (cont.) IgM normal or increased -LN show marked follicular hyperplasia within germinal centers -sequence analysis of causative gene, AICDA, confirm diagnosis Middleton’s Allergy 7th ed. 2009 (2): 806-807, 817-818 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 25. Molecular basis & Pathogenesis  CD40 gene located on autosome 20q12-13.2  rare form of autosomal recessive hyper-IgM syndrome  SHM is impaired  impaired function of monocyte-derived DC  reduced secretion of IL-12, impaired T cell priming diminished IFN-γ releasing Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Clinical Immunology,Principles and Practice 3th ed.2008:520-521 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64
  • 26. Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64
  • 27.  Clinical manifestations & Diagnosis  clinical presentations were similar to those with CD40L def (HIGM 1)  recurrent bacterial & opportunistic infection  severe biliary tract disease  increase mortality Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Clinical Immunology,Principles and Practice 3th ed.2008:520-521 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64
  • 28.  Clinical manifestations & Diagnosis (cont.) • Dx : -very low serum IgG & IgA levels, normal to increase IgM levels -decreased number of memory B cells -homozygous mutations of CD40 gene identified by flow cytometry -CD40-deficient B cells unable to undergo in-vitro CSR activation with CD40 agonist and cytokine Middleton’s Allergy 7th ed. 2009 (2): 806-807, 817-818 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 29. Molecular basis & Pathogenesis  HIGM-like phenotype, lacking demonstrable mutation in genes CD40, CD154, AID, UNG, NEMO  some immunologists defined as 1. other intrinsic B cell deficiency (not due to AID, UNG) a) genetically undefined hyper-IgM syndrome -found 6% , molecular basis is still unknown -milder CSR defect, unaffected SHM Clinical Immunology,Principles and Practice 3th ed.2008:520-521 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64
  • 30. Molecular basis & Pathogenesis 1. other intrinsic B cell deficiency (cont.) -defect located downstream from transcription step and upstream from DNA breaks -downstream from DNA cleavage 2. inducible costimulator & transmembrane activator and calcium modulating cyclophilin interacting protein def -deficiences in either ICOS or TACI -in ICOS-deficient mice found defective CSR caused by defective Th2 cytokine production Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376
  • 31. Molecular basis & Pathogenesis 2. inducible costimulator & tranmembrane activator and calcium modulating cyclophilin interacting protein def (cont.) -in TACI-deficiency found that BAFF & APRIL are involved in CSR to IgG & IgA via TACI-activation of naïve B cells Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376
  • 32.  Clinical manifestations & Diagnosis  resembles AID deficiency, with recurrent sinopulmonary & GI bacterial infection  milder lymphoid hyperplasia (50% of case) and not associated with giant germinal centers  milder defect of CSR  no evidence of specific IgG production in response to immunization  SHM & CD27+ memory B cells both normal  good prognosis and not prone to autoimmunity or tumors Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64
  • 33.  Clinical manifestations & Diagnosis  reduced number of memory B lymphocytes  normal SHM both pattern and frequency  susceptible to autoimmune manifestrations  possibly susceptible to tumors (lymphomas) Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64
  • 34. Molecular basis & Pathogenesis  UNG deficiency (uracil-DNA glycosylase def.)  AID deaminates cytosine into uracil then followed by uracil removal by UNG  until now only 3 pts. found mutations in this gene  rare autosomal recessive Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 35. Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64
