Hyper Ig M syndrome

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Hyper Ig M syndrome

Presented by Suparat Sirivimonpan, MD.

February 8, 2013

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Hyper Ig M syndrome

  1. 1. Hyper IgM syndrome Suparat Sirivimonpan, MD. 8/3/2013
  2. 2. Andre M. Vale,Harry W. Schroeder, Jr, JACI 2010;125:778-87
  3. 3. Abbas.Cellular and molecular immunoloby 7th edition
  4. 4. Abbas.Cellular and molecular immunoloby 7th edition
  5. 5. Abbas.Cellular and molecular immunoloby 7th edition
  6. 6. Abbas.Cellular and molecular immunoloby 7th edition
  7. 7. CD40L (CD154) (T cell) :trimeric membrane proteinthat is homologous to TNFCD40 (B cell) :member of the TNFreceptor superfamily IkB-kinase Abbas.Cellular and molecular immunoloby 7th edition
  8. 8. Abbas.Cellular and molecular immunoloby 7th edition
  9. 9. Abbas.Cellular and molecular immunoloby 7th edition
  10. 10. switch regions for μ switch regions for ε Abbas.Cellular and molecular immunoloby 7th edition
  11. 11. SHM Require Helper T cells and CD40:CD40L interactions affinity maturation is observed only in antibody responses to T-dependent protein antigens extensive somatic mutation occurs in germinal centers The mechanisms underlying somatic mutation in Ig genes are partially understood Abbas.Cellular and molecular immunoloby 7th edition
  12. 12.  Both CSR and SHM require transcription through target S and V regions on V(D)J exons and DNA editing, which requires two crucial enzymes expressed by germinal center B cells, AID and UNG Although representing unique modification processes, CSR and SHM are interdependent and nonredundant Pediatr Res. 2004 Oct;56(4):519-25
  13. 13. Hyper IgM syndrome immunologic phenotype presenting with  Low IgG, IgA, and IgE levels with  normal or increased IgM levels The term hyper-IgM is a misnomer (IgM levels are not necessarily high) The relative excess of IgM is due to a defect in class- switch recombination (CSR) In certain cases somatic hypermutation (SHM) is also affected Uygungil B, Bonilla F, Lederman H. J Allergy Clin Immunol. 2012 Jun;129(6):1692-3.e4
  14. 14. Hyper IgM syndrome uncommon In the United States  estimated minimal incidence of the XHIGM syndrome averaged ○ 1 /1,035,000 total births per year or ○ 1/517,000 male births per year Medicine 2003 Nov;82(6):373-84 The European internet-based patient and research database for primary immunodeficiencies: results 2006- 2008.  prevalence is 0.66/1,000,000 Clin Exp Immunol 2009;157:3-11
  15. 15. 0 J Clin Immunol (209) 29:357–364
  16. 16. HIGM J Allergy Clin Immunol.2011 Dec;128(6):1380-2
  17. 17. Ataxia-telangiecatasiacorrect diagnosis was established after a mean duration of 20months (range, 1-60 months). Such diagnostic delay may causefatal therapeutic errors J Allergy Clin Immunol.2011 Dec;128(6):1380-2
  18. 18.  elevated serum IgM level possesses both low sensitivity and specificity as a screening marker for HIGM syndrome‘‘B-cell class-switch defect’’-International Union of Immunological Society Committee onPrimary Immunodeficiencies decided in 2005 to abandonthe term ‘‘HIGM syndrome’’ and to refer to the specific genedefect- This decision has been maintained in all classifications ofprimary immune deficiencies that have been published since2006 J Allergy Clin Immunol.2011 Dec;128(6):1380-2
  19. 19. Pediatr Res. 2004 Oct;56(4):519-25(type1)(type3)(type6) (type2) (type5) Clinical Immunology (2010) 135, 193–203
  20. 20. HIGM as part of a combinedimmunodeficiency
  21. 21. CD40 ligand deficiency type1) CD40 L  Gene at chromosome Xq26  trimeric form on the cell surface (CD40 binding domain on the cell surface, short transmembrane domain and cytoplasmic tail)  Expression of the molecule is very tightly regulated occurring only transiently upon activation of CD4+ve T lymphocytes X-linked recessive Occasional symptomatic female carriers with skewed lyonization have been reported Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
  22. 22. CD40 ligand deficiency type1) humoral immunodeficiency  impaired production of IgG and IgA  susceptibility to bacterial infections esp.respiratory tract 50% elevated levels of IgM at presentation no response to protein antigens some IgM anti-polysaccharide antibodies, including isohemagglutinins, can be produced Memory (CD27+ve) B-cells are either absent or present in only very reduced numbers Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
