IgG Subclass Deficiency

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Introduction

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Patients with recurrent or refractory infections present a diagnostic and therapeutic challenge. While the differential diagnosis is extensive, several primary immunodeficiency states need to be considered. Among these are common variable immune deficiency (CVID), specific antibody deficiency (SAD), and immunoglobulin G (IgG) subclass deficiency (Table 1). These entities may be very similar in clinical presentation but can be differentiated by IgG quantitative and subclass evaluation. IgG subclass deficiency has been documented in approximately 25% of patients presenting with recurrent infections [1]. This article will review the clinical presentation of IgG subclass deficiency, as well as the approach to diagnosis and therapeutic options.

Table 1: Primary Immunodeficiency

	CVID	SAD	IgG1	IgG2	IgG3	IgG4
IgG total	Low	Normal	Normal	Normal	Normal	Normal
IgA total	Low	Normal	Normal	+/–	Normal	+/–
Sinopulmonary infections	+	+	+	+	+	+
Response to polysaccharide vaccine	Abnl	Abnl	Abnl	Abnl	+/–	+/–
Response to protein vaccine	Abnl	Normal	+/–	+/–	+/–	+/–

Abnl, abnormal; CVID, common variable immune deficiency; IgA, immunoglobulin A; IgG, immunoglobulin G; SAD, specific antibody deficiency; +, common; +/–, variable.

Definition

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To identify a patient as having an IgG subclass deficiency, two parameters must be present. First, one or more IgG subclasses must be decreased. Secondly, the total IgG concentration must be normal. The finding of decreased subclass deficiencies does not necessarily correlate with a clinically significant disorder. To qualify for this diagnosis, a patient must have recurrent infections plus an inadequate response to a vaccine challenge.

Review of IgG Subclasses

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Four IgG subclasses have been identified. It is important to recognize other disease entities that have been reported with individual or multiple subclass deficiencies. This may serve to identify occult immunodeficiencies, decreasing the time to diagnosis. IgG1: This antibody comprises over 60% of total IgG. Deficiencies in IgG1 are commonly found in patients with diffuse hypogammaglobulinemia, necessitating an evaluation for CVID. Since a patient must have a normal total IgG to be diagnosed with a subclass deficiency, an isolated IgG1 deficiency is rare. IgG2: A deficiency of IgG2 is more commonly identified in children and may occur as an individual deficiency or one associated with IgG4. In one study, 17% of pediatric patients with immunodeficiency disorders were diagnosed with IgG2 deficiency [2]. The natural course of this deficiency was delineated by Wolpert et al, who evaluated 120 children over 2 years of age. After 3 years of evaluation, over 85% of patients had normal immunoglobulin levels as well as a normal response to a polysaccharide vaccine challenge [3]. This is the principal subclass for responses to polysaccharide antigens. Subsequently, patients with IgG2 deficiency are at increased risk of infection with encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenzae type b (Hib), and Neisseria meningitidis. As documented below, numerous diseases have been associated with an IgG2 deficiency [4]. IgG3: A deficiency of IgG3 is more common in adults and may occur in combination with IgG1. This antibody is responsible for protection against Moraxella catarrhalis and, to a large extent, Streptococcus pyogenes. The latter is secondary to IgG3 activity against the M component of group A streptococcus. This antibody participates to a greater extent with immunologic responses to proteins. Accordingly, patients with an isolated IgG3 deficiency may have a normal response to a polysaccharide vaccine challenge [4,5]. IgG4: A deficiency of IgG4 is not uncommon, but most patients are asymptomatic, making diagnosis difficult. While IgG4 may be an isolated finding, it is commonly associated with IgG2 with or without an IgA deficiency. As is seen with IgG2, IgG4 deficiency is associated with many other disease states. The differentiation of IgG subclass deficiency from other immunodeficiency states is summarized in Table 1.

