Hyper Ig M syndrome

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





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

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

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

http://www.ncbi.nlm.nih.gov/pubmed/?term=The+Hyper+IgM+Syndrome%E2%80%94An+Evolving+Story


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


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


‘‘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


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


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)

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)


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


Liver disease is very common

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

Tuberculosisrelatively uncommon


Opportunistic infections


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


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



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


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

Clinical Immunology (2010) 135, 193–203Ann Allergy Asthma Immunol.2008 May;100(5):509-11


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



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


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



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


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

http://www.esid.org/workingparty.php?party=3&sub=2&id=73

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

http://www.esid.org/workingparty.php?party=3&sub=2&id=73

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


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


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


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


Genetic Counseling



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

Health & Medicine

Hyper Ig M syndrome