  23. 23. CD40 ligand deficiency type1) Impaired CD40L/CD40 interaction leads to defective T cell interactions with monocytes/dendritic cells with consequences as (1) impaired full maturation of dendritic cells, (2) impaired IL-12 production by dendritic cells and macrophages, (3) affected T cell priming, resulting in an abnormal cellular immune response  significant susceptibility to opportunistic infections  cannot be controlled by Ig substitution therapy  adversely affect prognosis Clinical Immunology (2010) 135, 193–203
  24. 24. Bacterial infections Recurrent sinopulmonary infections recurrent respiratory tract infections potentially leading to bronchiectasis, sinus infections and ear infections immunoglobulin replacement in adequate doses will largely prevent these complications Clinical Immunology (2010) 135, 193–203
  25. 25. Opportunistic infections Pneumocystis jiroveci (PCP)  pneumonia  presenting feature 40% of cases  presence of normal T lymphocyte counts and negative HIV test in male infants Chronic cryptosporidial infection  common  Symptomatic chronic intestinal cryptosporidiosis may occur,  failure to thrive, weight loss with persistent diarrhea  subclinical infection is common  in many cases the organism is not detectable by stool microscopy, but only by molecular testing (PCR) Clinical Immunology (2010) 135, 193–203
  26. 26. Opportunistic infectionsCholangiopathy Cryptosporidium found in the biliary tree common complication (clinical and subclinical infection) result in  disturbed liver function tests with raised GGT levels  development of sclerosing cholangitis  cirrhosis  risk of cholangiocarcinoma responsible for early death in many cases Liver disease is very common Clinical Immunology (2010) 135, 193–203
  27. 27. Opportunistic infections Invasive fungal infections, primarily Candida, Cryptococcus, Histoplasma, present a significant risk in affected individuals Tuberculosis  relatively uncommon Clinical Immunology (2010) 135, 193–203
  28. 28. CD40 ligand deficiency type1)Intermittent or chronic neutropenia common feature (approximately 50%) CD40 interactions are also important in granulopoiesis may cause persistent stomatitis, recurrent oral ulcers, or proctitis treatment with granulocyte colony-stimulating factor Other complications, such as auto-immune manifestations or cancers, reported in some cases, are not frequent Ann Allergy Asthma Immunol.2008 May;100(5):509-11 Clinical Immunology (2010) 135, 193–203
  29. 29. CD40 ligand deficiency type1) Flow cytometric assay is a useful screening test, followed by sequence analysis of CD40L Activated CD4 T cells from patients with XHIM fail to express CD40L on the cell surface Clinical Immunology (2010) 135, 193–203
  30. 30. Medicine 2003;82:373–384
  31. 31. Medicine 2003;82:373–384
  32. 32. Medicine 2003;82:373–384
  33. 33. Medicine 2003;82:373–384
  34. 34. CD40 deficiency (type3) rare cause of HIGM autosomal recessive (AR) inherited disease clinical and immunological findings are identical to those reported in CD40L deficiency Flow cytometric analysis of CD40 expression on B cells and mutation analysis can be used to confirm diagnosis Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
  35. 35. Mutations of NEMO Crosslinking of CD40  activation of the NF-κB signaling pathway  CSR mutations in the IKK gene coding for NEMO  NEMO (nuclear factor-κB essential modulator) : ○ scaffolding protein that binds to IKKα and IKKβ, two kinase proteins ○ required for NF-κB activation and nuclear translocation ectodermal dysplasia associated with immunodeficiency (EDA-ID) EDA-ID : X-linked trait Clinical Immunology (2010) 135, 193–203
  36. 36. Mutations of NEMO this syndrome can be characterized by  normal to increased IgM levels  low levels of serum IgG and IgA, and (abnormal CSR)  impaired antibody responses, particularly to polysaccharide antigens NF-B is involved in a number of T-cell and Toll receptor signalling pathways  bacterial and opportunistic infections present with bacterial (S. pneumoniae, S. aureus, and often atypical mycobacteria) infections Crohn disease is a frequent complication Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80. Ann Allergy Asthma Immunol.2008 May;100(5):509-11 Clinical Immunology (2010) 135, 193–203
  37. 37. HIGM syndrome associatedwith a pure humoral immunedefect
