This document outlines the molecular basis and clinical manifestations of different types of hyper-IgM syndrome. It discusses 6 types of HIGM defined by genetic defects such as CD40L, AICDA, CD40, and UNG deficiencies. The clinical features include recurrent infections, enlarged lymph nodes, impaired class switch recombination, and variable defects in somatic hypermutation. Diagnosis involves assessing serum immunoglobulin levels and identifying genetic mutations associated with each type.

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

41.  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

42. EDA-ID

43.  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

44. OUTLINES
• Types of hyper-IgM syndrome
• Molecular basis & Pathogenesis
• Clinical manifestations &
Diagnosis
• Treatment
• Conclusion

45.  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

46. -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

47. -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

48.  OUTLINES
› Types of hyper-IgM syndrome
› Molecular basis & Pathogenesis
› Clinical manifestations &
Diagnosis
› Treatment
› Conclusion

49. HYPER-IgM SYNDROME
Abbas et al. Cellular and Molecular Immunology 6th ed 2007 : 471

50. HYPER-IgM SYNDROME
Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64

51. HYPER-IgM SYNDROME
Middleton’s Allergy 7th ed. 2009 (2): 806-807, 817-818

52. HYPER-IgM SYNDROME
Notarangelo et al. J ALLERGY CLIN IMMUNOL 2006; 117(4): 855-64