IgG deficiency

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List of terms related to IgG deficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

Overview

IgG deficiency (Selective deficiency of immunoglobulin G) is a form of dysgammaglobulinemia where the proportional levels of the IgG isotype are reduced relative to other immunoglobulin isotypes. IgG deficiency is often found in children as transient hypogammaglobulinemia of infancy (THI), which may occur with or without additional decreases in IgA or IgM.

IgG has four subclasses: IgG₁, IgG₂, IgG₃, and IgG₄. It is possible to have either a global IgG deficiency, or a deficiency of one or more specific subclasses of IgG. The main clinically relevant form of IgG deficiency is IgG₂. IgG₃ deficiency is not usually encountered without other concomitant immunoglobulin deficiencies, and IgG₄ deficiency is very common but usually asymptomatic.

IgG1 is present in the bloodstream at a percentage of about 60-70%, IgG2-20-30%, IgG3 about 5-8 %, and IgG4 1-3 %. IgG subclass deficiencies affect only IgG subclasses (usually IgG2 or IgG3), with normal total IgG and IgM immunoglobulins and other components of the immune system being at normal levels. These deficiencies can affect only one subclass or involve an association of two subclasses, such as IgG2 and IgG4. IgG deficiencies are usually not diagnosed until the age of 10. Some of the IgG levels in the blood are undetectable and have a low percentage such as IgG4, which makes it hard to dertermine if a deficiency is actually present. IgG subclass deficiencies are sometimes correlated with bad responses to pneumoccal polyscaccharides, especially IgG2 and or IgG4 deficiency. Some of these deficiencies are also involved with pancreatitis and have been linked to IgG4 levels.

Historical Perspective

In 1952, Bruton described classic X-linked agammaglobulinemia due to B-cell deficiency in an 8-year-old boy. The child presented with frequent pyogenic infections, repeated episodes of sepsis with the same serotypes of pneumococcus, and multiple episodes of mumps, yet he had no antibodies against these pathogens. Serum protein electrophoresis had just become available, and it revealed that the g fraction was missing from the child’s blood. Subsequently, patients were described who had detectable lymphoid tissue and B-cells but had decreased IgG levels and/or lacked specific antibodies. These conditions are now recognized as fitting the categories of hyper-IgM syndromes and common variable immunodeficiency (CVID). A new subset of the latter was recently characterized by reduced C1 esterase inhibitor levels. ^[1]

In the early 1960s, following the discovery of the IgG subclasses, certain associations were also recognized between individual subclass deficiencies, decreased ability to respond to certain types of antigens (ie, bacterial polysaccharides), and recurrent infection. IgG deficiencies may occur as isolated deficiencies (eg, selective IgG deficiency) or in association with deficiencies of other immunoglobulin types. Moreover, even if the total IgG concentration is normal, deficiencies of one or more individual IgG subclasses, significant decreases in specific IgG antibodies, or both may be observed.

Classification

• [Disease name] may be classified according to [classification method] into [number] subtypes/groups:

• [group1]
• [group2]
• [group3]

• Other variants of [disease name] include [disease subtype 1], [disease subtype 2], and [disease subtype 3].