  38. 38. AID Deficiency(activation-induced cytidine deaminase) required for CSR most frequent cause of autosomal recessive HIGM AID-deficient patients present during early childhood with  recurrent bacterial sinorespiratory and gastrointestinal tract infections  do not develop opportunistic infections lymphoid hyperplasia (50-75%) is a prominent feature (enlarged tonsils and lymph nodes ) enlargement of germinal centers Clinical Immunology (2010) 135, 193–203 Ann Allergy Asthma Immunol.2008 May;100(5):509-11
  39. 39. AID Deficiency Autoimmunity  hemolytic anemia, thrombocytopenia, hepatitis, SLE  20% of the patients  auto-antibodies of IgM isotypeSequence analysis of the causative gene, AICDA, willconfirm the diagnosis Clinical Immunology (2010) 135, 193–203
  40. 40. AID Deficiency The prognosis for the patients is rather good upon regular infusion of Ig however, does not control the lymphoid hyperplasia and the auto-immune complications Clinical Immunology (2010) 135, 193–203
  41. 41. UNG deficiency Uracil-N-glycosylase rare autosomal recessive form of HIGM syndrome Patients suffer a similar clinical picture to AID deficiency UNG is preferentially expressed in activated B cells Sequence analysis of the UNG gene confirms the defect Ann Allergy Asthma Immunol.2008 May;100(5):509-11 Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
  42. 42. Post-meiotic segregation 2 (PMS2)deficiency PMS2 : one of the proteins involved in the complex mediating mismatch repair of DNA mutations in PMS2 have been identified as being associated with gastrointestinal adenocarcinomas patient with the most severe immunophenotype was reported as having severe bacterial infections prior to diagnosis and subsequently developed colonic adenocarcinoma Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
  43. 43. HIGM type 4 There are some HIGM patients with defective CSR and normal SHM who do not have CD40L, CD40, AID, and UNG defects HIGM type 4 patients exhibit a milder clinical phenotype The molecular defect, although yet unidentified Eur J Pediatr (2011) 170:1039–1047
  44. 44.  None of the patients experienced invasive bacterial infections, chronic lung disease, lymphoid hyperplasia, overt autoimmune manifestations, chronic liver disease, or malignancy Eur J Pediatr (2011) 170:1039–1047
  45. 45.  All showed improvement in both clinical findings and Ig levels during the follow-up period of 55.8± 14.8 months The total number of infections per year decreased from 7.9±3.6  2.4±0.8 Ages for normalization of IgG and IgA were 68.2±8.7 and 70.2±21.6 months, respectively Eur J Pediatr (2011) 170:1039–1047
  46. 46.  CSR was still abnormal in 5/8patients There was a transient CSR defect which was not observed in cases with transient hypogammaglobulinemia of infancy Eur J Pediatr (2011) 170:1039–1047
  47. 47. investigation1) Immunoglobulin levels2) CD markers3) Flow cytometry : screening assays4) Molecular analysis : final confirmation
  48. 48. Testing Normal or elevated serum concentrations of IgM and IgD Absent or very low serum concentrations of IgG and IgA Absent IgG specific antibodies Normal or increased number of B cells Normal number and distribution of CD4+ and CD8 + T-cell subsets Normal T-cell proliferation in response to mitogens Measurement by flow cytometry of CD40 ligand (CD40L), CD40 GeneReviews 1-3-13
  49. 49. Diagnosis
  50. 50. XHIM Definitive  Male patient with serum IgG concentration at least 2 SD below normal for age and one of the following: 1) Mutation in the CD40L gene 2) Maternal cousins, uncles, or nephews with confirmed diagnosis of XHIMProbableMale patient with serum IgG concentration at least 2 SD below the normal for age and all of thefollowing:1) Normal number of T cells and normal T cell proliferation to mitogens2) Normal or elevated numbers of B cells but no antigen specific IgG antibody3) One or more of the following infections or complications -Recurrent bacterial infections in the first 5 years of life -Pneumocystis carinii infection in the first year of life -Neutropenia -Cryptosporidium-related diarrhea -Sclerosing cholangitis -Parvovirus induced aplastic anemia4) Absent CD40 ligand cell surface staining on activated CD4+T cells as assessed by binding tosoluble CD40 or monoclonal antibody to CD40 ligand ESID Working Party. Diagnostic criteria for PID: X-linked hyper IgM. Available online. 2005. Accessed 6-3-13