Associated Disease States

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As stated previously, recurrent sinopulmonary infections are the most common presentation for a patient with IgG subclass deficiencies. Other disease states, however, may be present and may provide clues to the underlying immunodeficiency. Ataxia telangiectasia, interferon gamma deficiency, growth hormone deficiency, chronic mucocutaneous candidiasis, and allergic colitis have been associated with IgG2 and IgG4 deficiencies. Bronchospastic illness, chronic bronchitis, and recurrent lymphocytic meningitis have been associated with IgG3 deficiency [6,7].

Differential Diagnosis

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Secondary hypogammaglobulinemia is the most pertinent consideration in patients being evaluated for IgG subclass deficiency. This can result from either increased protein losses or a decreased production of immunoglobulin. Losses may occur through either the kidney (nephrotic syndrome) or gastrointestinal tract (protein-losing enteropathies). Production may be decreased due to any of the following factors:

References

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1. 1. Hanson, L.A.; Söderström, R.; Avanzini, A.; Bengtsson, U.; Björkander, J.; Söderström, T. Immunoglobulin subclass deficiency. Pediatr. Infect. Dis. J. 1988, 7 (5 Suppl), S17. [CrossRef]
   2. Javier, F.C., III; Moore, C.M.; Sorensen, R.U. Distribution of primary immunodeficiency diseases diagnosed in a pediatric tertiary hospital. Ann. Allergy Asthma. Immunol. 2000, 84, 25. [CrossRef]
   3. Wolpert, J.; Knutsen, A.P.; M.D.; Wall, L.A.; Dimitriades, V.R.; Sorensen, R.U.; Caruthers, C.; Convers, K.D.; Kariuki, B.M.; Hong, J.; et al. Natural history of selective antibody deficiency to bacterial polysaccharide antigens in children. Pediatr. Asthma Allergy Immunol. 1998, 12, 183. [CrossRef]
   4. Morell, A. Clinical relevance of IgG subclass deficiencies. Ann. Biol. Clin. 1994, 52, 49–52.
   5. Barton, J.C.; Bertoli, L.F.; Barton, J.C.; Acton, R.T. Selective subnormal IgG3 in 121 adult index patients with frequent or severe bacterial respiratory tract infections. Cell. Immunol. 2016, 299, 50–57. [CrossRef] [PubMed]
   6. Oxelius, V.A. IgG3 deficiency: common in obstructive lung disease. Hereditary in families with immunodeficiency and autoimmune disease. Monogr. Allergy 1986, 20, 106.
   7. Ochs, H.D.; Stiehm, E.R.; Winkelstein, J.A.; et al. Antibody deficiencies. In Immunologic Disorders in Infants and Children, 5th ed.; Ochs, H.D., Stiehm, E.R., Winkelstein, J.A., Eds.; Elsevier: Philadelphia, PA, USA, 2004.
   8. Sorensen, R.U.; Leiva, L.E.; Giangrosso, P.A.; Butler, B.; Javier, F.C.; Sacerdote, D.M.; Bradford, N.; Moore, C. Response to a heptavalent conjugate Streptococcus pneumoniae vaccine in children with recurrent infections who are unresponsive to the polysaccharide vaccine. Pediatr. Infect. Dis. J. 1998, 17, 685. [CrossRef] [PubMed]
   9. Rubin, L.G.; Levin, M.J.; Ljungman, P.; Davies, E.G.; Avery, R.; Tomblyn, M.; Bousvaros, A.; Dhanireddy, S.; Sung, L.; Keyserling, H.; et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin. Infect. Dis. 2014, 58, e44. [CrossRef] [PubMed]
   10. Abdou, N.I.; Greenwell, C.A.; Mehta, R.; Narra, M.; Hester, J.D.; Halsey, J.F. Efficacy of intravenous gammaglobulin for immunoglobulin G subclass and/or antibody deficiency in adults. Int. Arch. Allergy Immunol. 2009, 149, 267. [CrossRef] [PubMed]