Hypogammaglobulinemia

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Hypogammaglobulinemia
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Hypogammaglobulinemia is an immune system disorder in which not enough gamma globulins are produced in the blood (thus hypo- + gamma + globulin + -emia ). This results in a lower antibody count, which impairs the immune system, increasing risk of infection. Hypogammaglobulinemia may result from a variety of primary genetic immune system defects, such as common variable immunodeficiency, [1] or it may be caused by secondary effects such as medication, blood cancer, or poor nutrition, or loss of gamma globulins in urine, as in nonselective glomerular proteinuria.[ medical citation needed ] Patients with hypogammaglobulinemia have reduced immune function; important considerations include avoiding use of live vaccines, and take precautionary measures when traveling to regions with endemic disease or poor sanitation such as receiving immunizations, taking antibiotics abroad, drinking only safe or boiled water, arranging appropriate medical cover in advance of travel, and ensuring continuation of any immunoglobulin infusions needed. [2]

Contents

Types

The following lists types of "agammaglobulinemia" catalogued in the OMIM. Hypogammaglobulinemia can have other types; see sections "Causes" and "Etymology" below.

Type OMIM Gene
AGM1 601495 IGHM
AGM2 613500 IGLL1
AGM3 613501 CD79A
AGM4 613502 BLNK
AGM5 613506 LRRC8A
AGM6 612692 CD79B

Symptoms and signs

The presenting feature of hypogammaglobulinemia is usually a clinical history of recurrent, chronic, or atypical infections. These infections include but are not limited to: bronchitis, ear infections, meningitis, pneumonia, sinus infections, and skin infections. Such infections can potentially damage organs, leading to severe complications. Other symptoms of hypogammaglobulinemia include chronic diarrhea and complications from receiving live vaccines. Certain symptoms of chronic damage may be related to recurrent infection. For example, shortness of breath, chronic cough, and sputum production may indicate the presence of bronchiectasis. Sinus pain, nasal discharge, and postnasal drip may indicate the presence of chronic sinusitis. Diarrhea and steatorrhea may indicate malabsorption. [2] Another sign or symptom that may occur in patients is blotchiness of the skin color, especially noticed above the waist, on the arms, neck, and upper chest areas, however, it may occur anywhere on the skin.[ medical citation needed ]

Babies with transient hypogammaglobulinemia (THI) usually become symptomatic 6 to 12 months after birth, with the symptoms usually consisting of frequent ear, sinus, and lung infections. Other symptoms include respiratory tract infections, food allergies, eczema, urinary tract infections, and intestinal infections.[ medical citation needed ]

Causes

Hypogammaglobulinemia can be caused by either a primary or secondary immunodeficiency. Primary immunodeficiencies are caused by a mutation or series of mutations to the genome.[ medical citation needed ] For example, a study from 2012 found that a compound heterozygous deleterious mutation in the CD21 gene is associated with hypogammaglobulinemia. Genetic analysis revealed the patient was heterozygous for CD21, with the paternally inherited allele (also shared with one sister) having a disrupted splicing donor site at exon 6, while the maternally inherited allele had a mutation resulting in a premature stop codon in exon 13. Neither mutation was found in 100 healthy control subjects, showing the rarity of the mutations. [3]

Around 300 different genes have been identified which account for different forms of primary immunodeficiency (PID). These different forms can affect different parts of the immune system, including immunoglobulin production. Primary immunodeficiencies usually have a delay of several years between initial clinical presentation and diagnosis. Some primary immune deficiencies include ataxia-telangiectasia (A-T), autosomal recessive agammaglobulinemia (ARA), common variable immunodeficiency (CVID), hyper-IgM syndromes, IgG subclass deficiency, isolated non-IgG immunoglobulin deficiencies, severe combined immunodeficiency (SCID), specific antibody deficiency (SAD), Wiskott-Aldrich syndrome, or X-linked agammaglobulinemia. CVID is the most common form of primary immunodeficiency. SCID is considered a medical emergency and suspected cases require immediate specialist center referral for diagnosis and treatment. It is more often that hypogammaglobulinemia develops as a result of another condition, which are called secondary or acquired immune deficiencies. These include blood cancers such as chronic lymphocytic leukemia (CLL), lymphoma, or myeloma, HIV, nephrotic syndrome, poor nutrition, protein-losing enteropathy, getting an organ transplant, or radiation therapy. This also includes medications which can cause hypogammaglobulinemia, such as corticosteroids, chemotherapy drugs, or antiseizure medication.[ medical citation needed ]

