Hypergammaglobulinemia is a rare, hereditary medical condition in which the patient has increased levels of a certain immunoglobulin in the blood serum. This can result from conditions such as chronic bacterial infections, multiple myeloma, lymphomas, dysproteinemias, liver disease and chronic granulomatous inflammations. The exact symptoms depend on the type of gamma globulins involved and the severity of the condition.
There are different types of gamma globulins, and the ones that are checked for diagnosing hypergammaglobulinemia are immunoglobulins (IgS). In this hereditary condition, the level of immunoglobulin M (IgM) is abnormally high. IgMs are Y-shaped proteins generated by B cells to combat infections. However, in case of hypergammaglobulinemia, there are problems with B cell function, which results in excess production of IgM.
Most cases of hypergammaglobulinemia, apart from showing high levels of IgM, are characterized by low production of other types of immunoglobulins (antibodies). Thus, patients tend to have low levels of IgA, IgG, and IgE. In some patients, only the level of IgM is abnormally high, while the other main immunoglobulins are in the normal range.
There are 5 types of hypergammaglobulinemias
Type 1
X-linked immunodeficiency with hyper–immunoglobulin M, which is also called type 1 hyper IgM, is a rare form of primary immunodeficiency disease caused by a mutation in the Tumor Necrosis Factor Super Family member 5 (TNFSF5) gene, which codes for CD40 ligand. This gene is located on the long arm of the X chromosome at position 26, denoted Xq26. Normally, CD40 ligand is expressed on activated T cells, and is necessary to induce immunoglobulin class switching from IgM to the other immunoglobulin types. It does this by binding to its ligand, CD40, which is found expressed on the surface of B cells. The mutation in the TNFSF5 gene causes there to be no recognition of CD40 by CD40 ligand, and thus the T cells do not induce Ig class switching in B cells, so there are markedly reduced levels of IgG, IgA, and IgE, but have normal or elevated levels of IgM. CD40 ligand is also required in the functional maturation of T lymphocytes and macrophages, so patients with this disorder have a variable defect in T-lymphocyte and macrophage effector function, as well as hyper IgM.
Type 2
Immunodeficiency with hyper IgM type 2 is caused by a mutation in the Activation-Induced Cytidine Deaminase (AICDA) gene, which is located on the short arm of chromosome 12. The protein that is encoded by this gene is called Activation-Induced Cytidine Deaminase (AICDA) and functions as a DNA-editing deaminase that induces somatic hypermutation, class switch recombination, and immunoglobulin gene conversion in B cells. When a person is homozygous for the mutation in the AICDA gene, the protein fails to function, and thus somatic hypermutation, class switch recombination, and immunoglobulin gene conversion cannot occur, which creates an excess of IgM.
Type 3
Immunodeficiency with hyper IgM type 3 is caused by a mutation in the gene that codes for CD40. As mentioned above, CD40 is expressed on the surface of B cells, and its binding to CD40 ligand on activated T cells induces Ig class switching. When the mutation is present, there is no signal for B cells to undergo class switching, so there is an excess of IgM and little to no other immunoglobulin types produced.
Type 4
Immunodeficiency with hyper IgM type 4 is poorly characterized. All that is known is that there is an excess of IgM in the blood, with normal levels of the other immunoglobulins. The exact cause is yet to be determined.
Type 5
Immunodeficiency with hyper IgM type 5 is caused by a mutation in the Uracil-DNA glycosylase (UNG) gene, which, like AICDA, is located on chromosome 12. This codes for Uracil DNA Glycosylase, which is responsible for excising previous uracil bases that are due to cytosine deamination, or previous uracil misincorporation from double-stranded previous DNA substrates. This enzyme is also responsible for helping with gene conversion during somatic recombination in B cells. The mutation in the gene causes an enzyme that does not function properly, thus gene conversion does not proceed and class switching cannot occur.
Causes
Chronic ailments, particularly those that target the immune system, are responsible for causing hypergammaglobulinemia. They are mentioned below:
- HIV/AIDS
- Hepatitis C
- Rheumatic diseases
- Cirrhosis
Symptoms
One may think that the presence of excessive antibodies, like IgM, in hereditary conditions like hypergammaglobulinemia, may actually protect the body from bacteria, viruses and other disease-causing organisms. Unfortunately, a person affected with this condition is vulnerable to a wide range of infections. The excess production of IgM actually severely compromises the immune system.
