X-linked Immunodeficiency With Hyper IgM

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X-linked immunodeficiency with hyper–immunoglobulin M (XHIGM or HIGM1) is a rare form of primary immunodeficiency disease caused by mutations in the gene that codes for CD40 ligand (CD40L, also known as CD154 or TNFSF5 or gp39). CD40L is expressed on activated T lymphocytes and is necessary for T cells to induce B cells to undergo immunoglobulin (Ig) class-switching from immunoglobulin M (IgM) to immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE). [1]

Thus, patients with XHIGM have markedly reduced levels of IgG, IgA, and IgE but have normal or elevated levels of IgM. Because CD40L is required in the functional maturation of T lymphocytes, dendritic cells, and macrophages, patients with XHIGM also have a variable defect in T-lymphocyte, dendritic cells, and macrophage effector function. Clinically, patients with XHIGM have increased susceptibility to infection with a wide variety of bacteria, viruses, fungi, and parasites. In addition, they are at increased risk for developing autoimmune disorders and malignancies.

Since the first description of patients with XHIGM by Rosen et al in 1961, several other genetic defects have been reported that are associated with defective Ig class-switch recombination (CSR). In 1974, a World Health Organization (WHO) working party named the syndrome immunoglobulin deficiency with increased IgM (hyper-IgM syndrome [HIGM1]). [2]  The most common form of HIGM is XHIGM (or HIGM1) and is inherited as an X-linked recessive (XR) trait. Another XR form of the syndrome is associated with hypohidrotic ectodermal dysplasia. In addition, several autosomal recessive forms (AR) and an autosomal dominant form of HIGM have been reported (see Differentials). In 2015, the International Union of Immunology Societies (IUIS) Phenotypic Classification for Primary Immundeficiencies named it CD40 ligand deficiency and classified XHIGM under combined immunodeficiency without T cell lymphopenia. [35]

Humoral immunity, or antibody-mediated immune responses, plays a central role in defense against extracellular pathogens and some viruses. Humoral immunity depends on the generation of exquisite specificity and diversity of Igs. During the primary antibody response, B cells in the bone marrow produce IgM and immunoglobulin D (IgD) antibodies of low avidity. This process is largely antigen-independent.

Once IgM B cells are engaged with antigens, B cells start the secondary antibody repertoire generation by undergoing 2 genetic alterations to improve specificity and avidity of the antibody to specific microorganisms.

The first step is generation of Ig diversity by recombination of Ig heavy chain, known as class-switch recombination (CSR), switching from IgM to IgG, IgA, or IgE.

The second step is somatic hypermutation (SHM) and involves the introduction of point mutations in the V regions (antigen-binding sites) of the Ig genes, resulting in an expansion of the antibody repertoire to generate high-affinity antigen-specific antibodies. The secondary antibody repertoire generation is antigen and T-cell dependent and occurs in peripheral lymphoid organs, mainly through the interaction between CD40L (CD154), expressed on activated CD4+ T cells, and CD40, expressed on B cells (see image below).

B cells of patients with XHIGM are intrinsically normal, in that they can be induced to proliferate and undergo CSR upon in vitro activation by CD40 agonists and appropriate cytokines. CD40 activation is also necessary for B cells to act as antigen-presenting cells, further enhancing the adaptive (acquired) immune response of T cells and other cells. Although B cells mature to express CD19 and surface immunoglobulins in the absence of CD40L on T cells, differentiation to plasma cells does not occur.

Because CD40 is also expressed on monocytes and dendritic cells, impaired CD40L expression leads to defective T-cell interactions with monocytes and dendritic cells, resulting in abnormal cell-mediated immune function and increased susceptibility to opportunistic infections, fungal infection, malignancy, and autoimmune diseases (28).

Neutropenia is also a common feature of XHIGM and may result from a defective, stress-induced, CD40-dependent granulopoiesis as myeloid progenitors express CD40 molecules. CD40L and CD40 are widely expressed on hematopoietic cells, and CD40 triggering on stromal cells enhances the expression of granulopoiesis growth factors, such as granulocyte-colony-stimulating factor (G-CSF) and granulocyte/monocyte-colony-stimulating factor (GM-CSF). Disruption of the CD40L/CD40-signaling pathway can lead to neutropenia. [3]

Increased incidence of autoimmune disorders have been reported among patients with HIGM syndrome. Furthermore CD40L-CD40 interactions may play an important role in T-regulatory (T-reg) cells that are required for the establishment and maintenance of immune tolerance. Patients with CD40L deficiency displayed low numbers of T-reg cells and defects in B-cell tolerance.

United States

In 2003, the US XHIGM registry reported that the minimal incidence rate of XHIGM was approximately 1 in 1,000,000 live births from 1984-1993. [4] This may be an underestimation because not all physicians in the United States participated in the registry.