Screening

Screening of immunoglobulin levels in relatives of CVID and IgA patients finds a familial inheritance rate of 10% to 20%. In cases where a carrier of such a mutation would like to have children, preimplantation genetic diagnosis (PGD) has been offered. [2] PGD is defined as the testing of pre-implantation stage embryos or oocytes for genetic defects. It requires in vitro fertilization, embryo biopsy, and either fluorescent in situ hybridization or polymerase chain reaction on a singular cell, making it a complex procedure. While some question the ethicality of such artificial selection, it is generally seen as an important alternative to prenatal diagnosis. [4] Prevention of secondary immunodeficiency involves monitoring patients carefully with high risk of developing hypogammaglobulinemia. This entails measuring immunoglobulin levels in patients with hematologic malignancy, or those receiving chemotherapy or immunosuppressive therapy such as rituximab. [2]

Treatment

Protocols for different forms of primary immunodeficiency vary significantly. The aim of treatments implemented by specialist centers is usually to reduce the risk of complications. One method of treatment is by parenteral administration of gamma globulins, either monthly intravenously, subcutaneously, or more recently, by weekly self-administered hypodermoclysis. In either case, mild allergic reactions are common, and are usually manageable with oral diphenhydramine. Evidence comparing immunoglobulin replacement with no treatment is limited, and guidelines for treatment are therefore mainly derived from observational studies. Antibiotics are also frequently used as treatment. Other standard forms of treatment include a form of enzyme replacement therapy called PEG-ADA, and antibiotic treatment given for the prevention of Pneumocystis pneumonia. [2]

One emerging therapy is hematopoietic stem cell transplantation, which has been considered standard treatment for many combined primary immunodeficiencies including SCID, CD40 deficiency, CD40 ligand deficiency, and Wiskott-Aldrich syndrome, but has been extended to secondary immunodeficiencies over the last two decades. [5] Another emerging therapy is gene therapy, which has been used to treat X-linked SCID, SCID due to adenosine deaminase deficiency, and chronic granulomatous disease. [2]

Prognosis

Early detection and treatment of hypogammaglobulinemia is known to reduce rates of morbidity and the chance of long-term pulmonary complications. Evidence shows that there is an association between achieving higher IgG levels and reduced infection frequency. [6] If hypogammaglobulinemia remains undetected and untreated, outcomes are generally poor, especially if chronic lung damage or bronchiectasis has occurred. Unfortunately, the diagnosis of hypogammaglobulinemia is often significantly delayed. [2]

