Hyper Ig M syndrome

Hyper IgM syndrome

Suparat Sirivimonpan, MD.
8/3/2013

Andre M. Vale,Harry W. Schroeder, Jr, JACI 2010;125:778-87

Abbas.Cellular and molecular immunoloby 7th edition

CD40L (CD154) (T cell) :
trimeric membrane protein
that is homologous to TNF

CD40 (B cell) :
member of the TNF
receptor superfamily

IkB-kinase


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


 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
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

0

J Clin Immunol (209) 29:357–364

HIGM

J Allergy Clin Immunol.2011 Dec;128(6):1380-2

Ataxia-
telangiecatasia

correct diagnosis was established after a mean duration of 20
months (range, 1-60 months). Such diagnostic delay may cause
fatal therapeutic errors J Allergy Clin Immunol.2011 Dec;128(6):1380-2

 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 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

J Allergy Clin Immunol.2011 Dec;128(6):1380-2

Pediatr Res. 2004 Oct;56(4):519-25

(type1)

(type3)

(type6)

(type2)

(type5)

Clinical Immunology (2010) 135, 193–203

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.

 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

 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


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


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)

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

Liver disease is very common


 Invasive fungal infections, primarily Candida,
Cryptococcus, Histoplasma, present a significant risk in
affected individuals

 Tuberculosis
 relatively uncommon


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


 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


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


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


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


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 infections
 do not develop opportunistic infections

lymphoid hyperplasia (50-75%) is a prominent
feature (enlarged tonsils and lymph nodes )
enlargement of germinal centers


AID Deficiency

 Autoimmunity
 hemolytic anemia, thrombocytopenia, hepatitis, SLE
 20% of the patients
 auto-antibodies of IgM isotype

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


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


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


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

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

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 XHIM

Probable
Male 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 mitogens
2) Normal or elevated numbers of B cells but no antigen specific IgG antibody
3) 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
ESID Working Party. Diagnostic criteria for PID: X-linked hyper IgM. Available online. 2005. Accessed 6-3-13

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 criteria
1) Defects in T cell activation (i.e., defective expression of CD69 or CD25 after in vitro
T cell activation)
2) Human immunodeficiency virus infection
3) Congenital rubella infection
4) MHC class II deficiency
5) CD4+T cell deficiency
6) 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

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

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


Bone marrow transplantation
HIGM1
 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 investigated

CD40 deficiency and NF-KB
numbers of patients transplanted are too small to
derive firm conclusions

Management : HCT
Pure 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


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


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


Prevention of Primary
manifestations


Uygungil B, Bonilla F, Lederman H.
J Allergy Clin Immunol. 2012 Jun;129(6):1692-3.e4

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 defect
 defective CD40 signalling requiring consideration of
corrective therapy
 intrinsic B cell defects mostly require immunoglobulin
replacement therapy alone

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