  51. 51. XHIM Possible Male patient with serum IgG concentration at least 2 SD below normal for age, normal numbers of T cells and B cells and one or more of the following:  1) Serum IgM concentration at least 2 SD above normal for age  2) Pneumocystis carinii infection in the first year of life  3) Parvovirus induced aplastic anemia  4) Cryptosporidium-related diarrhea  5) Severe liver disease (sclerosing cholangitis)XHIM exclusion criteria1) Defects in T cell activation (i.e., defective expression of CD69 or CD25 after in vitroT cell activation)2) Human immunodeficiency virus infection3) Congenital rubella infection4) MHC class II deficiency5) CD4+T cell deficiency6) Drug or infection exposure known to influence the immune system ESID Working Party. Diagnostic criteria for PID: X-linked hyper IgM. Available online. 2005. Accessed 6-3-13
  52. 52. DDX Common variable immunodeficiency (CVID)  may be associated with a decreased number of total T cells or decreased T-cell function Severe combined immunodeficiency  usually presents with absent T-cell function, quantitative abnormalities of T lymphocyte populations, and markedly decreased mitogen function Agammaglobulinemia  XLA : recurrent bacterial infections but Opportunistic viral infections and neutropenia are rare, absence of CD19+ B cells HIV infection Transient hypogammaglobulinemia of infancy (THI)  normal antibody production, normal growth patterns, and lack of opportunistic infections
  53. 53. Management
  54. 54. Immunoglobulin replacementtherapy All type (HMI defect) should be initiated on diagnosis  reducing markedly the incidence of bacterial infections  reducing the likelihood of developing lymphoid hypertrophy  reducing the likelihood of the patient developing bronchiectasis and/or chronic sinusitis If complications are usually established before initiation of replacement therapy : may then progress despite treatment Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
  55. 55. Bone marrow transplantationHIGM1  only curative treatment currently available  ideally prior to onset of a life-threatening complication and organ damage  HLA-identical sibling as a donor  matched unrelated donors are less satisfactory  gene therapy is being investigatedCD40 deficiency and NF-KB numbers of patients transplanted are too small to derive firm conclusions Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
  56. 56. Management : HCTPure humoral deficiencies  bone marrow transplantation, cannot generally be justified given the fact that these are pure humoral deficiencies showing good response to Ig therapy  Theoretically, such an approach might be justified in patients with uncontrollable autoimmune manifestations or in those who have developed lymphoid malignancies Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
  57. 57. Management : other Total parenteral nutrition Treat chronic neutropenia with recombinant G-CSF Institute appropriate antimicrobial therapy for infections Aggressively evaluate pulmonary infections End-stage sclerosing cholangitis : orthotropic liver transplantation Treat lymphomas and GI cancer autoimmune disorders : immunosuppressants Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
  58. 58. Prevention of Primarymanifestations Antibiotic prophylaxis  Prophylaxis for PCP is indicated (combined) ○ high risk of developing PCP during first two years of life  Trimethoprim-sulfamethoxazole orally or pentamidine by intravenous or inhalation therapy Additional antibiotic prophylaxis  should be evaluated on a case-by-case basis Routine childhood immunizations  killed vaccines may be safely administered Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
  59. 59. Prevention of Primarymanifestations Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
  60. 60. Genetic Counseling
  61. 61. Uygungil B, Bonilla F, Lederman H.J Allergy Clin Immunol. 2012 Jun;129(6):1692-3.e4
  62. 62. Uygungil B, Bonilla F, Lederman H.J Allergy Clin Immunol. 2012 Jun;129(6):1692-3.e4
  63. 63. Luigi D. et al JACI 2006; 117
  64. 64. Take home message A thorough history and a high index of suspicion are required to make the diagnosis of hyper-IgM syndrome, especially if IgM levels are within the normal range Timely diagnosis is critical in many of these diseases to minimize end-organ damage, especially in cases in which early bone marrow transplantation might be beneficial (eg, CD40L deficiency)
  65. 65. Take home message Studies on patients with HIGM syndrome can now identify the genetic cause in around 75–80% of cases The remainder is currently undiagnosed at the genetic level Treatment options depend on the type of defect  defective CD40 signalling requiring consideration of corrective therapy  intrinsic B cell defects mostly require immunoglobulin replacement therapy alone

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