Research

In 2015, a journal article by McDermott et al. reported on a case in which chromothripsis, normally a catastrophic event in which chromosomes undergo massive deletion and rearrangement within a single stem cell's DNA, cured a patient with WHIM syndrome, a primary immunodeficiency disease. WHIM is autosomal dominant and is caused by a gain-of-function mutation of the chemokine receptor CXCR4. The mutation in CXCR4 increases signaling because it disrupts negative regulatory elements usually present, creating exaggerated functions of the receptor. The term "WHIM" is an acronym for the main manifestations of the disease: warts, hypogammaglobulinemia, recurrent infections, and myelokathexis. Myelokathexis is impaired escape of mature neutrophils from bone marrow, causing neutropenia. Patients with WHIM syndrome have severely reduced peripheral blood B cells and some reduction in peripheral blood T cells and monocytes (McDermott). The cured patient, designated WHIM-09, is a white female presented at age 58. She also presented with her two daughters, WHIM-10 (age 21) and WHIM-11 (age 23). Both daughters fulfilled all of the clinical criteria for WHIM syndrome, while WHIM-09 did not. She reported that she had had many serious infections from childhood until age 38 but had had none in the past 20 years. She has fulfilled none of the criteria for WHIM syndrome except for mild hypogammaglobulinemia since then. WHIM-09 was the first patient ever described with myelokathexis, the "M" in WHIM syndrome, and her parents and siblings showed no sign of the syndrome. Therefore, the evidence is compatible with a WHIM mutation occurring de novo in patient WHIM-09, an autosomal dominant transition to two of her three daughters, and a spontaneous and complete remission in WHIM-09. This provides the first evidence that chromothripsis may result in clinical benefit, in particular, the cure of a genetic disease. If a cell with chromothripsis dies, it is clinically undetectable, making the true frequency of its occurrence hard to determine. Therefore, it is only detected if it acquires a strong selective advantage creating a clinically apparent clonal population harboring the same pattern of deletions and arrangements. This results in either cancer, or if the location is fortuitous, the cure of a genetic condition as occurred in patient WHIM-09. [7]

Effect on viral evolution

One study of the genomic variation in the hepatitis C virus in patients with and without hypogammaglobulinemia found that patients with hypogammaglobulinemia had fewer nucleotide substitutions per year than the control patients, suggesting that in the absence of selective pressure caused by the immune system, the frequency of the occurrence of genetic variation in the major viral species is reduced. They used five control patients and four patients with CVID, a particularly severe form of hypogammaglobulinemia. The control patients had a mean nucleotide rate-of-change of 6.954 nucleotide substitutions per year while the patients with CVID had 0.415 nucleotide substitutions per year. While the mutations still occur in the patients with CVID, they tend to remain as a minor species in the absence of immune selection. [8]

Terminology

"Hypogammaglobulinemia" is largely synonymous with "agammaglobulinemia". When the latter term is used (as in "X-linked agammaglobulinemia") it implies that gamma globulins are not merely reduced, but completely absent. Modern assays have allowed most agammaglobulinemias to be more precisely defined as hypogammaglobulinemias, [9] but the distinction is not usually clinically relevant.

"Hypogammaglobulinemia" is distinguished from dysgammaglobulinemia, which is a reduction in some types of gamma globulins, but not others. [10]

Related Research Articles

<span class="mw-page-title-main">Severe combined immunodeficiency</span> Genetic disorder leading to severe impairment of the immune system

Severe combined immunodeficiency (SCID), also known as Swiss-type agammaglobulinemia, is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in differing clinical presentations. SCID involves defective antibody response due to either direct involvement with B lymphocytes or through improper B lymphocyte activation due to non-functional T-helper cells. Consequently, both "arms" of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is the most severe form of primary immunodeficiencies, and there are now at least nine different known genes in which mutations lead to a form of SCID. It is also known as the bubble boy disease and bubble baby disease because its victims are extremely vulnerable to infectious diseases and some of them, such as David Vetter, have become famous for living in a sterile environment. SCID is the result of an immune system so highly compromised that it is considered almost absent.

<span class="mw-page-title-main">Gamma globulin</span> Class of blood proteins

Gamma globulins are a class of globulins, identified by their position after serum protein electrophoresis. The most significant gamma globulins are immunoglobulins (antibodies), although some immunoglobulins are not gamma globulins, and some gamma globulins are not immunoglobulins.

Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition. Immunocompromisation may also be due to genetic diseases/flaws such as SCID.

