Immunodeficiency with hyper-IgM
Immunodeficiency with hyper-IgM, also known as hyper-IgM syndrome, is a rare group of immune disorders marked by normal or elevated levels of immunoglobulin M (IgM) while having deficient or absent levels of immunoglobulins G (IgG), A (IgA), and E (IgE). This condition arises due to genetic defects affecting the antibody isotype switching process, which is crucial for producing high-affinity antibodies necessary for effective immune responses. Primarily impacting males, particularly with X-linked hyper-IgM types, the syndrome increases the risk of recurrent infections from various pathogens due to impaired immune responses. Symptoms typically manifest after maternal antibodies wane, with patients experiencing frequent respiratory infections, gastrointestinal issues, and potential complications such as autoimmune disorders and malignancies.
Diagnosis is based on clinical assessments, including immunoglobulin level evaluations and genetic testing. Treatment primarily involves lifelong immunoglobulin replacement therapy and prophylactic measures to prevent infections. Although there is no means of prevention, genetic counseling is advisable for affected families. Early intervention is vital, as patients may face significant health challenges throughout their lives, including chronic infections and other serious complications if left untreated. Advances in gene therapy and cell treatments are being explored, offering hope for improved outcomes for individuals with this condition.
Immunodeficiency with hyper-IgM
ALSO KNOWN AS: Hyper-IgM syndrome (HIM or HIGM); dysgammaglobulinemia with hyper-IgM
DEFINITION Immunodeficiency with hyper-IgM describes a family of rare immune disorders characterized by normal or elevated serum IgM levels with deficient or absent IgG, IgA, and IgE levels caused by a genetic defect in the antibody (immunoglobulin) isotype switch process. The disease increases susceptibility to infections.
Risk Factors
Men are largely affected with X-linked hyper-IgM types (XHIM, HIGM1 as the most common), which are absent in women. The US National Library of Medicine's Genetics Home Reference reported in 2014 that the estimated incidence of XHIM is two per million newborn boys. The autosomal recessive forms types 2, 3, 4, and 5 affect men and women equally. Family history is a risk factor for HIGM1. The son of a female genetic carrier, who has the abnormal gene on one of her two X chromosomes, has a fifty percent higher risk of inheriting the disorder. No known environmental or natural risk factors are associated with immunodeficiency with hyper-IgM.
Etiology and Genetics
Immunodeficiency with hyper-IgM syndrome is caused by several genetic defects affecting the (immunoglobulin) isotype switch from IgM to IgG, IgA, and IgE. This leads to normal-to-elevated serum levels of IgM with lows levels of IgG and IgA. A variety of genetic defects are involved.
During the course of a humoral immune response, a healthy B cell initially produces IgM antibodies followed by secondary IgG, IgA, or IgE antibody generation. This T-cell dependent class switching happens through the interactions between CD40 ligand (CD154 or TNFSF5) on activated CD4+ T cells and CD40 receptor expressed on B cells. Patients who suffer from immunodeficiency with hyper-IgM have that continue to produce IgM antibodies but are unable to switch and produce a different kind of antibody.
IgM molecules are pentamers with ten low-affinity antigen-binding sites. Antibody class switching is required to produce smaller, high-affinity antibodies such as IgG and IgA with particular functional activity and body compartments distribution. Tissue distribution and high affinity to antigens are critical for optimal antibody effectiveness. The lack of these characteristics in IgM increases the susceptibility to infection by a wide variety of bacteria, viruses, fungi, and parasites. Apart from immunodeficiency with hyper-IgM, these patients suffer from impaired cellular immune responses due to decreased T-cell activation and a higher risk for other autoimmune disorders and malignancies.
The seven hyper-IgM genetic defects exist in X-linked or autosomal recessive forms. The three X-linked mutant variants include X-linked hyper-IgM type 1 syndrome (HIGM1), immunodeficiency with hypohidrotic ectodermal dysplasia, and immunodeficiency without anhidrotic ectodermal dysplasia. The four autosomal recessive forms of immunodeficiency with hyper-IgM include hyper-IgM syndrome type 2 (HIGM2), hyper-IgM syndrome type 3 (HIGM3), hyper-IgM syndrome type 4 (HIGM4), and hyper-IgM syndrome type 5 (HIGM5). The most common type is HIGM1. A mutation in the CD40LG gene of the X chromosome causes X-linked HIGM1. Genetics Home Reference reported in 2014 that more than 150 mutations in CD40LG are known to cause XHIM. In chromosome 12, the mutation of the activation-induced cytidine deaminase (AICDA) gene results in autosomal recessive HIGM2. The CD40 gene mutation of chromosome 20 causes the autosomal recessive HIGM3. In chromosome 12, the mutation in the uracil-DNA glycosylase (UNG) gene is responsible for the autosomal recessive HIGM5. Mutations in the IKK-gamma gene (IKBKG) of the X chromosome are associated with hypohidrotic ectodermal dysplasia with immune deficiency. A mutation in the NF-kappa-B essential modulator (NEMO) gene (IKBKG) of the X chromosome results in immunodeficiency without anhidrotic ectodermal dysplasia.