International

Establishing reasonable estimates of XHIGM incidence has been difficult because most primary immunodeficiency disease registries combine data regarding XHIGM with data regarding genetic defects with resultant hyper-IgM. All forms of HIGM constitute 0.3-2.9% of all patients with primary immunodeficiencies in Europe, Asia, and South America. One registry in Spain reported that the incidence rate of all forms of HIGM is 1 per 20 million live births. XHIGM represents about 65-70% of all HIGMs. [5]

A retrospective study of the Registry of the European Society for Immune Deficiency of 56 affected males showed a 20% survival rate in individuals aged 25 years. [6] The US XHIGM Registry reported that 11 of 61 surviving patients were aged 20 years or older. [4]

The leading cause of death was pneumonia, encephalitis, or malignancy. Other patients died of liver failure secondary to sclerosing cholangitis and cirrhosis.

Major causes of morbidity include infection with bacteria, fungi, or viruses and opportunistic infections such as those involving Pneumocystis carinii. The respiratory (sinopulmonary) system, CNS, hepatobiliary system, and skin are commonly affected. Chronic diarrhea with or without infection has been frequently reported. Neutropenia, anemia, and thrombocytopenia are common. An increased risk of GI tract malignancies has been reported. Morbidity due to infection has markedly improved with the advent of intravenous immunoglobulin (IVIG) replacement therapy and better recognition of Pneumocystis jiroveci pneumonia and early initiation of Pneumocystis prophylaxis.

Studies are inadequate to provide ethnic data regarding XHIGM incidence. The US XHIGM Registry reported the racial background of 75 patients. [4] Fifty two of the patients were white, 12 were black, 9 were Asian, 1 was both black and Asian, and 1 was white and Asian.

CD40L deficiency affects males because it is an inherited in XR trait. Female carriers, even with extreme lyonization, have been immunocompetent and without clinical illness. Females with hypogammaglobulinemia and high IgM levels should be tested for gene mutations that affect other forms of HIGM.

Most patients are diagnosed before age 4 years. Over one half of patients develop symptoms of immunodeficiency by age 1 year, and nearly all develop symptoms by age 4 years.

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Winkelstein JA, Marino MC, Ochs H, et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore). 2003 Nov. 82(6):373-84. [Medline].

Matamoros Flori N, Mila Llambi J, Espanol Boren T, et al. Primary immunodeficiency syndrome in Spain: first report of the National Registry in Children and Adults. J Clin Immunol. 1997 Jul. 17(4):333-9. [Medline].

Levy J, Espanol-Boren T, Thomas C, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr. 1997 Jul. 131(1 Pt 1):47-54. [Medline].

Aschermann Z, Gomori E, Kovacs GG, et al. X-linked hyper-IgM syndrome associated with a rapid course of multifocal leukoencephalopathy. Arch Neurol. 2007 Feb. 64(2):273-6. [Medline].

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Lopez-Granados E, Temmerman ST, Wu L, et al. Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis. Proc Natl Acad Sci U S A. 2007 Mar 20. 104(12):5056-61. [Medline].

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Jain A, Kovacs JA, Nelson DL, et al. Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand. Blood. 2011 Oct 6. 118(14):3811-7. [Medline].

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Cabral-Marques O, Arslanian C, Ramos RN, et al. Dendritic cells from X-linked hyper-IgM patients present impaired responses to Candida albicans and Paracoccidioides brasiliensis. J Allergy Clin Immunol. 2012 Mar. 129(3):778-86. [Medline].

Cunningham CK, Bonville CA, Ochs HD, et al. Enteroviral meningoencephalitis as a complication of X-linked hyper IgM syndrome. J Pediatr. 1999 May. 134(5):584-8. [Medline].

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Durandy A, Schiff C, Bonnefoy JY, et al. Induction by anti-CD40 antibody or soluble CD40 ligand and cytokines of IgG, IgA and IgE production by B cells from patients with X-linked hyper IgM syndrome. Eur J Immunol. 1993 Sep. 23(9):2294-9. [Medline].

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Eijkhout HW, van Der Meer JW, Kallenberg CG, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med. 2001 Aug 7. 135(3):165-74. [Medline]. [Full Text].

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Herve M, Isnardi I, Ng YS, et al. CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance. J Exp Med. 2007 Jul 9. 204(7):1583-93. [Medline].

Hollenbaugh D, Wu LH, Ochs HD, et al. The random inactivation of the X chromosome carrying the defective gene responsible for X-linked hyper IgM syndrome (X-HIM) in female carriers of HIGM1. J Clin Invest. 1994 Aug. 94(2):616-22. [Medline]. [Full Text].

Lin Q, Rohrer J, Allen RC, Larché M, Greene JM, Shigeoka AO, et al. A single strand conformation polymorphism study of CD40 ligand. Efficient mutation analysis and carrier detection for X-linked hyper IgM syndrome. J Clin Invest. 1996 Jan 1. 97(1):196-201. [Medline]. [Full Text].

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Revy P, Muto T, Levy Y, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell. 2000 Sep 1. 102(5):565-75. [Medline].