<span class="mw-page-title-main">X-linked agammaglobulinemia</span> Medical condition

X-linked agammaglobulinemia (XLA) is a rare genetic disorder discovered in 1952 that affects the body's ability to fight infection. As the form of agammaglobulinemia that is X-linked, it is much more common in males. In people with XLA, the white blood cell formation process does not generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globulins, including antibodies, in their bloodstream. B cells are part of the immune system and normally manufacture antibodies, which defend the body from infections by sustaining a humoral immunity response. Patients with untreated XLA are prone to develop serious and even fatal infections. A mutation occurs at the Bruton's tyrosine kinase (Btk) gene that leads to a severe block in B cell development and a reduced immunoglobulin production in the serum. Btk is particularly responsible for mediating B cell development and maturation through a signaling effect on the B cell receptor BCR. Patients typically present in early childhood with recurrent infections, in particular with extracellular, encapsulated bacteria. XLA is deemed to have a relatively low incidence of disease, with an occurrence rate of approximately 1 in 200,000 live births and a frequency of about 1 in 100,000 male newborns. It has no ethnic predisposition. XLA is treated by infusion of human antibody. Treatment with pooled gamma globulin cannot restore a functional population of B cells, but it is sufficient to reduce the severity and number of infections due to the passive immunity granted by the exogenous antibodies.

Common variable immunodeficiency (CVID) is an immune disorder characterized by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA. Symptoms generally include high susceptibility to foreign invaders, chronic lung disease, and inflammation and infection of the gastrointestinal tract. CVID affects males and females equally. The condition can be found in children or teens but is generally not diagnosed or recognized until adulthood. The average age of diagnosis is between 20 and 50. However, symptoms vary greatly between people. "Variable" refers to the heterogeneous clinical manifestations of this disorder, which include recurrent bacterial infections, increased risk for autoimmune disease and lymphoma, as well as gastrointestinal disease. CVID is a lifelong disease.

Hyperimmunoglobulinemia E syndrome (HIES), of which the autosomal dominant form is called Job's syndrome or Buckley syndrome, is a heterogeneous group of immune disorders. Job's is also very rare at about 300 cases currently in the literature.

<span class="mw-page-title-main">X-linked severe combined immunodeficiency</span> Medical condition

X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells.

<span class="mw-page-title-main">Hyper IgM syndrome</span> Primary immune deficiency disorders

Hyper IgM syndrome is a rare primary immune deficiency disorders characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM.

<span class="mw-page-title-main">Hyper-IgM syndrome type 5</span> Primary immune deficiency disorder

The fifth type of hyper-IgM syndrome has been characterized in three patients from France and Japan. The symptoms are similar to hyper IgM syndrome type 2, but the AICDA gene is intact.

Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a primary immunodeficiency (PID), the immune deficiency must be inborn, not caused by secondary factors such as other disease, drug treatment, or environmental exposure to toxins. Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. While there are over 430 recognized inborn errors of immunity (IEIs) as of 2019, the vast majority of which are PIDs, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency. Immune deficiencies can result in persistent or recurring infections, auto-inflammatory disorders, tumors, and disorders of various organs. There are currently limited treatments available for these conditions; most are specific to a particular type of PID. Research is currently evaluating the use of stem cell transplants (HSCT) and experimental gene therapies as avenues for treatment in limited subsets of PIDs.

<span class="mw-page-title-main">WHIM syndrome</span> Medical condition

WHIM syndrome is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.

An immune disorder is a dysfunction of the immune system. These disorders can be characterized in several different ways:

<span class="mw-page-title-main">IgG deficiency</span> Form of immune disorder

IgG deficiency is a form of dysgammaglobulinemia where the proportional levels of the IgG isotype are reduced relative to other immunoglobulin isotypes.

<span class="mw-page-title-main">Humoral immune deficiency</span> Medical condition

Humoral immune deficiencies are conditions which cause impairment of humoral immunity, which can lead to immunodeficiency. It can be mediated by insufficient number or function of B cells, the plasma cells they differentiate into, or the antibody secreted by the plasma cells. The most common such immunodeficiency is inherited selective IgA deficiency, occurring between 1 in 100 and 1 in 1000 persons, depending on population. They are associated with increased vulnerability to infection, but can be difficult to detect in the absence of infection.