Symptoms
In both X-linked or autosomal hyper-IgM immunodeficiency, children develop clinical symptoms after the maternal antibodies clear from their system, typically between six months and two years of age. Characteristics include a high susceptibility to opportunistic infections, recurrent upper and lower respiratory tract infections, and frequent and severe ear, throat, and chest infections. If the underlying immunodeficiency is not discovered in time and treated accordingly, permanent damage to lungs and ears can occur. Thus, a doctor’s diagnosis is essential. Recurrent pus-producing bacterial lung infections might be the first manifestation of the X-linked form of the disorder. Other symptoms include lung infections caused by cytomegalovirus and cryptococcus, and oral ulcers and proctitis associated with neutropenia. Gastrointestinal ailments include diarrhea and malabsorption.
Screening and Diagnosis
Diagnosis is clinical. Characterization of low or absent IgG and IgA and normal-to-elevated IgM serum levels in any baby boy with hypogammaglobulinemia is advised. Unexpressed or reduced expression of CD40 ligand on activated T cells might be an important discovery. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis of CD40 ligand gene mutations is used both to screen for the mutation and to diagnose hyper-IgM immunodeficiency type 1. Mutation analysis of genes known to cause several forms of autosomal recessive HIM or ectodermal dysplasia can help in the diagnosis.
Treatment and Therapy
Treatment depends on the correct identification of the numerous types of hyper-IgM immunodeficiencies. The main therapy is lifelong IV immunoglobulin replacement therapy (400mg/kg once a month), which reduces the number of infections. Early diagnosed baby boys are immediately placed on prophylactic treatment against Pneumocystis carinii/jirovecii pneumonia with trimethoprimsulfamethoxazole (Bactrim, Septra). Granulocyte colony-stimulating factor (G-CSF) can be used to treat persistent neutropenia. No patient should receive live virus vaccines because of the possibility that the vaccine strain might cause disease. Boiled drinking water protects patients against cryptosporidium infection. Bone marrow transplantation is recommended in all affected boys because of the high rate of liver disease and malignancy associated with X-linked hyper-IgM. Although it is still challenging, in the future, gene therapy might provide greater hope in treating this disease.
Other treatments under consideration include cell therapy. In 2023, the Hyper IgM Foundation announced it funded a grant to the Milan, Italy-based San Raffaele Telethon Institute for Gene Therapy. The research was directed to finding t-cell treatments for X-Linked Hyper IgM Syndrome (X-HIGM), which is treatable only with stem cell transplantation.
Prevention and Outcomes
There is no effective means of prevention; therefore, genetic counseling should be provided. Patients with hyper-IgM syndrome will face health problems such as recurrent infections throughout their lives. Cryptosporidium susceptibility will cause sclerosing cholangitis, a severe liver disease. Bones and joints may be affected by osteomyelitis or arthritis. Autosomal recessive patients might show enlarged lymph nodes, tonsils, spleen, and liver. Some patients will exhibit autoimmune diseases such as hypothyroidism, thrombocytopenia, hemolytic anemia, and renal disease. Early diagnosis is critical in improving patient outcome since some patients die before puberty and those who survive puberty usually develop cirrhosis or B-cell lymphomas.
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"The Hyper IgM Foundation Awards $100,000 Grant to Dr. Daniele Canarutto and Prof. Luigi Naldini at the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy." Hyper IgM Foundation, 14 Nov. 2023, hyperigm.org/2023/11/the-hyper-igm-foundation-awards-100000-grant-to-dr-daniele-canarutto-and-prof-luigi-naldini-at-the-san-raffaele-telethon-institute-for-gene-therapy/. Accessed 9 Sept. 2024.
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