hyper ig m syndrome
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Suparat Sirivimonpan, MD.8/3/2013
Hyper IgM syndrome
Andre M. Vale,Harry W. Schroeder, Jr, JACI 2010;125:778-87
Abbas.Cellular and molecular immunoloby 7th edition
Abbas.Cellular and molecular immunoloby 7th edition
Abbas.Cellular and molecular immunoloby 7th edition
Abbas.Cellular and molecular immunoloby 7th edition
Abbas.Cellular and molecular immunoloby 7th edition
CD40 (B cell) : member of the TNF receptor superfamily
CD40L (CD154) (T cell) : trimeric membrane protein that is homologous to TNF
IkB-kinase
Abbas.Cellular and molecular immunoloby 7th edition
Abbas.Cellular and molecular immunoloby 7th edition
Abbas.Cellular and molecular immunoloby 7th edition
switch regions for μ switch regions for ε
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
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
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
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
The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008.prevalence is 0.66/1,000,000
Medicine 2003 Nov;82(6):373-84
Clin Exp Immunol 2009;157:3-11
0
J Clin Immunol (209) 29:357–364
J Allergy Clin Immunol.2011 Dec;128(6):1380-2
HIGM
Ataxia-telangiecatasia
J Allergy Clin Immunol.2011 Dec;128(6):1380-2
correct diagnosis was established after a mean duration of 20 months (range, 1-60 months). Such diagnostic delay may cause fatal therapeutic errors
elevated serum IgM level possesses both low sensitivity and specificity as a screening marker for HIGM syndrome
J Allergy Clin Immunol.2011 Dec;128(6):1380-2
‘‘B-cell class-switch defect’’-International Union of Immunological Society Committee on Primary Immunodeficiencies decided in 2005 to abandon the term ‘‘HIGM syndrome’’ and to refer to the specific gene defect- This decision has been maintained in all classifications of primary immune deficiencies that have been published since 2006
Clinical Immunology (2010) 135, 193–203
Pediatr Res. 2004 Oct;56(4):519-25
(type1)
(type6)
(type3)
(type2)
(type5)
HIGM as part of a combined immunodeficiency
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.
CD40 ligand deficiency (type1)
humoral immunodeficiency impaired production of IgG and IgAsusceptibility 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.
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
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
Opportunistic infections Pneumocystis jiroveci (PCP)
pneumoniapresenting feature 40% of casespresence 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
Cholangiopathy 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
Opportunistic infections
Clinical Immunology (2010) 135, 193–203
Liver disease is very common
Invasive fungal infections, primarily Candida, Cryptococcus, Histoplasma, present a significant risk in affected individuals
Tuberculosisrelatively uncommon
Clinical Immunology (2010) 135, 193–203
Opportunistic infections
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
Clinical Immunology (2010) 135, 193–203
Ann Allergy Asthma Immunol.2008 May;100(5):509-11
Other complications, such as auto-immune manifestations or cancers, reported in some cases, are not frequent
CD40 ligand deficiency (type1)
Clinical Immunology (2010) 135, 193–203
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
Medicine 2003;82:373–384
Medicine 2003;82:373–384
Medicine 2003;82:373–384
Medicine 2003;82:373–384
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.
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
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
Clinical Immunology (2010) 135, 193–203Ann Allergy Asthma Immunol.2008 May;100(5):509-11
Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
HIGM syndrome associated with a pure humoral immune defect
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 infectionsdo not develop opportunistic infections
Ann Allergy Asthma Immunol.2008 May;100(5):509-11
Clinical Immunology (2010) 135, 193–203
lymphoid hyperplasia (50-75%) is a prominent feature (enlarged tonsils and lymph nodes )
enlargement of germinal centers
AID Deficiency
Autoimmunity hemolytic anemia, thrombocytopenia, hepatitis, SLE20% of the patientsauto-antibodies of IgM isotype
Clinical Immunology (2010) 135, 193–203
Sequence analysis of the causative gene, AICDA, will confirm the diagnosis
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
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.
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.
Post-meiotic segregation 2 (PMS2) deficiency
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
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
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
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
investigation
1) Immunoglobulin levels
2) CD markers
3) Flow cytometry : screening assays
4) Molecular analysis : final confirmation
TestingNormal or elevated serum concentrations of IgM and IgD Absent or very low serum concentrations of IgG and IgAAbsent IgG specific antibodiesNormal or increased number of B cells Normal number and distribution of CD4+ and CD8 + T-cell
subsets Normal T-cell proliferation in response to mitogensMeasurement by flow cytometry of CD40 ligand (CD40L),
CD40
GeneReviews1-3-13
Diagnosis
XHIMDefinitive 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 XHIM
ESID Working Party. Diagnostic criteria for PID: X-linked hyper IgM. Available online. 2005. Accessed 6-3-13
ProbableMale patient with serum IgG concentration at least 2 SD below the normal for age and all of the following: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 anemia
4) Absent CD40 ligand cell surface staining on activated CD4+T cells as assessed by binding to soluble CD40 or monoclonal antibody to CD40 ligand
XHIM
PossibleMale 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)
ESID Working Party. Diagnostic criteria for PID: X-linked hyper IgM. Available online. 2005. Accessed 6-3-13
XHIM exclusion criteria1) Defects in T cell activation (i.e., defective expression of CD69 or CD25 after in vitro T 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
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
Management
Immunoglobulin replacement therapy 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.
Bone marrow transplantationHIGM1
only curative treatment currently availableideally prior to onset of a life-threatening
complication and organ damage HLA-identical sibling as a donormatched unrelated donors are less satisfactorygene therapy is being investigated
Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
CD40 deficiency and NF-KB numbers of patients transplanted are too small to derive firm conclusions
Management : HCT
Pure humoral deficienciesbone 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.
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.
Prevention of Primary manifestations 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.
Prevention of Primary manifestations
Davies EG, Thrasher AJ.Br J Haematol 2010;149:167-80.
Genetic Counseling
Uygungil B, Bonilla F, Lederman H.J Allergy Clin Immunol. 2012 Jun;129(6):1692-3.e4
Uygungil B, Bonilla F, Lederman H.J Allergy Clin Immunol. 2012 Jun;129(6):1692-3.e4
Luigi D. et al JACI 2006; 117
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)
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 defectdefective CD40 signalling requiring consideration of
corrective therapy intrinsic B cell defects mostly require immunoglobulin
replacement therapy alone
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