Thymoma with immunodeficiency is a rare disorder that occurs in adults in whom hypogammaglobulinemia, deficient cell-mediated immunity, and thymoma may develop almost simultaneously. Most reported cases are in Europe, though it occurs globally.

Hans Dieter Ochs, is an immunologist and pediatrician. He is Professor of Pediatrics, Division of Immunology, Department of Pediatrics, University of Washington School of Medicine, Seattle.

JAK3 deficiency is a dysfunction in cytokine receptor signalling and their production of cytokines.

<span class="mw-page-title-main">DOCK8 deficiency</span> Medical condition

DOCK8 deficiency, also called DOCK8 immunodeficiency syndrome, is the autosomal recessive form of hyperimmunoglobulin E syndrome, a genetic disorder characterized by elevated immunoglobulin E levels, eosinophilia, and recurrent infections with staphylococcus and viruses. It is caused by a mutation in the DOCK8 gene.

Granulomatous–lymphocytic interstitial lung disease (GLILD) is a lung complication of common variable immunodeficiency disorders (CVID). It is seen in approximately 15% of patients with CVID. It has been defined histologically as the presence of (non-caseating) granuloma and lymphoproliferation in the lung. However, as GLILD is often associated with other auto-immune features such as splenomegaly, adenopathy and cytopenias, a definition based on abnormalities on lung imaging together with evidence of granulomatous inflammation elsewhere has also been employed.

References

  1. ↑ " common variable immunodeficiency " at Dorland's Medical Dictionary
  2. 1 2 3 4 5 6 7 Barmettler, Sara (14 September 2021). "Hypogammaglobulinemia: Prognosis". Epocrates . Archived from the original on 5 December 2021. Retrieved 31 May 2022.
  3. ↑ Thiel, Jens; Kimmig, Lucas; Salzer, Ulrich; et al. (2012). "Genetic CD21 deficiency is associated with hypogammaglobulinemia". Journal of Allergy and Clinical Immunology. 129 (3): 801–810.e6. doi:10.1016/j.jaci.2011.09.027. PMID   22035880.
  4. ↑ Geraedts, JPM; De Wert, Gmwr (2009). "Preimplantation genetic diagnosis". Clinical Genetics. 76 (4): 315–325. doi:10.1111/j.1399-0004.2009.01273.x. PMID   19793305. S2CID   39510284.
  5. ↑ Compagno, Nicolò; Malipiero, Giacomo; Cinetto, Francesco; Agostini, Carlo (8 December 2014). "Immunoglobulin Replacement Therapy in Secondary Hypogammaglobulinemia". Frontiers in Immunology . 5: 626. doi: 10.3389/fimmu.2014.00626 . ISSN   1664-3224. OCLC   731654964. PMC   4259107 . PMID   25538710.
  6. ↑ Roifman, Chaim M.; Schroeder, Harry; Berger, Melvin; et al. (2003). "Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency". International Immunopharmacology. 3 (9): 1325–1333. doi:10.1016/S1567-5769(03)00134-6. PMID   12890430.
  7. ↑ McDermott, David H.; Gao, Ji-Liang; Liu, Qian; et al. (2015). "Chromothriptic Cure of WHIM Syndrome". Cell. 160 (4): 686–699. doi:10.1016/j.cell.2015.01.014. PMC   4329071 . PMID   25662009.
  8. ↑ Booth, Jonathan C.; Kumar, Umesh; Webster, David; Monjardino, John; Thomas, Howard C. (1998). "Comparison of the rate of sequence variation in the hypervariable region of E2/NS1 region of hepatitis C virus in normal and hypogammaglobulinemic patients". Hepatology. 27 (1): 223–227. doi: 10.1002/hep.510270134 . PMID   9425941. S2CID   28147132.
  9. ↑ " agammaglobulinemia " at Dorland's Medical Dictionary
  10. ↑ " Dysgammaglobulinemia " at Dorland's Medical Dictionary

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