Pathophysiology

• Immunodeficiency diseases are described according to involvement one or more of the 4 major components of the immune system. These components are 1) B cells ; 2) T cells, 3) phagocytes; and 4) complement
• B-cell or humoral immunity, is mediated by the immunoglobulins There are five types or classes of immunoglobulin: IgG, IgA, IgM, IgD and IgE. The IgG class of antibodies is composed of four different subtypes of IgG molecules called the IgG subclasses. These are designated IgG1, IgG2, IgG3 and IgG4. The term "IgG subclass deficiency" refers to a significant decrease in the serum concentrations of one or more subclasses of IgG in a patient whose total IgG concentration is normal
• PATHOGENESIS — The primary mechanisms underlying IgG subclass deficiency are unclear. Gene deletions, transcription errors, cytokine dysregulation, immunosuppressive therapy, and allotypic variations are some mechanisms that have been described:
• ●Gene deletions – Heterozygous gene deletions causes reduction in the serum concentration of the corresponding subclass. Deletions have been described for genes C-gamma-1, C-gamma-2, and C-gamma-4 [13].
• . Homozygous deletions of large portions of the immunoglobulin heavy chain gene, resulting in the absence of multiple immunoglobulin classes, are also described. Such patients may have no detectable IgG1, IgG2, IgG4, IgA1, or IgE [15,16]. Such deletions are thought to arise from unequal crossover, resulting from extensive homology among the immunoglobulin heavy chain genes on chromosome 14. ●Transcription errors – Alteration of germline transcription and restriction fragment length polymorphisms 5' of the S-gamma-4 loci within the gamma-chain constant region gene complex have been specifically documented in patients with IgG4 deficiency patients compared with controls [17]. ●Effect of allotype – Some IgG subclass deficiencies may be influenced by allotype. A lack of the G2m(n) allotype and homozygosity for the G3m(g) and G3m(b) allotypes has been described among Caucasian patients[18,19].

Causes

• There are no established causes for IgG deficiency, and mechanisms underlying IgG subclass deficiency are unclear. Genetic, transcription errors, allotypic variations,and immunosuppressive therapy are some mechanisms that have been proposed.

Differentiating [disease name] from other Diseases

• IgG must be differentiated from other diseases that cause recurrent infections , especially recurrent sinopulmonary infections include otitis media, rhinosinusitis, and pneumonia. More serious infections that can occur include osteomyelitis, meningitis, septicemia, diarrhea, and various skin infections [2].

• Malignancy
• Viral infections
• Certain medications

Epidemiology and Demographics

• Among patient populations with more frequent or severe infections, IgG subclass deficiency is a common finding: ●In two large series from France, IgG subclass deficiency was detected in 21 percent of 483 patients with abnormally frequent, prolonged, or severe infections who had been recruited from clinical immunology, pediatrics, and infectious diseases departments [5,9]. IgG3 was the most frequently deficient subclass, which has also been observed in other studies [2-4,12]. ●In a report of 1175 adults with symptoms suggestive of an antibody defect, decreased IgG1, IgG2, IgG3, and IgG4 levels were noted in 28, 17, 13, and 9 percent, respectively (table 2) [11].

Age

• Both children and adults are affected. Children younger than 24 months cannot make much IgG2; hence, measuring the IgG2 subclass concentration before this age is not meaningful. The most common subclass deficiency in early childhood is IgG2 deficiency; in adults, IgG1 and IgG3 deficiencies predominate. IgG1 accounts for a higher proportion of the total IgG in children as compared to adults. Although children rapidly attain adult levels of IgG1 and IgG3, the development of IgG2 and IgG4 is slower. In some children, maturation of the full range of IgG subclasses may be delayed until the teenage years. Note the figure below.

Gender

• [The sex distribution of IgG subclass deficiency differs in children and adults. In children, IgG subclass deficiencies are more common in boys by a ratio of 3:1 [2,3]. In contrast, there is a predominance of females after age 16. This shift in sex distribution may be due to hormonal influences upon the development and maturation of the immune system.

Race

• There is no racial predilection for IgG deficiency.

Risk Factors

• Common risk factors in the development of IgG deficiency
• Protein-losing conditions such as enteropathy and nephropathy can result in apparent selective deficiency of IgG
• Intense exercise or excessive physical stress
• Smoking
• Aging
• Certain medications systemic glucocorticoids, sulfasalazine, and the antiepileptics zonisamide, phenytoin, and carbamazepine, have been associated with acquired cases of IgG subclass deficiency