To put it simply, low immunity is commonly associated with this medical condition. Hypergammaglobulinemia can make it very difficult to manage some minor infections such as common cold. Thus, lesser infections that are not a cause for concern in otherwise healthy people, can become quite serious in patients affected with hypergammaglobulinemia. For instance, common cold may turn into full blown bronchitis or pneumonia in people affected with this condition
Individuals with this condition tend to have chronic infections, such sinusitis, and suffer from serious lung infections such as tuberculosis and pneumonia frequently. Some even feel sick 24/7, which can completely disrupt their day-to-day routine.
Other symptoms that have been linked to this hereditary condition are given below:
- Fatigue
- Anemia
- Enlargement of the spleen, liver, lymph nodes, and tonsils
- Stiffness in joints such as knees and hips
Diagnosis
Exams and Tests
Your doctor might think you have an immunodeficiency disorder if you have:
- Infections that keep coming back or do not go away
- Severe infection from bacteria or other germs that do not usually cause severe infection
- Other signs include:
- Poor response to treatment for infections
- Delayed or incomplete recovery from illness
- Certain types of cancers (such as Kaposi’s sarcoma or non-Hodgkin’s lymphoma)
- Certain infections (including some forms of pneumonia or repeated yeast infections)
Tests used to help diagnose an immunodeficiency disorder may include:
- Complement levels in the blood, or other tests to measure substances released by the immune system
- HIV test
- Immunoglobulin levels in the blood
- Protein electrophoresis (blood or urine)
- T (thymus derived) lymphocyte count
- White blood cell count
Immunoglobulin (IgG) replacement therapy is the treatment of choice for most primary immunodeficiency syndromes, including X-linked agammaglobulinemia (Bruton disease; XLA), common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), hyper-IgM, adenosine deaminase (ADA) deficiency, and Wiskott-Aldrich syndrome (WAS). IgG is usually routinely administered intravenously (IVIG) or subcutaneously (SCIG). IgG replacement is usually needed for at least 1 year after hematopoietic stem cell transplantation (HSCT) in patients with SCID.
Patients with IgG subclass deficiency should not be given IVIG unless they fail to produce antibodies to protein and polysaccharide antigens and they have significant morbidity due to infection that cannot be managed with antibiotics alone. In selective IgA deficiency, IVIG therapy is not indicated.
Effort should be focused on the treatment of infections, allergic reactions, autoimmune diseases, and gastrointestinal diseases. Aggressive and prolonged antibiotic therapy covering S pneumoniae and H influenza is indicated. Because of the high frequency of G lamblia infection in these patients, an empiric course of metronidazole may result in dramatic improvement of the diarrhea and, to a certain extent, of malabsorption syndrome.
The treatment of secondary hypogammaglobulinemia is directed at the underlying cause. Successful treatment of nephrotic syndrome and protein-losing enteropathy may result in improvement of Ig levels.
IVIG is not indicated for the treatment of lymphoproliferative disorders, unless Ig levels are low in association with recurrent infections or if IVIG is being used for autoimmune conditions such as immune thrombocytopenic purpura (ITP) or immune hemolytic anemia, which may accompany these disorders.
Live vaccines (eg, bacille Calmette-Guérin, polio, measles, rubella, mumps) should not be given to patients with T-cell disorders, XLA, or other severe B-cell disorders or to the family members of such patients. In patients with IgA deficiency, live vaccines are not an absolute contraindication if given intramuscularly.
High doses of IVIG or intrathecal Ig may be beneficial in patients with XLA who have enteroviral meningoencephalitis.
HSCT is the treatment of choice for patients with SCID and, if a matched donor is available, for a patient with ADA deficiency.[1]
In patients with ADA deficiency who lack an HLA-identical sibling, enzyme replacement with polyethylene glycol-ADA (PEG-ADA) may be an effective alternative therapeutic agent.
Tumor necrosis factor (TNF) inhibitors have been used to treat granulomatous diseases in patients with CVID.
Gene therapy has been shown to be successful in reconstituting immune function in infants with X-linked SCID, but efficacy is less proven in older children and young adults.[2] Gene therapy for ADA deficiency is most effective when patients receive myeloablative chemotherapy and are withdrawn from PEG-ADA beforehand. Case series of ADA-deficient patients receiving gene therapy have shown excellent results at 4-year follow-up.