  • 36.  Clinical manifestations & Diagnosis  recurrent respiratory infections in early childhood  large tonsils and LN (lymphoid hyperplasia)  profoundly impaired CSR, partial defect in SHM (different from AID def.)  develop autoimmune complications • Dx : -low serum IgG & IgA, increase IgM levels -lack of IgG response to vaccine antigens Middleton’s Allergy 7th ed. 2009 (2): 806-807, 817-818 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 37.  Clinical manifestations & Diagnosis (cont.) • Dx : -in vitro fail to be induced CSR by CD40 agonist plus cytokine -normal number of CD27+ B cells -sequence analysis of UNG gene confirm the defect Middleton’s Allergy 7th ed. 2009 (2): 806-807, 817-818 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 38. Molecular basis & Pathogenesis  nucler factor kappaB (NF-κB) essential modulator (NEMO) key role in CD40 signal transduction pathway  NEMO gene (IKBKG) is located in Xq-28 chromosome & its protein also influences ectodermal development  NEMO necessary for activation NF-κB  activation NF-κB leads to increase expression of gene encoded TNF-α, IL-12,  signal through NEMO & NF-κB necessary for ectodermal dysplasia Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Clinical Immunology,Principles and Practice 3th ed.2008:520-521 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 39. Molecular basis & Pathogenesis  hypomorphic mutation in zinc-finger domain of NEMO (also known as IKK-γ) caused EDA-ID but mutation outside zinc-finger domain not associated with Ig levels Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Clinical Immunology,Principles and Practice 3th ed.2008:520-521 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 40.  Clinical manifestations & Diagnosis  clinically as anhidrotic ectodermal dysplasia with associated immunodeficiency (EDA-ID)  conical teeth, absence of eccrine sweat glands, paucity of hair follicles, osteopetrosis, lymphedema  affected boy present with bacterial (Strep.pneumoniae, Staph. Aureus and atypical mucobacteria) infections  Crohn dz. frequent complication  respond poorly to immunizations Middleton’s Allergy 7th ed. 2009 (2): 806-807,817-818 Clinical Immunology,Principles and Practice 3th ed.2008:520-521 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 41. EDA-ID
  • 42.  Clinical manifestations & Diagnosis (cont.) • Dx : -remarkable defect of switched memory (CD27+) B cell -variability for CSR on in vitro activation of B cells with CD40 agonist -SHM is also found variability (normal or defect) -impaired NF-κB activation in fibroblasts : screening test -sequence analysis of NEMO gene : confirm test Middleton’s Allergy 7th ed. 2009 (2): 806-807, 817-818 Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64 Anne Durandy et al. Current Opinion in Rheumatology 2006; 18: 369-376 Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 43. OUTLINES • Types of hyper-IgM syndrome • Molecular basis & Pathogenesis • Clinical manifestations & Diagnosis • Treatment • Conclusion
  • 44.  Treatment 1) Treatment of choice : HLA-identical bone marrow transplant for HIGM 1 and NEMO mutation 2) monthy IVIG is indicated 3) children with mutations of CD40 or CD40L : P jiroveci porphylaxis & protection from exposure to Cryptosporidium from drinking contasminated water 4) Neutropenia in HGIM 1(XHIM) : GCSF treatment 5) In NEMO should anticipate about atypical mycobacteria infection, chronic in flam. bowel dz. Middleton’s Allergy 7th ed. 2009 (2): 806-807, 817-818 conclusion Hans D. Ochs. Annals of Allergy, Asthma & Immunology 2008 ; 100 : 509-511
  • 45. -retrospective analysis -38 European pts. Undergoing HSCT for CD40L def in 8 Europen countries between 1993-2002 -26 (68%) survived : 22 (58%) cured, 3 had autologous reconstitution, 1 engrafted but poor T-cell reconstitution -12 (32%) died from infection-related complication -6/12 from cryptosporidium parvum -3/12 from disseminated CMV -2/12 from disseminated aspergillosis -1/12 from adenovirus infection Andrew R et al. Blood 2004 ;103(3) : 1152-1157
  • 46. -79 American pts. from 60 unrelated families registered between jan. 1997-july 2002 -all received Ig Tx IM or IV -8/79 (10%) had died -2 of pneumonia (1 P jiroveci, 1 CMV) -2 of encephalitis (1 ECHO, 1CMV) -2 of malignancy (hepatocellularCA) -1 of sclerosing cholangitis -1 of hemolytic uremic syn. Jerry A et al. Medicine 2003; 82(6): 373-384
  • 47.  OUTLINES › Types of hyper-IgM syndrome › Molecular basis & Pathogenesis › Clinical manifestations & Diagnosis › Treatment › Conclusion
  • 48. HYPER-IgM SYNDROME Abbas et al. Cellular and Molecular Immunology 6th ed 2007 : 471
  • 49. HYPER-IgM SYNDROME Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64
  • 50. HYPER-IgM SYNDROME Middleton’s Allergy 7th ed. 2009 (2): 806-807, 817-818
  • 51. HYPER-IgM SYNDROME Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64

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