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XHIGM

CD40 defect

EDA-ID

AR-AID

AID- Cter

AID-Δ C

UNG defect

CSR defect- upstream from DNA cleavage

CSR defect-downstream from DNA cleavage

Defect

CD40LG

CD40

NEMO

AICDA

AICDA

AICDA

UNG

Unknown

Unknown

Inheritance

XL

AR

XL

AR

AR

AD

AR

AR

AR

Lymphadenopathy

++

++

++

+

+

+

Opportunistic Infection

+

+

Autoimmunity

±

±

+

+

+

+

+

Serum IgM

N or ↑

N or ↑

N or ↑

↑ ↑

↑ ↑

↑ ↑

N or ↑

N or ↑

CD40-induced CSR

N

UD

Variable

UD

UD

UD

UD

UD

UD

SHM

Variable

↓ ↓

N

N

N but biased

N

N

Brand (Manufacturer)

Virus Inactivation process

pH; Additives *

Osmolality (mOsm/kg)

Parenteral Form & Final Concentrations

IgA Content ( µg/ml)

IV or SC

Bivigam (Biotest Pharmaceuticals)

Cold ethanol fractionation, solvent/detergent, nanofiltration

4.0-4.6;

glycine, polysorbate 80

Unspecified

Liquid 10%

<200 µg/mL

IV

Flebogamma DIF(Grifols)

Pasteurization, solvent/detergent, nanofiltration, fractionation, low pH treatment

5.0-6.0;

D-Sorbitol

240-370

Liquid 5%, 10%

<50µg/mL in a 5% solution, <100µg/mL in a 10% solution

IV

Gammagard S/D Low IgA (Baxter)

Cold ethanol fractionation, solvent/detergent 

6.4-7.2;

Albumin, glycine, glucose, PEG, tri-n-butyl phosphate, octoxynol, polysorbate 80

5%=636; 10%=250

Lyophilized powder

5%, 10%

<1µg/mL in a 5% solution

IV

Gammaplex

(Bio Products Laboratory)

Solvent/detergent, nanofiltraion, low pH incubation

4.8-5.1;   

D- sorbitol, glycine,  polysorbate 80

420-500

Liquid 5%

</td>

IV

Octagam (Octapharma)

Cold ethanol fractionation, solvent/detergent, pH4 treatment

5.1-6.0;

maltose

310-380

Liquid 5%

<200 µg/mL

IV

Privigen

(CSL Behring)

pH 4 incubation, nanofiltration, depth filtration

4.6-5.0;

L-proline

240-440

Liquid 10%

<25 µg/mL

IV

Gammagard Liquid

(Baxter)

Solvent/detergent, nanofiltration, low pH incubation at elevated temp

4.6-5.1;

glycine

240-300

Liquid 10%

37 µg/mL

IV or Subcutaneous

Gamunex-C

(Grifolis)

Caprylate precipitation, depth filtration, chromatography, pH 4 incubation

4-4.5;

glycine

258

Liquid 10%

46 µg/mL

IV or Subcutaneous

Gammaked (Kedrion Biopharma)

Caprylate precipitation, depth filtration, chromatography, low pH incubation

4.0-4.5;

glycine

258

Liquid 10%

46 µg/mL

IV or Subcutaneous

Cuvitru

(Shire)

Fractionation, SD treatment,  nanofiltration, low pH treatment

4.6-5.1;

glycine

280-292

Liquid 20%

80 µg/mL

Subcutaneous

Hizentra

(CSL Behring)

Cold alcohol fractionation, octanoic acid fractionation, and anion exchange chromatography

4.6-5.2;

L-proline, polysorbate 80

380

Liquid 20%

</td>

Subcutaneous

HyQvia

(Baxter Healthcare)

Solvent/detergent, nanofiltration, low pH incubation

4.6-5.1;

recombinant human hyaluronidase (pH 7.4)

240-300; (290-350)

Liquid 10%

37 µg/mL

Subcutaneous

C Lucy Park, MD Chief, Division of Allergy, Immunology, and Pulmonology, Associate Professor, Department of Pediatrics, University of Illinois at Chicago College of Medicine

C Lucy Park, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, Chicago Medical Society, American Medical Association, Clinical Immunology Society, Illinois State Medical Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David J Valacer, MD 

David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, New York Academy of Sciences

Disclosure: Nothing to disclose.

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter’s University Hospital

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.

James M Oleske, MD, MPH François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, Rutgers New Jersey Medical School; Professor, Department of Quantitative Methods, Rutgers New Jersey Medical School

James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Allergy Asthma and Immunology, American Academy of Hospice and Palliative Medicine, American Association of Public Health Physicians, American College of Preventive Medicine, American Pain Society, Infectious Diseases Society of America, Infectious Diseases Society of New Jersey, Medical Society of New Jersey, Pediatric Infectious Diseases Society, Arab Board of Family Medicine, American Academy of Pain Management, National Association of Pediatric Nurse Practitioners, Association of Clinical Researchers and Educators, American Academy of HIV Medicine, American Thoracic Society, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

X-linked Immunodeficiency With Hyper IgM

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