Natural History, Complications and Prognosis

• The majority of patients with IgG deficiency remain asymptomatic for In addition, there are patients with complete deficiencies of multiple subclasses (combinations of IgG1, IgG2, IgG4, IgE, or IgA) who remain healthy and free of infections [29-32].
• Early clinical features include recurrent sinopulmonary infections. More serious infections that can occur include osteomyelitis, meningitis, septicemia, diarrhea, and various skin infections
• If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
• Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].
• Prognosis is generally influenced by the age of the patient as well as the degree of deficiency.
• Evidence suggests that the majority of children younger than six to eight years of age with clinically significant IgG subclass deficiency and diminished specific antibody responses will normalize both antibody responsiveness and IgG subclass level(s) [10,41]. This appears to be particularly true for young children with IgG2 and IgA deficiency and impaired responses to polysaccharide antigens. In contrast, if the condition persists beyond the age of six years, it is likely to be permanent.
• Adults with clinically significant IgG subclass deficiency and diminished specific antibody responses will rarely achieve normalization of a deficient IgG subclass level

Diagnosis

Diagnostic Criteria

IgG subclass deficiency is a laboratory finding that does not necessarily equate to a clinical disorder. The diagnosis of a clinically significant IgG subclass deficiency requires evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge.

• The diagnosis of IgG deficiency is made when at least one of the following two diagnostic criteria are met:

• low IgG subclass levels
• poor antibody response to vaccine challenge

Symptoms

• IgG deficiency is usually asymptomatic.
• Symptoms of IgG deficiency may include the symptoms of recurrent sinopulmonary infections include otitis media, rhinosinusitis, and pneumonia and More serious infections that can occur include osteomyelitis, meningitis, septicemia, diarrhea, and various skin infections:

Physical Examination

• Physical examination of patients with longstanding immune defectsmay may be remarkable for:

• low body mass index (BMI)
• scarring (of tympanic membranes or skin)
• signs of chronic lung disease (chronic cough, absent gag reflex, clubbing, crackles, or wheezing to suggest bronchiectasis)
• ongoing infection (signs of chronic sinusitis, oral thrush, warts, or dermatophyte infections)

Laboratory Findings

• IgG subclass deficiency is a laboratory finding that does not necessarily equate to a clinical disorder.

The normal ranges for IgG subclasses are broad and vary with the age of the population studied, presence or absence of disease, and the method of analysis (table 1) [2-9].

For children 4 to 10 years of age, levels below the following are considered abnormal:

●IgG1 level <250 mg/dL

●IgG2 level <50 mg/dL

●IgG3 level <15 mg/dL

●IgG4 level <1 mg/dL

For individuals older than 10 years of age, levels below the following are considered abnormal:

●IgG1 level <300 mg/dL

●IgG2 level <50 mg/dL

●IgG3 level <25 mg/dL

●IgG4 level <1 mg/dL

Vaccine Challange Response

IgG subclass deficiency is a laboratory finding that does not necessarily equate to a clinical disorder. The diagnosis of a clinically significant IgG subclass deficiency requires evidence of antibody dysfunction in the form of recurrent infections and an inadequate response to vaccine challenge.

Vaccine response is part of the evaluation of possible immunodeficiency. The clinical indications for assessing vaccine responsiveness include frequent and recurrent sinopulmonary or ear infections, chronic gastrointestinal infections, any severe or unusual infections, and abnormal need for antibiotics (table 1). Most patients have already had serum levels of immunoglobulin (Ig)G, IgA, and IgM measured, but if not, these can be obtained at the same time that vaccine response is assessed. The different warning signs of immunodeficiency are reviewed in more detail elsewhere:

Titers of IgG antibodies to tetanus and diphtheria in vaccinated children and adults are used to evaluate immune responsiveness to protein antigens. Results are reported as IgG in general, although the antibody responses generated by these vaccines are largely (but not exclusively) composed of IgG1 and IgG3 antibodies, which is sometimes important in evaluation of IgG subclass deficiency.

Treatment

Medical Therapy

• There is no treatment for [disease name]; the mainstay of therapy is supportive care.

• The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
• [Medical therapy 1] acts by [mechanism of action 1].
• Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

Surgery

• Surgery is the mainstay of therapy for [disease name].
• [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
• [Surgical procedure] can only be performed for patients with [disease stage] [disease name].

Prevention

• There are no primary preventive measures available for [disease name].

• Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

• Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].